Conference Coverage

SAVANNAH, GEORGIA – The investigational monoclonal antibody nipocalimab (Johnson & Johnson) is associated with significant improvement in patients with generalized myasthenia gravis (gMG) over a 24-week period, according to topline results from the phase 3 VIVACITY-MG3 study.

The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.

Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. 
 

Autoantibody Depletion

FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies. 

The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.

The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.

They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.

The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002). 
 

Clinically Meaningful Changes?

“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release. 

Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001). 

Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).

Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.

“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu. 

In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
 

Encouraging Findings

Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.

“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.” 

Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease. 

“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said. 

“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”

Additionally, she said there are some early data suggesting its safety in pregnancy.

Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen. 
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA – The investigational monoclonal antibody nipocalimab (Johnson & Johnson) is associated with significant improvement in patients with generalized myasthenia gravis (gMG) over a 24-week period, according to topline results from the phase 3 VIVACITY-MG3 study.

The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.

Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. 
 

Autoantibody Depletion

FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies. 

The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.

The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.

They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.

The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002). 
 

Clinically Meaningful Changes?

“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release. 

Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001). 

Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).

Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.

“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu. 

In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
 

Encouraging Findings

Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.

“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.” 

Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease. 

“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said. 

“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”

Additionally, she said there are some early data suggesting its safety in pregnancy.

Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen. 
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA – The investigational monoclonal antibody nipocalimab (Johnson & Johnson) is associated with significant improvement in patients with generalized myasthenia gravis (gMG) over a 24-week period, according to topline results from the phase 3 VIVACITY-MG3 study.

The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.

Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. 
 

Autoantibody Depletion

FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies. 

The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.

The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.

They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.

The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002). 
 

Clinically Meaningful Changes?

“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release. 

Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001). 

Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).

Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.

“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu. 

In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
 

Encouraging Findings

Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.

“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.” 

Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease. 

“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said. 

“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”

Additionally, she said there are some early data suggesting its safety in pregnancy.

Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen. 
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Inebilizumab, a first-in-class anti-CD19 B-cell depleting agent, demonstrated both safety and superior efficacy compared with placebo in patients with seropositive generalized myasthenia gravis (gMG), new phase 3 data showed.

“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.

The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
 

Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease

The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.

“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.

Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.

Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.

The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.

“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.

This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).

In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.

In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.

“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.

Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”

“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.

Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
 

New, Novel, Exciting

Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”

Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.

She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.

However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”

She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.

The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.

Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).

Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Inebilizumab, a first-in-class anti-CD19 B-cell depleting agent, demonstrated both safety and superior efficacy compared with placebo in patients with seropositive generalized myasthenia gravis (gMG), new phase 3 data showed.

“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.

The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
 

Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease

The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.

“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.

Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.

Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.

The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.

“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.

This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).

In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.

In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.

“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.

Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”

“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.

Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
 

New, Novel, Exciting

Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”

Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.

She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.

However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”

She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.

The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.

Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).

Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Inebilizumab, a first-in-class anti-CD19 B-cell depleting agent, demonstrated both safety and superior efficacy compared with placebo in patients with seropositive generalized myasthenia gravis (gMG), new phase 3 data showed.

“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.

The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
 

Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease

The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.

“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.

Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.

Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.

The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.

“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.

This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).

In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.

In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.

“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.

Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”

“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.

Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
 

New, Novel, Exciting

Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”

Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.

She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.

However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”

She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.

The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.

Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).

Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
 

A version of this article appeared on Medscape.com.

“Obesity only recently caught the public’s attention as a disease,” Matthias Blüher, MD, professor of medicine at the Leipzig University and director of the Helmholtz Institute for Metabolism, Obesity and Vascular Research, Leipzig, Germany, told attendees in a thought-provoking presentation at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

Even though the attitudes around how obesity is perceived may be relatively new, Blüher believes they are nonetheless significant. As a sign of how the cultural headwinds have shifted, he noted the 2022 film The Whale, which focuses on a character struggling with obesity. As Blüher pointed out, not only did the film’s star, Brendan Fraser, receive an Academy Award for his portrayal but he also theorized that the majority of celebrities in the audience were likely taking new weight loss medications.

“I strongly believe that in the future, obesity treatment will carry less stigma. It will be considered not as a cosmetic problem, but as a progressive disease.”

He sees several changes in the management of obesity likely to occur on the near horizon, beginning with when interventions directed at treating it will begin.

Obesity treatment should start at a young age, he said, because if you have overweight at ages 3-6 years, the likelihood of becoming an adult with obesity is approximately 90%. “Looking ahead, shouldn’t we put more emphasis on this age group?”

Furthermore, he hopes that clinical trials will move beyond body weight and body mass index (BMI) as their main outcome parameters. Instead, “we should talk about fat distribution, fat or adipose tissue function, muscle loss, body composition, and severity of disease.”

Blüher pointed to the recently published framework for the diagnosis, staging, and management of obesity in adults put forward by the European Association for the Study of Obesity. It states that obesity should be staged not based on BMI or body weight alone but also on an individual›s medical, functional, and psychological (eg, mental health and eating behavior) status.

“The causes of obesity are too complex to be individually targeted,” he continued, unlike examples such as hypercholesterolemia or smoking cessation, where clinicians may have one target to address.

“But overeating, slow metabolism, and low physical activity involve socio-cultural factors, global food marketing, and many other factors. Therefore, clinicians should be setting health targets, such as improving sleep apnea and improving physical functioning, rather than a kilogram number.”
 

Three Pillars of Treatment

Right now, clinicians have three pillars of treatments available, Blüher said. The first is behavioral intervention, including strategies such as counseling, diet, exercise, self-monitoring, stress management, and sleep management.

“We know that these behavioral aspects typically lack adherence and effect size, but they’re important, and for a certain group of people, they may be the best and safest treatment.”

The second pillar is pharmacotherapy, and the third is surgery.

Each pillar poses questions for future research, he explained.

“First, do we really need more evidence that behavioral interventions typically fail in the long run and are prone to rebound of body weight and health issues? No. Or which diet is best? We have hundreds of diet interventions, all of which basically show very similar outcomes. They lead to an average weight loss of 3% to 5% and do improve health conditions associated with obesity.”

When it comes to pharmacotherapies, Blüher does believe clinicians need more options.

Depending on affordability and access, glucagon-like peptide 1 (GLP-1) semaglutide will likely become the first-line therapy for most people living with obesity who want to take medications, he suggested. The dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 tirzepatide will be reserved for those with more severe conditions.

“But this is not the end of the story,” he said. “The pipelines for obesity pharmacotherapies are full, and they have different categories. We are optimistic that we will have more therapies not only for type 2 diabetes (T2D) but also for obesity. Combinations such as CagriSema (cagrilintide + semaglutide, currently indicated for T2D) may outperform the monotherapies. We have to see if they’re as safe, and we have to wait for phase 3 trials and long-term outcomes.”

“The field is open for many combinations, ideas and interactions among the incretin-based signaling systems, but personally, I think that the triple agonists have a very bright future,” Blüher said.

For example, retatrutide, an agonist of the GIP, GLP-1, and glucagon receptors, showed promise in a phase 2 trial. Although that was not a comparative study, “the average changes in body weight suggest that in a dose-dependent manner, you can expect even more weight loss than with tirzepatide.”
 

Treating the Causes

The future of obesity therapy might also be directed at the originating factors that cause it, Blüher suggested, adding that “treating the causes is a dream of mine.”

One example of treating the cause is leptin therapy, as shown in a 1999 study of recombinant leptin in a child with congenital leptin deficiency. A more recent example is setmelanotide treatment for proopiomelanocortin deficiency.

“We are at the beginning for these causative treatments of obesity, and I hope that the future will hold much more of these insights and targets, as in cancer therapy.”

“Finally,” he said, “We eat with our brain. And so in the future, we also will be better able to use our knowledge about the complex neural circuits that are obesogenic, and how to target them. In doing so, we can learn from surgeons because obesity surgery is very effective in changing the anatomy, and we also observe hormonal changes. We see that ghrelin, GLP-1, peptide YY, and many others are affected when the anatomy changes. Why can’t we use that knowledge to design drugs that resemble or mimic the effect size of bariatric surgery?”

And that goes to the third pillar of treatment and the question of whether the new weight loss drugs may replace surgery, which also was the topic of another EASD session.

Blüher doesn’t see that happening for at least a decade, given that there is still an effect-size gap between tirzepatide and surgery, especially for individuals with T2D. In addition, he noted, there will still be nonresponders to drugs, and clinicians are not treating to target yet. Looking ahead, he foresees a combination of surgery and multi-receptor agonists.

“I believe that obesity won’t be cured in the future, but we will have increasingly better lifelong management with a multidisciplinary approach, although behavioral interventions still will not be as successful as pharmacotherapy and bariatric surgery,” he concluded.
 

Q&A

During the question-and-answer session following his lecture, several attendees asked Blüher for his thoughts around other emerging areas in this field. One wanted to know whether microbiome changes might be a future target for obesity treatment.

“So far, we don’t really understand which bacteria, which composition, at which age, and at which part of the intestine need to be targeted,” Blüher responded. “Before we know that mechanistically, I think it would be difficult, but it could be an avenue to go for, though I’m a little less optimistic about it compared to other approaches.”

Given that obesity is not one disease, are there cluster subtypes, as for T2D — eg, the hungry brain, the hungry gut, low metabolism — that might benefit from individualized treatment, another attendee asked.

“We do try to subcluster people living with obesity,” Blüher said. “We did that based on adipose tissue expression signatures, and indeed there is large heterogeneity. But we are far from addressing the root causes and all subtypes of the disease, and that would be a requirement before we could personalize treatment in that way.”

Next, an attendee asked what is responsible for the differential weight loss in people with diabetes and people without? Blüher responded that although he doesn’t have the answer, he does have hypotheses.

“One could be that the disease process — eg, deterioration of beta cell function, of the balance of hormones such as insulin and leptin, of inflammatory parameters, of insulin resistance — is much more advanced in diseases such as T2D and sleep apnea. Maybe it then takes more to address comorbid conditions such as inflammation and insulin resistance. Therefore, combining current therapies with insulin sensitizers, for example, could produce better results.”

What about using continuous glucose monitoring to help people stick to their diet?

“That’s an important question that speaks to personalized treatment,” he said. “It applies not only to continuous glucose monitoring but also to nutrition and other modes of self-monitoring, which seem to be among the most successful tools for long-term weight maintenance.”

Blüher finished by saying, “As we look into the future, I hope that there will be better approaches for all aspects of personalized medicine, whether it is nutrition, exercise, pharmacotherapy, or even surgical procedures.”

Blüher received honoraria for lectures and/or served as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novo Nordisk, Novartis, Pfizer, and Sanofi.
 

A version of this article first appeared on Medscape.com.

“Obesity only recently caught the public’s attention as a disease,” Matthias Blüher, MD, professor of medicine at the Leipzig University and director of the Helmholtz Institute for Metabolism, Obesity and Vascular Research, Leipzig, Germany, told attendees in a thought-provoking presentation at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

Even though the attitudes around how obesity is perceived may be relatively new, Blüher believes they are nonetheless significant. As a sign of how the cultural headwinds have shifted, he noted the 2022 film The Whale, which focuses on a character struggling with obesity. As Blüher pointed out, not only did the film’s star, Brendan Fraser, receive an Academy Award for his portrayal but he also theorized that the majority of celebrities in the audience were likely taking new weight loss medications.

“I strongly believe that in the future, obesity treatment will carry less stigma. It will be considered not as a cosmetic problem, but as a progressive disease.”

He sees several changes in the management of obesity likely to occur on the near horizon, beginning with when interventions directed at treating it will begin.

Obesity treatment should start at a young age, he said, because if you have overweight at ages 3-6 years, the likelihood of becoming an adult with obesity is approximately 90%. “Looking ahead, shouldn’t we put more emphasis on this age group?”

Furthermore, he hopes that clinical trials will move beyond body weight and body mass index (BMI) as their main outcome parameters. Instead, “we should talk about fat distribution, fat or adipose tissue function, muscle loss, body composition, and severity of disease.”

Blüher pointed to the recently published framework for the diagnosis, staging, and management of obesity in adults put forward by the European Association for the Study of Obesity. It states that obesity should be staged not based on BMI or body weight alone but also on an individual›s medical, functional, and psychological (eg, mental health and eating behavior) status.

“The causes of obesity are too complex to be individually targeted,” he continued, unlike examples such as hypercholesterolemia or smoking cessation, where clinicians may have one target to address.

“But overeating, slow metabolism, and low physical activity involve socio-cultural factors, global food marketing, and many other factors. Therefore, clinicians should be setting health targets, such as improving sleep apnea and improving physical functioning, rather than a kilogram number.”
 

Three Pillars of Treatment

Right now, clinicians have three pillars of treatments available, Blüher said. The first is behavioral intervention, including strategies such as counseling, diet, exercise, self-monitoring, stress management, and sleep management.

“We know that these behavioral aspects typically lack adherence and effect size, but they’re important, and for a certain group of people, they may be the best and safest treatment.”

The second pillar is pharmacotherapy, and the third is surgery.

Each pillar poses questions for future research, he explained.

“First, do we really need more evidence that behavioral interventions typically fail in the long run and are prone to rebound of body weight and health issues? No. Or which diet is best? We have hundreds of diet interventions, all of which basically show very similar outcomes. They lead to an average weight loss of 3% to 5% and do improve health conditions associated with obesity.”

When it comes to pharmacotherapies, Blüher does believe clinicians need more options.

Depending on affordability and access, glucagon-like peptide 1 (GLP-1) semaglutide will likely become the first-line therapy for most people living with obesity who want to take medications, he suggested. The dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 tirzepatide will be reserved for those with more severe conditions.

“But this is not the end of the story,” he said. “The pipelines for obesity pharmacotherapies are full, and they have different categories. We are optimistic that we will have more therapies not only for type 2 diabetes (T2D) but also for obesity. Combinations such as CagriSema (cagrilintide + semaglutide, currently indicated for T2D) may outperform the monotherapies. We have to see if they’re as safe, and we have to wait for phase 3 trials and long-term outcomes.”

“The field is open for many combinations, ideas and interactions among the incretin-based signaling systems, but personally, I think that the triple agonists have a very bright future,” Blüher said.

For example, retatrutide, an agonist of the GIP, GLP-1, and glucagon receptors, showed promise in a phase 2 trial. Although that was not a comparative study, “the average changes in body weight suggest that in a dose-dependent manner, you can expect even more weight loss than with tirzepatide.”
 

Treating the Causes

The future of obesity therapy might also be directed at the originating factors that cause it, Blüher suggested, adding that “treating the causes is a dream of mine.”

One example of treating the cause is leptin therapy, as shown in a 1999 study of recombinant leptin in a child with congenital leptin deficiency. A more recent example is setmelanotide treatment for proopiomelanocortin deficiency.

“We are at the beginning for these causative treatments of obesity, and I hope that the future will hold much more of these insights and targets, as in cancer therapy.”

“Finally,” he said, “We eat with our brain. And so in the future, we also will be better able to use our knowledge about the complex neural circuits that are obesogenic, and how to target them. In doing so, we can learn from surgeons because obesity surgery is very effective in changing the anatomy, and we also observe hormonal changes. We see that ghrelin, GLP-1, peptide YY, and many others are affected when the anatomy changes. Why can’t we use that knowledge to design drugs that resemble or mimic the effect size of bariatric surgery?”

And that goes to the third pillar of treatment and the question of whether the new weight loss drugs may replace surgery, which also was the topic of another EASD session.

Blüher doesn’t see that happening for at least a decade, given that there is still an effect-size gap between tirzepatide and surgery, especially for individuals with T2D. In addition, he noted, there will still be nonresponders to drugs, and clinicians are not treating to target yet. Looking ahead, he foresees a combination of surgery and multi-receptor agonists.

“I believe that obesity won’t be cured in the future, but we will have increasingly better lifelong management with a multidisciplinary approach, although behavioral interventions still will not be as successful as pharmacotherapy and bariatric surgery,” he concluded.
 

Q&A

During the question-and-answer session following his lecture, several attendees asked Blüher for his thoughts around other emerging areas in this field. One wanted to know whether microbiome changes might be a future target for obesity treatment.

“So far, we don’t really understand which bacteria, which composition, at which age, and at which part of the intestine need to be targeted,” Blüher responded. “Before we know that mechanistically, I think it would be difficult, but it could be an avenue to go for, though I’m a little less optimistic about it compared to other approaches.”

Given that obesity is not one disease, are there cluster subtypes, as for T2D — eg, the hungry brain, the hungry gut, low metabolism — that might benefit from individualized treatment, another attendee asked.

“We do try to subcluster people living with obesity,” Blüher said. “We did that based on adipose tissue expression signatures, and indeed there is large heterogeneity. But we are far from addressing the root causes and all subtypes of the disease, and that would be a requirement before we could personalize treatment in that way.”

Next, an attendee asked what is responsible for the differential weight loss in people with diabetes and people without? Blüher responded that although he doesn’t have the answer, he does have hypotheses.

“One could be that the disease process — eg, deterioration of beta cell function, of the balance of hormones such as insulin and leptin, of inflammatory parameters, of insulin resistance — is much more advanced in diseases such as T2D and sleep apnea. Maybe it then takes more to address comorbid conditions such as inflammation and insulin resistance. Therefore, combining current therapies with insulin sensitizers, for example, could produce better results.”

What about using continuous glucose monitoring to help people stick to their diet?

“That’s an important question that speaks to personalized treatment,” he said. “It applies not only to continuous glucose monitoring but also to nutrition and other modes of self-monitoring, which seem to be among the most successful tools for long-term weight maintenance.”

Blüher finished by saying, “As we look into the future, I hope that there will be better approaches for all aspects of personalized medicine, whether it is nutrition, exercise, pharmacotherapy, or even surgical procedures.”

Blüher received honoraria for lectures and/or served as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novo Nordisk, Novartis, Pfizer, and Sanofi.
 

A version of this article first appeared on Medscape.com.

“Obesity only recently caught the public’s attention as a disease,” Matthias Blüher, MD, professor of medicine at the Leipzig University and director of the Helmholtz Institute for Metabolism, Obesity and Vascular Research, Leipzig, Germany, told attendees in a thought-provoking presentation at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

Even though the attitudes around how obesity is perceived may be relatively new, Blüher believes they are nonetheless significant. As a sign of how the cultural headwinds have shifted, he noted the 2022 film The Whale, which focuses on a character struggling with obesity. As Blüher pointed out, not only did the film’s star, Brendan Fraser, receive an Academy Award for his portrayal but he also theorized that the majority of celebrities in the audience were likely taking new weight loss medications.

“I strongly believe that in the future, obesity treatment will carry less stigma. It will be considered not as a cosmetic problem, but as a progressive disease.”

He sees several changes in the management of obesity likely to occur on the near horizon, beginning with when interventions directed at treating it will begin.

Obesity treatment should start at a young age, he said, because if you have overweight at ages 3-6 years, the likelihood of becoming an adult with obesity is approximately 90%. “Looking ahead, shouldn’t we put more emphasis on this age group?”

Furthermore, he hopes that clinical trials will move beyond body weight and body mass index (BMI) as their main outcome parameters. Instead, “we should talk about fat distribution, fat or adipose tissue function, muscle loss, body composition, and severity of disease.”

Blüher pointed to the recently published framework for the diagnosis, staging, and management of obesity in adults put forward by the European Association for the Study of Obesity. It states that obesity should be staged not based on BMI or body weight alone but also on an individual›s medical, functional, and psychological (eg, mental health and eating behavior) status.

“The causes of obesity are too complex to be individually targeted,” he continued, unlike examples such as hypercholesterolemia or smoking cessation, where clinicians may have one target to address.

“But overeating, slow metabolism, and low physical activity involve socio-cultural factors, global food marketing, and many other factors. Therefore, clinicians should be setting health targets, such as improving sleep apnea and improving physical functioning, rather than a kilogram number.”
 

Three Pillars of Treatment

Right now, clinicians have three pillars of treatments available, Blüher said. The first is behavioral intervention, including strategies such as counseling, diet, exercise, self-monitoring, stress management, and sleep management.

“We know that these behavioral aspects typically lack adherence and effect size, but they’re important, and for a certain group of people, they may be the best and safest treatment.”

The second pillar is pharmacotherapy, and the third is surgery.

Each pillar poses questions for future research, he explained.

“First, do we really need more evidence that behavioral interventions typically fail in the long run and are prone to rebound of body weight and health issues? No. Or which diet is best? We have hundreds of diet interventions, all of which basically show very similar outcomes. They lead to an average weight loss of 3% to 5% and do improve health conditions associated with obesity.”

When it comes to pharmacotherapies, Blüher does believe clinicians need more options.

Depending on affordability and access, glucagon-like peptide 1 (GLP-1) semaglutide will likely become the first-line therapy for most people living with obesity who want to take medications, he suggested. The dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 tirzepatide will be reserved for those with more severe conditions.

“But this is not the end of the story,” he said. “The pipelines for obesity pharmacotherapies are full, and they have different categories. We are optimistic that we will have more therapies not only for type 2 diabetes (T2D) but also for obesity. Combinations such as CagriSema (cagrilintide + semaglutide, currently indicated for T2D) may outperform the monotherapies. We have to see if they’re as safe, and we have to wait for phase 3 trials and long-term outcomes.”

“The field is open for many combinations, ideas and interactions among the incretin-based signaling systems, but personally, I think that the triple agonists have a very bright future,” Blüher said.

For example, retatrutide, an agonist of the GIP, GLP-1, and glucagon receptors, showed promise in a phase 2 trial. Although that was not a comparative study, “the average changes in body weight suggest that in a dose-dependent manner, you can expect even more weight loss than with tirzepatide.”
 

Treating the Causes

The future of obesity therapy might also be directed at the originating factors that cause it, Blüher suggested, adding that “treating the causes is a dream of mine.”

One example of treating the cause is leptin therapy, as shown in a 1999 study of recombinant leptin in a child with congenital leptin deficiency. A more recent example is setmelanotide treatment for proopiomelanocortin deficiency.

“We are at the beginning for these causative treatments of obesity, and I hope that the future will hold much more of these insights and targets, as in cancer therapy.”

“Finally,” he said, “We eat with our brain. And so in the future, we also will be better able to use our knowledge about the complex neural circuits that are obesogenic, and how to target them. In doing so, we can learn from surgeons because obesity surgery is very effective in changing the anatomy, and we also observe hormonal changes. We see that ghrelin, GLP-1, peptide YY, and many others are affected when the anatomy changes. Why can’t we use that knowledge to design drugs that resemble or mimic the effect size of bariatric surgery?”

And that goes to the third pillar of treatment and the question of whether the new weight loss drugs may replace surgery, which also was the topic of another EASD session.

Blüher doesn’t see that happening for at least a decade, given that there is still an effect-size gap between tirzepatide and surgery, especially for individuals with T2D. In addition, he noted, there will still be nonresponders to drugs, and clinicians are not treating to target yet. Looking ahead, he foresees a combination of surgery and multi-receptor agonists.

“I believe that obesity won’t be cured in the future, but we will have increasingly better lifelong management with a multidisciplinary approach, although behavioral interventions still will not be as successful as pharmacotherapy and bariatric surgery,” he concluded.
 

Q&A

During the question-and-answer session following his lecture, several attendees asked Blüher for his thoughts around other emerging areas in this field. One wanted to know whether microbiome changes might be a future target for obesity treatment.

“So far, we don’t really understand which bacteria, which composition, at which age, and at which part of the intestine need to be targeted,” Blüher responded. “Before we know that mechanistically, I think it would be difficult, but it could be an avenue to go for, though I’m a little less optimistic about it compared to other approaches.”

Given that obesity is not one disease, are there cluster subtypes, as for T2D — eg, the hungry brain, the hungry gut, low metabolism — that might benefit from individualized treatment, another attendee asked.

“We do try to subcluster people living with obesity,” Blüher said. “We did that based on adipose tissue expression signatures, and indeed there is large heterogeneity. But we are far from addressing the root causes and all subtypes of the disease, and that would be a requirement before we could personalize treatment in that way.”

Next, an attendee asked what is responsible for the differential weight loss in people with diabetes and people without? Blüher responded that although he doesn’t have the answer, he does have hypotheses.

“One could be that the disease process — eg, deterioration of beta cell function, of the balance of hormones such as insulin and leptin, of inflammatory parameters, of insulin resistance — is much more advanced in diseases such as T2D and sleep apnea. Maybe it then takes more to address comorbid conditions such as inflammation and insulin resistance. Therefore, combining current therapies with insulin sensitizers, for example, could produce better results.”

What about using continuous glucose monitoring to help people stick to their diet?

“That’s an important question that speaks to personalized treatment,” he said. “It applies not only to continuous glucose monitoring but also to nutrition and other modes of self-monitoring, which seem to be among the most successful tools for long-term weight maintenance.”

Blüher finished by saying, “As we look into the future, I hope that there will be better approaches for all aspects of personalized medicine, whether it is nutrition, exercise, pharmacotherapy, or even surgical procedures.”

Blüher received honoraria for lectures and/or served as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novo Nordisk, Novartis, Pfizer, and Sanofi.
 

A version of this article first appeared on Medscape.com.

TOPLINE:

VIENNA, AUSTRIA — Participants with type 2 diabetes who were able to stop insulin for up to 12 months after receiving the novel recellularization via electroporation therapy (ReCET) procedure in combination with treatment with semaglutide maintained their response at 24 months.

METHODOLOGY:

• ReCET technology, manufactured by Endogenex, uses a specialized catheter that ablates the duodenal mucosa with electroporation, enhancing sensitivity to endogenous insulin.
• In the first-in-human study, a total of 14 participants (aged 28-75 years; body mass index, 24-40) underwent the ReCET procedure. They then followed a 2-week isocaloric liquid diet, after which they were initiated on semaglutide and gradually titrated up to 1 mg/wk.
• Patients were followed for a total of 24 months.

TAKEAWAY:

• Of the 14 participants, 12 (86%) no longer required insulin at the 6- and 12-month follow-ups.
• At the 24-month follow-up, 11 patients were still insulin-free while maintaining A1c levels below 7.5%. (One patient withdrew consent at 18 months.)
• Semaglutide at the maximum dose was well-tolerated by 93% of participants. One patient experienced nausea that limited titration to the maximum dose. There were no serious adverse events to the ReCET procedure.
• Researchers have started the EMINENT-2 trial that will compare the use of ReCET with a sham procedure. All patients will still receive semaglutide.

IN PRACTICE:

• “These findings are very encouraging, suggesting that ReCET is a safe and feasible procedure that, when combined with semaglutide, can effectively eliminate the need for insulin therapy,” said the study’s lead author.
• It’s a novel way of treating type 2 diabetes using a single endoscopic procedure instead of repeated insulin injections, Busch explained. “But we do need to consider whether repeat treatment will be necessary because I don’t believe this will be forever.”

SOURCE:

This study was led by Celine Busch, MBBS, a PhD candidate in gastroenterology at Amsterdam University Medical Center, Amsterdam, the Netherlands, and was presented (abstract OP049) at the United European Gastroenterology (UEG) Week 2024 in Vienna, Austria, on October 14, 2024.

LIMITATIONS:

Limitations included the small sample size, uncontrolled nature, and bias due to combination therapy.

DISCLOSURES:

This study received an unrestricted research grant from Endogenex. No other relevant disclosures were declared.

A version of this article first appeared on Medscape.com.

TOPLINE:

VIENNA, AUSTRIA — Participants with type 2 diabetes who were able to stop insulin for up to 12 months after receiving the novel recellularization via electroporation therapy (ReCET) procedure in combination with treatment with semaglutide maintained their response at 24 months.

METHODOLOGY:

• ReCET technology, manufactured by Endogenex, uses a specialized catheter that ablates the duodenal mucosa with electroporation, enhancing sensitivity to endogenous insulin.
• In the first-in-human study, a total of 14 participants (aged 28-75 years; body mass index, 24-40) underwent the ReCET procedure. They then followed a 2-week isocaloric liquid diet, after which they were initiated on semaglutide and gradually titrated up to 1 mg/wk.
• Patients were followed for a total of 24 months.

TAKEAWAY:

• Of the 14 participants, 12 (86%) no longer required insulin at the 6- and 12-month follow-ups.
• At the 24-month follow-up, 11 patients were still insulin-free while maintaining A1c levels below 7.5%. (One patient withdrew consent at 18 months.)
• Semaglutide at the maximum dose was well-tolerated by 93% of participants. One patient experienced nausea that limited titration to the maximum dose. There were no serious adverse events to the ReCET procedure.
• Researchers have started the EMINENT-2 trial that will compare the use of ReCET with a sham procedure. All patients will still receive semaglutide.

IN PRACTICE:

• “These findings are very encouraging, suggesting that ReCET is a safe and feasible procedure that, when combined with semaglutide, can effectively eliminate the need for insulin therapy,” said the study’s lead author.
• It’s a novel way of treating type 2 diabetes using a single endoscopic procedure instead of repeated insulin injections, Busch explained. “But we do need to consider whether repeat treatment will be necessary because I don’t believe this will be forever.”

SOURCE:

This study was led by Celine Busch, MBBS, a PhD candidate in gastroenterology at Amsterdam University Medical Center, Amsterdam, the Netherlands, and was presented (abstract OP049) at the United European Gastroenterology (UEG) Week 2024 in Vienna, Austria, on October 14, 2024.

LIMITATIONS:

Limitations included the small sample size, uncontrolled nature, and bias due to combination therapy.

DISCLOSURES:

This study received an unrestricted research grant from Endogenex. No other relevant disclosures were declared.

A version of this article first appeared on Medscape.com.

TOPLINE:

VIENNA, AUSTRIA — Participants with type 2 diabetes who were able to stop insulin for up to 12 months after receiving the novel recellularization via electroporation therapy (ReCET) procedure in combination with treatment with semaglutide maintained their response at 24 months.

METHODOLOGY:

• ReCET technology, manufactured by Endogenex, uses a specialized catheter that ablates the duodenal mucosa with electroporation, enhancing sensitivity to endogenous insulin.
• In the first-in-human study, a total of 14 participants (aged 28-75 years; body mass index, 24-40) underwent the ReCET procedure. They then followed a 2-week isocaloric liquid diet, after which they were initiated on semaglutide and gradually titrated up to 1 mg/wk.
• Patients were followed for a total of 24 months.

TAKEAWAY:

• Of the 14 participants, 12 (86%) no longer required insulin at the 6- and 12-month follow-ups.
• At the 24-month follow-up, 11 patients were still insulin-free while maintaining A1c levels below 7.5%. (One patient withdrew consent at 18 months.)
• Semaglutide at the maximum dose was well-tolerated by 93% of participants. One patient experienced nausea that limited titration to the maximum dose. There were no serious adverse events to the ReCET procedure.
• Researchers have started the EMINENT-2 trial that will compare the use of ReCET with a sham procedure. All patients will still receive semaglutide.

IN PRACTICE:

• “These findings are very encouraging, suggesting that ReCET is a safe and feasible procedure that, when combined with semaglutide, can effectively eliminate the need for insulin therapy,” said the study’s lead author.
• It’s a novel way of treating type 2 diabetes using a single endoscopic procedure instead of repeated insulin injections, Busch explained. “But we do need to consider whether repeat treatment will be necessary because I don’t believe this will be forever.”

SOURCE:

This study was led by Celine Busch, MBBS, a PhD candidate in gastroenterology at Amsterdam University Medical Center, Amsterdam, the Netherlands, and was presented (abstract OP049) at the United European Gastroenterology (UEG) Week 2024 in Vienna, Austria, on October 14, 2024.

LIMITATIONS:

Limitations included the small sample size, uncontrolled nature, and bias due to combination therapy.

DISCLOSURES:

This study received an unrestricted research grant from Endogenex. No other relevant disclosures were declared.

A version of this article first appeared on Medscape.com.

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

A version of this article first appeared on Medscape.com.

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

A version of this article first appeared on Medscape.com.

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

A version of this article first appeared on Medscape.com.

LIVERPOOL — “Healthy doctors make healthy patients”, stated a GP during a workshop at the Royal College of General Practitioners (RCGP) annual meeting. The session aimed to encourage GPs to embed lifestyle medicine into primary care through collaborative action.

Callum Leese from Aberfeldy Medical Practice in Scotland, who is also a lecturer at the University of Dundee for the Scottish Clinical Research Excellence Development Scheme (SCREDS), discussed the benefits of lifestyle medicine services in addressing lifestyle-related diseases, reducing their contribution towards the prevalence of chronic conditions, and helping prevent premature mortality. 

Leese is leading a project to make Aberfeldy the healthiest town in Scotland by promoting physical activities, such as the 2-km, 5-km, and 7-km Santa Stride walking group in November, and a recent food festival to encourage healthy cooking and eating. “There’s loads of things that can be done to try and inspire change,” he said. “The research is fairly unequivocal in that healthy doctors make healthy patients,” Leese asserted. “The most important thing we can do is target our doctors and our nurses and make them advocates for what we want to see with our patients.”

Speaking to this news organization, he emphasized that, “if the doctors are moving, they’re much more likely to promote it, and if they’re eating well, they’re much more likely to be able to be evangelistic.” 
 

Physical Activity Advice Shows High Return

About one-third of the population in the United Kingdom are physically inactive, which costs the economy £7.2 billion, with £1 billion attributed directly to the NHS, he informed the workshop.

As an honorary support fellow in physical activity and lifestyle medicine at the RCGP, Leese specializes in integrating physical activity into primary care settings. “We know it’s cost effective. If we compare it to smoking cessation advice, we know that we need to give advice to one person about 50 times for one person to stop smoking in primary care. But for physical activity, you need to give advice to 12 people for one person to increase their physical activity levels to meet the guidance,” he noted.

Leese stressed the importance of short but effective discussions between GPs and patients. He gave examples of online resources to recommend to patients, such as Moving Medicine, which aims to help healthcare professionals integrate physical activity into routine clinical conversations, or the RCGP toolkit (the Physical Activity Hub). “It really takes 1 minute of asking if the patient has ever considered being more active, and briefly explaining that being more active might have really significant outcomes for their condition,” he said.

In primary care, most patients who need to be more physically activity are directed toward 12-week exercise referral schemes, and sometimes we use social prescribing, for example, inviting patients to walk in groups, Leese explained. “However, despite the best intentions, about 78% of GPs aren’t doing it [advising on physical activity] regularly,” he noted. He cited four main challenges: lack of time, knowledge, resources, and financial support.
 

Geographical Variation in Social Prescribing

Social prescribing, which links patients with non–medical community support, also varies widely across the United Kingdom. “Social prescribing is a real example of that because it’s really well established in some places and not in others,” Leese remarked. He noted that inner-city and rural areas often have different needs. Contrary to some expectations, city dwellers are sometimes more active than those living in rural areas because despite having lots of green space for physical activity, “they tend to park the car outside the front door and park again right outside their place of work, whereas in London, for example, you can persuade people to get off a stop early on the Tube or a stop early in the bus.”

MAN v FAT 5-a-side Football

Leese also emphasized the importance of innovation in implementing lifestyle medicine, pointing out that nonmedical personnel, social prescribers, and health coaches can alleviate time pressures on GPs.

Citing an example of a physical activity-related intervention, he described a UK-wide organization developed for men in the 40s-50s age group, called MAN v FAT, which involves a novel weight-related way of playing five-a-side football. Players have a weigh-in before each game and teams are rewarded with points on the pitch for every pound lost as a team since their last match.

However, Leese acknowledged the need to tailor physical activity advice to different age groups. For example, “in an 80-year-old, physical activity might improve their balance and they’re less likely to fall and break something.” 
 

Lifestyle Clinics

Leese cited the PCN Lifestyle Clinics, originating from the Leamington Primary Care Network (PCN), as an example of successful lifestyle medicine integration to help address the needs of people living with chronic conditions. “We don’t want to prescribe a model, but we can draw on a program run by the Leamington Spa PCN, that involves four group sessions of 6-10 people focused on lifestyle,” he said. 

The weekly group-based sessions are run by a GP, a health and wellbeing coach, a dietitian, and a psychiatrist. Together, they cover four aspects of lifestyle and health comprising individual challenges, how community influences behavior and vice versa, food and nutrition, and physical activity for health and wellbeing.

“We try to debunk some of those myths around nutrition, compared with diet, and physical activity, compared with exercise. So, for example, the idea that exercise is usually considered to be using an elliptical cross-trainer whereas physical activity, which might be just dancing in your kitchen while you’re making dinner, is something that can be done more easily,” explained Leese.

Physical activities include running and swimming in collaboration with a leisure center. “It’s an amazing program,” he remarked. 

Outcomes from 142 patients who attended the Lifestyle Clinic at a North Leamington GP practice over 14 months showed that 53% gained confidence in making lifestyle changes, 60% noticed a positive impact on their physical health, and 77% reported positive impacts on their mental health.
 

GP Embraces Lifestyle Medicine

Rachel Burnett, a GP from Park Medical Practice in Derby, a delegate who attended the session, commented on the central idea of incorporating lifestyle medicine into primary care practice. She told this news organization that, “I think it could prevent a lot of ill health and therefore a lot of health inequalities just by embedding lifestyle medicine into our work. To hear about the Leamington Spa project and how it›s been a success was really inspiring.”

Referring to her own practice, Burnett said: “My patients are familiar with the way I go on and on about lifestyle measures, but I believe the way forward is with group sessions because we need to give the same advice to a large number of patients, for example, with prediabetes. This could save time and resource, and I think patients who are more likely to make the changes will actually attend the sessions so we’re not wasting our breath.” 

Neither Leese nor Burnett declared any relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

LIVERPOOL — “Healthy doctors make healthy patients”, stated a GP during a workshop at the Royal College of General Practitioners (RCGP) annual meeting. The session aimed to encourage GPs to embed lifestyle medicine into primary care through collaborative action.

Callum Leese from Aberfeldy Medical Practice in Scotland, who is also a lecturer at the University of Dundee for the Scottish Clinical Research Excellence Development Scheme (SCREDS), discussed the benefits of lifestyle medicine services in addressing lifestyle-related diseases, reducing their contribution towards the prevalence of chronic conditions, and helping prevent premature mortality. 

Leese is leading a project to make Aberfeldy the healthiest town in Scotland by promoting physical activities, such as the 2-km, 5-km, and 7-km Santa Stride walking group in November, and a recent food festival to encourage healthy cooking and eating. “There’s loads of things that can be done to try and inspire change,” he said. “The research is fairly unequivocal in that healthy doctors make healthy patients,” Leese asserted. “The most important thing we can do is target our doctors and our nurses and make them advocates for what we want to see with our patients.”

Speaking to this news organization, he emphasized that, “if the doctors are moving, they’re much more likely to promote it, and if they’re eating well, they’re much more likely to be able to be evangelistic.” 
 

Physical Activity Advice Shows High Return

About one-third of the population in the United Kingdom are physically inactive, which costs the economy £7.2 billion, with £1 billion attributed directly to the NHS, he informed the workshop.

As an honorary support fellow in physical activity and lifestyle medicine at the RCGP, Leese specializes in integrating physical activity into primary care settings. “We know it’s cost effective. If we compare it to smoking cessation advice, we know that we need to give advice to one person about 50 times for one person to stop smoking in primary care. But for physical activity, you need to give advice to 12 people for one person to increase their physical activity levels to meet the guidance,” he noted.

Leese stressed the importance of short but effective discussions between GPs and patients. He gave examples of online resources to recommend to patients, such as Moving Medicine, which aims to help healthcare professionals integrate physical activity into routine clinical conversations, or the RCGP toolkit (the Physical Activity Hub). “It really takes 1 minute of asking if the patient has ever considered being more active, and briefly explaining that being more active might have really significant outcomes for their condition,” he said.

In primary care, most patients who need to be more physically activity are directed toward 12-week exercise referral schemes, and sometimes we use social prescribing, for example, inviting patients to walk in groups, Leese explained. “However, despite the best intentions, about 78% of GPs aren’t doing it [advising on physical activity] regularly,” he noted. He cited four main challenges: lack of time, knowledge, resources, and financial support.
 

Geographical Variation in Social Prescribing

Social prescribing, which links patients with non–medical community support, also varies widely across the United Kingdom. “Social prescribing is a real example of that because it’s really well established in some places and not in others,” Leese remarked. He noted that inner-city and rural areas often have different needs. Contrary to some expectations, city dwellers are sometimes more active than those living in rural areas because despite having lots of green space for physical activity, “they tend to park the car outside the front door and park again right outside their place of work, whereas in London, for example, you can persuade people to get off a stop early on the Tube or a stop early in the bus.”

MAN v FAT 5-a-side Football

Leese also emphasized the importance of innovation in implementing lifestyle medicine, pointing out that nonmedical personnel, social prescribers, and health coaches can alleviate time pressures on GPs.

Citing an example of a physical activity-related intervention, he described a UK-wide organization developed for men in the 40s-50s age group, called MAN v FAT, which involves a novel weight-related way of playing five-a-side football. Players have a weigh-in before each game and teams are rewarded with points on the pitch for every pound lost as a team since their last match.

However, Leese acknowledged the need to tailor physical activity advice to different age groups. For example, “in an 80-year-old, physical activity might improve their balance and they’re less likely to fall and break something.” 
 

Lifestyle Clinics

Leese cited the PCN Lifestyle Clinics, originating from the Leamington Primary Care Network (PCN), as an example of successful lifestyle medicine integration to help address the needs of people living with chronic conditions. “We don’t want to prescribe a model, but we can draw on a program run by the Leamington Spa PCN, that involves four group sessions of 6-10 people focused on lifestyle,” he said. 

The weekly group-based sessions are run by a GP, a health and wellbeing coach, a dietitian, and a psychiatrist. Together, they cover four aspects of lifestyle and health comprising individual challenges, how community influences behavior and vice versa, food and nutrition, and physical activity for health and wellbeing.

“We try to debunk some of those myths around nutrition, compared with diet, and physical activity, compared with exercise. So, for example, the idea that exercise is usually considered to be using an elliptical cross-trainer whereas physical activity, which might be just dancing in your kitchen while you’re making dinner, is something that can be done more easily,” explained Leese.

Physical activities include running and swimming in collaboration with a leisure center. “It’s an amazing program,” he remarked. 

Outcomes from 142 patients who attended the Lifestyle Clinic at a North Leamington GP practice over 14 months showed that 53% gained confidence in making lifestyle changes, 60% noticed a positive impact on their physical health, and 77% reported positive impacts on their mental health.
 

GP Embraces Lifestyle Medicine

Rachel Burnett, a GP from Park Medical Practice in Derby, a delegate who attended the session, commented on the central idea of incorporating lifestyle medicine into primary care practice. She told this news organization that, “I think it could prevent a lot of ill health and therefore a lot of health inequalities just by embedding lifestyle medicine into our work. To hear about the Leamington Spa project and how it›s been a success was really inspiring.”

Referring to her own practice, Burnett said: “My patients are familiar with the way I go on and on about lifestyle measures, but I believe the way forward is with group sessions because we need to give the same advice to a large number of patients, for example, with prediabetes. This could save time and resource, and I think patients who are more likely to make the changes will actually attend the sessions so we’re not wasting our breath.” 

Neither Leese nor Burnett declared any relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

LIVERPOOL — “Healthy doctors make healthy patients”, stated a GP during a workshop at the Royal College of General Practitioners (RCGP) annual meeting. The session aimed to encourage GPs to embed lifestyle medicine into primary care through collaborative action.

Callum Leese from Aberfeldy Medical Practice in Scotland, who is also a lecturer at the University of Dundee for the Scottish Clinical Research Excellence Development Scheme (SCREDS), discussed the benefits of lifestyle medicine services in addressing lifestyle-related diseases, reducing their contribution towards the prevalence of chronic conditions, and helping prevent premature mortality. 

Leese is leading a project to make Aberfeldy the healthiest town in Scotland by promoting physical activities, such as the 2-km, 5-km, and 7-km Santa Stride walking group in November, and a recent food festival to encourage healthy cooking and eating. “There’s loads of things that can be done to try and inspire change,” he said. “The research is fairly unequivocal in that healthy doctors make healthy patients,” Leese asserted. “The most important thing we can do is target our doctors and our nurses and make them advocates for what we want to see with our patients.”

Speaking to this news organization, he emphasized that, “if the doctors are moving, they’re much more likely to promote it, and if they’re eating well, they’re much more likely to be able to be evangelistic.” 
 

Physical Activity Advice Shows High Return

About one-third of the population in the United Kingdom are physically inactive, which costs the economy £7.2 billion, with £1 billion attributed directly to the NHS, he informed the workshop.

As an honorary support fellow in physical activity and lifestyle medicine at the RCGP, Leese specializes in integrating physical activity into primary care settings. “We know it’s cost effective. If we compare it to smoking cessation advice, we know that we need to give advice to one person about 50 times for one person to stop smoking in primary care. But for physical activity, you need to give advice to 12 people for one person to increase their physical activity levels to meet the guidance,” he noted.

Leese stressed the importance of short but effective discussions between GPs and patients. He gave examples of online resources to recommend to patients, such as Moving Medicine, which aims to help healthcare professionals integrate physical activity into routine clinical conversations, or the RCGP toolkit (the Physical Activity Hub). “It really takes 1 minute of asking if the patient has ever considered being more active, and briefly explaining that being more active might have really significant outcomes for their condition,” he said.

In primary care, most patients who need to be more physically activity are directed toward 12-week exercise referral schemes, and sometimes we use social prescribing, for example, inviting patients to walk in groups, Leese explained. “However, despite the best intentions, about 78% of GPs aren’t doing it [advising on physical activity] regularly,” he noted. He cited four main challenges: lack of time, knowledge, resources, and financial support.
 

Geographical Variation in Social Prescribing

Social prescribing, which links patients with non–medical community support, also varies widely across the United Kingdom. “Social prescribing is a real example of that because it’s really well established in some places and not in others,” Leese remarked. He noted that inner-city and rural areas often have different needs. Contrary to some expectations, city dwellers are sometimes more active than those living in rural areas because despite having lots of green space for physical activity, “they tend to park the car outside the front door and park again right outside their place of work, whereas in London, for example, you can persuade people to get off a stop early on the Tube or a stop early in the bus.”

MAN v FAT 5-a-side Football

Leese also emphasized the importance of innovation in implementing lifestyle medicine, pointing out that nonmedical personnel, social prescribers, and health coaches can alleviate time pressures on GPs.

Citing an example of a physical activity-related intervention, he described a UK-wide organization developed for men in the 40s-50s age group, called MAN v FAT, which involves a novel weight-related way of playing five-a-side football. Players have a weigh-in before each game and teams are rewarded with points on the pitch for every pound lost as a team since their last match.

However, Leese acknowledged the need to tailor physical activity advice to different age groups. For example, “in an 80-year-old, physical activity might improve their balance and they’re less likely to fall and break something.” 
 

Lifestyle Clinics

Leese cited the PCN Lifestyle Clinics, originating from the Leamington Primary Care Network (PCN), as an example of successful lifestyle medicine integration to help address the needs of people living with chronic conditions. “We don’t want to prescribe a model, but we can draw on a program run by the Leamington Spa PCN, that involves four group sessions of 6-10 people focused on lifestyle,” he said. 

The weekly group-based sessions are run by a GP, a health and wellbeing coach, a dietitian, and a psychiatrist. Together, they cover four aspects of lifestyle and health comprising individual challenges, how community influences behavior and vice versa, food and nutrition, and physical activity for health and wellbeing.

“We try to debunk some of those myths around nutrition, compared with diet, and physical activity, compared with exercise. So, for example, the idea that exercise is usually considered to be using an elliptical cross-trainer whereas physical activity, which might be just dancing in your kitchen while you’re making dinner, is something that can be done more easily,” explained Leese.

Physical activities include running and swimming in collaboration with a leisure center. “It’s an amazing program,” he remarked. 

Outcomes from 142 patients who attended the Lifestyle Clinic at a North Leamington GP practice over 14 months showed that 53% gained confidence in making lifestyle changes, 60% noticed a positive impact on their physical health, and 77% reported positive impacts on their mental health.
 

GP Embraces Lifestyle Medicine

Rachel Burnett, a GP from Park Medical Practice in Derby, a delegate who attended the session, commented on the central idea of incorporating lifestyle medicine into primary care practice. She told this news organization that, “I think it could prevent a lot of ill health and therefore a lot of health inequalities just by embedding lifestyle medicine into our work. To hear about the Leamington Spa project and how it›s been a success was really inspiring.”

Referring to her own practice, Burnett said: “My patients are familiar with the way I go on and on about lifestyle measures, but I believe the way forward is with group sessions because we need to give the same advice to a large number of patients, for example, with prediabetes. This could save time and resource, and I think patients who are more likely to make the changes will actually attend the sessions so we’re not wasting our breath.” 

Neither Leese nor Burnett declared any relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

CARLSBAD, CALIF. — Lasers and energy-based treatments alone or in combination with medical therapy may improve outcomes for patients with moderate to severe acne, according to Arielle Kauvar, MD.

At the Controversies and Conversations in Laser and Cosmetic Surgery annual symposium, Kauvar, director of New York Laser & Skin Care, New York City, highlighted several reasons why using lasers for acne is beneficial. “First, we know that topical therapy alone is often ineffective, and antibiotic treatment does not address the cause of acne and can alter the skin and gut microbiome,” she said. “Isotretinoin is highly effective, but there’s an increasing reluctance to use it. Lasers and energy devices are effective in treating acne and may also treat the post-inflammatory hyperpigmentation and scarring associated with it.”

The pathogenesis of acne is multifactorial, she continued, including a disruption of sebaceous gland activity, with overproduction and alteration of sebum and abnormal follicular keratinization. Acne also causes an imbalance of the skin microbiome, local inflammation, and activation of both innate and adaptive immunity.

“Many studies point to the fact that inflammation and immune system activation may actually be the primary event” of acne formation, said Kauvar, who is also a clinical professor of dermatology at New York University, New York City. “This persistent immune activation is also associated with scarring,” she noted. “So, are we off the mark in terms of trying to kill sebaceous glands? Should we be concentrating on anti-inflammatory approaches?” 

AviClear became the first 1726-nm laser cleared by the US Food and Drug Administration (FDA) for the treatment of mild to severe acne vulgaris in 2022, followed a few months later with the FDA clearance of another 1726-nm laser, the Accure Acne Laser System in November 2022. These lasers cause selective photothermolysis of sebaceous glands, but according to Kauvar, “access to these devices is somewhat limited at this time.”

What is available includes her go-to device, the pulsed dye laser (PDL), which has been widely studied and shown in a systematic review and meta-analysis of studies to be effective for acne. The PDL “targets dermal blood vessels facilitating inflammation, upregulates TGF-beta, and inhibits CD4+ T cell-mediated inflammation,” she said. “It can also treat PIH [post-inflammatory hyperpigmentation] and may be helpful in scar prevention.”

In an abstract presented at The American Society for Laser Medicine and Surgery (ASLMS) 2024 annual meeting, Kauvar and colleagues conducted a real-world study of PDL therapy in 15 adult women with recalcitrant acne who were maintained on their medical treatment regimen. Their mean age was 27 years, and they had skin types II-IV; they underwent four monthly PDL treatments with follow-up at 1 and 3 months. At each visit, the researchers took digital photographs and counted inflammatory acne lesions, non-inflammatory acne lesions, and post-inflammatory pigment alteration (PIPA) lesions.

The main outcomes of interest were the investigator global assessment (IGA) scores at the 1- and 3-month follow-up visits. Kauvar and colleagues observed a significant improvement in IGA scores at the 1- and 3-month follow-up visits (P < .05), with an average decrease of 1.8 and 1.6 points in the acne severity scale, respectively, from a baseline score of 3.4. By the 3-month follow-up visits, counts of inflammatory and non-inflammatory lesions decreased significantly (P < .05), and 61% of study participants showed a decrease in the PIPA count. No adverse events occurred. 

Kauvar disclosed that she has conducted research for Candela, Lumenis, and Sofwave, and is an adviser to Acclaro.

A version of this article first appeared on Medscape.com.

CARLSBAD, CALIF. — Lasers and energy-based treatments alone or in combination with medical therapy may improve outcomes for patients with moderate to severe acne, according to Arielle Kauvar, MD.

At the Controversies and Conversations in Laser and Cosmetic Surgery annual symposium, Kauvar, director of New York Laser & Skin Care, New York City, highlighted several reasons why using lasers for acne is beneficial. “First, we know that topical therapy alone is often ineffective, and antibiotic treatment does not address the cause of acne and can alter the skin and gut microbiome,” she said. “Isotretinoin is highly effective, but there’s an increasing reluctance to use it. Lasers and energy devices are effective in treating acne and may also treat the post-inflammatory hyperpigmentation and scarring associated with it.”

The pathogenesis of acne is multifactorial, she continued, including a disruption of sebaceous gland activity, with overproduction and alteration of sebum and abnormal follicular keratinization. Acne also causes an imbalance of the skin microbiome, local inflammation, and activation of both innate and adaptive immunity.

“Many studies point to the fact that inflammation and immune system activation may actually be the primary event” of acne formation, said Kauvar, who is also a clinical professor of dermatology at New York University, New York City. “This persistent immune activation is also associated with scarring,” she noted. “So, are we off the mark in terms of trying to kill sebaceous glands? Should we be concentrating on anti-inflammatory approaches?” 

AviClear became the first 1726-nm laser cleared by the US Food and Drug Administration (FDA) for the treatment of mild to severe acne vulgaris in 2022, followed a few months later with the FDA clearance of another 1726-nm laser, the Accure Acne Laser System in November 2022. These lasers cause selective photothermolysis of sebaceous glands, but according to Kauvar, “access to these devices is somewhat limited at this time.”

What is available includes her go-to device, the pulsed dye laser (PDL), which has been widely studied and shown in a systematic review and meta-analysis of studies to be effective for acne. The PDL “targets dermal blood vessels facilitating inflammation, upregulates TGF-beta, and inhibits CD4+ T cell-mediated inflammation,” she said. “It can also treat PIH [post-inflammatory hyperpigmentation] and may be helpful in scar prevention.”

In an abstract presented at The American Society for Laser Medicine and Surgery (ASLMS) 2024 annual meeting, Kauvar and colleagues conducted a real-world study of PDL therapy in 15 adult women with recalcitrant acne who were maintained on their medical treatment regimen. Their mean age was 27 years, and they had skin types II-IV; they underwent four monthly PDL treatments with follow-up at 1 and 3 months. At each visit, the researchers took digital photographs and counted inflammatory acne lesions, non-inflammatory acne lesions, and post-inflammatory pigment alteration (PIPA) lesions.

The main outcomes of interest were the investigator global assessment (IGA) scores at the 1- and 3-month follow-up visits. Kauvar and colleagues observed a significant improvement in IGA scores at the 1- and 3-month follow-up visits (P < .05), with an average decrease of 1.8 and 1.6 points in the acne severity scale, respectively, from a baseline score of 3.4. By the 3-month follow-up visits, counts of inflammatory and non-inflammatory lesions decreased significantly (P < .05), and 61% of study participants showed a decrease in the PIPA count. No adverse events occurred. 

Kauvar disclosed that she has conducted research for Candela, Lumenis, and Sofwave, and is an adviser to Acclaro.

A version of this article first appeared on Medscape.com.

CARLSBAD, CALIF. — Lasers and energy-based treatments alone or in combination with medical therapy may improve outcomes for patients with moderate to severe acne, according to Arielle Kauvar, MD.

At the Controversies and Conversations in Laser and Cosmetic Surgery annual symposium, Kauvar, director of New York Laser & Skin Care, New York City, highlighted several reasons why using lasers for acne is beneficial. “First, we know that topical therapy alone is often ineffective, and antibiotic treatment does not address the cause of acne and can alter the skin and gut microbiome,” she said. “Isotretinoin is highly effective, but there’s an increasing reluctance to use it. Lasers and energy devices are effective in treating acne and may also treat the post-inflammatory hyperpigmentation and scarring associated with it.”

The pathogenesis of acne is multifactorial, she continued, including a disruption of sebaceous gland activity, with overproduction and alteration of sebum and abnormal follicular keratinization. Acne also causes an imbalance of the skin microbiome, local inflammation, and activation of both innate and adaptive immunity.

“Many studies point to the fact that inflammation and immune system activation may actually be the primary event” of acne formation, said Kauvar, who is also a clinical professor of dermatology at New York University, New York City. “This persistent immune activation is also associated with scarring,” she noted. “So, are we off the mark in terms of trying to kill sebaceous glands? Should we be concentrating on anti-inflammatory approaches?” 

AviClear became the first 1726-nm laser cleared by the US Food and Drug Administration (FDA) for the treatment of mild to severe acne vulgaris in 2022, followed a few months later with the FDA clearance of another 1726-nm laser, the Accure Acne Laser System in November 2022. These lasers cause selective photothermolysis of sebaceous glands, but according to Kauvar, “access to these devices is somewhat limited at this time.”

What is available includes her go-to device, the pulsed dye laser (PDL), which has been widely studied and shown in a systematic review and meta-analysis of studies to be effective for acne. The PDL “targets dermal blood vessels facilitating inflammation, upregulates TGF-beta, and inhibits CD4+ T cell-mediated inflammation,” she said. “It can also treat PIH [post-inflammatory hyperpigmentation] and may be helpful in scar prevention.”

In an abstract presented at The American Society for Laser Medicine and Surgery (ASLMS) 2024 annual meeting, Kauvar and colleagues conducted a real-world study of PDL therapy in 15 adult women with recalcitrant acne who were maintained on their medical treatment regimen. Their mean age was 27 years, and they had skin types II-IV; they underwent four monthly PDL treatments with follow-up at 1 and 3 months. At each visit, the researchers took digital photographs and counted inflammatory acne lesions, non-inflammatory acne lesions, and post-inflammatory pigment alteration (PIPA) lesions.

The main outcomes of interest were the investigator global assessment (IGA) scores at the 1- and 3-month follow-up visits. Kauvar and colleagues observed a significant improvement in IGA scores at the 1- and 3-month follow-up visits (P < .05), with an average decrease of 1.8 and 1.6 points in the acne severity scale, respectively, from a baseline score of 3.4. By the 3-month follow-up visits, counts of inflammatory and non-inflammatory lesions decreased significantly (P < .05), and 61% of study participants showed a decrease in the PIPA count. No adverse events occurred. 

Kauvar disclosed that she has conducted research for Candela, Lumenis, and Sofwave, and is an adviser to Acclaro.

A version of this article first appeared on Medscape.com.

Getting drugs to the brain is difficult. The very thing designed to protect the brain’s environment — the blood-brain barrier (BBB) — is one of the main reasons diseases like Alzheimer’s are so hard to treat.

And even if a drug can cross the BBB, it’s difficult to ensure it reaches specific areas of the brain like the hippocampus, which is located deep within the brain and notoriously difficult to target with conventional drugs.

However, new research shows that novel bioengineered proteins can target neurons in the hippocampus. Using a mouse model, the researchers found that these proteins could be delivered to the hippocampus intranasally — through the nose via a spray.

“This is an urgent topic because many potential therapeutic agents do not readily cross the blood-brain barrier or have limited effects even after intranasal delivery,” said Konrad Talbot, PhD, professor of neurosurgery and pathology at Loma Linda University, Loma Linda, California, who was not involved in the study.

This is the first time a protein drug, which is larger than many drug molecules, has been specifically delivered to the hippocampus, said Noriyasu Kamei, PhD, a professor of pharmaceutical science at Kobe Gakuin University in Kobe, Japan, and lead author of the study.
 

How Did They Do It?

“Smuggle” may be a flip term, but it’s not inaccurate.

Insulin has the ability to cross the BBB, so the team began with insulin as the vehicle. By attaching other molecules to an insulin fragment, researchers theorized they could create an insulin fusion protein that can be transported across the BBB and into the brain via a process called macropinocytosis.

They executed this technique in mice by fusing florescent proteins to insulin. To treat Alzheimer’s or other diseases, they would want to fuse therapeutic molecules to the insulin for brain delivery — a future step for their research.

Other groups are studying a similar approach using transferrin receptor instead of insulin to shuttle molecules across the BBB. However, the transferrin receptor doesn’t make it to the hippocampus, Kamei said.

A benefit of their system, Kamei pointed out, is that because the method just requires a small piece of insulin to work, it’s straightforward to produce in bacteria. Importantly, he said, the insulin fusion protein should not affect blood glucose levels.
 

Why Insulin?

Aside from its ability to cross the BBB, the team thought to use insulin as the basis of a fusion protein because of their previous work.

“I found that insulin has the unique characteristics to be accumulated specifically in the hippocampal neuronal layers,” Kamei explained. That potential for accumulation is key, as they can deliver more of a drug that way.

In their past work, Kamei and colleagues also found that it could be delivered from the nose to the brain, indicating that it may be possible to use a simple nasal spray.

“The potential for noninvasive delivery of proteins by intranasal administration to the hippocampal neurons is novel,” said John Varghese, PhD, professor of neurology at University of California Los Angeles (he was not involved in the study). He noted that it’s also possible that this method could be harnessed to treat other brain diseases.

There are other drugs that treat central nervous system diseases, such as desmopressin and buserelin, which are available as nasal sprays. However, these drugs are synthetic hormones, and though relatively small molecules, they do not cross the BBB.

There are also antibody treatments for Alzheimer’s, such as aducanumab (which will soon be discontinued), lecanemab, and donanemab; however, they aren’t always effective and they require an intravenous infusion, and while they cross the BBB to a degree, to bolster delivery to the brain, studies have proposed additional methods like focused ultrasound.

“Neuronal uptake of drugs potentially therapeutic for Alzheimer’s may be significantly enhanced by fusion of those drugs with insulin. This should be a research priority,” said Talbot.

While this is exciting and has potential, such drugs won’t be available anytime soon. Kamei would like to complete the research at a basic level in 5 years, including testing insulin fused with larger proteins such as therapeutic antibodies. If all goes well, they’ll move on to testing insulin fusion drugs in people.
 

A version of this article first appeared on Medscape.com.

Getting drugs to the brain is difficult. The very thing designed to protect the brain’s environment — the blood-brain barrier (BBB) — is one of the main reasons diseases like Alzheimer’s are so hard to treat.

And even if a drug can cross the BBB, it’s difficult to ensure it reaches specific areas of the brain like the hippocampus, which is located deep within the brain and notoriously difficult to target with conventional drugs.

However, new research shows that novel bioengineered proteins can target neurons in the hippocampus. Using a mouse model, the researchers found that these proteins could be delivered to the hippocampus intranasally — through the nose via a spray.

“This is an urgent topic because many potential therapeutic agents do not readily cross the blood-brain barrier or have limited effects even after intranasal delivery,” said Konrad Talbot, PhD, professor of neurosurgery and pathology at Loma Linda University, Loma Linda, California, who was not involved in the study.

This is the first time a protein drug, which is larger than many drug molecules, has been specifically delivered to the hippocampus, said Noriyasu Kamei, PhD, a professor of pharmaceutical science at Kobe Gakuin University in Kobe, Japan, and lead author of the study.
 

How Did They Do It?

“Smuggle” may be a flip term, but it’s not inaccurate.

Insulin has the ability to cross the BBB, so the team began with insulin as the vehicle. By attaching other molecules to an insulin fragment, researchers theorized they could create an insulin fusion protein that can be transported across the BBB and into the brain via a process called macropinocytosis.

They executed this technique in mice by fusing florescent proteins to insulin. To treat Alzheimer’s or other diseases, they would want to fuse therapeutic molecules to the insulin for brain delivery — a future step for their research.

Other groups are studying a similar approach using transferrin receptor instead of insulin to shuttle molecules across the BBB. However, the transferrin receptor doesn’t make it to the hippocampus, Kamei said.

A benefit of their system, Kamei pointed out, is that because the method just requires a small piece of insulin to work, it’s straightforward to produce in bacteria. Importantly, he said, the insulin fusion protein should not affect blood glucose levels.
 

Why Insulin?

Aside from its ability to cross the BBB, the team thought to use insulin as the basis of a fusion protein because of their previous work.

“I found that insulin has the unique characteristics to be accumulated specifically in the hippocampal neuronal layers,” Kamei explained. That potential for accumulation is key, as they can deliver more of a drug that way.

In their past work, Kamei and colleagues also found that it could be delivered from the nose to the brain, indicating that it may be possible to use a simple nasal spray.

“The potential for noninvasive delivery of proteins by intranasal administration to the hippocampal neurons is novel,” said John Varghese, PhD, professor of neurology at University of California Los Angeles (he was not involved in the study). He noted that it’s also possible that this method could be harnessed to treat other brain diseases.

There are other drugs that treat central nervous system diseases, such as desmopressin and buserelin, which are available as nasal sprays. However, these drugs are synthetic hormones, and though relatively small molecules, they do not cross the BBB.

There are also antibody treatments for Alzheimer’s, such as aducanumab (which will soon be discontinued), lecanemab, and donanemab; however, they aren’t always effective and they require an intravenous infusion, and while they cross the BBB to a degree, to bolster delivery to the brain, studies have proposed additional methods like focused ultrasound.

“Neuronal uptake of drugs potentially therapeutic for Alzheimer’s may be significantly enhanced by fusion of those drugs with insulin. This should be a research priority,” said Talbot.

While this is exciting and has potential, such drugs won’t be available anytime soon. Kamei would like to complete the research at a basic level in 5 years, including testing insulin fused with larger proteins such as therapeutic antibodies. If all goes well, they’ll move on to testing insulin fusion drugs in people.
 

A version of this article first appeared on Medscape.com.

Getting drugs to the brain is difficult. The very thing designed to protect the brain’s environment — the blood-brain barrier (BBB) — is one of the main reasons diseases like Alzheimer’s are so hard to treat.

And even if a drug can cross the BBB, it’s difficult to ensure it reaches specific areas of the brain like the hippocampus, which is located deep within the brain and notoriously difficult to target with conventional drugs.

However, new research shows that novel bioengineered proteins can target neurons in the hippocampus. Using a mouse model, the researchers found that these proteins could be delivered to the hippocampus intranasally — through the nose via a spray.

“This is an urgent topic because many potential therapeutic agents do not readily cross the blood-brain barrier or have limited effects even after intranasal delivery,” said Konrad Talbot, PhD, professor of neurosurgery and pathology at Loma Linda University, Loma Linda, California, who was not involved in the study.

This is the first time a protein drug, which is larger than many drug molecules, has been specifically delivered to the hippocampus, said Noriyasu Kamei, PhD, a professor of pharmaceutical science at Kobe Gakuin University in Kobe, Japan, and lead author of the study.
 

How Did They Do It?

“Smuggle” may be a flip term, but it’s not inaccurate.

Insulin has the ability to cross the BBB, so the team began with insulin as the vehicle. By attaching other molecules to an insulin fragment, researchers theorized they could create an insulin fusion protein that can be transported across the BBB and into the brain via a process called macropinocytosis.

They executed this technique in mice by fusing florescent proteins to insulin. To treat Alzheimer’s or other diseases, they would want to fuse therapeutic molecules to the insulin for brain delivery — a future step for their research.

Other groups are studying a similar approach using transferrin receptor instead of insulin to shuttle molecules across the BBB. However, the transferrin receptor doesn’t make it to the hippocampus, Kamei said.

A benefit of their system, Kamei pointed out, is that because the method just requires a small piece of insulin to work, it’s straightforward to produce in bacteria. Importantly, he said, the insulin fusion protein should not affect blood glucose levels.
 

Why Insulin?

Aside from its ability to cross the BBB, the team thought to use insulin as the basis of a fusion protein because of their previous work.

“I found that insulin has the unique characteristics to be accumulated specifically in the hippocampal neuronal layers,” Kamei explained. That potential for accumulation is key, as they can deliver more of a drug that way.

In their past work, Kamei and colleagues also found that it could be delivered from the nose to the brain, indicating that it may be possible to use a simple nasal spray.

“The potential for noninvasive delivery of proteins by intranasal administration to the hippocampal neurons is novel,” said John Varghese, PhD, professor of neurology at University of California Los Angeles (he was not involved in the study). He noted that it’s also possible that this method could be harnessed to treat other brain diseases.

There are other drugs that treat central nervous system diseases, such as desmopressin and buserelin, which are available as nasal sprays. However, these drugs are synthetic hormones, and though relatively small molecules, they do not cross the BBB.

There are also antibody treatments for Alzheimer’s, such as aducanumab (which will soon be discontinued), lecanemab, and donanemab; however, they aren’t always effective and they require an intravenous infusion, and while they cross the BBB to a degree, to bolster delivery to the brain, studies have proposed additional methods like focused ultrasound.

“Neuronal uptake of drugs potentially therapeutic for Alzheimer’s may be significantly enhanced by fusion of those drugs with insulin. This should be a research priority,” said Talbot.

While this is exciting and has potential, such drugs won’t be available anytime soon. Kamei would like to complete the research at a basic level in 5 years, including testing insulin fused with larger proteins such as therapeutic antibodies. If all goes well, they’ll move on to testing insulin fusion drugs in people.
 

A version of this article first appeared on Medscape.com.

PHILADELPHIA — Pimavanserin (Nuplazid, Acadia) is noninferior to quetiapine in patients with Parkinson’s disease psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with Parkinson’s disease and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat Parkinson’s disease psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Dr. Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only Food and Drug Administration–approved medication for Parkinson’s disease psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with Parkinson’s disease psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in Parkinson’s disease psychosis, he said.

The findings were presented in a late-breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.
 

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with Parkinson’s disease for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of Parkinson’s disease medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) nine-item total scores improved from baseline in both groups at all visits (P < .0001) and was significantly greater at 42 days with pimavanserin than with quetiapine (−7.15 vs −6.33; P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Dr. Mane said.
 

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Dr. Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.
 

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic in Ohio, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or 2. I was just wondering if that’s validated or just anecdotal experience,” he said.

Dr. Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Dr. Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Dr. Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Dr. Mane is an employee of Sun Pharma Laboratories. Dr. Katzenschlager reported having no relevant financial relationships.

A version of this article appeared on Medscape.com.

PHILADELPHIA — Pimavanserin (Nuplazid, Acadia) is noninferior to quetiapine in patients with Parkinson’s disease psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with Parkinson’s disease and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat Parkinson’s disease psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Dr. Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only Food and Drug Administration–approved medication for Parkinson’s disease psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with Parkinson’s disease psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in Parkinson’s disease psychosis, he said.

The findings were presented in a late-breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.
 

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with Parkinson’s disease for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of Parkinson’s disease medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) nine-item total scores improved from baseline in both groups at all visits (P < .0001) and was significantly greater at 42 days with pimavanserin than with quetiapine (−7.15 vs −6.33; P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Dr. Mane said.
 

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Dr. Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.
 

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic in Ohio, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or 2. I was just wondering if that’s validated or just anecdotal experience,” he said.

Dr. Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Dr. Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Dr. Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Dr. Mane is an employee of Sun Pharma Laboratories. Dr. Katzenschlager reported having no relevant financial relationships.

A version of this article appeared on Medscape.com.

PHILADELPHIA — Pimavanserin (Nuplazid, Acadia) is noninferior to quetiapine in patients with Parkinson’s disease psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with Parkinson’s disease and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat Parkinson’s disease psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Dr. Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only Food and Drug Administration–approved medication for Parkinson’s disease psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with Parkinson’s disease psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in Parkinson’s disease psychosis, he said.

The findings were presented in a late-breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.
 

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with Parkinson’s disease for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of Parkinson’s disease medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) nine-item total scores improved from baseline in both groups at all visits (P < .0001) and was significantly greater at 42 days with pimavanserin than with quetiapine (−7.15 vs −6.33; P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Dr. Mane said.
 

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Dr. Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.
 

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic in Ohio, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or 2. I was just wondering if that’s validated or just anecdotal experience,” he said.

Dr. Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Dr. Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Dr. Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Dr. Mane is an employee of Sun Pharma Laboratories. Dr. Katzenschlager reported having no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — Chimeric antigen receptor (CAR) T-cell therapies offer the tantalizing prospect of dramatically altering the outcome of lung cancers, but there are many hurdles to treating patients with them, according to experts.

These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.

“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.

He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.

Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.

Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.

He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”

A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
 

Identifying the Right Target

“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.

“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.

“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.

“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”

To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”

Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”

“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”
 

A Question of Time

Another aspect of CAR T-cell therapy that is proving difficult is its delivery.

Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.

This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.

There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.

“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
 

Life-Threatening Toxicities

To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.

This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”

“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.

Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.

“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.

Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”

Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.

“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
 

‘At What Cost’ to Patients?

The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.

“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.

Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”

This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.

Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.

This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”

For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.

“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”

“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.

No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — Chimeric antigen receptor (CAR) T-cell therapies offer the tantalizing prospect of dramatically altering the outcome of lung cancers, but there are many hurdles to treating patients with them, according to experts.

These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.

“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.

He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.

Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.

Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.

He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”

A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
 

Identifying the Right Target

“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.

“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.

“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.

“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”

To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”

Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”

“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”
 

A Question of Time

Another aspect of CAR T-cell therapy that is proving difficult is its delivery.

Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.

This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.

There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.

“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
 

Life-Threatening Toxicities

To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.

This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”

“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.

Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.

“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.

Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”

Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.

“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
 

‘At What Cost’ to Patients?

The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.

“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.

Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”

This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.

Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.

This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”

For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.

“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”

“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.

No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — Chimeric antigen receptor (CAR) T-cell therapies offer the tantalizing prospect of dramatically altering the outcome of lung cancers, but there are many hurdles to treating patients with them, according to experts.

These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.

“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.

He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.

Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.

Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.

He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”

A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
 

Identifying the Right Target

“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.

“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.

“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.

“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”

To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”

Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”

“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”
 

A Question of Time

Another aspect of CAR T-cell therapy that is proving difficult is its delivery.

Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.

This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.

There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.

“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
 

Life-Threatening Toxicities

To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.

This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”

“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.

Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.

“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.

Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”

Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.

“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
 

‘At What Cost’ to Patients?

The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.

“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.

Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”

This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.

Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.

This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”

For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.

“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”

“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.

No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.

A version of this article appeared on Medscape.com.