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Gene therapy moves from promise to reality
After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.
Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.
That’s on top of a small number of regulatory approvals in the United States and Europe, she said. “Along with that, there’s a lot of interest and now involvement from biotechnology companies and even large pharmaceutical companies. I think all those factors really have to come together to create this kind of acceleration, and I’ve never seen anything like this previously.”
Dr. Dunbar – a former editor in chief of the journal Blood – and her colleagues recently published a review of current developments and emerging gene therapy technologies in the journal Science (2018 Jan 12. doi: 10.1126/science.aan4672).
“We really felt it was the right time to write the article,” she said.
Milestones
A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.
“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”
But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.
“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.
Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).
While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).
“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”
Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
Future trends, challenges
Looking forward, she said.
Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).
But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.
“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.
Dr. Dunbar reported having no relevant financial disclosures.
After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.
Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.
That’s on top of a small number of regulatory approvals in the United States and Europe, she said. “Along with that, there’s a lot of interest and now involvement from biotechnology companies and even large pharmaceutical companies. I think all those factors really have to come together to create this kind of acceleration, and I’ve never seen anything like this previously.”
Dr. Dunbar – a former editor in chief of the journal Blood – and her colleagues recently published a review of current developments and emerging gene therapy technologies in the journal Science (2018 Jan 12. doi: 10.1126/science.aan4672).
“We really felt it was the right time to write the article,” she said.
Milestones
A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.
“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”
But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.
“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.
Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).
While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).
“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”
Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
Future trends, challenges
Looking forward, she said.
Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).
But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.
“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.
Dr. Dunbar reported having no relevant financial disclosures.
After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.
Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.
That’s on top of a small number of regulatory approvals in the United States and Europe, she said. “Along with that, there’s a lot of interest and now involvement from biotechnology companies and even large pharmaceutical companies. I think all those factors really have to come together to create this kind of acceleration, and I’ve never seen anything like this previously.”
Dr. Dunbar – a former editor in chief of the journal Blood – and her colleagues recently published a review of current developments and emerging gene therapy technologies in the journal Science (2018 Jan 12. doi: 10.1126/science.aan4672).
“We really felt it was the right time to write the article,” she said.
Milestones
A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.
“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”
But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.
“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.
Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).
While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).
“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”
Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
Future trends, challenges
Looking forward, she said.
Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).
But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.
“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.
Dr. Dunbar reported having no relevant financial disclosures.
Sotatercept promising for treatment of anemia in MDS
A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.
Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.
Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.
“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.
There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.
In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.
All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.
Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.
Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).
The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
Sotatercept appears to have promise in treating anemia in patients with lower-risk myelodysplastic syndromes, and has also demonstrated an acceptable safety profile, according to Valeria Santini, MD.
“Ameliorating anemia in myelodysplastic syndromes by reversing ineffective erythropoiesis secondary to aberrant TGF [transforming growth factor]-beta stimulation is indeed an interesting new therapeutic avenue for these patients,” she wrote.
Dr. Santini also pointed out that the “most intriguing aspect of sotatercept” is its unique mechanism of action. The current study demonstrated the agent’s erythroid-stimulating and antiosteoporotic activity, which should encourage continuing research into the mutifaceted and extremely complex TGF-beta pathway.
While important results were demonstrated in this study, several questions remain, Dr. Santini noted. For example, what are the clinical characteristics of the patients who were sensitive to and responded to treatment with sotatercept? Are these patients different from those who responded to a different agent, luspatercept?
Dr. Santini is with department of hematology at the University of Florence (Italy). She reported giving lectures in supported symposia for Celgene, Janssen, and Novartis and serving on the advisory boards for Abbvie, Otsuka, and Janssen. Her remarks were adapted from an accompanying editorial (Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026[18]30003-6).
Sotatercept appears to have promise in treating anemia in patients with lower-risk myelodysplastic syndromes, and has also demonstrated an acceptable safety profile, according to Valeria Santini, MD.
“Ameliorating anemia in myelodysplastic syndromes by reversing ineffective erythropoiesis secondary to aberrant TGF [transforming growth factor]-beta stimulation is indeed an interesting new therapeutic avenue for these patients,” she wrote.
Dr. Santini also pointed out that the “most intriguing aspect of sotatercept” is its unique mechanism of action. The current study demonstrated the agent’s erythroid-stimulating and antiosteoporotic activity, which should encourage continuing research into the mutifaceted and extremely complex TGF-beta pathway.
While important results were demonstrated in this study, several questions remain, Dr. Santini noted. For example, what are the clinical characteristics of the patients who were sensitive to and responded to treatment with sotatercept? Are these patients different from those who responded to a different agent, luspatercept?
Dr. Santini is with department of hematology at the University of Florence (Italy). She reported giving lectures in supported symposia for Celgene, Janssen, and Novartis and serving on the advisory boards for Abbvie, Otsuka, and Janssen. Her remarks were adapted from an accompanying editorial (Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026[18]30003-6).
Sotatercept appears to have promise in treating anemia in patients with lower-risk myelodysplastic syndromes, and has also demonstrated an acceptable safety profile, according to Valeria Santini, MD.
“Ameliorating anemia in myelodysplastic syndromes by reversing ineffective erythropoiesis secondary to aberrant TGF [transforming growth factor]-beta stimulation is indeed an interesting new therapeutic avenue for these patients,” she wrote.
Dr. Santini also pointed out that the “most intriguing aspect of sotatercept” is its unique mechanism of action. The current study demonstrated the agent’s erythroid-stimulating and antiosteoporotic activity, which should encourage continuing research into the mutifaceted and extremely complex TGF-beta pathway.
While important results were demonstrated in this study, several questions remain, Dr. Santini noted. For example, what are the clinical characteristics of the patients who were sensitive to and responded to treatment with sotatercept? Are these patients different from those who responded to a different agent, luspatercept?
Dr. Santini is with department of hematology at the University of Florence (Italy). She reported giving lectures in supported symposia for Celgene, Janssen, and Novartis and serving on the advisory boards for Abbvie, Otsuka, and Janssen. Her remarks were adapted from an accompanying editorial (Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026[18]30003-6).
A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.
Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.
Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.
“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.
There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.
In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.
All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.
Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.
Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).
The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.
Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.
Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.
“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.
There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.
In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.
All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.
Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.
Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).
The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
FROM LANCET HAEMATOLOGY
Key clinical point:
Major finding: In all, 36 patients (49%) achieved hematologic improvement–erythroid and 20 patients (27%) achieved independence from transfusion for at least 56 days.
Data source: A phase 2 trial that included 74 patients with lower-risk myelodysplastic syndromes who did not respond to erythropoiesis-stimulating agents.
Disclosures: Celgene funded the study. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.
Source: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.
Low inhibitor rate observed in PUPs with hemophilia A
Researchers have observed a low inhibitor rate in previously untreated patients (PUPs) with severe hemophilia A who received treatment with Octanate®.
The study included 51 PUPs who received octanate, a plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate.
Five of these patients (9.8%) developed FVIII inhibitors, all of whom were receiving on-demand treatment.
The hemostatic efficacy of octanate was rated as “excellent” for 99.6% of all infusions, and tolerability was rated “very good” for 99.98% of infusions.
“We are very excited by the low inhibitor rates and the excellent efficacy and tolerability achieved with octanate® in this particularly challenging patient population,” said Larisa Belyanskaya, head of IBU Haematology at Octapharma AG, the company marketing octanate.
Octapharma sponsored this study, the results of which were published in Haemophilia.
The study enrolled 51 Caucasian males with previously untreated, severe hemophilia A. They had a median age at study entry of 7.7 months (range, 0.1 months to 67.3 months).
Patients received octanate, either prophylactically or on-demand, for 100 exposure days (EDs) or 5 years, whichever came first.
There were a mean of 136.33 (±246.3) EDs, and the mean dose of octanate was 38.4 (±28.6) IU/kg/ED. Most patients (78.4%) had at least 100 EDs. The total number of EDs was 6953.
Prophylaxis accounted for 3027 EDs, immune tolerance induction for 1869 EDs, treatment of bleeds for 1817 EDs, surgical procedures for 149 EDs, and in vivo recovery assessments for 106 EDs.
Inhibitors
Five patients developed FVIII inhibitors, 4 of which were high titer and 1 low titer.
In 3 cases, the inhibitors were considered clinically relevant. In the other 2 cases, the inhibitors disappeared without a change in dose or treatment frequency.
All inhibitors developed during on-demand treatment, and all 4 high-titer inhibitors developed within the first 20 EDs.
All patients who developed inhibitors had major F8 gene defects (intron 22 inversions or large deletions of exons 7-12) that are associated with a high risk of inhibitor development.
Efficacy
The hemostatic efficacy of octanate was rated as “excellent” in 99.6% of infusions (n=4700), “good” in 0.3% (n=15), and “moderate” in 0.02% (n=1).
Most bleeds resolved within 1 day of treatment (81.2%) or within 2 days (14.3%).
Efficacy was rated as “excellent” for all but 1 of the 2611 prophylactic infusions. One was rated as “good.”
For treatment of bleeds, efficacy was rated as “excellent” for 99.2% of infusions (n=1809), “good” for 0.8% (n=14), and “moderate” for 0.05% (n=1).
There were 23 evaluable surgical procedures in 19 patients. The efficacy of octanate was rated as “excellent” in all cases (201 infusions).
Safety
There were 260 treatment-emergent adverse events (AEs) in 45 patients (88.2%). Seventy-eight of these AEs were serious.
Twenty-one AEs were considered probably or possibly related to octanate—asymptomatic parvovirus B19 seroconversions (n=16) and FVIII inhibitor development (n=5). These were classified as serious AEs according to the study protocol.
The tolerability of octanate was considered “very good” in 99.98% of infusions (n=8674) and “good” in 0.02% (n=2). 
Researchers have observed a low inhibitor rate in previously untreated patients (PUPs) with severe hemophilia A who received treatment with Octanate®.
The study included 51 PUPs who received octanate, a plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate.
Five of these patients (9.8%) developed FVIII inhibitors, all of whom were receiving on-demand treatment.
The hemostatic efficacy of octanate was rated as “excellent” for 99.6% of all infusions, and tolerability was rated “very good” for 99.98% of infusions.
“We are very excited by the low inhibitor rates and the excellent efficacy and tolerability achieved with octanate® in this particularly challenging patient population,” said Larisa Belyanskaya, head of IBU Haematology at Octapharma AG, the company marketing octanate.
Octapharma sponsored this study, the results of which were published in Haemophilia.
The study enrolled 51 Caucasian males with previously untreated, severe hemophilia A. They had a median age at study entry of 7.7 months (range, 0.1 months to 67.3 months).
Patients received octanate, either prophylactically or on-demand, for 100 exposure days (EDs) or 5 years, whichever came first.
There were a mean of 136.33 (±246.3) EDs, and the mean dose of octanate was 38.4 (±28.6) IU/kg/ED. Most patients (78.4%) had at least 100 EDs. The total number of EDs was 6953.
Prophylaxis accounted for 3027 EDs, immune tolerance induction for 1869 EDs, treatment of bleeds for 1817 EDs, surgical procedures for 149 EDs, and in vivo recovery assessments for 106 EDs.
Inhibitors
Five patients developed FVIII inhibitors, 4 of which were high titer and 1 low titer.
In 3 cases, the inhibitors were considered clinically relevant. In the other 2 cases, the inhibitors disappeared without a change in dose or treatment frequency.
All inhibitors developed during on-demand treatment, and all 4 high-titer inhibitors developed within the first 20 EDs.
All patients who developed inhibitors had major F8 gene defects (intron 22 inversions or large deletions of exons 7-12) that are associated with a high risk of inhibitor development.
Efficacy
The hemostatic efficacy of octanate was rated as “excellent” in 99.6% of infusions (n=4700), “good” in 0.3% (n=15), and “moderate” in 0.02% (n=1).
Most bleeds resolved within 1 day of treatment (81.2%) or within 2 days (14.3%).
Efficacy was rated as “excellent” for all but 1 of the 2611 prophylactic infusions. One was rated as “good.”
For treatment of bleeds, efficacy was rated as “excellent” for 99.2% of infusions (n=1809), “good” for 0.8% (n=14), and “moderate” for 0.05% (n=1).
There were 23 evaluable surgical procedures in 19 patients. The efficacy of octanate was rated as “excellent” in all cases (201 infusions).
Safety
There were 260 treatment-emergent adverse events (AEs) in 45 patients (88.2%). Seventy-eight of these AEs were serious.
Twenty-one AEs were considered probably or possibly related to octanate—asymptomatic parvovirus B19 seroconversions (n=16) and FVIII inhibitor development (n=5). These were classified as serious AEs according to the study protocol.
The tolerability of octanate was considered “very good” in 99.98% of infusions (n=8674) and “good” in 0.02% (n=2).
Researchers have observed a low inhibitor rate in previously untreated patients (PUPs) with severe hemophilia A who received treatment with Octanate®.
The study included 51 PUPs who received octanate, a plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate.
Five of these patients (9.8%) developed FVIII inhibitors, all of whom were receiving on-demand treatment.
The hemostatic efficacy of octanate was rated as “excellent” for 99.6% of all infusions, and tolerability was rated “very good” for 99.98% of infusions.
“We are very excited by the low inhibitor rates and the excellent efficacy and tolerability achieved with octanate® in this particularly challenging patient population,” said Larisa Belyanskaya, head of IBU Haematology at Octapharma AG, the company marketing octanate.
Octapharma sponsored this study, the results of which were published in Haemophilia.
The study enrolled 51 Caucasian males with previously untreated, severe hemophilia A. They had a median age at study entry of 7.7 months (range, 0.1 months to 67.3 months).
Patients received octanate, either prophylactically or on-demand, for 100 exposure days (EDs) or 5 years, whichever came first.
There were a mean of 136.33 (±246.3) EDs, and the mean dose of octanate was 38.4 (±28.6) IU/kg/ED. Most patients (78.4%) had at least 100 EDs. The total number of EDs was 6953.
Prophylaxis accounted for 3027 EDs, immune tolerance induction for 1869 EDs, treatment of bleeds for 1817 EDs, surgical procedures for 149 EDs, and in vivo recovery assessments for 106 EDs.
Inhibitors
Five patients developed FVIII inhibitors, 4 of which were high titer and 1 low titer.
In 3 cases, the inhibitors were considered clinically relevant. In the other 2 cases, the inhibitors disappeared without a change in dose or treatment frequency.
All inhibitors developed during on-demand treatment, and all 4 high-titer inhibitors developed within the first 20 EDs.
All patients who developed inhibitors had major F8 gene defects (intron 22 inversions or large deletions of exons 7-12) that are associated with a high risk of inhibitor development.
Efficacy
The hemostatic efficacy of octanate was rated as “excellent” in 99.6% of infusions (n=4700), “good” in 0.3% (n=15), and “moderate” in 0.02% (n=1).
Most bleeds resolved within 1 day of treatment (81.2%) or within 2 days (14.3%).
Efficacy was rated as “excellent” for all but 1 of the 2611 prophylactic infusions. One was rated as “good.”
For treatment of bleeds, efficacy was rated as “excellent” for 99.2% of infusions (n=1809), “good” for 0.8% (n=14), and “moderate” for 0.05% (n=1).
There were 23 evaluable surgical procedures in 19 patients. The efficacy of octanate was rated as “excellent” in all cases (201 infusions).
Safety
There were 260 treatment-emergent adverse events (AEs) in 45 patients (88.2%). Seventy-eight of these AEs were serious.
Twenty-one AEs were considered probably or possibly related to octanate—asymptomatic parvovirus B19 seroconversions (n=16) and FVIII inhibitor development (n=5). These were classified as serious AEs according to the study protocol.
The tolerability of octanate was considered “very good” in 99.98% of infusions (n=8674) and “good” in 0.02% (n=2).
EC approves product to treat hemophilia A
The European Commission (EC) has granted marketing authorization for rurioctocog alfa pegol (Adynovi).
Rurioctocog alfa pegol (formerly BAX 855) is a pegylated, full-length, recombinant factor VIII product built on a previously licensed recombinant factor VIII product (Advate).
Rurioctocog alfa pegol is now EC-approved for on-demand and prophylactic use in patients age 12 and older with hemophilia A.
With the EC’s approval, Shire is authorized to market rurioctocog alfa pegol in all member states of the European Union as well as in Iceland, Liechtenstein, and Norway.
The marketing authorization for rurioctocog alfa pegol is based on outcomes from three phase 3 trials—a study of adolescents and adults, a trial of patients undergoing surgical procedures, and a study of pediatric patients.
Trial of adolescents/adults
This study included 137 patients, ages 12 to 58, with previously treated hemophilia A. They were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with rurioctocog alfa pegol. One hundred and twenty-six patients completed the study.
Patients who received prophylaxis had a 90% reduction in annualized bleeding rate (ABR) compared to those who received on-demand treatment. The median ABR was 1.9 in the prophylactic arm and 41.5 in the on-demand arm.
There were 7 adverse events (occurring in 6 patients) that were considered possibly related to rurioctocog alfa pegol. These included diarrhea, nausea, headache, and flushing.
These results were published in Blood in July 2015.
Perioperative study
This study included 15 patients with severe hemophilia A who were undergoing surgical procedures (11 of them major and 4 minor).
The patients received rurioctocog alfa pegol at varying doses and schedules, depending on each patient’s pharmacokinetic profile for major procedures or rurioctocog alfa pegol incremental recovery for minor procedures.
Intra-operative and peri-operative hemostatic efficacy of rurioctocog alfa pegol was deemed “excellent” for all 15 patients. The “excellent” rating meant that blood loss was less than or equal to that expected for the type of procedure performed in a non-hemophilic population.
Post-operatively (day 1 after the procedure), hemostatic efficacy was rated “good” for 1 procedure and “excellent” for the rest. The “good” rating meant that post-operative blood loss was up to 50% more than expected for the type of procedure performed in a non-hemophilic population.
There were no treatment-related adverse events or signs of immunogenicity in this trial.
Results were published in Haemophilia in June 2016.
Pediatric trial
This study included 66 patients, ages 1 to 11, who had previously treated hemophilia A. They received twice-weekly prophylaxis with rurioctocog alfa pegol (50 ± 10 IU/kg) for at least 6 months or 50 exposure days, whichever occurred last.
The median ABR was 2.0, and 38% of patients did not have any bleeding episodes.
None of the patients developed inhibitory antibodies, and there were no treatment-related adverse events.
Results from this trial were presented at the World Federation of Hemophilia 2016 World Congress in July 2016 and published in Haemophilia in November 2016.
The European Commission (EC) has granted marketing authorization for rurioctocog alfa pegol (Adynovi).
Rurioctocog alfa pegol (formerly BAX 855) is a pegylated, full-length, recombinant factor VIII product built on a previously licensed recombinant factor VIII product (Advate).
Rurioctocog alfa pegol is now EC-approved for on-demand and prophylactic use in patients age 12 and older with hemophilia A.
With the EC’s approval, Shire is authorized to market rurioctocog alfa pegol in all member states of the European Union as well as in Iceland, Liechtenstein, and Norway.
The marketing authorization for rurioctocog alfa pegol is based on outcomes from three phase 3 trials—a study of adolescents and adults, a trial of patients undergoing surgical procedures, and a study of pediatric patients.
Trial of adolescents/adults
This study included 137 patients, ages 12 to 58, with previously treated hemophilia A. They were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with rurioctocog alfa pegol. One hundred and twenty-six patients completed the study.
Patients who received prophylaxis had a 90% reduction in annualized bleeding rate (ABR) compared to those who received on-demand treatment. The median ABR was 1.9 in the prophylactic arm and 41.5 in the on-demand arm.
There were 7 adverse events (occurring in 6 patients) that were considered possibly related to rurioctocog alfa pegol. These included diarrhea, nausea, headache, and flushing.
These results were published in Blood in July 2015.
Perioperative study
This study included 15 patients with severe hemophilia A who were undergoing surgical procedures (11 of them major and 4 minor).
The patients received rurioctocog alfa pegol at varying doses and schedules, depending on each patient’s pharmacokinetic profile for major procedures or rurioctocog alfa pegol incremental recovery for minor procedures.
Intra-operative and peri-operative hemostatic efficacy of rurioctocog alfa pegol was deemed “excellent” for all 15 patients. The “excellent” rating meant that blood loss was less than or equal to that expected for the type of procedure performed in a non-hemophilic population.
Post-operatively (day 1 after the procedure), hemostatic efficacy was rated “good” for 1 procedure and “excellent” for the rest. The “good” rating meant that post-operative blood loss was up to 50% more than expected for the type of procedure performed in a non-hemophilic population.
There were no treatment-related adverse events or signs of immunogenicity in this trial.
Results were published in Haemophilia in June 2016.
Pediatric trial
This study included 66 patients, ages 1 to 11, who had previously treated hemophilia A. They received twice-weekly prophylaxis with rurioctocog alfa pegol (50 ± 10 IU/kg) for at least 6 months or 50 exposure days, whichever occurred last.
The median ABR was 2.0, and 38% of patients did not have any bleeding episodes.
None of the patients developed inhibitory antibodies, and there were no treatment-related adverse events.
Results from this trial were presented at the World Federation of Hemophilia 2016 World Congress in July 2016 and published in Haemophilia in November 2016.
The European Commission (EC) has granted marketing authorization for rurioctocog alfa pegol (Adynovi).
Rurioctocog alfa pegol (formerly BAX 855) is a pegylated, full-length, recombinant factor VIII product built on a previously licensed recombinant factor VIII product (Advate).
Rurioctocog alfa pegol is now EC-approved for on-demand and prophylactic use in patients age 12 and older with hemophilia A.
With the EC’s approval, Shire is authorized to market rurioctocog alfa pegol in all member states of the European Union as well as in Iceland, Liechtenstein, and Norway.
The marketing authorization for rurioctocog alfa pegol is based on outcomes from three phase 3 trials—a study of adolescents and adults, a trial of patients undergoing surgical procedures, and a study of pediatric patients.
Trial of adolescents/adults
This study included 137 patients, ages 12 to 58, with previously treated hemophilia A. They were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with rurioctocog alfa pegol. One hundred and twenty-six patients completed the study.
Patients who received prophylaxis had a 90% reduction in annualized bleeding rate (ABR) compared to those who received on-demand treatment. The median ABR was 1.9 in the prophylactic arm and 41.5 in the on-demand arm.
There were 7 adverse events (occurring in 6 patients) that were considered possibly related to rurioctocog alfa pegol. These included diarrhea, nausea, headache, and flushing.
These results were published in Blood in July 2015.
Perioperative study
This study included 15 patients with severe hemophilia A who were undergoing surgical procedures (11 of them major and 4 minor).
The patients received rurioctocog alfa pegol at varying doses and schedules, depending on each patient’s pharmacokinetic profile for major procedures or rurioctocog alfa pegol incremental recovery for minor procedures.
Intra-operative and peri-operative hemostatic efficacy of rurioctocog alfa pegol was deemed “excellent” for all 15 patients. The “excellent” rating meant that blood loss was less than or equal to that expected for the type of procedure performed in a non-hemophilic population.
Post-operatively (day 1 after the procedure), hemostatic efficacy was rated “good” for 1 procedure and “excellent” for the rest. The “good” rating meant that post-operative blood loss was up to 50% more than expected for the type of procedure performed in a non-hemophilic population.
There were no treatment-related adverse events or signs of immunogenicity in this trial.
Results were published in Haemophilia in June 2016.
Pediatric trial
This study included 66 patients, ages 1 to 11, who had previously treated hemophilia A. They received twice-weekly prophylaxis with rurioctocog alfa pegol (50 ± 10 IU/kg) for at least 6 months or 50 exposure days, whichever occurred last.
The median ABR was 2.0, and 38% of patients did not have any bleeding episodes.
None of the patients developed inhibitory antibodies, and there were no treatment-related adverse events.
Results from this trial were presented at the World Federation of Hemophilia 2016 World Congress in July 2016 and published in Haemophilia in November 2016.
Emicizumab still available despite legal issues
The Roche Group has issued a statement reassuring the US hemophilia community that legal issues are not affecting patient access to emicizumab (Hemlibra), at least for the time being.
Emicizumab is a bispecific factor IXa- and factor X-directed antibody approved in the US as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A and factor VIII (FVIII) inhibitors.
The Roche Group—which consists of Genentech in the US, Chugai in Japan, and Roche in the rest of the world—said emicizumab is still available for these patients, despite a legal battle with Baxalta, a wholly owned subsidiary of Shire.
In May 2017, Baxalta sued Genentech and Chugai for allegedly infringing upon US Patent No. 7,033,590.
The patent covers factor IX/factor IXa antibodies and antibody derivatives. It was issued to Baxter in April 2006 and assigned to Baxalta in March 2016. The patent is still active.
According to Baxalta, Genentech and Chugai are infringing on the patent by manufacturing, selling, or importing emicizumab. Therefore, Baxalta is seeking judgment in its favor and monetary damages.
The trial for this case is scheduled for September 2019.
However, in December 2017, Baxalta filed a motion for a preliminary injunction that would prevent the sale of emicizumab in the US. If granted, the injunction would prevent the following patients from receiving emicizumab:
- Hemophilia A patients with inhibitors (an inhibitor titer of greater than 5 Bethesda units) who cannot be treated effectively with FVIII replacement therapy, unless (i) they have already started emicizumab before the injunction is granted or (ii) they have previous experience with on-demand or prophylactic bypassing agents and their needs are not being met, as defined by Shire using criteria that include experiencing certain life- or limb-threatening bleeds or venous access issues.
- Hemophilia A patients who have an inhibitor titer less than or equal to 5 Bethesda units or who can be effectively treated with FVIII replacement therapy, regardless of whether they have already started emicizumab.
- Hemophilia A patients without inhibitors, regardless of whether they have already started emicizumab.
The Roche Group said it believes Baxalta’s claim is not valid, emicizumab does not infringe upon the patent, and the group will oppose the injunction.
The court’s decision on the injunction is expected this summer. In the meantime, emicizumab is still available for the aforementioned patients.
The Roche Group has issued a statement reassuring the US hemophilia community that legal issues are not affecting patient access to emicizumab (Hemlibra), at least for the time being.
Emicizumab is a bispecific factor IXa- and factor X-directed antibody approved in the US as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A and factor VIII (FVIII) inhibitors.
The Roche Group—which consists of Genentech in the US, Chugai in Japan, and Roche in the rest of the world—said emicizumab is still available for these patients, despite a legal battle with Baxalta, a wholly owned subsidiary of Shire.
In May 2017, Baxalta sued Genentech and Chugai for allegedly infringing upon US Patent No. 7,033,590.
The patent covers factor IX/factor IXa antibodies and antibody derivatives. It was issued to Baxter in April 2006 and assigned to Baxalta in March 2016. The patent is still active.
According to Baxalta, Genentech and Chugai are infringing on the patent by manufacturing, selling, or importing emicizumab. Therefore, Baxalta is seeking judgment in its favor and monetary damages.
The trial for this case is scheduled for September 2019.
However, in December 2017, Baxalta filed a motion for a preliminary injunction that would prevent the sale of emicizumab in the US. If granted, the injunction would prevent the following patients from receiving emicizumab:
- Hemophilia A patients with inhibitors (an inhibitor titer of greater than 5 Bethesda units) who cannot be treated effectively with FVIII replacement therapy, unless (i) they have already started emicizumab before the injunction is granted or (ii) they have previous experience with on-demand or prophylactic bypassing agents and their needs are not being met, as defined by Shire using criteria that include experiencing certain life- or limb-threatening bleeds or venous access issues.
- Hemophilia A patients who have an inhibitor titer less than or equal to 5 Bethesda units or who can be effectively treated with FVIII replacement therapy, regardless of whether they have already started emicizumab.
- Hemophilia A patients without inhibitors, regardless of whether they have already started emicizumab.
The Roche Group said it believes Baxalta’s claim is not valid, emicizumab does not infringe upon the patent, and the group will oppose the injunction.
The court’s decision on the injunction is expected this summer. In the meantime, emicizumab is still available for the aforementioned patients.
The Roche Group has issued a statement reassuring the US hemophilia community that legal issues are not affecting patient access to emicizumab (Hemlibra), at least for the time being.
Emicizumab is a bispecific factor IXa- and factor X-directed antibody approved in the US as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A and factor VIII (FVIII) inhibitors.
The Roche Group—which consists of Genentech in the US, Chugai in Japan, and Roche in the rest of the world—said emicizumab is still available for these patients, despite a legal battle with Baxalta, a wholly owned subsidiary of Shire.
In May 2017, Baxalta sued Genentech and Chugai for allegedly infringing upon US Patent No. 7,033,590.
The patent covers factor IX/factor IXa antibodies and antibody derivatives. It was issued to Baxter in April 2006 and assigned to Baxalta in March 2016. The patent is still active.
According to Baxalta, Genentech and Chugai are infringing on the patent by manufacturing, selling, or importing emicizumab. Therefore, Baxalta is seeking judgment in its favor and monetary damages.
The trial for this case is scheduled for September 2019.
However, in December 2017, Baxalta filed a motion for a preliminary injunction that would prevent the sale of emicizumab in the US. If granted, the injunction would prevent the following patients from receiving emicizumab:
- Hemophilia A patients with inhibitors (an inhibitor titer of greater than 5 Bethesda units) who cannot be treated effectively with FVIII replacement therapy, unless (i) they have already started emicizumab before the injunction is granted or (ii) they have previous experience with on-demand or prophylactic bypassing agents and their needs are not being met, as defined by Shire using criteria that include experiencing certain life- or limb-threatening bleeds or venous access issues.
- Hemophilia A patients who have an inhibitor titer less than or equal to 5 Bethesda units or who can be effectively treated with FVIII replacement therapy, regardless of whether they have already started emicizumab.
- Hemophilia A patients without inhibitors, regardless of whether they have already started emicizumab.
The Roche Group said it believes Baxalta’s claim is not valid, emicizumab does not infringe upon the patent, and the group will oppose the injunction.
The court’s decision on the injunction is expected this summer. In the meantime, emicizumab is still available for the aforementioned patients.
Update of gene therapy in hemophilia A
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
Caplacizumab improves outcomes in aTTP
ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.
Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).
Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.
Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.
Patients and treatment
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.
If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.
“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.
“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”
According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).
The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).
The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).
For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).
Safety
“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.
The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).
Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.
Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).
Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.
Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.
Patients and treatment
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.
If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.
“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.
“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”
According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).
The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).
The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).
For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).
Safety
“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.
The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).
Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.
Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).
Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.
Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.
Patients and treatment
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.
If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.
“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.
“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”
According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).
The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).
The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).
For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).
Safety
“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.
The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).
Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
FDA grants breakthrough therapy designation for severe aplastic anemia drug
The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).
Eltrombopag already is approved as a second-line therapy in patients with refractory SAA and is approved for adults and children with refractory chronic immune thrombocytopenia (ITP).
“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement.
The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).
Eltrombopag already is approved as a second-line therapy in patients with refractory SAA and is approved for adults and children with refractory chronic immune thrombocytopenia (ITP).
“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement.
The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).
Eltrombopag already is approved as a second-line therapy in patients with refractory SAA and is approved for adults and children with refractory chronic immune thrombocytopenia (ITP).
“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement.
Study identifies predictors of acquired von Willebrand disease
ATLANTA – Waldenström macroglobulinemia can present as acquired von Willebrand disease (VWD), and when it does, the finding strongly correlates with high serum IgM levels and the presence of CXCR4 mutations, according to the results of a large, single-center retrospective study.
Further, successfully treating Waldenström macroglobulinemia often resolves acquired VWD, and the depth of treatment response predicts the degree of improvement, Jorge J. Castillo, MD, and his associates wrote in a poster presented at the annual meeting of the American Society of Hematology.
Acquired VWD is an uncommon, poorly understood presentation of Waldenström macroglobulinemia. Because affected patients require treatment, better characterizing this subgroup is important, the investigators noted.
At the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute in Boston, the researchers retrospectively studied 320 individuals with newly diagnosed Waldenström macroglobulinemia and used logistic regression analysis to seek predictors of acquired VWD, which they evaluated by measuring levels of VW factor antigen, VW factor activity, and factor VIII. Levels under 30% were considered VWD and levels between 30% and 50% were considered low-level VWD.
In all, 49 individuals had acquired VWD while 271 patients did not. These two groups were similar in terms of age, sex, hemoglobin level, platelet count, and bone marrow involvement. However, 45% of patients with acquired VWD had serum IgM levels above 6,000 mg/dL versus 6% of patients without acquired VWD (P less than .001), and 47% of patients with acquired VWD had serum IgM levels between 3,000 and 5,999 versus 31% of patients without acquired VWD (P less than .001). Also, 77% of patients with acquired VWD tested positive for CXCR4 mutation versus 37% of patients without acquired VWD (P less than .001).
A significantly higher proportion of patients without acquired VWD had white blood cell concentrations above 6,000/mcL (29% vs. 50%; P = .006). This finding lost statistical significance in the logistic regression model, but all the other variables remained significantly associated. Serum IgM levels above 6,000 mg/dL conferred a 55-fold increase in the odds of having acquired VWD (95% confidence interval, 17-177; P less than .001), and serum IgM levels between 3,000 and 5,999 mg/dL led to an 11-fold increase in these odds (95% CI, 4-34). The presence of CXCR4 mutations was associated with a sixfold increased odds of acquired VWD (95% CI, 2-15). The P value for each of these three associations was at or below .001.
Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment. After treatment, 78% of patients with acquired VWD had levels of all three measures above 50% (versus 0% before treatment; P less than .001). Patients with acquired VWD with the best responses to treatment had about a 90% decrease in IgM levels, while those with a partial response had about a two-thirds decrease and patients with stable disease had about a 20% decrease. A linear regression model confirmed that depth of treatment response, based on change in IgM level, correlated with degree of improvement in VWD – that is, the extent of improvement in levels of VW factor antigen, VW factor activity, and factor VIII.
No external funding sources were reported. Dr. Castillo disclosed consulting ties and research funding from Pharmacyclics and Janssen, and research funding from Millenium and Abbvie.
SOURCE: Castillo J, et al. ASH 2017 Abstract 1088.
ATLANTA – Waldenström macroglobulinemia can present as acquired von Willebrand disease (VWD), and when it does, the finding strongly correlates with high serum IgM levels and the presence of CXCR4 mutations, according to the results of a large, single-center retrospective study.
Further, successfully treating Waldenström macroglobulinemia often resolves acquired VWD, and the depth of treatment response predicts the degree of improvement, Jorge J. Castillo, MD, and his associates wrote in a poster presented at the annual meeting of the American Society of Hematology.
Acquired VWD is an uncommon, poorly understood presentation of Waldenström macroglobulinemia. Because affected patients require treatment, better characterizing this subgroup is important, the investigators noted.
At the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute in Boston, the researchers retrospectively studied 320 individuals with newly diagnosed Waldenström macroglobulinemia and used logistic regression analysis to seek predictors of acquired VWD, which they evaluated by measuring levels of VW factor antigen, VW factor activity, and factor VIII. Levels under 30% were considered VWD and levels between 30% and 50% were considered low-level VWD.
In all, 49 individuals had acquired VWD while 271 patients did not. These two groups were similar in terms of age, sex, hemoglobin level, platelet count, and bone marrow involvement. However, 45% of patients with acquired VWD had serum IgM levels above 6,000 mg/dL versus 6% of patients without acquired VWD (P less than .001), and 47% of patients with acquired VWD had serum IgM levels between 3,000 and 5,999 versus 31% of patients without acquired VWD (P less than .001). Also, 77% of patients with acquired VWD tested positive for CXCR4 mutation versus 37% of patients without acquired VWD (P less than .001).
A significantly higher proportion of patients without acquired VWD had white blood cell concentrations above 6,000/mcL (29% vs. 50%; P = .006). This finding lost statistical significance in the logistic regression model, but all the other variables remained significantly associated. Serum IgM levels above 6,000 mg/dL conferred a 55-fold increase in the odds of having acquired VWD (95% confidence interval, 17-177; P less than .001), and serum IgM levels between 3,000 and 5,999 mg/dL led to an 11-fold increase in these odds (95% CI, 4-34). The presence of CXCR4 mutations was associated with a sixfold increased odds of acquired VWD (95% CI, 2-15). The P value for each of these three associations was at or below .001.
Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment. After treatment, 78% of patients with acquired VWD had levels of all three measures above 50% (versus 0% before treatment; P less than .001). Patients with acquired VWD with the best responses to treatment had about a 90% decrease in IgM levels, while those with a partial response had about a two-thirds decrease and patients with stable disease had about a 20% decrease. A linear regression model confirmed that depth of treatment response, based on change in IgM level, correlated with degree of improvement in VWD – that is, the extent of improvement in levels of VW factor antigen, VW factor activity, and factor VIII.
No external funding sources were reported. Dr. Castillo disclosed consulting ties and research funding from Pharmacyclics and Janssen, and research funding from Millenium and Abbvie.
SOURCE: Castillo J, et al. ASH 2017 Abstract 1088.
ATLANTA – Waldenström macroglobulinemia can present as acquired von Willebrand disease (VWD), and when it does, the finding strongly correlates with high serum IgM levels and the presence of CXCR4 mutations, according to the results of a large, single-center retrospective study.
Further, successfully treating Waldenström macroglobulinemia often resolves acquired VWD, and the depth of treatment response predicts the degree of improvement, Jorge J. Castillo, MD, and his associates wrote in a poster presented at the annual meeting of the American Society of Hematology.
Acquired VWD is an uncommon, poorly understood presentation of Waldenström macroglobulinemia. Because affected patients require treatment, better characterizing this subgroup is important, the investigators noted.
At the Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute in Boston, the researchers retrospectively studied 320 individuals with newly diagnosed Waldenström macroglobulinemia and used logistic regression analysis to seek predictors of acquired VWD, which they evaluated by measuring levels of VW factor antigen, VW factor activity, and factor VIII. Levels under 30% were considered VWD and levels between 30% and 50% were considered low-level VWD.
In all, 49 individuals had acquired VWD while 271 patients did not. These two groups were similar in terms of age, sex, hemoglobin level, platelet count, and bone marrow involvement. However, 45% of patients with acquired VWD had serum IgM levels above 6,000 mg/dL versus 6% of patients without acquired VWD (P less than .001), and 47% of patients with acquired VWD had serum IgM levels between 3,000 and 5,999 versus 31% of patients without acquired VWD (P less than .001). Also, 77% of patients with acquired VWD tested positive for CXCR4 mutation versus 37% of patients without acquired VWD (P less than .001).
A significantly higher proportion of patients without acquired VWD had white blood cell concentrations above 6,000/mcL (29% vs. 50%; P = .006). This finding lost statistical significance in the logistic regression model, but all the other variables remained significantly associated. Serum IgM levels above 6,000 mg/dL conferred a 55-fold increase in the odds of having acquired VWD (95% confidence interval, 17-177; P less than .001), and serum IgM levels between 3,000 and 5,999 mg/dL led to an 11-fold increase in these odds (95% CI, 4-34). The presence of CXCR4 mutations was associated with a sixfold increased odds of acquired VWD (95% CI, 2-15). The P value for each of these three associations was at or below .001.
Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment. After treatment, 78% of patients with acquired VWD had levels of all three measures above 50% (versus 0% before treatment; P less than .001). Patients with acquired VWD with the best responses to treatment had about a 90% decrease in IgM levels, while those with a partial response had about a two-thirds decrease and patients with stable disease had about a 20% decrease. A linear regression model confirmed that depth of treatment response, based on change in IgM level, correlated with degree of improvement in VWD – that is, the extent of improvement in levels of VW factor antigen, VW factor activity, and factor VIII.
No external funding sources were reported. Dr. Castillo disclosed consulting ties and research funding from Pharmacyclics and Janssen, and research funding from Millenium and Abbvie.
SOURCE: Castillo J, et al. ASH 2017 Abstract 1088.
AT ASH 2017
Key clinical point: Successfully treating Waldenström macroglobulinemia often resolves acquired von Willebrand disease.
Major finding: Therapy for Waldenström macroglobulinemia led to statistically significant increases in levels of factor VIII, VW factor antigen, and VW factor activity (P less than .001) and the median of each level improved by at least 35% after treatment.
Data source: A single-center retrospective study of 320 patients with newly diagnosed Waldenström macroglobulinemia.
Disclosures: No external funding sources were reported. Dr. Castillo disclosed consultancy and research funding from Pharmacyclics and Janssen. He also disclosed research funding from Millenium and Abbvie.
Source: Castillo J, et al. ASH 2017 Abstract 1088.
FDA okays dosing software for hemophilia A
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The free, web-based software estimates a patient’s pharmokinetic curve using age, body weight, and local laboratory FVIII one-stage clotting activity measurements and allows physicians to estimate a full pharmokinetic curve with just two measurable blood samples, according to Shire, the software’s manufacturer. That’s much lower than the 9-11 blood samples recommendation from the International Society on Thrombosis and Haemostasis.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The free, web-based software estimates a patient’s pharmokinetic curve using age, body weight, and local laboratory FVIII one-stage clotting activity measurements and allows physicians to estimate a full pharmokinetic curve with just two measurable blood samples, according to Shire, the software’s manufacturer. That’s much lower than the 9-11 blood samples recommendation from the International Society on Thrombosis and Haemostasis.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The free, web-based software estimates a patient’s pharmokinetic curve using age, body weight, and local laboratory FVIII one-stage clotting activity measurements and allows physicians to estimate a full pharmokinetic curve with just two measurable blood samples, according to Shire, the software’s manufacturer. That’s much lower than the 9-11 blood samples recommendation from the International Society on Thrombosis and Haemostasis.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.