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Gene therapy demonstrates modest success in genetic blindness
SEATTLE – The therapy, delivered by intravitreal injection, uses an adeno-associated virus vector to deliver a corrected copy of the mutated ND4 mitochondrial gene.
LHON is a rare, maternally inherited mitochondrial mutation that can cause blindness, most commonly in young men, though it does not happen in all individuals with the mutation. The condition often starts with blindness in one eye, accompanied or followed shortly by blindness in the second eye. Researchers believe that the injected viral vector gets taken up retinal ganglion cells, where the mutated gene interferes with vision. Once synthesized, a mitochondria-targeting sequence facilitates transport of the protein to the mitochondria.
The study protocol called for injection of the therapy into one eye and a placebo into the other, using the patient as his or own placebo control. The results in the treated eye were encouraging, though modest. “This is not hitting it out of the ballpark. But for people whose vision is devastated by this disease, it certainly is a first step,” said Nancy J. Newman, MD, during a press conference held March 29 in advance of the 2022 annual meeting of the American Academy of Neurology.
Dr. Newman also noted a surprise finding: Visual improvement also occurred in the placebo-control eye. This was noted in previous studies, called RESCUE and REVERSE, and follow-up studies in monkeys found viral vector in the unaffected eye 3-6 months after an injection. “This would imply some kind of transport within retrograde up the opposite optic nerve after crossing in the chiasm to the eye, but this is going to take a fair bit of work to know exactly how that happens,” said Dr. Newman
Unfortunately, the phase 3 REFLECT study was designed before that process was understood. “This was not a case-control study by person, it was by eye. And that was a mistake, because it turns out there is a does appear to be second eye effects. We do not have naive controls here that did not receive any injection at all in any eye. That’s something that we will [do going] forward,” said Dr. Newman.
Despite the problem with placebo, the results were encouraging. “Those patients who had both eyes injected with the drug did better than in those who had one eye injected with drug and one eye injected with placebo, suggesting some sort of dose effect. There were no adverse events other than what we would expect from injecting [into] eyes. Those treated with the drug had more ocular inflammation, as would also be expected, but all were easily treated with topical medications,” said Dr. Newman.
What are the long-term effects?
Natalia Rost, MD, who chairs the AAN Science Committee, commented after the presentation: “We’re quite impressed with advances in gene therapy. The question is, are there early indications that this improvement in vision will have a lasting effect?”
Dr. Newman responded that ongoing data from earlier studies are also encouraging regarding the long-term effect of the treatment. At 4 years, there was a difference of 16.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters equivalent between treated patients and natural history controls (P < .01), “which [does] suggest that this effect is maintained,” said Dr. Newman, who is a professor of ophthalmology and neurology at Emory University, Atlanta.
Dr. Rost also wondered if it would be possible to capture patients earlier in their disease process, in the hopes of countering degeneration before it becomes severe enough to impact vision. Dr. Newman answered by noting another surprise from the research. Previous studies had shown that intervention while only a single eye is affected had little impact on spread of the condition to the second eye, “which was very disappointing,” said Dr. Newman. When they stratified patients by time since vision loss, they found that those who received the therapy 6 months or later after vision loss had better responses than those who were treated earlier.
The mechanism of this counter-intuitive finding remains uncertain, “but we do know that acutely in this disease when people are just starting to lose this vision, during the first couple of months, they get swelling of the axons from these retinal ganglion cells. Our hypothesis is that swelling may actually act as a barrier for the drug to get into the retinal ganglion cell bodies themselves and be transfected. So it turns out that earlier may not be better,” said Dr. Newman.
The study included patients at 13 sites worldwide; 48 were treated bilaterally and 50 treated unilaterally. Just under 80% were male, the mean age was 31.5 years, and the mean duration of vision loss was 8.30 months.
After 1.5 years, the improvement in best-corrected visual acuity between second-affected eyes was stronger in the treatment eye, equivalent to +3 ETDRS letters. The first-affected eye improved by 19 ETDRS letters, and the second-affected eye improved by 16 (P < .0001). Improvement in placebo eyes was +13 ETDRS letters (P < .0001).
Dr. Rost has served on a scientific advisory board or data monitoring board for Omniox. Dr. Newman has consulted for GenSight, Santhera/Chiesi, and Neurophoenix, and has received research support from GenSight and Santhera/Chiesi.
SEATTLE – The therapy, delivered by intravitreal injection, uses an adeno-associated virus vector to deliver a corrected copy of the mutated ND4 mitochondrial gene.
LHON is a rare, maternally inherited mitochondrial mutation that can cause blindness, most commonly in young men, though it does not happen in all individuals with the mutation. The condition often starts with blindness in one eye, accompanied or followed shortly by blindness in the second eye. Researchers believe that the injected viral vector gets taken up retinal ganglion cells, where the mutated gene interferes with vision. Once synthesized, a mitochondria-targeting sequence facilitates transport of the protein to the mitochondria.
The study protocol called for injection of the therapy into one eye and a placebo into the other, using the patient as his or own placebo control. The results in the treated eye were encouraging, though modest. “This is not hitting it out of the ballpark. But for people whose vision is devastated by this disease, it certainly is a first step,” said Nancy J. Newman, MD, during a press conference held March 29 in advance of the 2022 annual meeting of the American Academy of Neurology.
Dr. Newman also noted a surprise finding: Visual improvement also occurred in the placebo-control eye. This was noted in previous studies, called RESCUE and REVERSE, and follow-up studies in monkeys found viral vector in the unaffected eye 3-6 months after an injection. “This would imply some kind of transport within retrograde up the opposite optic nerve after crossing in the chiasm to the eye, but this is going to take a fair bit of work to know exactly how that happens,” said Dr. Newman
Unfortunately, the phase 3 REFLECT study was designed before that process was understood. “This was not a case-control study by person, it was by eye. And that was a mistake, because it turns out there is a does appear to be second eye effects. We do not have naive controls here that did not receive any injection at all in any eye. That’s something that we will [do going] forward,” said Dr. Newman.
Despite the problem with placebo, the results were encouraging. “Those patients who had both eyes injected with the drug did better than in those who had one eye injected with drug and one eye injected with placebo, suggesting some sort of dose effect. There were no adverse events other than what we would expect from injecting [into] eyes. Those treated with the drug had more ocular inflammation, as would also be expected, but all were easily treated with topical medications,” said Dr. Newman.
What are the long-term effects?
Natalia Rost, MD, who chairs the AAN Science Committee, commented after the presentation: “We’re quite impressed with advances in gene therapy. The question is, are there early indications that this improvement in vision will have a lasting effect?”
Dr. Newman responded that ongoing data from earlier studies are also encouraging regarding the long-term effect of the treatment. At 4 years, there was a difference of 16.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters equivalent between treated patients and natural history controls (P < .01), “which [does] suggest that this effect is maintained,” said Dr. Newman, who is a professor of ophthalmology and neurology at Emory University, Atlanta.
Dr. Rost also wondered if it would be possible to capture patients earlier in their disease process, in the hopes of countering degeneration before it becomes severe enough to impact vision. Dr. Newman answered by noting another surprise from the research. Previous studies had shown that intervention while only a single eye is affected had little impact on spread of the condition to the second eye, “which was very disappointing,” said Dr. Newman. When they stratified patients by time since vision loss, they found that those who received the therapy 6 months or later after vision loss had better responses than those who were treated earlier.
The mechanism of this counter-intuitive finding remains uncertain, “but we do know that acutely in this disease when people are just starting to lose this vision, during the first couple of months, they get swelling of the axons from these retinal ganglion cells. Our hypothesis is that swelling may actually act as a barrier for the drug to get into the retinal ganglion cell bodies themselves and be transfected. So it turns out that earlier may not be better,” said Dr. Newman.
The study included patients at 13 sites worldwide; 48 were treated bilaterally and 50 treated unilaterally. Just under 80% were male, the mean age was 31.5 years, and the mean duration of vision loss was 8.30 months.
After 1.5 years, the improvement in best-corrected visual acuity between second-affected eyes was stronger in the treatment eye, equivalent to +3 ETDRS letters. The first-affected eye improved by 19 ETDRS letters, and the second-affected eye improved by 16 (P < .0001). Improvement in placebo eyes was +13 ETDRS letters (P < .0001).
Dr. Rost has served on a scientific advisory board or data monitoring board for Omniox. Dr. Newman has consulted for GenSight, Santhera/Chiesi, and Neurophoenix, and has received research support from GenSight and Santhera/Chiesi.
SEATTLE – The therapy, delivered by intravitreal injection, uses an adeno-associated virus vector to deliver a corrected copy of the mutated ND4 mitochondrial gene.
LHON is a rare, maternally inherited mitochondrial mutation that can cause blindness, most commonly in young men, though it does not happen in all individuals with the mutation. The condition often starts with blindness in one eye, accompanied or followed shortly by blindness in the second eye. Researchers believe that the injected viral vector gets taken up retinal ganglion cells, where the mutated gene interferes with vision. Once synthesized, a mitochondria-targeting sequence facilitates transport of the protein to the mitochondria.
The study protocol called for injection of the therapy into one eye and a placebo into the other, using the patient as his or own placebo control. The results in the treated eye were encouraging, though modest. “This is not hitting it out of the ballpark. But for people whose vision is devastated by this disease, it certainly is a first step,” said Nancy J. Newman, MD, during a press conference held March 29 in advance of the 2022 annual meeting of the American Academy of Neurology.
Dr. Newman also noted a surprise finding: Visual improvement also occurred in the placebo-control eye. This was noted in previous studies, called RESCUE and REVERSE, and follow-up studies in monkeys found viral vector in the unaffected eye 3-6 months after an injection. “This would imply some kind of transport within retrograde up the opposite optic nerve after crossing in the chiasm to the eye, but this is going to take a fair bit of work to know exactly how that happens,” said Dr. Newman
Unfortunately, the phase 3 REFLECT study was designed before that process was understood. “This was not a case-control study by person, it was by eye. And that was a mistake, because it turns out there is a does appear to be second eye effects. We do not have naive controls here that did not receive any injection at all in any eye. That’s something that we will [do going] forward,” said Dr. Newman.
Despite the problem with placebo, the results were encouraging. “Those patients who had both eyes injected with the drug did better than in those who had one eye injected with drug and one eye injected with placebo, suggesting some sort of dose effect. There were no adverse events other than what we would expect from injecting [into] eyes. Those treated with the drug had more ocular inflammation, as would also be expected, but all were easily treated with topical medications,” said Dr. Newman.
What are the long-term effects?
Natalia Rost, MD, who chairs the AAN Science Committee, commented after the presentation: “We’re quite impressed with advances in gene therapy. The question is, are there early indications that this improvement in vision will have a lasting effect?”
Dr. Newman responded that ongoing data from earlier studies are also encouraging regarding the long-term effect of the treatment. At 4 years, there was a difference of 16.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters equivalent between treated patients and natural history controls (P < .01), “which [does] suggest that this effect is maintained,” said Dr. Newman, who is a professor of ophthalmology and neurology at Emory University, Atlanta.
Dr. Rost also wondered if it would be possible to capture patients earlier in their disease process, in the hopes of countering degeneration before it becomes severe enough to impact vision. Dr. Newman answered by noting another surprise from the research. Previous studies had shown that intervention while only a single eye is affected had little impact on spread of the condition to the second eye, “which was very disappointing,” said Dr. Newman. When they stratified patients by time since vision loss, they found that those who received the therapy 6 months or later after vision loss had better responses than those who were treated earlier.
The mechanism of this counter-intuitive finding remains uncertain, “but we do know that acutely in this disease when people are just starting to lose this vision, during the first couple of months, they get swelling of the axons from these retinal ganglion cells. Our hypothesis is that swelling may actually act as a barrier for the drug to get into the retinal ganglion cell bodies themselves and be transfected. So it turns out that earlier may not be better,” said Dr. Newman.
The study included patients at 13 sites worldwide; 48 were treated bilaterally and 50 treated unilaterally. Just under 80% were male, the mean age was 31.5 years, and the mean duration of vision loss was 8.30 months.
After 1.5 years, the improvement in best-corrected visual acuity between second-affected eyes was stronger in the treatment eye, equivalent to +3 ETDRS letters. The first-affected eye improved by 19 ETDRS letters, and the second-affected eye improved by 16 (P < .0001). Improvement in placebo eyes was +13 ETDRS letters (P < .0001).
Dr. Rost has served on a scientific advisory board or data monitoring board for Omniox. Dr. Newman has consulted for GenSight, Santhera/Chiesi, and Neurophoenix, and has received research support from GenSight and Santhera/Chiesi.
AT AAN 2022
First-line CAR T-cell therapy could help cure some lymphomas
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
FROM NATURE MEDICINE
Gene therapy for hemophilia A: `Truly transformative and liberating’
Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported in the New England Journal of Medicine.
‘Truly transformative and liberating’
“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia,” writes Courtney D. Thornburg, from the Hemophilia and Thrombosis Treatment Center at Rady Children’s Hospital, San Diego, in an accompanying editorial.
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. Although rare, it is nevertheless the most common type, affecting about 12 per 100,000. Hemophilia B affects about 3.7 per 100,000.
The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.
With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Dr. Thornburg noted.
Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.
Results from the phase 3 open-label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.
At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).
In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).
“Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years,” conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas (Brazil).
“We are very enthusiastic about the results of this phase 3 clinical trial,” Dr. Ozelo commented to this news organization.
“It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post infusion than with factor VIII prophylaxis,” she said. “In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up remain free of the use of additional prophylactic treatments.”
One issue that remains unanswered is how long the effects may last.
Valoctocogene roxaparvovec is a one-time infusion, she explained. “At least for now, redosing with the same AAV vector is not an option due to the immune response induced.”
“The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last,” she added.
In the study, Dr. Ozelo and colleagues noted that “expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”
Editorialist Dr. Thornburg touched on this point in an interview with this news organization.
Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. “Any increase of about 3%-5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.
“How long that will be sustained is an open question,” she added. “With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it’s still an open question for hemophilia A.”
Dr. Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.
GENEr8-1 study details and results
The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.
The patient sample included 20 men enrolled directly, and 110 participants in a prospective noninterventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.
Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.
They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.
A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV positive were excluded from the modified intention-to-treat efficacy analysis.
As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.
The most common adverse event was an elevation in alanine aminotransferase levels, the investigators noted.
These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients and could be safely managed with immunosuppressants, the authors commented.
Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.
“Overall, the risk-benefit profile appears favorable,” the team commented.
The study was supported by BioMarin Pharmaceutical. Dr. Ozelo disclosed grant support from the company. Dr. Thornburg disclosed serving as a consultant to BioMarin and others.
A version of this article first appeared on Medscape.com.
Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported in the New England Journal of Medicine.
‘Truly transformative and liberating’
“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia,” writes Courtney D. Thornburg, from the Hemophilia and Thrombosis Treatment Center at Rady Children’s Hospital, San Diego, in an accompanying editorial.
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. Although rare, it is nevertheless the most common type, affecting about 12 per 100,000. Hemophilia B affects about 3.7 per 100,000.
The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.
With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Dr. Thornburg noted.
Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.
Results from the phase 3 open-label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.
At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).
In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).
“Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years,” conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas (Brazil).
“We are very enthusiastic about the results of this phase 3 clinical trial,” Dr. Ozelo commented to this news organization.
“It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post infusion than with factor VIII prophylaxis,” she said. “In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up remain free of the use of additional prophylactic treatments.”
One issue that remains unanswered is how long the effects may last.
Valoctocogene roxaparvovec is a one-time infusion, she explained. “At least for now, redosing with the same AAV vector is not an option due to the immune response induced.”
“The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last,” she added.
In the study, Dr. Ozelo and colleagues noted that “expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”
Editorialist Dr. Thornburg touched on this point in an interview with this news organization.
Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. “Any increase of about 3%-5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.
“How long that will be sustained is an open question,” she added. “With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it’s still an open question for hemophilia A.”
Dr. Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.
GENEr8-1 study details and results
The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.
The patient sample included 20 men enrolled directly, and 110 participants in a prospective noninterventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.
Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.
They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.
A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV positive were excluded from the modified intention-to-treat efficacy analysis.
As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.
The most common adverse event was an elevation in alanine aminotransferase levels, the investigators noted.
These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients and could be safely managed with immunosuppressants, the authors commented.
Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.
“Overall, the risk-benefit profile appears favorable,” the team commented.
The study was supported by BioMarin Pharmaceutical. Dr. Ozelo disclosed grant support from the company. Dr. Thornburg disclosed serving as a consultant to BioMarin and others.
A version of this article first appeared on Medscape.com.
Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported in the New England Journal of Medicine.
‘Truly transformative and liberating’
“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia,” writes Courtney D. Thornburg, from the Hemophilia and Thrombosis Treatment Center at Rady Children’s Hospital, San Diego, in an accompanying editorial.
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. Although rare, it is nevertheless the most common type, affecting about 12 per 100,000. Hemophilia B affects about 3.7 per 100,000.
The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.
With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Dr. Thornburg noted.
Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.
Results from the phase 3 open-label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.
At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).
In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).
“Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years,” conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas (Brazil).
“We are very enthusiastic about the results of this phase 3 clinical trial,” Dr. Ozelo commented to this news organization.
“It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post infusion than with factor VIII prophylaxis,” she said. “In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up remain free of the use of additional prophylactic treatments.”
One issue that remains unanswered is how long the effects may last.
Valoctocogene roxaparvovec is a one-time infusion, she explained. “At least for now, redosing with the same AAV vector is not an option due to the immune response induced.”
“The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last,” she added.
In the study, Dr. Ozelo and colleagues noted that “expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”
Editorialist Dr. Thornburg touched on this point in an interview with this news organization.
Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. “Any increase of about 3%-5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.
“How long that will be sustained is an open question,” she added. “With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it’s still an open question for hemophilia A.”
Dr. Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.
GENEr8-1 study details and results
The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.
The patient sample included 20 men enrolled directly, and 110 participants in a prospective noninterventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.
Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.
They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.
A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV positive were excluded from the modified intention-to-treat efficacy analysis.
As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.
The most common adverse event was an elevation in alanine aminotransferase levels, the investigators noted.
These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients and could be safely managed with immunosuppressants, the authors commented.
Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.
“Overall, the risk-benefit profile appears favorable,” the team commented.
The study was supported by BioMarin Pharmaceutical. Dr. Ozelo disclosed grant support from the company. Dr. Thornburg disclosed serving as a consultant to BioMarin and others.
A version of this article first appeared on Medscape.com.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Gene therapy: A ‘one and done’ hemophilia B treatment?
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
REPORTING FROM EAHAD
New hemophilia treatments: ‘Our cup runneth over’
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
REPORTING FROM ASH 2021
NHL: As a second-line treatment in phase 3 trial, tisa-cel disappoints
according to results of a randomized, phase 3 trial.
The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.
Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.
“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.
Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.
The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.
About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.
The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.
“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”
Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.
The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.
While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.
In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.
Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.
“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.
There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.
“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.
In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.
Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m2 and 90 mg/m2, respectively.
Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.
Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.
according to results of a randomized, phase 3 trial.
The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.
Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.
“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.
Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.
The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.
About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.
The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.
“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”
Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.
The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.
While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.
In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.
Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.
“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.
There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.
“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.
In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.
Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m2 and 90 mg/m2, respectively.
Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.
Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.
according to results of a randomized, phase 3 trial.
The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.
Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.
“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.
Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.
The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.
About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.
The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.
“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”
Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.
The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.
While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.
In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.
Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.
“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.
There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.
“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.
In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.
Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m2 and 90 mg/m2, respectively.
Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.
Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.
FROM ASH 2021
Beta-thalassemia gene therapy achieves lasting transfusion independence
, an investigator reported at the annual meeting of the American Society of Hematology.
Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.
In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.
Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.
“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.
This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.
“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.
Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.
“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.
Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.
With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.
Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.
At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.
A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.
Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.
“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.
Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.
Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.
The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.
Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.
Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.
“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.
Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
, an investigator reported at the annual meeting of the American Society of Hematology.
Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.
In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.
Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.
“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.
This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.
“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.
Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.
“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.
Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.
With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.
Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.
At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.
A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.
Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.
“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.
Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.
Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.
The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.
Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.
Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.
“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.
Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
, an investigator reported at the annual meeting of the American Society of Hematology.
Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.
In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.
Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.
“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.
This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.
“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.
Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.
“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.
Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.
With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.
Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.
At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.
A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.
Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.
“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.
Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.
Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.
The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.
Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.
Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.
“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.
Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
FROM ASH 2021
Survey identifies clinicians’ unease with genetic testing
Before getting to work on developing guidelines for genetic testing in Parkinson’s disease, a task force of the Movement Disorders Society surveyed members worldwide to identify concerns they have about using genetic testing in practice. In results presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders,
“Some of the major outstanding issues are the clinical actionability of genetic testing – and this was highlighted by some survey participants,” senior study author Rachel Saunders-Pullman, MD, MPH, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York, said in an interview. The issue is “dynamic,” and will change even more radically when genetic therapies for Parkinson’s disease become available. “It is planned that, in the development of the MDS Task Force guidelines, scenarios which outline the changes in consideration of testing will depend on the availability of clinically actionable data,” she said.
Barriers to genetic testing
The MDS Task Force for Genetic Testing in Parkinson Disease conducted the survey, completed online by 568 MDS members. Respondents were from the four regions from which the MDS draws members: Africa, Europe, Asia/Oceania, and Pan-America. Half of the respondents considered themselves movement disorder specialists and 31% as general neurologists, said Maggie Markgraf, research coordinator at Mount Sinai Beth Israel in New York, who presented the survey findings.
Barriers to genetic testing that the clinicians cited included cost (57%), lack of availability of genetic counseling (37%), time for testing (20%) or time for counseling (17%). About 14%also cited a lack of knowledge, and only 8.5 % said they saw no barriers for genetic testing. Other concerns included a lack of therapeutic options if tests are positive and low overall positivity rates.
“Perceived barriers for general neurologists differed slightly, with limited knowledge being the most widely reported barrier, followed closely by cost and access to testing and genetic counseling,” Ms. Markgraf said.
Respondents were also asked to identify what they thought their patients perceived as barriers to genetic testing. The major one was cost (65%), followed by limited knowledge about genetics (43%), lack of access to genetic counseling (34%), and lack of access to testing separate from cost (30%). “Across all MDS regions, the perceived level of a patient’s knowledge about genetic testing is considered to be exceedingly low,” Ms. Markgraf said.
Europe had the highest availability to genetic tests, with 41.8% saying they’re accessible to general neurologists, followed by Asia/Oceania (31%) and Pan-America (30%).
“The area of most unmet need when it comes to PD genetic testing was cost for each MDS region, although the intertwined issue of access was also high, and over 50% reported that knowledge was an unmet need in their region,” Dr. Saunders-Pullman said.
Insurance coverage was another issue the survey respondents identified. In Europe, 53.6% said insurance or government programs cover genetic testing for PD, while only 14% in Pan-America and 10.3% in Asia/Oceania (and 0% in Africa) said such coverage was available.
“While there are limitations to this study, greater awareness of availability and barriers to genetic testing and counseling across different regions, as well as disparities among regions, will help inform development of the MDS Task Force guidelines,” Dr. Saunders-Pullman said.
Unmet needs
Connie Marras, MD, PhD, a professor of neurology at the University of Toronto, noted the survey suggested neurologists exhibit a “lack of comfort or lack of time” with genetic testing and counseling for Parkinson’s disease. “Even if we make genetic testing more widely available, we need health care providers that are comfortable and available to counsel patients before and after the testing, and clearly these are unmet needs,” Dr. Marras said in an interview.
“To date, pharmacologic treatment of Parkinson’s disease did not depend on genetics,” Dr. Marras said. “This may well change in the near future with treatments specifically targeting mechanisms related to two of the most common genetic risk factors for PD: LRRK2 and GBA gene variants being in clinical trials.” These developments may soon raise the urgency to reduce barriers to genetic testing.
Dr. Saunders-Pullman and Dr. Marras have no relevant relationships to disclose.
Before getting to work on developing guidelines for genetic testing in Parkinson’s disease, a task force of the Movement Disorders Society surveyed members worldwide to identify concerns they have about using genetic testing in practice. In results presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders,
“Some of the major outstanding issues are the clinical actionability of genetic testing – and this was highlighted by some survey participants,” senior study author Rachel Saunders-Pullman, MD, MPH, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York, said in an interview. The issue is “dynamic,” and will change even more radically when genetic therapies for Parkinson’s disease become available. “It is planned that, in the development of the MDS Task Force guidelines, scenarios which outline the changes in consideration of testing will depend on the availability of clinically actionable data,” she said.
Barriers to genetic testing
The MDS Task Force for Genetic Testing in Parkinson Disease conducted the survey, completed online by 568 MDS members. Respondents were from the four regions from which the MDS draws members: Africa, Europe, Asia/Oceania, and Pan-America. Half of the respondents considered themselves movement disorder specialists and 31% as general neurologists, said Maggie Markgraf, research coordinator at Mount Sinai Beth Israel in New York, who presented the survey findings.
Barriers to genetic testing that the clinicians cited included cost (57%), lack of availability of genetic counseling (37%), time for testing (20%) or time for counseling (17%). About 14%also cited a lack of knowledge, and only 8.5 % said they saw no barriers for genetic testing. Other concerns included a lack of therapeutic options if tests are positive and low overall positivity rates.
“Perceived barriers for general neurologists differed slightly, with limited knowledge being the most widely reported barrier, followed closely by cost and access to testing and genetic counseling,” Ms. Markgraf said.
Respondents were also asked to identify what they thought their patients perceived as barriers to genetic testing. The major one was cost (65%), followed by limited knowledge about genetics (43%), lack of access to genetic counseling (34%), and lack of access to testing separate from cost (30%). “Across all MDS regions, the perceived level of a patient’s knowledge about genetic testing is considered to be exceedingly low,” Ms. Markgraf said.
Europe had the highest availability to genetic tests, with 41.8% saying they’re accessible to general neurologists, followed by Asia/Oceania (31%) and Pan-America (30%).
“The area of most unmet need when it comes to PD genetic testing was cost for each MDS region, although the intertwined issue of access was also high, and over 50% reported that knowledge was an unmet need in their region,” Dr. Saunders-Pullman said.
Insurance coverage was another issue the survey respondents identified. In Europe, 53.6% said insurance or government programs cover genetic testing for PD, while only 14% in Pan-America and 10.3% in Asia/Oceania (and 0% in Africa) said such coverage was available.
“While there are limitations to this study, greater awareness of availability and barriers to genetic testing and counseling across different regions, as well as disparities among regions, will help inform development of the MDS Task Force guidelines,” Dr. Saunders-Pullman said.
Unmet needs
Connie Marras, MD, PhD, a professor of neurology at the University of Toronto, noted the survey suggested neurologists exhibit a “lack of comfort or lack of time” with genetic testing and counseling for Parkinson’s disease. “Even if we make genetic testing more widely available, we need health care providers that are comfortable and available to counsel patients before and after the testing, and clearly these are unmet needs,” Dr. Marras said in an interview.
“To date, pharmacologic treatment of Parkinson’s disease did not depend on genetics,” Dr. Marras said. “This may well change in the near future with treatments specifically targeting mechanisms related to two of the most common genetic risk factors for PD: LRRK2 and GBA gene variants being in clinical trials.” These developments may soon raise the urgency to reduce barriers to genetic testing.
Dr. Saunders-Pullman and Dr. Marras have no relevant relationships to disclose.
Before getting to work on developing guidelines for genetic testing in Parkinson’s disease, a task force of the Movement Disorders Society surveyed members worldwide to identify concerns they have about using genetic testing in practice. In results presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders,
“Some of the major outstanding issues are the clinical actionability of genetic testing – and this was highlighted by some survey participants,” senior study author Rachel Saunders-Pullman, MD, MPH, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York, said in an interview. The issue is “dynamic,” and will change even more radically when genetic therapies for Parkinson’s disease become available. “It is planned that, in the development of the MDS Task Force guidelines, scenarios which outline the changes in consideration of testing will depend on the availability of clinically actionable data,” she said.
Barriers to genetic testing
The MDS Task Force for Genetic Testing in Parkinson Disease conducted the survey, completed online by 568 MDS members. Respondents were from the four regions from which the MDS draws members: Africa, Europe, Asia/Oceania, and Pan-America. Half of the respondents considered themselves movement disorder specialists and 31% as general neurologists, said Maggie Markgraf, research coordinator at Mount Sinai Beth Israel in New York, who presented the survey findings.
Barriers to genetic testing that the clinicians cited included cost (57%), lack of availability of genetic counseling (37%), time for testing (20%) or time for counseling (17%). About 14%also cited a lack of knowledge, and only 8.5 % said they saw no barriers for genetic testing. Other concerns included a lack of therapeutic options if tests are positive and low overall positivity rates.
“Perceived barriers for general neurologists differed slightly, with limited knowledge being the most widely reported barrier, followed closely by cost and access to testing and genetic counseling,” Ms. Markgraf said.
Respondents were also asked to identify what they thought their patients perceived as barriers to genetic testing. The major one was cost (65%), followed by limited knowledge about genetics (43%), lack of access to genetic counseling (34%), and lack of access to testing separate from cost (30%). “Across all MDS regions, the perceived level of a patient’s knowledge about genetic testing is considered to be exceedingly low,” Ms. Markgraf said.
Europe had the highest availability to genetic tests, with 41.8% saying they’re accessible to general neurologists, followed by Asia/Oceania (31%) and Pan-America (30%).
“The area of most unmet need when it comes to PD genetic testing was cost for each MDS region, although the intertwined issue of access was also high, and over 50% reported that knowledge was an unmet need in their region,” Dr. Saunders-Pullman said.
Insurance coverage was another issue the survey respondents identified. In Europe, 53.6% said insurance or government programs cover genetic testing for PD, while only 14% in Pan-America and 10.3% in Asia/Oceania (and 0% in Africa) said such coverage was available.
“While there are limitations to this study, greater awareness of availability and barriers to genetic testing and counseling across different regions, as well as disparities among regions, will help inform development of the MDS Task Force guidelines,” Dr. Saunders-Pullman said.
Unmet needs
Connie Marras, MD, PhD, a professor of neurology at the University of Toronto, noted the survey suggested neurologists exhibit a “lack of comfort or lack of time” with genetic testing and counseling for Parkinson’s disease. “Even if we make genetic testing more widely available, we need health care providers that are comfortable and available to counsel patients before and after the testing, and clearly these are unmet needs,” Dr. Marras said in an interview.
“To date, pharmacologic treatment of Parkinson’s disease did not depend on genetics,” Dr. Marras said. “This may well change in the near future with treatments specifically targeting mechanisms related to two of the most common genetic risk factors for PD: LRRK2 and GBA gene variants being in clinical trials.” These developments may soon raise the urgency to reduce barriers to genetic testing.
Dr. Saunders-Pullman and Dr. Marras have no relevant relationships to disclose.
FROM MDS VIRTUAL CONGRESS 2021
FDA places clinical hold on sickle cell gene therapy
The Food and Drug Administration placed a clinical hold yesterday on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.
The company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.
Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.
The gene therapy “space” is one with spectacular successes – for a form of retinal blindness and spinal muscular atrophy – rising against a backdrop of recent setbacks and failures – for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.
A lentiviral vector
The retooled lentivirus used in the SCD trials, LentiGlobin, delivers a beta-globin gene with one amino acid replacement to hematopoietic stem cells outside the patient’s body. The modified cells are then infused back into the patient. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.
What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.
The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.
Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.
Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.
Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.
Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”
Pinpointing causality
At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”
Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.
In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.
Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
A patient’s view
SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy
Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.
Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.
“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration placed a clinical hold yesterday on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.
The company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.
Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.
The gene therapy “space” is one with spectacular successes – for a form of retinal blindness and spinal muscular atrophy – rising against a backdrop of recent setbacks and failures – for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.
A lentiviral vector
The retooled lentivirus used in the SCD trials, LentiGlobin, delivers a beta-globin gene with one amino acid replacement to hematopoietic stem cells outside the patient’s body. The modified cells are then infused back into the patient. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.
What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.
The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.
Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.
Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.
Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.
Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”
Pinpointing causality
At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”
Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.
In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.
Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
A patient’s view
SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy
Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.
Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.
“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration placed a clinical hold yesterday on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.
The company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.
Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.
The gene therapy “space” is one with spectacular successes – for a form of retinal blindness and spinal muscular atrophy – rising against a backdrop of recent setbacks and failures – for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.
A lentiviral vector
The retooled lentivirus used in the SCD trials, LentiGlobin, delivers a beta-globin gene with one amino acid replacement to hematopoietic stem cells outside the patient’s body. The modified cells are then infused back into the patient. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.
What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.
The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.
Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.
Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.
Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.
Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”
Pinpointing causality
At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”
Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.
In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.
Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
A patient’s view
SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy
Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.
Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.
“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”
A version of this article first appeared on Medscape.com.
Gene therapy effective in hemophilia B patients with neutralizing antibodies
The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.
All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.
These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.
Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.
Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.
AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).
The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.
All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.
Efficacy
Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.
At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.
All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.
Safety
Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.
There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.
Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.
Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.
Next steps
This study is ongoing, and patients will be followed for 5 years. Dr. Pipe said the main focus of follow-up will be to determine if patients maintain durable expression of FIX.
A phase 3 trial of etranacogene dezaparvovec is ongoing as well. The trial, HOPE-B (NCT03569891), is fully enrolled, and dosing is planned for 55 patients.
“We’re looking forward to data analysis later this year,” Dr. Pipe said. “This will be the only phase 3 study, and really the only platform so far, that is not planning to exclude patients based on preexisting immunity.”
If all goes well in the phase 3 study, etranacogene dezaparvovec could be approved by the Food and Drug Administration very soon, Dr. Pipe added.
UniQure, the company developing etranacogene dezaparvovec, is planning to submit the biologics license application to the FDA next year. Etranacogene dezaparvovec was granted breakthrough designation from the FDA and is therefore eligible for priority review, so the gene therapy could be approved as early as 2021.
The phase 2b trial of etranacogene dezaparvovec is sponsored by uniQure. Dr. Pipe disclosed relationships with uniQure and other companies.
SOURCE: Pipe SW et al. EAHAD 2020, Abstract OR10.
The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.
All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.
These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.
Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.
Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.
AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).
The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.
All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.
Efficacy
Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.
At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.
All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.
Safety
Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.
There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.
Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.
Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.
Next steps
This study is ongoing, and patients will be followed for 5 years. Dr. Pipe said the main focus of follow-up will be to determine if patients maintain durable expression of FIX.
A phase 3 trial of etranacogene dezaparvovec is ongoing as well. The trial, HOPE-B (NCT03569891), is fully enrolled, and dosing is planned for 55 patients.
“We’re looking forward to data analysis later this year,” Dr. Pipe said. “This will be the only phase 3 study, and really the only platform so far, that is not planning to exclude patients based on preexisting immunity.”
If all goes well in the phase 3 study, etranacogene dezaparvovec could be approved by the Food and Drug Administration very soon, Dr. Pipe added.
UniQure, the company developing etranacogene dezaparvovec, is planning to submit the biologics license application to the FDA next year. Etranacogene dezaparvovec was granted breakthrough designation from the FDA and is therefore eligible for priority review, so the gene therapy could be approved as early as 2021.
The phase 2b trial of etranacogene dezaparvovec is sponsored by uniQure. Dr. Pipe disclosed relationships with uniQure and other companies.
SOURCE: Pipe SW et al. EAHAD 2020, Abstract OR10.
The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.
All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.
These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.
Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.
Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.
AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).
The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.
All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.
Efficacy
Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.
At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.
All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.
Safety
Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.
There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.
Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.
Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.
Next steps
This study is ongoing, and patients will be followed for 5 years. Dr. Pipe said the main focus of follow-up will be to determine if patients maintain durable expression of FIX.
A phase 3 trial of etranacogene dezaparvovec is ongoing as well. The trial, HOPE-B (NCT03569891), is fully enrolled, and dosing is planned for 55 patients.
“We’re looking forward to data analysis later this year,” Dr. Pipe said. “This will be the only phase 3 study, and really the only platform so far, that is not planning to exclude patients based on preexisting immunity.”
If all goes well in the phase 3 study, etranacogene dezaparvovec could be approved by the Food and Drug Administration very soon, Dr. Pipe added.
UniQure, the company developing etranacogene dezaparvovec, is planning to submit the biologics license application to the FDA next year. Etranacogene dezaparvovec was granted breakthrough designation from the FDA and is therefore eligible for priority review, so the gene therapy could be approved as early as 2021.
The phase 2b trial of etranacogene dezaparvovec is sponsored by uniQure. Dr. Pipe disclosed relationships with uniQure and other companies.
SOURCE: Pipe SW et al. EAHAD 2020, Abstract OR10.
REPORTING FROM EAHAD 2020