Video

What's new with potential treatment options such as tildrakizumab? Given the roles obesity and metabolic disease play in psoriatic arthritis, how does weight loss affect treatment response? Alexis Ogdie, MD, director of the psoriatic arthritis clinic at the University of Pennsylvania in Philadelphia, talks about the latest developments in psoriatic arthritis research.

What's new with potential treatment options such as tildrakizumab? Given the roles obesity and metabolic disease play in psoriatic arthritis, how does weight loss affect treatment response? Alexis Ogdie, MD, director of the psoriatic arthritis clinic at the University of Pennsylvania in Philadelphia, talks about the latest developments in psoriatic arthritis research.

What's new with potential treatment options such as tildrakizumab? Given the roles obesity and metabolic disease play in psoriatic arthritis, how does weight loss affect treatment response? Alexis Ogdie, MD, director of the psoriatic arthritis clinic at the University of Pennsylvania in Philadelphia, talks about the latest developments in psoriatic arthritis research.

MADRID – RSLV-132, a novel drug that eliminates circulating nucleic acids, improved the symptoms of mental fatigue in patients with primary Sjögren’s syndrome (pSS) in a phase 2, double-blind, randomized, placebo-controlled “proof-of-concept” study.

Vidyard Video

The mental component of fatigue on the Profile of Fatigue (PRO-F) scale improved by 1.53 points among the patients given RSLV-132, while there was a worsening of 0.06 points in the placebo group (P = .046). Scores range from 0 to 7 on the PRO-F.

There were also improvements in some patient-reported outcomes, namely the EULAR pSS Patient Reported Index (ESSPRI) and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F), and improvement of neuropsychological measures of cognitive function, but none were statistically significant. All of these outcomes, including fatigue, were secondary outcomes of the study.

“Fatigue is a major issue for patients with Sjögren’s syndrome,” Wan-Fai Ng, MBChB, PhD, said in an interview at the European Congress of Rheumatology. Indeed, fatigue can be disabling in the majority of individuals, he added.

Currently, the best way to manage fatigue is to first ask about it, said Dr. Ng, who is professor of rheumatology at the Institute of Cellular Medicine at Newcastle University, Newcastle-upon-Tyne, England. He then checks for any underlying problem that could be better managed – sleep problems or anemia, for example – and optimizes treatment for any underlying disease. “I think many people would at least feel satisfied that people take the symptoms seriously.”

Dr. Ng and his coauthors investigated the effects of RSLV-132, a first-in-class human RNase fused to the human Fc domain of human immunoglobulin (Ig) G1, in the RESOLVE 132-04 study. This novel drug been designed to increase serum RNase activity to digest RNA-associated immune complexes, Dr. Ng and associates observed in their abstract. As a consequence of this, they say, activation of toll-like receptors and the production of interferon (IFN) is affected, as is B-cell proliferation and the production of autoantibodies – all mechanisms that are “key to pSS pathogenesis.”

The IFN pathway has been implicated in fatigue, Dr. Ng observed when he presented the RESOLVE 132-04 study’s findings, which involved 30 patients with pSS who had been treated for 3 months. Inclusion criteria were pSS as defined by the American-European Consensus Group 2002 criteria, anti-Ro antibody positivity, and increased expression of three IFN-regulated genes: HERC5, EPSTI1, and CMPK2. Exclusion criteria were the use of hydroxychloroquine, prednisolone at daily doses above 10 mg, and the use of biologic disease-modifying antirheumatic drugs.

Patients were randomized in a 3:1 ratio to receive either 10 mg/kg of RSLV-132 (n = 20) or placebo (n = 8) at weeks 0, 1, 2, and then every fortnight until week 12. Dr. Ng noted that although 30 patients were randomized, two patients had dropped out in the placebo group before they could be “treated.”

The primary endpoint was the change in the blood cell gene expression or serum protein levels indicative of reduced inflammation. The results indicated reductions in noncoding RNA molecules in patients who received RSLV-132 versus placebo, “consistent with the mode of action of the molecule.” In addition, “the majority of inflammatory markers were reduced,” Dr. Ng said.

Another finding showed a nonsignificant trend for improvement of 0.8 units in the physical component in the RSLV-132 group, compared against 0.06 units with placebo (P = .142).

Patients who received RSLV-132 reduced the time needed to complete the Digital Symbol Substitution Test by 16.4 s, compared with an increase of 2.8 s for placebo (P = .024).

Similar trends were observed for ESSPRI and FACIT-F scores.

These are very early data and clearly a bigger study would be needed before any conclusions could be drawn, Dr. Ng said in an interview. What these data suggest is that “maybe there is some way that we could manage fatigue, and we just need to go and explore that.”

RSLV-132 has also been studied in patients with systemic lupus erythematosus (Lupus. 2017;26:825-34).

The trial was sponsored by Resolve Therapeutics. Dr. Ng was an investigator in the trial and disclosed other research collaborations with electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb.

Source: Fisher B et al. Ann Rheum Dis. 2019 Jun;78(suppl 2):177, Abstract OP0202. doi: 10.1136/annrheumdis-2019-eular.3098.

MADRID – RSLV-132, a novel drug that eliminates circulating nucleic acids, improved the symptoms of mental fatigue in patients with primary Sjögren’s syndrome (pSS) in a phase 2, double-blind, randomized, placebo-controlled “proof-of-concept” study.

Vidyard Video

The mental component of fatigue on the Profile of Fatigue (PRO-F) scale improved by 1.53 points among the patients given RSLV-132, while there was a worsening of 0.06 points in the placebo group (P = .046). Scores range from 0 to 7 on the PRO-F.

There were also improvements in some patient-reported outcomes, namely the EULAR pSS Patient Reported Index (ESSPRI) and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F), and improvement of neuropsychological measures of cognitive function, but none were statistically significant. All of these outcomes, including fatigue, were secondary outcomes of the study.

“Fatigue is a major issue for patients with Sjögren’s syndrome,” Wan-Fai Ng, MBChB, PhD, said in an interview at the European Congress of Rheumatology. Indeed, fatigue can be disabling in the majority of individuals, he added.

Currently, the best way to manage fatigue is to first ask about it, said Dr. Ng, who is professor of rheumatology at the Institute of Cellular Medicine at Newcastle University, Newcastle-upon-Tyne, England. He then checks for any underlying problem that could be better managed – sleep problems or anemia, for example – and optimizes treatment for any underlying disease. “I think many people would at least feel satisfied that people take the symptoms seriously.”

Dr. Ng and his coauthors investigated the effects of RSLV-132, a first-in-class human RNase fused to the human Fc domain of human immunoglobulin (Ig) G1, in the RESOLVE 132-04 study. This novel drug been designed to increase serum RNase activity to digest RNA-associated immune complexes, Dr. Ng and associates observed in their abstract. As a consequence of this, they say, activation of toll-like receptors and the production of interferon (IFN) is affected, as is B-cell proliferation and the production of autoantibodies – all mechanisms that are “key to pSS pathogenesis.”

The IFN pathway has been implicated in fatigue, Dr. Ng observed when he presented the RESOLVE 132-04 study’s findings, which involved 30 patients with pSS who had been treated for 3 months. Inclusion criteria were pSS as defined by the American-European Consensus Group 2002 criteria, anti-Ro antibody positivity, and increased expression of three IFN-regulated genes: HERC5, EPSTI1, and CMPK2. Exclusion criteria were the use of hydroxychloroquine, prednisolone at daily doses above 10 mg, and the use of biologic disease-modifying antirheumatic drugs.

Patients were randomized in a 3:1 ratio to receive either 10 mg/kg of RSLV-132 (n = 20) or placebo (n = 8) at weeks 0, 1, 2, and then every fortnight until week 12. Dr. Ng noted that although 30 patients were randomized, two patients had dropped out in the placebo group before they could be “treated.”

The primary endpoint was the change in the blood cell gene expression or serum protein levels indicative of reduced inflammation. The results indicated reductions in noncoding RNA molecules in patients who received RSLV-132 versus placebo, “consistent with the mode of action of the molecule.” In addition, “the majority of inflammatory markers were reduced,” Dr. Ng said.

Another finding showed a nonsignificant trend for improvement of 0.8 units in the physical component in the RSLV-132 group, compared against 0.06 units with placebo (P = .142).

Patients who received RSLV-132 reduced the time needed to complete the Digital Symbol Substitution Test by 16.4 s, compared with an increase of 2.8 s for placebo (P = .024).

Similar trends were observed for ESSPRI and FACIT-F scores.

These are very early data and clearly a bigger study would be needed before any conclusions could be drawn, Dr. Ng said in an interview. What these data suggest is that “maybe there is some way that we could manage fatigue, and we just need to go and explore that.”

RSLV-132 has also been studied in patients with systemic lupus erythematosus (Lupus. 2017;26:825-34).

The trial was sponsored by Resolve Therapeutics. Dr. Ng was an investigator in the trial and disclosed other research collaborations with electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb.

Source: Fisher B et al. Ann Rheum Dis. 2019 Jun;78(suppl 2):177, Abstract OP0202. doi: 10.1136/annrheumdis-2019-eular.3098.

MADRID – RSLV-132, a novel drug that eliminates circulating nucleic acids, improved the symptoms of mental fatigue in patients with primary Sjögren’s syndrome (pSS) in a phase 2, double-blind, randomized, placebo-controlled “proof-of-concept” study.

Vidyard Video

The mental component of fatigue on the Profile of Fatigue (PRO-F) scale improved by 1.53 points among the patients given RSLV-132, while there was a worsening of 0.06 points in the placebo group (P = .046). Scores range from 0 to 7 on the PRO-F.

There were also improvements in some patient-reported outcomes, namely the EULAR pSS Patient Reported Index (ESSPRI) and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F), and improvement of neuropsychological measures of cognitive function, but none were statistically significant. All of these outcomes, including fatigue, were secondary outcomes of the study.

“Fatigue is a major issue for patients with Sjögren’s syndrome,” Wan-Fai Ng, MBChB, PhD, said in an interview at the European Congress of Rheumatology. Indeed, fatigue can be disabling in the majority of individuals, he added.

Currently, the best way to manage fatigue is to first ask about it, said Dr. Ng, who is professor of rheumatology at the Institute of Cellular Medicine at Newcastle University, Newcastle-upon-Tyne, England. He then checks for any underlying problem that could be better managed – sleep problems or anemia, for example – and optimizes treatment for any underlying disease. “I think many people would at least feel satisfied that people take the symptoms seriously.”

Dr. Ng and his coauthors investigated the effects of RSLV-132, a first-in-class human RNase fused to the human Fc domain of human immunoglobulin (Ig) G1, in the RESOLVE 132-04 study. This novel drug been designed to increase serum RNase activity to digest RNA-associated immune complexes, Dr. Ng and associates observed in their abstract. As a consequence of this, they say, activation of toll-like receptors and the production of interferon (IFN) is affected, as is B-cell proliferation and the production of autoantibodies – all mechanisms that are “key to pSS pathogenesis.”

The IFN pathway has been implicated in fatigue, Dr. Ng observed when he presented the RESOLVE 132-04 study’s findings, which involved 30 patients with pSS who had been treated for 3 months. Inclusion criteria were pSS as defined by the American-European Consensus Group 2002 criteria, anti-Ro antibody positivity, and increased expression of three IFN-regulated genes: HERC5, EPSTI1, and CMPK2. Exclusion criteria were the use of hydroxychloroquine, prednisolone at daily doses above 10 mg, and the use of biologic disease-modifying antirheumatic drugs.

Patients were randomized in a 3:1 ratio to receive either 10 mg/kg of RSLV-132 (n = 20) or placebo (n = 8) at weeks 0, 1, 2, and then every fortnight until week 12. Dr. Ng noted that although 30 patients were randomized, two patients had dropped out in the placebo group before they could be “treated.”

The primary endpoint was the change in the blood cell gene expression or serum protein levels indicative of reduced inflammation. The results indicated reductions in noncoding RNA molecules in patients who received RSLV-132 versus placebo, “consistent with the mode of action of the molecule.” In addition, “the majority of inflammatory markers were reduced,” Dr. Ng said.

Another finding showed a nonsignificant trend for improvement of 0.8 units in the physical component in the RSLV-132 group, compared against 0.06 units with placebo (P = .142).

Patients who received RSLV-132 reduced the time needed to complete the Digital Symbol Substitution Test by 16.4 s, compared with an increase of 2.8 s for placebo (P = .024).

Similar trends were observed for ESSPRI and FACIT-F scores.

These are very early data and clearly a bigger study would be needed before any conclusions could be drawn, Dr. Ng said in an interview. What these data suggest is that “maybe there is some way that we could manage fatigue, and we just need to go and explore that.”

RSLV-132 has also been studied in patients with systemic lupus erythematosus (Lupus. 2017;26:825-34).

The trial was sponsored by Resolve Therapeutics. Dr. Ng was an investigator in the trial and disclosed other research collaborations with electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb.

Source: Fisher B et al. Ann Rheum Dis. 2019 Jun;78(suppl 2):177, Abstract OP0202. doi: 10.1136/annrheumdis-2019-eular.3098.

MADRID – Response to rituximab in patients with systemic lupus erythematosus (SLE) might be dictated by the presence of a genetic variant that encodes the Fc gamma receptors (FcGRs), expressed on natural killer (NK) cells, according to findings from a single-center, longitudinal cohort study.

Vidyard Video

It is well known that not everyone with SLE will respond well to rituximab, but that some will, first author Md Yuzaiful Md Yusof, MBChB, PhD, explained in an interview at the European Congress of Rheumatology.

Although data from clinical trials with rituximab in this patient setting have been essentially negative, the methodology of those trials has since been disputed, he observed. Indeed, subsequent data (Ann Rheum Dis. 2017;76:1829-36) have suggested that as many as 80% of patients could achieve a response with rituximab, particularly if there is complete B-cell depletion.

Previous researchers (Ann Rheum Dis. 2012;71:875-7) have shown that a polymorphism (158V) in the Fc gamma receptor IIIA (FCGR3A) gene is associated with the response to rituximab-based therapy in patients with rheumatoid arthritis (RA). This gene is important for antibody-dependent cellular-mediated cytotoxicity (ADCC).

The objective of the current study – an observational, prospective, longitudinal cohort study conducted in Leeds (England) – was therefore to see if the FCGR3A-158V polymorphism might influence response in patients with SLE.

“We were trying to find pretreatment biomarkers that could predict response to rituximab in SLE,” Dr. Md Yusof explained.

For the study, 85 patients who were treated with rituximab were assessed. The cohort was predominantly female (96%), with a mean age of 40 years. All of the patients had antinuclear antibodies, with just over half having anti–double-stranded DNA antibodies, and two-thirds having extractable nuclear antigens. One-third had low complement (C3/C4) levels.

Complete B-cell depletion occurred in 63% of patients with the FCGR3A-158V allele, a significantly higher rate than the 40% observed among those with 158 FF genotype (odds ratio, 2.73; P = .041). A significantly higher percentage of patients with the FCGR3A-158V allele also achieved a major BILAG (British Isles Lupus Assessment Group) response when compared against patients with the 158 FF variant (48% vs. 23%), with an odds ratio of 3.06 (P = .033).

Rituximab’s effect on NK cell-mediated B-cell killing may have played a key role in treatment response. Carrying the FCGR3A-158V allele was associated with greater degranulation activity versus the 158 FF variant.

Lastly, patients were more likely to remain on treatment with rituximab over a 10-year period if they had the FCGR3A-158V allele, compared with the 158 FF variant.

“These data suggest one mechanism by which patients with SLE might become resistant to the effects of rituximab, and could be used to guide therapy in the future,” Dr. Md Yusof suggested.

“Once this finding is validated, the clinical implication is that this genetic testing could be done prior to rituximab to identify those who will respond to therapy,” he postulated. “People with SLE who have this genetic variant with high affinity for rituximab are the ones that are better suited for rituximab therapy,” he added, otherwise a different CD20-directed antibody or alternative B-cell blockade therapies should be used.

The U.K. National Institute for Health Research funded the study. Dr. Md Yusof had no conflicts of interest to disclose; some coauthors disclosed ties to Roche, GlaxoSmithKline, and AstraZeneca, among other companies.

SOURCE: Md Yusof MY et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1069-70. Abstract SAT0009, doi: 10.1136/annrheumdis-2019-eular.6919.

MADRID – Response to rituximab in patients with systemic lupus erythematosus (SLE) might be dictated by the presence of a genetic variant that encodes the Fc gamma receptors (FcGRs), expressed on natural killer (NK) cells, according to findings from a single-center, longitudinal cohort study.

Vidyard Video

It is well known that not everyone with SLE will respond well to rituximab, but that some will, first author Md Yuzaiful Md Yusof, MBChB, PhD, explained in an interview at the European Congress of Rheumatology.

Although data from clinical trials with rituximab in this patient setting have been essentially negative, the methodology of those trials has since been disputed, he observed. Indeed, subsequent data (Ann Rheum Dis. 2017;76:1829-36) have suggested that as many as 80% of patients could achieve a response with rituximab, particularly if there is complete B-cell depletion.

Previous researchers (Ann Rheum Dis. 2012;71:875-7) have shown that a polymorphism (158V) in the Fc gamma receptor IIIA (FCGR3A) gene is associated with the response to rituximab-based therapy in patients with rheumatoid arthritis (RA). This gene is important for antibody-dependent cellular-mediated cytotoxicity (ADCC).

The objective of the current study – an observational, prospective, longitudinal cohort study conducted in Leeds (England) – was therefore to see if the FCGR3A-158V polymorphism might influence response in patients with SLE.

“We were trying to find pretreatment biomarkers that could predict response to rituximab in SLE,” Dr. Md Yusof explained.

For the study, 85 patients who were treated with rituximab were assessed. The cohort was predominantly female (96%), with a mean age of 40 years. All of the patients had antinuclear antibodies, with just over half having anti–double-stranded DNA antibodies, and two-thirds having extractable nuclear antigens. One-third had low complement (C3/C4) levels.

Complete B-cell depletion occurred in 63% of patients with the FCGR3A-158V allele, a significantly higher rate than the 40% observed among those with 158 FF genotype (odds ratio, 2.73; P = .041). A significantly higher percentage of patients with the FCGR3A-158V allele also achieved a major BILAG (British Isles Lupus Assessment Group) response when compared against patients with the 158 FF variant (48% vs. 23%), with an odds ratio of 3.06 (P = .033).

Rituximab’s effect on NK cell-mediated B-cell killing may have played a key role in treatment response. Carrying the FCGR3A-158V allele was associated with greater degranulation activity versus the 158 FF variant.

Lastly, patients were more likely to remain on treatment with rituximab over a 10-year period if they had the FCGR3A-158V allele, compared with the 158 FF variant.

“These data suggest one mechanism by which patients with SLE might become resistant to the effects of rituximab, and could be used to guide therapy in the future,” Dr. Md Yusof suggested.

“Once this finding is validated, the clinical implication is that this genetic testing could be done prior to rituximab to identify those who will respond to therapy,” he postulated. “People with SLE who have this genetic variant with high affinity for rituximab are the ones that are better suited for rituximab therapy,” he added, otherwise a different CD20-directed antibody or alternative B-cell blockade therapies should be used.

The U.K. National Institute for Health Research funded the study. Dr. Md Yusof had no conflicts of interest to disclose; some coauthors disclosed ties to Roche, GlaxoSmithKline, and AstraZeneca, among other companies.

SOURCE: Md Yusof MY et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1069-70. Abstract SAT0009, doi: 10.1136/annrheumdis-2019-eular.6919.

MADRID – Response to rituximab in patients with systemic lupus erythematosus (SLE) might be dictated by the presence of a genetic variant that encodes the Fc gamma receptors (FcGRs), expressed on natural killer (NK) cells, according to findings from a single-center, longitudinal cohort study.

Vidyard Video

It is well known that not everyone with SLE will respond well to rituximab, but that some will, first author Md Yuzaiful Md Yusof, MBChB, PhD, explained in an interview at the European Congress of Rheumatology.

Although data from clinical trials with rituximab in this patient setting have been essentially negative, the methodology of those trials has since been disputed, he observed. Indeed, subsequent data (Ann Rheum Dis. 2017;76:1829-36) have suggested that as many as 80% of patients could achieve a response with rituximab, particularly if there is complete B-cell depletion.

Previous researchers (Ann Rheum Dis. 2012;71:875-7) have shown that a polymorphism (158V) in the Fc gamma receptor IIIA (FCGR3A) gene is associated with the response to rituximab-based therapy in patients with rheumatoid arthritis (RA). This gene is important for antibody-dependent cellular-mediated cytotoxicity (ADCC).

The objective of the current study – an observational, prospective, longitudinal cohort study conducted in Leeds (England) – was therefore to see if the FCGR3A-158V polymorphism might influence response in patients with SLE.

“We were trying to find pretreatment biomarkers that could predict response to rituximab in SLE,” Dr. Md Yusof explained.

For the study, 85 patients who were treated with rituximab were assessed. The cohort was predominantly female (96%), with a mean age of 40 years. All of the patients had antinuclear antibodies, with just over half having anti–double-stranded DNA antibodies, and two-thirds having extractable nuclear antigens. One-third had low complement (C3/C4) levels.

Complete B-cell depletion occurred in 63% of patients with the FCGR3A-158V allele, a significantly higher rate than the 40% observed among those with 158 FF genotype (odds ratio, 2.73; P = .041). A significantly higher percentage of patients with the FCGR3A-158V allele also achieved a major BILAG (British Isles Lupus Assessment Group) response when compared against patients with the 158 FF variant (48% vs. 23%), with an odds ratio of 3.06 (P = .033).

Rituximab’s effect on NK cell-mediated B-cell killing may have played a key role in treatment response. Carrying the FCGR3A-158V allele was associated with greater degranulation activity versus the 158 FF variant.

Lastly, patients were more likely to remain on treatment with rituximab over a 10-year period if they had the FCGR3A-158V allele, compared with the 158 FF variant.

“These data suggest one mechanism by which patients with SLE might become resistant to the effects of rituximab, and could be used to guide therapy in the future,” Dr. Md Yusof suggested.

“Once this finding is validated, the clinical implication is that this genetic testing could be done prior to rituximab to identify those who will respond to therapy,” he postulated. “People with SLE who have this genetic variant with high affinity for rituximab are the ones that are better suited for rituximab therapy,” he added, otherwise a different CD20-directed antibody or alternative B-cell blockade therapies should be used.

The U.K. National Institute for Health Research funded the study. Dr. Md Yusof had no conflicts of interest to disclose; some coauthors disclosed ties to Roche, GlaxoSmithKline, and AstraZeneca, among other companies.

SOURCE: Md Yusof MY et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1069-70. Abstract SAT0009, doi: 10.1136/annrheumdis-2019-eular.6919.

MADRID – Tanezumab, an investigational monoclonal antibody directed against nerve growth factor that is under development to treat osteoarthritis pain, met most of the coprimary efficacy endpoints set for the drug in a randomized, double-blind, parallel-group, placebo-controlled phase 3 study.

At the end of a 24-week, double-blind treatment period, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and WOMAC physical function subscale scores were significantly improved, compared with placebo in the two tanezumab (2.5 mg and 5 mg) dose groups.

The least squares (ls) mean change from baseline in WOMAC pain scores were –2.24 for placebo, –2.70 for tanezumab 2.5 mg, and –2.85 for tanezumab 5 mg (P less than or equal to .01 and P less than or equal to .001 vs. placebo).

The ls mean change from baseline in WOMAC physical function scores were a respective –2.11, –2.70, and –2.82 (P less than or equal to .001 for both vs. placebo).

The coprimary endpoint of patients’ global assessment of OA (PGA-OA) was also significantly improved with tanezumab 5 mg (–0.90; P less than or equal to .05) but not 2.5 mg (–0.82) versus placebo (–0.72).

As the 2.5-mg dose of tanezumab didn’t meet one of the three coprimary endpoints, further hypothesis testing was not possible, but exploratory findings suggested that tanezumab at 2.5 mg or 5 mg yielded higher proportions of patients with reductions from baseline in WOMAC pain scores when compared against placebo. This was the case for reductions of at least 30% (65.6%, 68.7%, 56.6%, respectively), 50% (45.4%, 47.9%, 33.8%), or 70% (21.3%, 23.2%, 17.8%).

“I think that we have now a lot of studies with tanezumab showing a significant effect on hip and knee OA pain and function, so we have the studies in order to have the drug on the market,” study first author Francis Berenbaum, MD, PhD, of Saint-Antoine Hospital, Sorbonne Université in Paris, said in an interview at the European Congress of Rheumatology.

“Of course, because of the safety issue with rapid progressive osteoarthritis (RPOA), what we are discussing now is: ‘For which patients will there be an optimal benefit-to-risk?’ So, it’s now more a discussion around the population of patients who can benefit the most with the drug,” Dr. Berenbaum added.

A possible link between the use of tanezumab and a risk for developing RPOA was first suggested by preclinical and early clinical trial data, prompting the U.S. Food and Drug Administration to place partial holds on its clinical development in 2010, and again in 2012.

However, Dr. Berenbaum noted that a “mitigation plan” had been put in place for the phase 3 program to try to lower the likelihood of RPOA. This included: lowering the dose of the drug used and delivering it subcutaneously rather than intravenously; not prescribing it with NSAIDs and testing its possible effects and safety in a difficult-to-treat population of patients with no known risk factors for the potentially very serious adverse event.

“Based on this mitigation plan, the risk of rapid progressive osteoarthritis has considerably decreased,” Dr. Berenbaum observed. Indeed, in the phase 3 study he presented at the meeting, he said that around 2% of patients developed RPOA, which is “exactly in line with what has already been shown.” RPOA was reported in none of the placebo-treated patients, in 1.4% of those treated with tanezumab 2.5 mg, and in 2.8% in those treated with tanezumab 5 mg.

However, a “striking” finding of the current study was that despite the small increase in RPOA seen, there was no difference between the tanezumab and placebo groups in the number of patients needing total joint replacement (TJR). The percentages of patients undergoing at least one TJR was 6.7% in the placebo group, 7.8% in the tanezumab 2.5-mg group, and 7.0% in the tanezumab 5-mg group.

The joint safety events seen in the study, including TJRs, were adjudicated as being part of the normal progression of OA in the majority (73.4%) of cases. Other joint events of note were one case of subchondral insufficiency fracture occurring in a patient treated with tanezumab 2.5 mg and one case of primary osteonecrosis in a patient treated with tanezumab 5 mg.

During his presentation of the findings in a late-breaking oral abstract session, Dr. Berenbaum noted that this was a difficult-to-treat population of patients. All 849 patients who had been recruited had moderate to severe OA pain of the knee or hip and had a history of insufficient pain relief or intolerance to treatment with acetaminophen, oral NSAIDs, and tramadol and were also not responding to, or unwilling to take, opioid painkillers. Patients had to have no radiographic evidence of specified bone conditions, including RPOA.

Patients had been treated with subcutaneous tanezumab 2.5 mg (n = 283) or 5 mg (n = 284) or placebo (n = 282) at baseline, week 8, and week 16, with the three coprimary efficacy endpoints assessed at week 24.


Discussing the risk-to-benefit ratio of the drug after his presentation, Dr. Berenbaum said: “You have to keep in mind that, first, it was in very difficult-to-treat patients, compared to the other trials in the field of OA symptoms.”

He added: “Second, is that compared to the other trials, this one was able to include patients with Kellgren-Lawrence grade 4, meaning that this is a more serious population,” and third, “when you look at the responders – WOMAC 30%, 50%, 70% – there is a strong difference in terms of responders.”

Dr. Berenbaum and his coauthors noted on the poster that accompanied the late-breaking oral presentation that “an active-controlled study will provide data to further characterize the risk-benefit of tanezumab in patients with OA.”

The study was sponsored by Pfizer and Eli Lilly. Dr. Berenbaum disclosed receiving research funding through his institution from Pfizer and acting as a consultant to, and speaker for, the company as well as multiple other pharmaceutical companies. Coauthors of the study also disclosed research funding or consultancy agreements with Pfizer or Eli Lilly or were employees of the companies.

SOURCE: Berenbaum F et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):262-4. Abstract LB0007, doi: 10.1136/annrheumdis-2019-eular.8660

MADRID – Tanezumab, an investigational monoclonal antibody directed against nerve growth factor that is under development to treat osteoarthritis pain, met most of the coprimary efficacy endpoints set for the drug in a randomized, double-blind, parallel-group, placebo-controlled phase 3 study.

At the end of a 24-week, double-blind treatment period, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and WOMAC physical function subscale scores were significantly improved, compared with placebo in the two tanezumab (2.5 mg and 5 mg) dose groups.

The least squares (ls) mean change from baseline in WOMAC pain scores were –2.24 for placebo, –2.70 for tanezumab 2.5 mg, and –2.85 for tanezumab 5 mg (P less than or equal to .01 and P less than or equal to .001 vs. placebo).

The ls mean change from baseline in WOMAC physical function scores were a respective –2.11, –2.70, and –2.82 (P less than or equal to .001 for both vs. placebo).

The coprimary endpoint of patients’ global assessment of OA (PGA-OA) was also significantly improved with tanezumab 5 mg (–0.90; P less than or equal to .05) but not 2.5 mg (–0.82) versus placebo (–0.72).

As the 2.5-mg dose of tanezumab didn’t meet one of the three coprimary endpoints, further hypothesis testing was not possible, but exploratory findings suggested that tanezumab at 2.5 mg or 5 mg yielded higher proportions of patients with reductions from baseline in WOMAC pain scores when compared against placebo. This was the case for reductions of at least 30% (65.6%, 68.7%, 56.6%, respectively), 50% (45.4%, 47.9%, 33.8%), or 70% (21.3%, 23.2%, 17.8%).

“I think that we have now a lot of studies with tanezumab showing a significant effect on hip and knee OA pain and function, so we have the studies in order to have the drug on the market,” study first author Francis Berenbaum, MD, PhD, of Saint-Antoine Hospital, Sorbonne Université in Paris, said in an interview at the European Congress of Rheumatology.

“Of course, because of the safety issue with rapid progressive osteoarthritis (RPOA), what we are discussing now is: ‘For which patients will there be an optimal benefit-to-risk?’ So, it’s now more a discussion around the population of patients who can benefit the most with the drug,” Dr. Berenbaum added.

A possible link between the use of tanezumab and a risk for developing RPOA was first suggested by preclinical and early clinical trial data, prompting the U.S. Food and Drug Administration to place partial holds on its clinical development in 2010, and again in 2012.

However, Dr. Berenbaum noted that a “mitigation plan” had been put in place for the phase 3 program to try to lower the likelihood of RPOA. This included: lowering the dose of the drug used and delivering it subcutaneously rather than intravenously; not prescribing it with NSAIDs and testing its possible effects and safety in a difficult-to-treat population of patients with no known risk factors for the potentially very serious adverse event.

“Based on this mitigation plan, the risk of rapid progressive osteoarthritis has considerably decreased,” Dr. Berenbaum observed. Indeed, in the phase 3 study he presented at the meeting, he said that around 2% of patients developed RPOA, which is “exactly in line with what has already been shown.” RPOA was reported in none of the placebo-treated patients, in 1.4% of those treated with tanezumab 2.5 mg, and in 2.8% in those treated with tanezumab 5 mg.

However, a “striking” finding of the current study was that despite the small increase in RPOA seen, there was no difference between the tanezumab and placebo groups in the number of patients needing total joint replacement (TJR). The percentages of patients undergoing at least one TJR was 6.7% in the placebo group, 7.8% in the tanezumab 2.5-mg group, and 7.0% in the tanezumab 5-mg group.

The joint safety events seen in the study, including TJRs, were adjudicated as being part of the normal progression of OA in the majority (73.4%) of cases. Other joint events of note were one case of subchondral insufficiency fracture occurring in a patient treated with tanezumab 2.5 mg and one case of primary osteonecrosis in a patient treated with tanezumab 5 mg.

During his presentation of the findings in a late-breaking oral abstract session, Dr. Berenbaum noted that this was a difficult-to-treat population of patients. All 849 patients who had been recruited had moderate to severe OA pain of the knee or hip and had a history of insufficient pain relief or intolerance to treatment with acetaminophen, oral NSAIDs, and tramadol and were also not responding to, or unwilling to take, opioid painkillers. Patients had to have no radiographic evidence of specified bone conditions, including RPOA.

Patients had been treated with subcutaneous tanezumab 2.5 mg (n = 283) or 5 mg (n = 284) or placebo (n = 282) at baseline, week 8, and week 16, with the three coprimary efficacy endpoints assessed at week 24.


Discussing the risk-to-benefit ratio of the drug after his presentation, Dr. Berenbaum said: “You have to keep in mind that, first, it was in very difficult-to-treat patients, compared to the other trials in the field of OA symptoms.”

He added: “Second, is that compared to the other trials, this one was able to include patients with Kellgren-Lawrence grade 4, meaning that this is a more serious population,” and third, “when you look at the responders – WOMAC 30%, 50%, 70% – there is a strong difference in terms of responders.”

Dr. Berenbaum and his coauthors noted on the poster that accompanied the late-breaking oral presentation that “an active-controlled study will provide data to further characterize the risk-benefit of tanezumab in patients with OA.”

The study was sponsored by Pfizer and Eli Lilly. Dr. Berenbaum disclosed receiving research funding through his institution from Pfizer and acting as a consultant to, and speaker for, the company as well as multiple other pharmaceutical companies. Coauthors of the study also disclosed research funding or consultancy agreements with Pfizer or Eli Lilly or were employees of the companies.

SOURCE: Berenbaum F et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):262-4. Abstract LB0007, doi: 10.1136/annrheumdis-2019-eular.8660

MADRID – Tanezumab, an investigational monoclonal antibody directed against nerve growth factor that is under development to treat osteoarthritis pain, met most of the coprimary efficacy endpoints set for the drug in a randomized, double-blind, parallel-group, placebo-controlled phase 3 study.

At the end of a 24-week, double-blind treatment period, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and WOMAC physical function subscale scores were significantly improved, compared with placebo in the two tanezumab (2.5 mg and 5 mg) dose groups.

The least squares (ls) mean change from baseline in WOMAC pain scores were –2.24 for placebo, –2.70 for tanezumab 2.5 mg, and –2.85 for tanezumab 5 mg (P less than or equal to .01 and P less than or equal to .001 vs. placebo).

The ls mean change from baseline in WOMAC physical function scores were a respective –2.11, –2.70, and –2.82 (P less than or equal to .001 for both vs. placebo).

The coprimary endpoint of patients’ global assessment of OA (PGA-OA) was also significantly improved with tanezumab 5 mg (–0.90; P less than or equal to .05) but not 2.5 mg (–0.82) versus placebo (–0.72).

As the 2.5-mg dose of tanezumab didn’t meet one of the three coprimary endpoints, further hypothesis testing was not possible, but exploratory findings suggested that tanezumab at 2.5 mg or 5 mg yielded higher proportions of patients with reductions from baseline in WOMAC pain scores when compared against placebo. This was the case for reductions of at least 30% (65.6%, 68.7%, 56.6%, respectively), 50% (45.4%, 47.9%, 33.8%), or 70% (21.3%, 23.2%, 17.8%).

“I think that we have now a lot of studies with tanezumab showing a significant effect on hip and knee OA pain and function, so we have the studies in order to have the drug on the market,” study first author Francis Berenbaum, MD, PhD, of Saint-Antoine Hospital, Sorbonne Université in Paris, said in an interview at the European Congress of Rheumatology.

“Of course, because of the safety issue with rapid progressive osteoarthritis (RPOA), what we are discussing now is: ‘For which patients will there be an optimal benefit-to-risk?’ So, it’s now more a discussion around the population of patients who can benefit the most with the drug,” Dr. Berenbaum added.

A possible link between the use of tanezumab and a risk for developing RPOA was first suggested by preclinical and early clinical trial data, prompting the U.S. Food and Drug Administration to place partial holds on its clinical development in 2010, and again in 2012.

However, Dr. Berenbaum noted that a “mitigation plan” had been put in place for the phase 3 program to try to lower the likelihood of RPOA. This included: lowering the dose of the drug used and delivering it subcutaneously rather than intravenously; not prescribing it with NSAIDs and testing its possible effects and safety in a difficult-to-treat population of patients with no known risk factors for the potentially very serious adverse event.

“Based on this mitigation plan, the risk of rapid progressive osteoarthritis has considerably decreased,” Dr. Berenbaum observed. Indeed, in the phase 3 study he presented at the meeting, he said that around 2% of patients developed RPOA, which is “exactly in line with what has already been shown.” RPOA was reported in none of the placebo-treated patients, in 1.4% of those treated with tanezumab 2.5 mg, and in 2.8% in those treated with tanezumab 5 mg.

However, a “striking” finding of the current study was that despite the small increase in RPOA seen, there was no difference between the tanezumab and placebo groups in the number of patients needing total joint replacement (TJR). The percentages of patients undergoing at least one TJR was 6.7% in the placebo group, 7.8% in the tanezumab 2.5-mg group, and 7.0% in the tanezumab 5-mg group.

The joint safety events seen in the study, including TJRs, were adjudicated as being part of the normal progression of OA in the majority (73.4%) of cases. Other joint events of note were one case of subchondral insufficiency fracture occurring in a patient treated with tanezumab 2.5 mg and one case of primary osteonecrosis in a patient treated with tanezumab 5 mg.

During his presentation of the findings in a late-breaking oral abstract session, Dr. Berenbaum noted that this was a difficult-to-treat population of patients. All 849 patients who had been recruited had moderate to severe OA pain of the knee or hip and had a history of insufficient pain relief or intolerance to treatment with acetaminophen, oral NSAIDs, and tramadol and were also not responding to, or unwilling to take, opioid painkillers. Patients had to have no radiographic evidence of specified bone conditions, including RPOA.

Patients had been treated with subcutaneous tanezumab 2.5 mg (n = 283) or 5 mg (n = 284) or placebo (n = 282) at baseline, week 8, and week 16, with the three coprimary efficacy endpoints assessed at week 24.


Discussing the risk-to-benefit ratio of the drug after his presentation, Dr. Berenbaum said: “You have to keep in mind that, first, it was in very difficult-to-treat patients, compared to the other trials in the field of OA symptoms.”

He added: “Second, is that compared to the other trials, this one was able to include patients with Kellgren-Lawrence grade 4, meaning that this is a more serious population,” and third, “when you look at the responders – WOMAC 30%, 50%, 70% – there is a strong difference in terms of responders.”

Dr. Berenbaum and his coauthors noted on the poster that accompanied the late-breaking oral presentation that “an active-controlled study will provide data to further characterize the risk-benefit of tanezumab in patients with OA.”

The study was sponsored by Pfizer and Eli Lilly. Dr. Berenbaum disclosed receiving research funding through his institution from Pfizer and acting as a consultant to, and speaker for, the company as well as multiple other pharmaceutical companies. Coauthors of the study also disclosed research funding or consultancy agreements with Pfizer or Eli Lilly or were employees of the companies.

SOURCE: Berenbaum F et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):262-4. Abstract LB0007, doi: 10.1136/annrheumdis-2019-eular.8660

Read the article: Fibroids: Patient considerations in medical and surgical management

Read the article: Fibroids: Patient considerations in medical and surgical management

Read the article: Fibroids: Patient considerations in medical and surgical management

MADRID – Tocilizumab (Actemra) preserved lung function in patients with early systemic sclerosis (SSc), according to a secondary endpoint analysis of the phase 3, double-blind, randomized, controlled focuSSced trial.

Vidyard Video

After 48 weeks, a significantly lower proportion of patients treated with tocilizumab than placebo experienced any decline in lung function from baseline (50.5% versus 70.3% (P = .015), as defined by the percentage increase in predicted forced vital capacity (%pFVC). When only patients with interstitial lung disease (ILD) were considered, the respective percentages were 51.7% and 75.5% (P = .003).

In SSc-ILD patients, a clinically meaningful decline of 10% or more of the %pFVC in lung function was seen in 24.5% given placebo but in just 8.6% of those treated with tocilizumab.

“ILD is a major complication of scleroderma; it has high morbidity and mortality ... and it’s largely irreversible,” Dinesh Khanna, MD, said at the European Congress of Rheumatology.

“In this day and age, when we treat ILD, we wait for a patient to develop clinical ILD,” added Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor. Clinical ILD can be defined by symptoms, abnormal pulmonary function tests, and marked abnormalities on high resolution computed tomography (HRCT) scans. He indicated that if improving ILD was not possible, then the next best thing would be to stabilize the disease and ensure there was no worsening in lung function.

As yet, there are no disease-modifying treatments available to treat SSc but there are “ample data that interleukin-6 plays a very important role in the pathogenesis of scleroderma,” Dr. Khanna observed. Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor.

Data from the phase 2 faSScinate trial showed initial promise for the drug in SSc where a numerical, but not statistically significant, improvement in skin thickening was seen, and the results had hinted at a possible benefit on lung function (Lancet. 2016 Jun 25;387:2630-40).

However, in the phase 3 focuSSced trial, there was no statistically significant difference in the change from baseline to week 48 modified Rodnan skin score (mRSS) between tocilizumab and placebo, which was the primary endpoint. The least square mean change in mRSS was –6.14 for tocilizumab and –4.41 for placebo (P = .0983).

A total of 205 patients with SSc were studied and randomized, 1:1 in a double-blind fashion, to receive either a once-weekly, subcutaneous dose of 162 mg tocilizumab or a weekly subcutaneous placebo injection for 48 weeks.

For inclusion in the study, patients had to have SSc that met American College of Rheumatology and European League Against Rheumatism (EULAR) criteria and be diagnosed less than 60 months previously. Patients had to have an mRSS of 10-35 units and active disease with one or more of the following: C-reactive protein of 6 mg/L or higher; erythrocyte sedimentation rate of 28 mm/h or higher; and platelet count of330 x 10⁹ L.


“What was astonishing in the trial was that every patient had HRCT at baseline and at the end of the study,” Dr. Khanna reported. These scans showed that 64% of patients had evidence of ILD at baseline and that those treated with tocilizumab had less evidence of fibrosis at week 48 versus placebo, indicating a stabilization rather than worsening of disease.

A time to treatment failure analysis also favored tocilizumab over placebo, but there were no significant changes in patient-reported outcomes.

Dr. Khanna’s slides stated that “given that the primary endpoint for mRSS was not met, all other P values are presented for information purposes only and cannot be considered statistically significant despite the strength of the evidence.” During the Q&A after his presentation, he noted that it was unlikely that the study’s sponsors (Roche/Genentech) will now pursue a license for tocilizumab in SSc.

Nevertheless, Dr. Khanna concluded, “we have the opportunity, based on these data, to treat these patients early on, where you can preserve the lung function, which is a paradigm shift versus waiting for the lung function to decline, become clinically meaningful, significant, and then treat this patient population.”

Roche/Genentech sponsored the study. Dr. Khanna acts as a consultant to Roche/Genentech and eight other pharmaceutical companies. He owns stock in Eicos Sciences.

SOURCE: Khanna D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):202-3. Abstract OP0245, doi: 10.1136/annrheumdis-2019-eular.2120

MADRID – Tocilizumab (Actemra) preserved lung function in patients with early systemic sclerosis (SSc), according to a secondary endpoint analysis of the phase 3, double-blind, randomized, controlled focuSSced trial.

Vidyard Video

After 48 weeks, a significantly lower proportion of patients treated with tocilizumab than placebo experienced any decline in lung function from baseline (50.5% versus 70.3% (P = .015), as defined by the percentage increase in predicted forced vital capacity (%pFVC). When only patients with interstitial lung disease (ILD) were considered, the respective percentages were 51.7% and 75.5% (P = .003).

In SSc-ILD patients, a clinically meaningful decline of 10% or more of the %pFVC in lung function was seen in 24.5% given placebo but in just 8.6% of those treated with tocilizumab.

“ILD is a major complication of scleroderma; it has high morbidity and mortality ... and it’s largely irreversible,” Dinesh Khanna, MD, said at the European Congress of Rheumatology.

“In this day and age, when we treat ILD, we wait for a patient to develop clinical ILD,” added Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor. Clinical ILD can be defined by symptoms, abnormal pulmonary function tests, and marked abnormalities on high resolution computed tomography (HRCT) scans. He indicated that if improving ILD was not possible, then the next best thing would be to stabilize the disease and ensure there was no worsening in lung function.

As yet, there are no disease-modifying treatments available to treat SSc but there are “ample data that interleukin-6 plays a very important role in the pathogenesis of scleroderma,” Dr. Khanna observed. Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor.

Data from the phase 2 faSScinate trial showed initial promise for the drug in SSc where a numerical, but not statistically significant, improvement in skin thickening was seen, and the results had hinted at a possible benefit on lung function (Lancet. 2016 Jun 25;387:2630-40).

However, in the phase 3 focuSSced trial, there was no statistically significant difference in the change from baseline to week 48 modified Rodnan skin score (mRSS) between tocilizumab and placebo, which was the primary endpoint. The least square mean change in mRSS was –6.14 for tocilizumab and –4.41 for placebo (P = .0983).

A total of 205 patients with SSc were studied and randomized, 1:1 in a double-blind fashion, to receive either a once-weekly, subcutaneous dose of 162 mg tocilizumab or a weekly subcutaneous placebo injection for 48 weeks.

For inclusion in the study, patients had to have SSc that met American College of Rheumatology and European League Against Rheumatism (EULAR) criteria and be diagnosed less than 60 months previously. Patients had to have an mRSS of 10-35 units and active disease with one or more of the following: C-reactive protein of 6 mg/L or higher; erythrocyte sedimentation rate of 28 mm/h or higher; and platelet count of330 x 10⁹ L.


“What was astonishing in the trial was that every patient had HRCT at baseline and at the end of the study,” Dr. Khanna reported. These scans showed that 64% of patients had evidence of ILD at baseline and that those treated with tocilizumab had less evidence of fibrosis at week 48 versus placebo, indicating a stabilization rather than worsening of disease.

A time to treatment failure analysis also favored tocilizumab over placebo, but there were no significant changes in patient-reported outcomes.

Dr. Khanna’s slides stated that “given that the primary endpoint for mRSS was not met, all other P values are presented for information purposes only and cannot be considered statistically significant despite the strength of the evidence.” During the Q&A after his presentation, he noted that it was unlikely that the study’s sponsors (Roche/Genentech) will now pursue a license for tocilizumab in SSc.

Nevertheless, Dr. Khanna concluded, “we have the opportunity, based on these data, to treat these patients early on, where you can preserve the lung function, which is a paradigm shift versus waiting for the lung function to decline, become clinically meaningful, significant, and then treat this patient population.”

Roche/Genentech sponsored the study. Dr. Khanna acts as a consultant to Roche/Genentech and eight other pharmaceutical companies. He owns stock in Eicos Sciences.

SOURCE: Khanna D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):202-3. Abstract OP0245, doi: 10.1136/annrheumdis-2019-eular.2120

MADRID – Tocilizumab (Actemra) preserved lung function in patients with early systemic sclerosis (SSc), according to a secondary endpoint analysis of the phase 3, double-blind, randomized, controlled focuSSced trial.

Vidyard Video

After 48 weeks, a significantly lower proportion of patients treated with tocilizumab than placebo experienced any decline in lung function from baseline (50.5% versus 70.3% (P = .015), as defined by the percentage increase in predicted forced vital capacity (%pFVC). When only patients with interstitial lung disease (ILD) were considered, the respective percentages were 51.7% and 75.5% (P = .003).

In SSc-ILD patients, a clinically meaningful decline of 10% or more of the %pFVC in lung function was seen in 24.5% given placebo but in just 8.6% of those treated with tocilizumab.

“ILD is a major complication of scleroderma; it has high morbidity and mortality ... and it’s largely irreversible,” Dinesh Khanna, MD, said at the European Congress of Rheumatology.

“In this day and age, when we treat ILD, we wait for a patient to develop clinical ILD,” added Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor. Clinical ILD can be defined by symptoms, abnormal pulmonary function tests, and marked abnormalities on high resolution computed tomography (HRCT) scans. He indicated that if improving ILD was not possible, then the next best thing would be to stabilize the disease and ensure there was no worsening in lung function.

As yet, there are no disease-modifying treatments available to treat SSc but there are “ample data that interleukin-6 plays a very important role in the pathogenesis of scleroderma,” Dr. Khanna observed. Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor.

Data from the phase 2 faSScinate trial showed initial promise for the drug in SSc where a numerical, but not statistically significant, improvement in skin thickening was seen, and the results had hinted at a possible benefit on lung function (Lancet. 2016 Jun 25;387:2630-40).

However, in the phase 3 focuSSced trial, there was no statistically significant difference in the change from baseline to week 48 modified Rodnan skin score (mRSS) between tocilizumab and placebo, which was the primary endpoint. The least square mean change in mRSS was –6.14 for tocilizumab and –4.41 for placebo (P = .0983).

A total of 205 patients with SSc were studied and randomized, 1:1 in a double-blind fashion, to receive either a once-weekly, subcutaneous dose of 162 mg tocilizumab or a weekly subcutaneous placebo injection for 48 weeks.

For inclusion in the study, patients had to have SSc that met American College of Rheumatology and European League Against Rheumatism (EULAR) criteria and be diagnosed less than 60 months previously. Patients had to have an mRSS of 10-35 units and active disease with one or more of the following: C-reactive protein of 6 mg/L or higher; erythrocyte sedimentation rate of 28 mm/h or higher; and platelet count of330 x 10⁹ L.


“What was astonishing in the trial was that every patient had HRCT at baseline and at the end of the study,” Dr. Khanna reported. These scans showed that 64% of patients had evidence of ILD at baseline and that those treated with tocilizumab had less evidence of fibrosis at week 48 versus placebo, indicating a stabilization rather than worsening of disease.

A time to treatment failure analysis also favored tocilizumab over placebo, but there were no significant changes in patient-reported outcomes.

Dr. Khanna’s slides stated that “given that the primary endpoint for mRSS was not met, all other P values are presented for information purposes only and cannot be considered statistically significant despite the strength of the evidence.” During the Q&A after his presentation, he noted that it was unlikely that the study’s sponsors (Roche/Genentech) will now pursue a license for tocilizumab in SSc.

Nevertheless, Dr. Khanna concluded, “we have the opportunity, based on these data, to treat these patients early on, where you can preserve the lung function, which is a paradigm shift versus waiting for the lung function to decline, become clinically meaningful, significant, and then treat this patient population.”

Roche/Genentech sponsored the study. Dr. Khanna acts as a consultant to Roche/Genentech and eight other pharmaceutical companies. He owns stock in Eicos Sciences.

SOURCE: Khanna D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):202-3. Abstract OP0245, doi: 10.1136/annrheumdis-2019-eular.2120

MADRID – Electrically stimulating the vagus nerve produced clinically meaningful responses in disease activity measures in patients with refractory RA in a small safety study.

A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.

The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.

“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.

“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.

He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”

Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.

“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.

Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.

For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.

Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.

All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.

“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”

While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.

Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.

SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716

MADRID – Electrically stimulating the vagus nerve produced clinically meaningful responses in disease activity measures in patients with refractory RA in a small safety study.

A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.

The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.

“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.

“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.

He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”

Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.

“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.

Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.

For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.

Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.

All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.

“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”

While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.

Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.

SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716

MADRID – Electrically stimulating the vagus nerve produced clinically meaningful responses in disease activity measures in patients with refractory RA in a small safety study.

A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.

The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.

“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.

“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.

He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”

Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.

“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.

Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.

For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.

Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.

All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.

“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”

While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.

Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.

SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716