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Early results with ‘optimized’ gene therapy in hemophilia A
First-in-human results suggest a gene therapy, BAY 2599023, can increase factor VIII levels in patients with hemophilia A, but it isn’t clear if BAY 2599023 can eliminate the need for prophylaxis.
Of four patients who received BAY 2599023, three achieved clinically meaningful factor VIII levels, and all were able to stop prophylaxis at some point. However, one patient had to resume prophylaxis, and all four have experienced bleeds since receiving BAY 2599023.
This is a dose-escalating trial (NCT03588299), so researchers are still attempting to determine the optimal dose of BAY 2599023. Upcoming results in two patients treated at the highest dose should provide more insight, according to Steven W. Pipe, MD, of the University of Michigan in Ann Arbor.
Dr. Pipe presented results with BAY 2599023 at the annual congress of the European Association for Haemophilia and Allied Disorders.
He noted that between 30% and 70% of hemophilia patients may have preexisting neutralizing antibodies to specific adeno-associated virus (AAV) serotypes. Developing gene therapies with varying serotypes could reduce this problem and increase eligibility for gene therapy. Bayer had this in mind when developing BAY 2599023.
BAY 2599023 is a non-replicating AAV vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted factor VIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression, Dr. Pipe explained.
He presented results with BAY 2599023 in four patients with severe hemophilia A. At baseline, patients were receiving prophylaxis and did not have factor VIII inhibitors or detectable immunity to the AAVhu37 capsid.
First cohort
Two patients received BAY 2599023 at a dose of 0.5 × 1013 GC/kg. One patient achieved a factor VIII level above 5% at this dose and was able to stop prophylaxis temporarily. The patient experienced two bleeds on study and had to resume prophylaxis because of a target joint.
“He came into the study with a particularly challenging target joint in his ankle, and he had known from experience on prophylaxis that, if his factor level got too low, he would have breakthrough bleeds,” Dr. Pipe explained. “So we agreed that if he didn’t achieve a sustained level above 5%, he would go back on prophylaxis. He was able to stay off prophylaxis for 6 weeks, but we had to put him back on because of breakthrough bleeding.”
Dr. Pipe and colleagues have been following this patient for about a year, and the patient still has factor VIII levels of about 2% to 3% after a washout of prophylaxis.
The other patient who received a dose of 0.5 × 1013 GC/kg came off prophylaxis early on and has sustained factor VIII levels of 20%. This patient had four bleeds early in the trial but has since done very well, Dr. Pipe said. The patient had 99 bleeds in the year prior to receiving BAY 2599023.
Second cohort
Two subsequent patients received BAY 2599023 at a dose of 1 × 1013 GC/kg. Both patients have stopped prophylaxis.
One patient achieved factor VIII levels in the 5%-10% range and stopped prophylaxis at day 49. The patient has received on-demand treatment for four bleeds. The other patient achieved “robust” factor VIII expression levels “well above 20%,” according to Dr. Pipe. This patient stopped prophylaxis at day 10 and experienced bleeds early on but has remained bleed-free and treatment-free for 7 months.
Dr. Pipe noted that this patient experienced a spike in transaminases “very early on” after receiving BAY 2599023.
“So he was put on prednisone, but his liver enzymes almost immediately corrected to within the normal range,” Dr. Pipe said. “He has finished the cascading dose of prednisone, his liver enzymes have remained stable, his factor VIII expression has remained stable, and he continues to do very well.”
Next steps
Based on results in the first two cohorts, researchers are proceeding with a higher dose of BAY 2599023.
“The overall goal of this study is to identify the optimal dose that can be taken forward to the planned phase 3 study,” Dr. Pipe said. “What they [Bayer] would like to bring to the community is a product that offers a chance for maximum eligibility based on low screen out because of preexisting immunity and maximize the number of patients who are in the normal range.”
“For patients to embrace gene therapy, it really has to get them at least the possibility to land within the normal range and, hopefully, be not just liberated from prophylaxis but maybe liberated from the need for factor VIII at all,” Dr. Pipe added. “I think if these AAV platform therapies can’t deliver that on a relatively consistent basis, it’s going to be challenging to get patients to embrace this technology.”
The phase 1/2 trial is sponsored by Bayer in collaboration with Ultragenyx Pharmaceutical Inc. Dr. Pipe disclosed relationships with Bayer and other companies.
SOURCE: Pipe SW et al. EAHAD 2020. Abstract P190.
First-in-human results suggest a gene therapy, BAY 2599023, can increase factor VIII levels in patients with hemophilia A, but it isn’t clear if BAY 2599023 can eliminate the need for prophylaxis.
Of four patients who received BAY 2599023, three achieved clinically meaningful factor VIII levels, and all were able to stop prophylaxis at some point. However, one patient had to resume prophylaxis, and all four have experienced bleeds since receiving BAY 2599023.
This is a dose-escalating trial (NCT03588299), so researchers are still attempting to determine the optimal dose of BAY 2599023. Upcoming results in two patients treated at the highest dose should provide more insight, according to Steven W. Pipe, MD, of the University of Michigan in Ann Arbor.
Dr. Pipe presented results with BAY 2599023 at the annual congress of the European Association for Haemophilia and Allied Disorders.
He noted that between 30% and 70% of hemophilia patients may have preexisting neutralizing antibodies to specific adeno-associated virus (AAV) serotypes. Developing gene therapies with varying serotypes could reduce this problem and increase eligibility for gene therapy. Bayer had this in mind when developing BAY 2599023.
BAY 2599023 is a non-replicating AAV vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted factor VIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression, Dr. Pipe explained.
He presented results with BAY 2599023 in four patients with severe hemophilia A. At baseline, patients were receiving prophylaxis and did not have factor VIII inhibitors or detectable immunity to the AAVhu37 capsid.
First cohort
Two patients received BAY 2599023 at a dose of 0.5 × 1013 GC/kg. One patient achieved a factor VIII level above 5% at this dose and was able to stop prophylaxis temporarily. The patient experienced two bleeds on study and had to resume prophylaxis because of a target joint.
“He came into the study with a particularly challenging target joint in his ankle, and he had known from experience on prophylaxis that, if his factor level got too low, he would have breakthrough bleeds,” Dr. Pipe explained. “So we agreed that if he didn’t achieve a sustained level above 5%, he would go back on prophylaxis. He was able to stay off prophylaxis for 6 weeks, but we had to put him back on because of breakthrough bleeding.”
Dr. Pipe and colleagues have been following this patient for about a year, and the patient still has factor VIII levels of about 2% to 3% after a washout of prophylaxis.
The other patient who received a dose of 0.5 × 1013 GC/kg came off prophylaxis early on and has sustained factor VIII levels of 20%. This patient had four bleeds early in the trial but has since done very well, Dr. Pipe said. The patient had 99 bleeds in the year prior to receiving BAY 2599023.
Second cohort
Two subsequent patients received BAY 2599023 at a dose of 1 × 1013 GC/kg. Both patients have stopped prophylaxis.
One patient achieved factor VIII levels in the 5%-10% range and stopped prophylaxis at day 49. The patient has received on-demand treatment for four bleeds. The other patient achieved “robust” factor VIII expression levels “well above 20%,” according to Dr. Pipe. This patient stopped prophylaxis at day 10 and experienced bleeds early on but has remained bleed-free and treatment-free for 7 months.
Dr. Pipe noted that this patient experienced a spike in transaminases “very early on” after receiving BAY 2599023.
“So he was put on prednisone, but his liver enzymes almost immediately corrected to within the normal range,” Dr. Pipe said. “He has finished the cascading dose of prednisone, his liver enzymes have remained stable, his factor VIII expression has remained stable, and he continues to do very well.”
Next steps
Based on results in the first two cohorts, researchers are proceeding with a higher dose of BAY 2599023.
“The overall goal of this study is to identify the optimal dose that can be taken forward to the planned phase 3 study,” Dr. Pipe said. “What they [Bayer] would like to bring to the community is a product that offers a chance for maximum eligibility based on low screen out because of preexisting immunity and maximize the number of patients who are in the normal range.”
“For patients to embrace gene therapy, it really has to get them at least the possibility to land within the normal range and, hopefully, be not just liberated from prophylaxis but maybe liberated from the need for factor VIII at all,” Dr. Pipe added. “I think if these AAV platform therapies can’t deliver that on a relatively consistent basis, it’s going to be challenging to get patients to embrace this technology.”
The phase 1/2 trial is sponsored by Bayer in collaboration with Ultragenyx Pharmaceutical Inc. Dr. Pipe disclosed relationships with Bayer and other companies.
SOURCE: Pipe SW et al. EAHAD 2020. Abstract P190.
First-in-human results suggest a gene therapy, BAY 2599023, can increase factor VIII levels in patients with hemophilia A, but it isn’t clear if BAY 2599023 can eliminate the need for prophylaxis.
Of four patients who received BAY 2599023, three achieved clinically meaningful factor VIII levels, and all were able to stop prophylaxis at some point. However, one patient had to resume prophylaxis, and all four have experienced bleeds since receiving BAY 2599023.
This is a dose-escalating trial (NCT03588299), so researchers are still attempting to determine the optimal dose of BAY 2599023. Upcoming results in two patients treated at the highest dose should provide more insight, according to Steven W. Pipe, MD, of the University of Michigan in Ann Arbor.
Dr. Pipe presented results with BAY 2599023 at the annual congress of the European Association for Haemophilia and Allied Disorders.
He noted that between 30% and 70% of hemophilia patients may have preexisting neutralizing antibodies to specific adeno-associated virus (AAV) serotypes. Developing gene therapies with varying serotypes could reduce this problem and increase eligibility for gene therapy. Bayer had this in mind when developing BAY 2599023.
BAY 2599023 is a non-replicating AAV vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted factor VIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression, Dr. Pipe explained.
He presented results with BAY 2599023 in four patients with severe hemophilia A. At baseline, patients were receiving prophylaxis and did not have factor VIII inhibitors or detectable immunity to the AAVhu37 capsid.
First cohort
Two patients received BAY 2599023 at a dose of 0.5 × 1013 GC/kg. One patient achieved a factor VIII level above 5% at this dose and was able to stop prophylaxis temporarily. The patient experienced two bleeds on study and had to resume prophylaxis because of a target joint.
“He came into the study with a particularly challenging target joint in his ankle, and he had known from experience on prophylaxis that, if his factor level got too low, he would have breakthrough bleeds,” Dr. Pipe explained. “So we agreed that if he didn’t achieve a sustained level above 5%, he would go back on prophylaxis. He was able to stay off prophylaxis for 6 weeks, but we had to put him back on because of breakthrough bleeding.”
Dr. Pipe and colleagues have been following this patient for about a year, and the patient still has factor VIII levels of about 2% to 3% after a washout of prophylaxis.
The other patient who received a dose of 0.5 × 1013 GC/kg came off prophylaxis early on and has sustained factor VIII levels of 20%. This patient had four bleeds early in the trial but has since done very well, Dr. Pipe said. The patient had 99 bleeds in the year prior to receiving BAY 2599023.
Second cohort
Two subsequent patients received BAY 2599023 at a dose of 1 × 1013 GC/kg. Both patients have stopped prophylaxis.
One patient achieved factor VIII levels in the 5%-10% range and stopped prophylaxis at day 49. The patient has received on-demand treatment for four bleeds. The other patient achieved “robust” factor VIII expression levels “well above 20%,” according to Dr. Pipe. This patient stopped prophylaxis at day 10 and experienced bleeds early on but has remained bleed-free and treatment-free for 7 months.
Dr. Pipe noted that this patient experienced a spike in transaminases “very early on” after receiving BAY 2599023.
“So he was put on prednisone, but his liver enzymes almost immediately corrected to within the normal range,” Dr. Pipe said. “He has finished the cascading dose of prednisone, his liver enzymes have remained stable, his factor VIII expression has remained stable, and he continues to do very well.”
Next steps
Based on results in the first two cohorts, researchers are proceeding with a higher dose of BAY 2599023.
“The overall goal of this study is to identify the optimal dose that can be taken forward to the planned phase 3 study,” Dr. Pipe said. “What they [Bayer] would like to bring to the community is a product that offers a chance for maximum eligibility based on low screen out because of preexisting immunity and maximize the number of patients who are in the normal range.”
“For patients to embrace gene therapy, it really has to get them at least the possibility to land within the normal range and, hopefully, be not just liberated from prophylaxis but maybe liberated from the need for factor VIII at all,” Dr. Pipe added. “I think if these AAV platform therapies can’t deliver that on a relatively consistent basis, it’s going to be challenging to get patients to embrace this technology.”
The phase 1/2 trial is sponsored by Bayer in collaboration with Ultragenyx Pharmaceutical Inc. Dr. Pipe disclosed relationships with Bayer and other companies.
SOURCE: Pipe SW et al. EAHAD 2020. Abstract P190.
REPORTING FROM EAHAD 2020
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
Fear drives activity changes in hemophilia patients
Fear of negative events can drive changes in activity levels among patients with hemophilia A, results of the HemACTIVE study suggest.
Patients were more likely to adjust their level of physical activity due to fear of bleeding and joint damage rather than previously experienced bleeding or joint damage.
However, past experience was more likely than fear to make patients stop physical activities altogether.
Mark Skinner, of the Institute for Policy Advancement in Washington, D.C., and colleagues presented these findings in a poster from the annual congress of the European Association for Haemophilia and Allied Disorders.
Mr. Skinner, who is a hemophilia patient himself, said the goal of the HemACTIVE study is to better understand how hemophilia affects patients’ lives.
“We wanted to understand the limitations, challenges, and compromises of individuals living with hemophilia,” Mr. Skinner said. “What has motivated them or prevented them from living more full, active lives doing the kind of work, leisure, and social activities that those without hemophilia do? Is it treatment choice, is it satisfaction with treatment, is it fear?
“We wanted to do a comprehensive study that really looked at the intersection of treatment adherence and satisfaction, the emotional components that relate to those decisions, and the challenges and compromises so that we could better identify what we need to consider as patients think about either changing their therapy or changing their treatment regimen on existing therapy.”
Previous results from the HemACTIVE study showed that, although activity levels differed among hemophilia patients, all patients surveyed wanted greater activity levels, better protection from bleeding, better pain relief, and less-frequent infusions (EAHAD 2019, Abstract P084). In addition, patients who used factor VIII products with an extended half-life were more active and more likely to adhere to their prescribed treatment (ISTH 2019, Abstract PB0210).
The results reported at EAHAD 2020 focus on patients’ reasons for modifying physical activity. Patients and caregivers completed a screening phone interview, followed by a 25-minute, web-based questionnaire on patient activity.
There were 275 respondents – 194 patients with hemophilia A and 81 caregivers – from Canada, France, Germany, Italy, and the United States. Patients had severe (61%) or moderate (39%) hemophilia A, and most (67%) were receiving prophylaxis.
Most patients (70%) were “active” or “extremely/very active,” 77% of patients adjusted their activities because of their hemophilia, and nearly half of patients stopped activities because of their disease.
Fear drives adjustments in activity
Patients were sometimes more likely to adjust their activities based on fear of experiencing an event, as opposed to previously experiencing that event.
Specifically, 44% of patients adjusted their activities due to fear of joint damage, compared with 36% of patients who made adjustments because of past significant joint damage.
Similarly, 41% of patients adjusted activities due to fear of breakthrough bleeds, compared with 36% of patients who made adjustments because of past experience with bleeds and 25% who made adjustments because of significant past bleeds.
On the other hand, a similar percentage of patients adjusted activities because of past experience with pain (43%) and fear of pain (41%). And a similar percentage of patients adjusted activities because of existing joint damage restrictions (35%) and fear of joint deterioration (32%).
Past experience prompts discontinuation of activity
Overall, 47% of patients said anxiety was the most common emotional reason for stopping physical activities. However, patients were consistently more likely to stop activities because of past experience rather than fear or anxiety.
Specifically, 50% of patients stopped activities because of significant past joint damage, 46% stopped because of developing joint problems, and 38% stopped due to fear of joint damage.
More patients stopped activities because of significant past bleeds (41%) rather than fear of breakthrough bleeds (26%). More patients stopped activities because they developed chronic pain (38%) rather than fear of pain (less than 15%). And more patients stopped activities because of existing joint damage restrictions (62%) rather than fear of joint damage (34%).
Applying results to practice: Changing the conversation
Ideally, these findings would be used to promote individualized treatment of hemophilia driven by patients’ goals, Mr. Skinner said. By better understanding patients’ feelings and motivations, clinicians may devise more personalized treatment regimens that align with patients’ goals and improve their quality of life.
Rather than adjusting treatment based only on “hard metrics” such as bleeding events, “we need to take a more holistic approach to looking at outcomes that are more important to patients,” Mr. Skinner said. This type of approach is particularly important to Mr. Skinner as someone who has severe hemophilia A.
“Because hemophilia is a life-long disease, and you’re born with it, you make conscious or unconscious adaptations throughout your life,” he explained. “Your expectations or aspirations adjust to what you’ve been told you can or cannot do because of your hemophilia. The choices I made for my career, where I live, the type of vacations I go on, the type of sports I participate in have all been limited over the course of time, which has meant that I’ve made compromises. There are a lot of individuals with hemophilia who are making decisions that are not what their life goals are.
“What this research helps me understand is that we can change the conversation and build it around an individual patient and understand what their aspirations are. If a clinician understands what I’m wanting to achieve in life … we can build a treatment regime around helping me achieve those goals. That is known to improve adherence.
“The goal, really, is to have hemophilia as a secondary consideration. Instead of saying: ‘You have hemophilia, so these are the options available to you,’ you can say, ‘what is it that you would like to achieve, and then we’ll figure out how your treatment for hemophilia can be adjusted to help you achieve those goals.’ It may sound like a nuance, but it really is reversing the conversation. The goal setting first versus your disease comes first.”
The HemACTIVE study was supported by Bayer. Mr. Skinner disclosed relationships with Bayer and other pharmaceutical companies.
SOURCE: Skinner M et al. EAHAD 2020, Abstract P304.
Fear of negative events can drive changes in activity levels among patients with hemophilia A, results of the HemACTIVE study suggest.
Patients were more likely to adjust their level of physical activity due to fear of bleeding and joint damage rather than previously experienced bleeding or joint damage.
However, past experience was more likely than fear to make patients stop physical activities altogether.
Mark Skinner, of the Institute for Policy Advancement in Washington, D.C., and colleagues presented these findings in a poster from the annual congress of the European Association for Haemophilia and Allied Disorders.
Mr. Skinner, who is a hemophilia patient himself, said the goal of the HemACTIVE study is to better understand how hemophilia affects patients’ lives.
“We wanted to understand the limitations, challenges, and compromises of individuals living with hemophilia,” Mr. Skinner said. “What has motivated them or prevented them from living more full, active lives doing the kind of work, leisure, and social activities that those without hemophilia do? Is it treatment choice, is it satisfaction with treatment, is it fear?
“We wanted to do a comprehensive study that really looked at the intersection of treatment adherence and satisfaction, the emotional components that relate to those decisions, and the challenges and compromises so that we could better identify what we need to consider as patients think about either changing their therapy or changing their treatment regimen on existing therapy.”
Previous results from the HemACTIVE study showed that, although activity levels differed among hemophilia patients, all patients surveyed wanted greater activity levels, better protection from bleeding, better pain relief, and less-frequent infusions (EAHAD 2019, Abstract P084). In addition, patients who used factor VIII products with an extended half-life were more active and more likely to adhere to their prescribed treatment (ISTH 2019, Abstract PB0210).
The results reported at EAHAD 2020 focus on patients’ reasons for modifying physical activity. Patients and caregivers completed a screening phone interview, followed by a 25-minute, web-based questionnaire on patient activity.
There were 275 respondents – 194 patients with hemophilia A and 81 caregivers – from Canada, France, Germany, Italy, and the United States. Patients had severe (61%) or moderate (39%) hemophilia A, and most (67%) were receiving prophylaxis.
Most patients (70%) were “active” or “extremely/very active,” 77% of patients adjusted their activities because of their hemophilia, and nearly half of patients stopped activities because of their disease.
Fear drives adjustments in activity
Patients were sometimes more likely to adjust their activities based on fear of experiencing an event, as opposed to previously experiencing that event.
Specifically, 44% of patients adjusted their activities due to fear of joint damage, compared with 36% of patients who made adjustments because of past significant joint damage.
Similarly, 41% of patients adjusted activities due to fear of breakthrough bleeds, compared with 36% of patients who made adjustments because of past experience with bleeds and 25% who made adjustments because of significant past bleeds.
On the other hand, a similar percentage of patients adjusted activities because of past experience with pain (43%) and fear of pain (41%). And a similar percentage of patients adjusted activities because of existing joint damage restrictions (35%) and fear of joint deterioration (32%).
Past experience prompts discontinuation of activity
Overall, 47% of patients said anxiety was the most common emotional reason for stopping physical activities. However, patients were consistently more likely to stop activities because of past experience rather than fear or anxiety.
Specifically, 50% of patients stopped activities because of significant past joint damage, 46% stopped because of developing joint problems, and 38% stopped due to fear of joint damage.
More patients stopped activities because of significant past bleeds (41%) rather than fear of breakthrough bleeds (26%). More patients stopped activities because they developed chronic pain (38%) rather than fear of pain (less than 15%). And more patients stopped activities because of existing joint damage restrictions (62%) rather than fear of joint damage (34%).
Applying results to practice: Changing the conversation
Ideally, these findings would be used to promote individualized treatment of hemophilia driven by patients’ goals, Mr. Skinner said. By better understanding patients’ feelings and motivations, clinicians may devise more personalized treatment regimens that align with patients’ goals and improve their quality of life.
Rather than adjusting treatment based only on “hard metrics” such as bleeding events, “we need to take a more holistic approach to looking at outcomes that are more important to patients,” Mr. Skinner said. This type of approach is particularly important to Mr. Skinner as someone who has severe hemophilia A.
“Because hemophilia is a life-long disease, and you’re born with it, you make conscious or unconscious adaptations throughout your life,” he explained. “Your expectations or aspirations adjust to what you’ve been told you can or cannot do because of your hemophilia. The choices I made for my career, where I live, the type of vacations I go on, the type of sports I participate in have all been limited over the course of time, which has meant that I’ve made compromises. There are a lot of individuals with hemophilia who are making decisions that are not what their life goals are.
“What this research helps me understand is that we can change the conversation and build it around an individual patient and understand what their aspirations are. If a clinician understands what I’m wanting to achieve in life … we can build a treatment regime around helping me achieve those goals. That is known to improve adherence.
“The goal, really, is to have hemophilia as a secondary consideration. Instead of saying: ‘You have hemophilia, so these are the options available to you,’ you can say, ‘what is it that you would like to achieve, and then we’ll figure out how your treatment for hemophilia can be adjusted to help you achieve those goals.’ It may sound like a nuance, but it really is reversing the conversation. The goal setting first versus your disease comes first.”
The HemACTIVE study was supported by Bayer. Mr. Skinner disclosed relationships with Bayer and other pharmaceutical companies.
SOURCE: Skinner M et al. EAHAD 2020, Abstract P304.
Fear of negative events can drive changes in activity levels among patients with hemophilia A, results of the HemACTIVE study suggest.
Patients were more likely to adjust their level of physical activity due to fear of bleeding and joint damage rather than previously experienced bleeding or joint damage.
However, past experience was more likely than fear to make patients stop physical activities altogether.
Mark Skinner, of the Institute for Policy Advancement in Washington, D.C., and colleagues presented these findings in a poster from the annual congress of the European Association for Haemophilia and Allied Disorders.
Mr. Skinner, who is a hemophilia patient himself, said the goal of the HemACTIVE study is to better understand how hemophilia affects patients’ lives.
“We wanted to understand the limitations, challenges, and compromises of individuals living with hemophilia,” Mr. Skinner said. “What has motivated them or prevented them from living more full, active lives doing the kind of work, leisure, and social activities that those without hemophilia do? Is it treatment choice, is it satisfaction with treatment, is it fear?
“We wanted to do a comprehensive study that really looked at the intersection of treatment adherence and satisfaction, the emotional components that relate to those decisions, and the challenges and compromises so that we could better identify what we need to consider as patients think about either changing their therapy or changing their treatment regimen on existing therapy.”
Previous results from the HemACTIVE study showed that, although activity levels differed among hemophilia patients, all patients surveyed wanted greater activity levels, better protection from bleeding, better pain relief, and less-frequent infusions (EAHAD 2019, Abstract P084). In addition, patients who used factor VIII products with an extended half-life were more active and more likely to adhere to their prescribed treatment (ISTH 2019, Abstract PB0210).
The results reported at EAHAD 2020 focus on patients’ reasons for modifying physical activity. Patients and caregivers completed a screening phone interview, followed by a 25-minute, web-based questionnaire on patient activity.
There were 275 respondents – 194 patients with hemophilia A and 81 caregivers – from Canada, France, Germany, Italy, and the United States. Patients had severe (61%) or moderate (39%) hemophilia A, and most (67%) were receiving prophylaxis.
Most patients (70%) were “active” or “extremely/very active,” 77% of patients adjusted their activities because of their hemophilia, and nearly half of patients stopped activities because of their disease.
Fear drives adjustments in activity
Patients were sometimes more likely to adjust their activities based on fear of experiencing an event, as opposed to previously experiencing that event.
Specifically, 44% of patients adjusted their activities due to fear of joint damage, compared with 36% of patients who made adjustments because of past significant joint damage.
Similarly, 41% of patients adjusted activities due to fear of breakthrough bleeds, compared with 36% of patients who made adjustments because of past experience with bleeds and 25% who made adjustments because of significant past bleeds.
On the other hand, a similar percentage of patients adjusted activities because of past experience with pain (43%) and fear of pain (41%). And a similar percentage of patients adjusted activities because of existing joint damage restrictions (35%) and fear of joint deterioration (32%).
Past experience prompts discontinuation of activity
Overall, 47% of patients said anxiety was the most common emotional reason for stopping physical activities. However, patients were consistently more likely to stop activities because of past experience rather than fear or anxiety.
Specifically, 50% of patients stopped activities because of significant past joint damage, 46% stopped because of developing joint problems, and 38% stopped due to fear of joint damage.
More patients stopped activities because of significant past bleeds (41%) rather than fear of breakthrough bleeds (26%). More patients stopped activities because they developed chronic pain (38%) rather than fear of pain (less than 15%). And more patients stopped activities because of existing joint damage restrictions (62%) rather than fear of joint damage (34%).
Applying results to practice: Changing the conversation
Ideally, these findings would be used to promote individualized treatment of hemophilia driven by patients’ goals, Mr. Skinner said. By better understanding patients’ feelings and motivations, clinicians may devise more personalized treatment regimens that align with patients’ goals and improve their quality of life.
Rather than adjusting treatment based only on “hard metrics” such as bleeding events, “we need to take a more holistic approach to looking at outcomes that are more important to patients,” Mr. Skinner said. This type of approach is particularly important to Mr. Skinner as someone who has severe hemophilia A.
“Because hemophilia is a life-long disease, and you’re born with it, you make conscious or unconscious adaptations throughout your life,” he explained. “Your expectations or aspirations adjust to what you’ve been told you can or cannot do because of your hemophilia. The choices I made for my career, where I live, the type of vacations I go on, the type of sports I participate in have all been limited over the course of time, which has meant that I’ve made compromises. There are a lot of individuals with hemophilia who are making decisions that are not what their life goals are.
“What this research helps me understand is that we can change the conversation and build it around an individual patient and understand what their aspirations are. If a clinician understands what I’m wanting to achieve in life … we can build a treatment regime around helping me achieve those goals. That is known to improve adherence.
“The goal, really, is to have hemophilia as a secondary consideration. Instead of saying: ‘You have hemophilia, so these are the options available to you,’ you can say, ‘what is it that you would like to achieve, and then we’ll figure out how your treatment for hemophilia can be adjusted to help you achieve those goals.’ It may sound like a nuance, but it really is reversing the conversation. The goal setting first versus your disease comes first.”
The HemACTIVE study was supported by Bayer. Mr. Skinner disclosed relationships with Bayer and other pharmaceutical companies.
SOURCE: Skinner M et al. EAHAD 2020, Abstract P304.
REPORTING FROM EAHAD 2020