Bleeding Disorders

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 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.

[email protected]

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 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.

[email protected]

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 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.

[email protected]

Structure of RNA

The US Food and Drug Administration (FDA) has lifted the hold on clinical trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

The hold encompassed a phase 2 open-label extension study and the ATLAS phase 3 program, which includes 3 separate trials.

Dosing was suspended in these trials after a fatal thrombotic event was reported in a patient enrolled on the phase 2 trial.

The patient had hemophilia A without inhibitors. He developed exercise-induced right hip pain that was treated with 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

The patient then developed a cerebral venous sinus thrombosis that was considered possibly related to treatment. He ultimately died of cerebral edema.

As a result of this death, Alnylam Pharmaceuticals, Inc., (the company developing fitusiran with Sanofi Genzyme) announced the hold on fitusiran trials in September.

Since then, Alnylam has reached an agreement with the FDA on new clinical risk mitigation measures for fitusiran trials. This includes protocol-specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds in fitusiran studies.

With these protocol amendments in place and clinical materials updated, the FDA has lifted the hold on fitusiran trials.

“We are pleased with the FDA’s decision to lift the clinical hold, as fitusiran holds the potential to help improve the lives of people living with hemophilia,” said Akin Akinc, PhD, vice-president and general manager of fitusiran at Alnylam.

“With the additional risk mitigation measures in place, we look forward to the continued late-stage development of fitusiran and expect to resume dosing around year-end.”

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin. It is in development for the treatment of hemophilia A and B, with and without inhibitors.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

Fitusiran is under investigation in a phase 2 open-label extension study of patients with moderate or severe hemophilia A or B who have participated in a previous clinical study of fitusiran.

The therapy is also being tested in the phase 3 ATLAS program, which includes 3 trials.

The ATLAS-INH trial is a 9-month, randomized, active controlled study designed to enroll approximately 50 patients with hemophilia A or B with inhibitors who received prior on-demand therapy.

The ATLAS-A/B trial is a 9-month, randomized, active controlled study designed to enroll approximately 100 patients with hemophilia A or B without inhibitors who received prior on-demand therapy.

The ATLAS-PPX trial is a one-way crossover study designed to enroll approximately 100 patients with hemophilia A or B, with or without inhibitors, receiving prophylaxis therapy as prior standard of care.

In ATLAS-PPX, patients receive standard of care prophylaxis for 6 months and then transition to fitusiran treatment for 7 months. The study’s primary endpoint is the annualized bleeding rate in the fitusiran period and in the factor/bypassing agent prophylaxis period.

Structure of RNA

The US Food and Drug Administration (FDA) has lifted the hold on clinical trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

The hold encompassed a phase 2 open-label extension study and the ATLAS phase 3 program, which includes 3 separate trials.

Dosing was suspended in these trials after a fatal thrombotic event was reported in a patient enrolled on the phase 2 trial.

The patient had hemophilia A without inhibitors. He developed exercise-induced right hip pain that was treated with 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

The patient then developed a cerebral venous sinus thrombosis that was considered possibly related to treatment. He ultimately died of cerebral edema.

As a result of this death, Alnylam Pharmaceuticals, Inc., (the company developing fitusiran with Sanofi Genzyme) announced the hold on fitusiran trials in September.

Since then, Alnylam has reached an agreement with the FDA on new clinical risk mitigation measures for fitusiran trials. This includes protocol-specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds in fitusiran studies.

With these protocol amendments in place and clinical materials updated, the FDA has lifted the hold on fitusiran trials.

“We are pleased with the FDA’s decision to lift the clinical hold, as fitusiran holds the potential to help improve the lives of people living with hemophilia,” said Akin Akinc, PhD, vice-president and general manager of fitusiran at Alnylam.

“With the additional risk mitigation measures in place, we look forward to the continued late-stage development of fitusiran and expect to resume dosing around year-end.”

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin. It is in development for the treatment of hemophilia A and B, with and without inhibitors.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

Fitusiran is under investigation in a phase 2 open-label extension study of patients with moderate or severe hemophilia A or B who have participated in a previous clinical study of fitusiran.

The therapy is also being tested in the phase 3 ATLAS program, which includes 3 trials.

The ATLAS-INH trial is a 9-month, randomized, active controlled study designed to enroll approximately 50 patients with hemophilia A or B with inhibitors who received prior on-demand therapy.

The ATLAS-A/B trial is a 9-month, randomized, active controlled study designed to enroll approximately 100 patients with hemophilia A or B without inhibitors who received prior on-demand therapy.

The ATLAS-PPX trial is a one-way crossover study designed to enroll approximately 100 patients with hemophilia A or B, with or without inhibitors, receiving prophylaxis therapy as prior standard of care.

In ATLAS-PPX, patients receive standard of care prophylaxis for 6 months and then transition to fitusiran treatment for 7 months. The study’s primary endpoint is the annualized bleeding rate in the fitusiran period and in the factor/bypassing agent prophylaxis period.

Structure of RNA

The US Food and Drug Administration (FDA) has lifted the hold on clinical trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

The hold encompassed a phase 2 open-label extension study and the ATLAS phase 3 program, which includes 3 separate trials.

Dosing was suspended in these trials after a fatal thrombotic event was reported in a patient enrolled on the phase 2 trial.

The patient had hemophilia A without inhibitors. He developed exercise-induced right hip pain that was treated with 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

The patient then developed a cerebral venous sinus thrombosis that was considered possibly related to treatment. He ultimately died of cerebral edema.

As a result of this death, Alnylam Pharmaceuticals, Inc., (the company developing fitusiran with Sanofi Genzyme) announced the hold on fitusiran trials in September.

Since then, Alnylam has reached an agreement with the FDA on new clinical risk mitigation measures for fitusiran trials. This includes protocol-specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds in fitusiran studies.

With these protocol amendments in place and clinical materials updated, the FDA has lifted the hold on fitusiran trials.

“We are pleased with the FDA’s decision to lift the clinical hold, as fitusiran holds the potential to help improve the lives of people living with hemophilia,” said Akin Akinc, PhD, vice-president and general manager of fitusiran at Alnylam.

“With the additional risk mitigation measures in place, we look forward to the continued late-stage development of fitusiran and expect to resume dosing around year-end.”

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin. It is in development for the treatment of hemophilia A and B, with and without inhibitors.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

Fitusiran is under investigation in a phase 2 open-label extension study of patients with moderate or severe hemophilia A or B who have participated in a previous clinical study of fitusiran.

The therapy is also being tested in the phase 3 ATLAS program, which includes 3 trials.

The ATLAS-INH trial is a 9-month, randomized, active controlled study designed to enroll approximately 50 patients with hemophilia A or B with inhibitors who received prior on-demand therapy.

The ATLAS-A/B trial is a 9-month, randomized, active controlled study designed to enroll approximately 100 patients with hemophilia A or B without inhibitors who received prior on-demand therapy.

The ATLAS-PPX trial is a one-way crossover study designed to enroll approximately 100 patients with hemophilia A or B, with or without inhibitors, receiving prophylaxis therapy as prior standard of care.

In ATLAS-PPX, patients receive standard of care prophylaxis for 6 months and then transition to fitusiran treatment for 7 months. The study’s primary endpoint is the annualized bleeding rate in the fitusiran period and in the factor/bypassing agent prophylaxis period.

Atlanta – Adding caplacizumab, an anti–Von Willebrand Factor humanized single variable domain immunoglobulin, to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly hastened platelet normalization and improved several key clinical endpoints in a pivotal randomized placebo-controlled phase 3 trial of 145 patients (HERCULES).

At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) versus placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01), Marie Scully, MD, reported in late-breaking oral presentation at the annual meeting of the American Society for Hematology.Caplacizumab also significantly reduced the rate of aTTP recurrence, compared with placebo (13% vs. 38%; P less than .001) and cut days of plasma exchange, plasma volume, and ICU and hospital stays by 31% to 65%, compared with placebo, reported Dr. Scully of University College Hospital, London, UK. HERCULES enrolled patients with an acute episode of aTTP and at least one prior plasma exchange (PE). Patients received caplacizumab (10 mg) or placebo plus daily PE plus corticosteroids. The caplacizumab group received a single IV dose before their first on-study PE followed by daily subcutaneous doses during PE therapy and for 30 days afterward.

Phase 2 data on aTTP earned caplacizumab fast track designation from the Food and Drug Administration in July 2017. In this video, Dr. Scully highlights key findings of the phase 3 HERCULES trial and discusses how physicians could integrate caplacizumab into their current aTTP treatment approach.

HERCULES was sponsored by Ablynx. Dr. Scully disclosed honoraria and research funding from Ablynx, Shire, Novartis, and Alexion.

Atlanta – Adding caplacizumab, an anti–Von Willebrand Factor humanized single variable domain immunoglobulin, to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly hastened platelet normalization and improved several key clinical endpoints in a pivotal randomized placebo-controlled phase 3 trial of 145 patients (HERCULES).

At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) versus placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01), Marie Scully, MD, reported in late-breaking oral presentation at the annual meeting of the American Society for Hematology.Caplacizumab also significantly reduced the rate of aTTP recurrence, compared with placebo (13% vs. 38%; P less than .001) and cut days of plasma exchange, plasma volume, and ICU and hospital stays by 31% to 65%, compared with placebo, reported Dr. Scully of University College Hospital, London, UK. HERCULES enrolled patients with an acute episode of aTTP and at least one prior plasma exchange (PE). Patients received caplacizumab (10 mg) or placebo plus daily PE plus corticosteroids. The caplacizumab group received a single IV dose before their first on-study PE followed by daily subcutaneous doses during PE therapy and for 30 days afterward.

Phase 2 data on aTTP earned caplacizumab fast track designation from the Food and Drug Administration in July 2017. In this video, Dr. Scully highlights key findings of the phase 3 HERCULES trial and discusses how physicians could integrate caplacizumab into their current aTTP treatment approach.

HERCULES was sponsored by Ablynx. Dr. Scully disclosed honoraria and research funding from Ablynx, Shire, Novartis, and Alexion.

Atlanta – Adding caplacizumab, an anti–Von Willebrand Factor humanized single variable domain immunoglobulin, to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly hastened platelet normalization and improved several key clinical endpoints in a pivotal randomized placebo-controlled phase 3 trial of 145 patients (HERCULES).

At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) versus placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01), Marie Scully, MD, reported in late-breaking oral presentation at the annual meeting of the American Society for Hematology.Caplacizumab also significantly reduced the rate of aTTP recurrence, compared with placebo (13% vs. 38%; P less than .001) and cut days of plasma exchange, plasma volume, and ICU and hospital stays by 31% to 65%, compared with placebo, reported Dr. Scully of University College Hospital, London, UK. HERCULES enrolled patients with an acute episode of aTTP and at least one prior plasma exchange (PE). Patients received caplacizumab (10 mg) or placebo plus daily PE plus corticosteroids. The caplacizumab group received a single IV dose before their first on-study PE followed by daily subcutaneous doses during PE therapy and for 30 days afterward.

Phase 2 data on aTTP earned caplacizumab fast track designation from the Food and Drug Administration in July 2017. In this video, Dr. Scully highlights key findings of the phase 3 HERCULES trial and discusses how physicians could integrate caplacizumab into their current aTTP treatment approach.

HERCULES was sponsored by Ablynx. Dr. Scully disclosed honoraria and research funding from Ablynx, Shire, Novartis, and Alexion.

Photo courtesy of ASH

ATLANTA—Updated results from the HAVEN 2 trial have shown that emicizumab prophylaxis can reduce bleeds in children with hemophilia A and factor VIII inhibitors.

Sixty-five percent of all patients enrolled in HAVEN 2 had no bleeds while on emicizumab, and 95% had no treated bleeds.

Among patients who had been on emicizumab for at least 12 weeks, 35% had no bleeds, and 87% had no treated bleeds.

The most common adverse events (AEs) in this trial were viral upper respiratory tract infections and injection site reactions.

Guy Young, MD, of Children’s Hospital Los Angeles in California, presented these results at the 2017 ASH Annual Meeting (abstract 85). The trial was sponsored by Hoffmann-La Roche.

HAVEN 2 enrolled 60 patients, ages 1 to 17, who had hemophilia A and inhibitors. Most patients (95%) had severe hemophilia, 3.3% (n=2) had mild disease, and 1.7% (n=1) had moderate disease.

Nearly a quarter of patients (73.3%) had previously received prophylaxis, and 26.7% had previously received episodic treatment.

The median number of bleeds in the previous 24 weeks was 6.0 (range, 0-155), and 38.3% of patients had target joints.

Patients received emicizumab prophylaxis at 3 mg/kg/week for 4 weeks and 1.5 mg/kg/week thereafter. The median observation time was 9 weeks (range, 1.6 to 41.6 weeks).

Efficacy

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

There were a total of 65 bleeds in 20 patients. Eight were joint bleeds, 2 were muscle bleeds, and the rest were classified as “other.” Of the 55 “other’’ bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) were traumatic, and 3 (4.6%) were due to a procedure/surgery.

A subset of 23 patients received emicizumab for at least 12 weeks. They had a median treatment duration of 38.1 weeks (range, 12.7 to 41.6 weeks).

Of these patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds and 0 treated joint bleeds. There were a total of 41 bleeds in 15 of these patients. Three bleeds (joint, muscle, and hip) were treated.

The median annualized bleeding rate (ABR) for the 23 patients was 1.5 for all bleeds and 0.0 for all types of treated bleeds.

There were 13 patients who had participated in a non-interventional study prior to enrolling in HAVEN 2, so these patients could serve as their own controls. The patients had an overall reduction in ABR of 99% with emicizumab.

Safety

All 60 patients were evaluated for safety. Forty patients had a total of 201 AEs. The most common AEs were viral upper respiratory tract infection (16.7%) and injection site reactions (16.7%)

There were 7 serious AEs in 6 patients—muscle hemorrhage (n=2), eye pain, catheter site injection, device-related infection, mouth hemorrhage, and appendicitis. None of these events were considered treatment-related.

There were no thromboembolic or thrombotic microangiopathy events, and none of the patients tested positive for anti-drug antibodies.

“The safety profile of emicizumab was favorable and well-tolerated,” Dr Young said. “And these updated results from the HAVEN 2 study confirm our prior efficacy results, presented at ISTH, that emicizumab successfully prevents or reduces bleeds.”

Photo courtesy of ASH

ATLANTA—Updated results from the HAVEN 2 trial have shown that emicizumab prophylaxis can reduce bleeds in children with hemophilia A and factor VIII inhibitors.

Sixty-five percent of all patients enrolled in HAVEN 2 had no bleeds while on emicizumab, and 95% had no treated bleeds.

Among patients who had been on emicizumab for at least 12 weeks, 35% had no bleeds, and 87% had no treated bleeds.

The most common adverse events (AEs) in this trial were viral upper respiratory tract infections and injection site reactions.

Guy Young, MD, of Children’s Hospital Los Angeles in California, presented these results at the 2017 ASH Annual Meeting (abstract 85). The trial was sponsored by Hoffmann-La Roche.

HAVEN 2 enrolled 60 patients, ages 1 to 17, who had hemophilia A and inhibitors. Most patients (95%) had severe hemophilia, 3.3% (n=2) had mild disease, and 1.7% (n=1) had moderate disease.

Nearly a quarter of patients (73.3%) had previously received prophylaxis, and 26.7% had previously received episodic treatment.

The median number of bleeds in the previous 24 weeks was 6.0 (range, 0-155), and 38.3% of patients had target joints.

Patients received emicizumab prophylaxis at 3 mg/kg/week for 4 weeks and 1.5 mg/kg/week thereafter. The median observation time was 9 weeks (range, 1.6 to 41.6 weeks).

Efficacy

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

There were a total of 65 bleeds in 20 patients. Eight were joint bleeds, 2 were muscle bleeds, and the rest were classified as “other.” Of the 55 “other’’ bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) were traumatic, and 3 (4.6%) were due to a procedure/surgery.

A subset of 23 patients received emicizumab for at least 12 weeks. They had a median treatment duration of 38.1 weeks (range, 12.7 to 41.6 weeks).

Of these patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds and 0 treated joint bleeds. There were a total of 41 bleeds in 15 of these patients. Three bleeds (joint, muscle, and hip) were treated.

The median annualized bleeding rate (ABR) for the 23 patients was 1.5 for all bleeds and 0.0 for all types of treated bleeds.

There were 13 patients who had participated in a non-interventional study prior to enrolling in HAVEN 2, so these patients could serve as their own controls. The patients had an overall reduction in ABR of 99% with emicizumab.

Safety

All 60 patients were evaluated for safety. Forty patients had a total of 201 AEs. The most common AEs were viral upper respiratory tract infection (16.7%) and injection site reactions (16.7%)

There were 7 serious AEs in 6 patients—muscle hemorrhage (n=2), eye pain, catheter site injection, device-related infection, mouth hemorrhage, and appendicitis. None of these events were considered treatment-related.

There were no thromboembolic or thrombotic microangiopathy events, and none of the patients tested positive for anti-drug antibodies.

“The safety profile of emicizumab was favorable and well-tolerated,” Dr Young said. “And these updated results from the HAVEN 2 study confirm our prior efficacy results, presented at ISTH, that emicizumab successfully prevents or reduces bleeds.”

Photo courtesy of ASH

ATLANTA—Updated results from the HAVEN 2 trial have shown that emicizumab prophylaxis can reduce bleeds in children with hemophilia A and factor VIII inhibitors.

Sixty-five percent of all patients enrolled in HAVEN 2 had no bleeds while on emicizumab, and 95% had no treated bleeds.

Among patients who had been on emicizumab for at least 12 weeks, 35% had no bleeds, and 87% had no treated bleeds.

The most common adverse events (AEs) in this trial were viral upper respiratory tract infections and injection site reactions.

Guy Young, MD, of Children’s Hospital Los Angeles in California, presented these results at the 2017 ASH Annual Meeting (abstract 85). The trial was sponsored by Hoffmann-La Roche.

HAVEN 2 enrolled 60 patients, ages 1 to 17, who had hemophilia A and inhibitors. Most patients (95%) had severe hemophilia, 3.3% (n=2) had mild disease, and 1.7% (n=1) had moderate disease.

Nearly a quarter of patients (73.3%) had previously received prophylaxis, and 26.7% had previously received episodic treatment.

The median number of bleeds in the previous 24 weeks was 6.0 (range, 0-155), and 38.3% of patients had target joints.

Patients received emicizumab prophylaxis at 3 mg/kg/week for 4 weeks and 1.5 mg/kg/week thereafter. The median observation time was 9 weeks (range, 1.6 to 41.6 weeks).

Efficacy

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

There were a total of 65 bleeds in 20 patients. Eight were joint bleeds, 2 were muscle bleeds, and the rest were classified as “other.” Of the 55 “other’’ bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) were traumatic, and 3 (4.6%) were due to a procedure/surgery.

A subset of 23 patients received emicizumab for at least 12 weeks. They had a median treatment duration of 38.1 weeks (range, 12.7 to 41.6 weeks).

Of these patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds and 0 treated joint bleeds. There were a total of 41 bleeds in 15 of these patients. Three bleeds (joint, muscle, and hip) were treated.

The median annualized bleeding rate (ABR) for the 23 patients was 1.5 for all bleeds and 0.0 for all types of treated bleeds.

There were 13 patients who had participated in a non-interventional study prior to enrolling in HAVEN 2, so these patients could serve as their own controls. The patients had an overall reduction in ABR of 99% with emicizumab.

Safety

All 60 patients were evaluated for safety. Forty patients had a total of 201 AEs. The most common AEs were viral upper respiratory tract infection (16.7%) and injection site reactions (16.7%)

There were 7 serious AEs in 6 patients—muscle hemorrhage (n=2), eye pain, catheter site injection, device-related infection, mouth hemorrhage, and appendicitis. None of these events were considered treatment-related.

There were no thromboembolic or thrombotic microangiopathy events, and none of the patients tested positive for anti-drug antibodies.

“The safety profile of emicizumab was favorable and well-tolerated,” Dr Young said. “And these updated results from the HAVEN 2 study confirm our prior efficacy results, presented at ISTH, that emicizumab successfully prevents or reduces bleeds.”

ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.

After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

Even more strikingly, intrabone gene therapy obviated the need for blood transfusions in three children with beta-thalassemia, including one who is beta-0/beta-0 (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.

All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.

Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.

Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.

“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.

To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.

For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.

This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.

Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.

“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”

Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.

SOURCE: Marktel S et al. ASH 2017 Abstract 355.

ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.

After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

Even more strikingly, intrabone gene therapy obviated the need for blood transfusions in three children with beta-thalassemia, including one who is beta-0/beta-0 (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.

All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.

Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.

Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.

“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.

To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.

For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.

This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.

Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.

“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”

Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.

SOURCE: Marktel S et al. ASH 2017 Abstract 355.

ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.

After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

Even more strikingly, intrabone gene therapy obviated the need for blood transfusions in three children with beta-thalassemia, including one who is beta-0/beta-0 (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.

All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.

Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.

Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.

“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.

To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.

For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.

This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.

Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.

“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”

Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.

SOURCE: Marktel S et al. ASH 2017 Abstract 355.

ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 10¹³ vector genomes/kg) and then received a higher dose ( 6 x 10¹³ VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 10¹³ VG/kg dose and the GENEr8-2 trial will use the 4 x 10¹³ VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603

ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 10¹³ vector genomes/kg) and then received a higher dose ( 6 x 10¹³ VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 10¹³ VG/kg dose and the GENEr8-2 trial will use the 4 x 10¹³ VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603

ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 10¹³ vector genomes/kg) and then received a higher dose ( 6 x 10¹³ VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 10¹³ VG/kg dose and the GENEr8-2 trial will use the 4 x 10¹³ VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603

ATLANTA – The bispecific humanized monoclonal antibody emicizumab safely prevents or substantially reduces bleeds in children with hemophilia A with inhibitors that render standard factor VIII replacement therapies ineffective, according to an updated interim analysis of data from the open-label phase 3 HAVEN 2 study.

The findings have life-changing implications for patients and suggest that emicizumab prophylaxis represents a new standard of care for hemophilia A patients with inhibitors, Guy Young, MD, said during a press briefing at the annual meeting of the American Society of Hematology.

Of 57 patients under age 12 years receiving weekly subcutaneous emicizumab (Hemlibra) for bleeding prophylaxis at the data cutoff, 54 (94.7%) had zero treated bleeds, said Dr. Young of the University of Southern California, Los Angeles.

“That’s, honestly, truly remarkable. I mean, most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that,” he said.

Further, of 23 patients who were treated for at least 12 weeks and had a median efficacy period of 38.1 weeks, 87% had no bleeding events whatsoever (annual bleed rate of 0.2 events vs. a usual annual bleed rate of 1.3 events in patients without inhibitors). The annual treated joint bleed and treated target joint bleed rates each were 0.1, he said.

Overall, only three treated bleeds occurred in the 57 patients, and only one was a spontaneous bleed; one occurred in a joint, one occurred in a muscle, and one occurred in the hip and was classified as “other,” he noted.

The findings expand upon those from a previously reported interim analysis of data on 20 children from the study, which also showed that once-weekly subcutaneous emicizumab prophylaxis prevented or reduced bleeds, and provided clinically meaningful reductions in the annualized bleed rate when compared with prior bypassing agent treatment, Dr Young said.

In that prior analysis of participants aged 2-12 years (or up to 17 years with weight below 40 kg), which was presented in July at the annual meeting of the International Society on Thrombosis and Haemostasis, the data cutoff was Oct. 28, 2016. The current analysis had a May 8, 2017 cutoff, and therefore included about 6 additional months of data.

The treatment, which is given at a dose of 3 mg/kg per week for 4 weeks and then 1.5 mg/kg per week thereafter, was well tolerated. Ten nonserious, treatment-related adverse events occurred, and mainly involved injection site reactions. Serious adverse events occurred in six patients but were mainly related to the disease or to the use of catheters, or were otherwise unrelated to emicizumab. There were no thromboembolic or thrombotic microangiopathy events reported. Mean steady state trough concentrations (approximately 50 mcg/mL) were consistent with the pharmacokinetic profile seen in prior studies in the adolescent/adult population.

Health-related quality of life improvements were considerable, and in many cases, dramatic, Dr. Young said, noting in an interview that, for some patients, the effects were life changing both for the patients and their families. He described one young patient who had experienced scores of debilitating ankle bleeds, but had had no bleeds since he began receiving treatment as part of this study.

Emicizumab, which recently received Food and Drug Administration approval for use in patients of all ages with hemophilia A with inhibitors, bridges factor IXa and factor X to “bring them into proper alignment, which is really what the function of factor VIII is,” he said.

“So, it’s essentially replacing, or mimicking, the function of factor VIII, but without being factor VIII,” he said, explaining that it can be used to treat patients with inhibitors, because the antibodies they develop are specifically to factor VIII.

“This is not factor VIII, it’s just doing the job of factor VIII,” he added.

Studies of emicizumab for hemophilia A without inhibitors are ongoing (HAVEN 3), and could result in expanded indications, he noted.

The primary efficacy results of HAVEN 2 will be reported 52 weeks after the last patient is enrolled. These interim findings, however, demonstrate the potential for weekly subcutaneous injections of emicizumab to safely and conveniently reduce overall disease burden, as well as overall treatment burden in patients with hemophilia A with inhibitors, as these patients previously had to undergo intravenous treatment multiple times per week – and sometimes multiple times per day, he said.

The HAVEN 2 study is sponsored by Hoffman-La Roche. Dr. Young has received honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire.

[email protected]

SOURCE: Young G et al. ASH 2017 Abstract 85.

ATLANTA – The bispecific humanized monoclonal antibody emicizumab safely prevents or substantially reduces bleeds in children with hemophilia A with inhibitors that render standard factor VIII replacement therapies ineffective, according to an updated interim analysis of data from the open-label phase 3 HAVEN 2 study.

The findings have life-changing implications for patients and suggest that emicizumab prophylaxis represents a new standard of care for hemophilia A patients with inhibitors, Guy Young, MD, said during a press briefing at the annual meeting of the American Society of Hematology.

Of 57 patients under age 12 years receiving weekly subcutaneous emicizumab (Hemlibra) for bleeding prophylaxis at the data cutoff, 54 (94.7%) had zero treated bleeds, said Dr. Young of the University of Southern California, Los Angeles.

“That’s, honestly, truly remarkable. I mean, most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that,” he said.

Further, of 23 patients who were treated for at least 12 weeks and had a median efficacy period of 38.1 weeks, 87% had no bleeding events whatsoever (annual bleed rate of 0.2 events vs. a usual annual bleed rate of 1.3 events in patients without inhibitors). The annual treated joint bleed and treated target joint bleed rates each were 0.1, he said.

Overall, only three treated bleeds occurred in the 57 patients, and only one was a spontaneous bleed; one occurred in a joint, one occurred in a muscle, and one occurred in the hip and was classified as “other,” he noted.

The findings expand upon those from a previously reported interim analysis of data on 20 children from the study, which also showed that once-weekly subcutaneous emicizumab prophylaxis prevented or reduced bleeds, and provided clinically meaningful reductions in the annualized bleed rate when compared with prior bypassing agent treatment, Dr Young said.

In that prior analysis of participants aged 2-12 years (or up to 17 years with weight below 40 kg), which was presented in July at the annual meeting of the International Society on Thrombosis and Haemostasis, the data cutoff was Oct. 28, 2016. The current analysis had a May 8, 2017 cutoff, and therefore included about 6 additional months of data.

The treatment, which is given at a dose of 3 mg/kg per week for 4 weeks and then 1.5 mg/kg per week thereafter, was well tolerated. Ten nonserious, treatment-related adverse events occurred, and mainly involved injection site reactions. Serious adverse events occurred in six patients but were mainly related to the disease or to the use of catheters, or were otherwise unrelated to emicizumab. There were no thromboembolic or thrombotic microangiopathy events reported. Mean steady state trough concentrations (approximately 50 mcg/mL) were consistent with the pharmacokinetic profile seen in prior studies in the adolescent/adult population.

Health-related quality of life improvements were considerable, and in many cases, dramatic, Dr. Young said, noting in an interview that, for some patients, the effects were life changing both for the patients and their families. He described one young patient who had experienced scores of debilitating ankle bleeds, but had had no bleeds since he began receiving treatment as part of this study.

Emicizumab, which recently received Food and Drug Administration approval for use in patients of all ages with hemophilia A with inhibitors, bridges factor IXa and factor X to “bring them into proper alignment, which is really what the function of factor VIII is,” he said.

“So, it’s essentially replacing, or mimicking, the function of factor VIII, but without being factor VIII,” he said, explaining that it can be used to treat patients with inhibitors, because the antibodies they develop are specifically to factor VIII.

“This is not factor VIII, it’s just doing the job of factor VIII,” he added.

Studies of emicizumab for hemophilia A without inhibitors are ongoing (HAVEN 3), and could result in expanded indications, he noted.

The primary efficacy results of HAVEN 2 will be reported 52 weeks after the last patient is enrolled. These interim findings, however, demonstrate the potential for weekly subcutaneous injections of emicizumab to safely and conveniently reduce overall disease burden, as well as overall treatment burden in patients with hemophilia A with inhibitors, as these patients previously had to undergo intravenous treatment multiple times per week – and sometimes multiple times per day, he said.

The HAVEN 2 study is sponsored by Hoffman-La Roche. Dr. Young has received honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire.

[email protected]

SOURCE: Young G et al. ASH 2017 Abstract 85.

ATLANTA – The bispecific humanized monoclonal antibody emicizumab safely prevents or substantially reduces bleeds in children with hemophilia A with inhibitors that render standard factor VIII replacement therapies ineffective, according to an updated interim analysis of data from the open-label phase 3 HAVEN 2 study.

The findings have life-changing implications for patients and suggest that emicizumab prophylaxis represents a new standard of care for hemophilia A patients with inhibitors, Guy Young, MD, said during a press briefing at the annual meeting of the American Society of Hematology.

Of 57 patients under age 12 years receiving weekly subcutaneous emicizumab (Hemlibra) for bleeding prophylaxis at the data cutoff, 54 (94.7%) had zero treated bleeds, said Dr. Young of the University of Southern California, Los Angeles.

“That’s, honestly, truly remarkable. I mean, most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that,” he said.

Further, of 23 patients who were treated for at least 12 weeks and had a median efficacy period of 38.1 weeks, 87% had no bleeding events whatsoever (annual bleed rate of 0.2 events vs. a usual annual bleed rate of 1.3 events in patients without inhibitors). The annual treated joint bleed and treated target joint bleed rates each were 0.1, he said.

Overall, only three treated bleeds occurred in the 57 patients, and only one was a spontaneous bleed; one occurred in a joint, one occurred in a muscle, and one occurred in the hip and was classified as “other,” he noted.

The findings expand upon those from a previously reported interim analysis of data on 20 children from the study, which also showed that once-weekly subcutaneous emicizumab prophylaxis prevented or reduced bleeds, and provided clinically meaningful reductions in the annualized bleed rate when compared with prior bypassing agent treatment, Dr Young said.

In that prior analysis of participants aged 2-12 years (or up to 17 years with weight below 40 kg), which was presented in July at the annual meeting of the International Society on Thrombosis and Haemostasis, the data cutoff was Oct. 28, 2016. The current analysis had a May 8, 2017 cutoff, and therefore included about 6 additional months of data.

The treatment, which is given at a dose of 3 mg/kg per week for 4 weeks and then 1.5 mg/kg per week thereafter, was well tolerated. Ten nonserious, treatment-related adverse events occurred, and mainly involved injection site reactions. Serious adverse events occurred in six patients but were mainly related to the disease or to the use of catheters, or were otherwise unrelated to emicizumab. There were no thromboembolic or thrombotic microangiopathy events reported. Mean steady state trough concentrations (approximately 50 mcg/mL) were consistent with the pharmacokinetic profile seen in prior studies in the adolescent/adult population.

Health-related quality of life improvements were considerable, and in many cases, dramatic, Dr. Young said, noting in an interview that, for some patients, the effects were life changing both for the patients and their families. He described one young patient who had experienced scores of debilitating ankle bleeds, but had had no bleeds since he began receiving treatment as part of this study.

Emicizumab, which recently received Food and Drug Administration approval for use in patients of all ages with hemophilia A with inhibitors, bridges factor IXa and factor X to “bring them into proper alignment, which is really what the function of factor VIII is,” he said.

“So, it’s essentially replacing, or mimicking, the function of factor VIII, but without being factor VIII,” he said, explaining that it can be used to treat patients with inhibitors, because the antibodies they develop are specifically to factor VIII.

“This is not factor VIII, it’s just doing the job of factor VIII,” he added.

Studies of emicizumab for hemophilia A without inhibitors are ongoing (HAVEN 3), and could result in expanded indications, he noted.

The primary efficacy results of HAVEN 2 will be reported 52 weeks after the last patient is enrolled. These interim findings, however, demonstrate the potential for weekly subcutaneous injections of emicizumab to safely and conveniently reduce overall disease burden, as well as overall treatment burden in patients with hemophilia A with inhibitors, as these patients previously had to undergo intravenous treatment multiple times per week – and sometimes multiple times per day, he said.

The HAVEN 2 study is sponsored by Hoffman-La Roche. Dr. Young has received honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire.

[email protected]

SOURCE: Young G et al. ASH 2017 Abstract 85.

ATLANTA – Voxelotor, an investigational inhibitor of hemoglobin polymerization, demonstrated consistent and sustained improvements in hemoglobin levels in adolescents with sickle cell disease (SCD), according to first results of a phase 2b study.

A hemoglobin response of at least 1 g/dL was achieved in 55% of patients (6 of 11) at 16 weeks, in results of the ongoing open-label, 24-week study presented at the annual meeting of the American Society of Hematology.

The treatment was well tolerated, associated with mostly grade 1-2 adverse events, and also improved patient-reported symptoms, according to Carolyn C. Hoppe, MD, of University of California, San Francisco, Benioff Children’s Hospital.

“These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with sickle cell disease,” Dr. Hoppe said at a press conference. “We need therapies to treat this disease and prevent the complications.”

Dr. Hoppe presented data on the first 12 patients in a study designed to assess the safety, pharmacokinetics, and efficacy of voxelotor in adolescent patients with homozygous hemoglobin SS or hemoglobin S beta-0 thalassemia.

All patients except one were already receiving standard care with hydroxyurea, suggesting that the two drugs may provide additive effects, according to investigators.

Treatment with voxelotor was associated with improvements in hemoglobin at 16 weeks, along with improvements in clinical measures of hemolysis – a 34% median reductions in reticulocytes and a 27% reduction in indirect bilirubin, Dr. Hoppe reported.

Patient-reported symptoms improved in 10 of 12 patients, with a median reduction of 94% in total symptom scores (TSS) at week 16, including 5 subjects with a mean TSS of 0.

Voxelotor is designed to address the cause of sickle cell disease, according to Dr. Hoppe, by modulating hemoglobin’s affinity for oxygen, which in turn inhibits hemoglobin polymerization.

“If we can interrupt that early on, we can hopefully disrupt or interrupt the biologic pathways that lead to the consequences of the disease,” she said.

The study is ongoing, as is a phase 3 clinical trial evaluating voxelotor in patients aged 12 years and older with SCD.

Voxelotor was previously known as GBT440

The study was sponsored by Global Blood Therapeutics. Dr. Hoppe reported research funding from and advisory relationships with Global Blood Therapeutics. Several coauthors are employees of the company.

SOURCE: Hoppe C et al. ASH 2017. Abstract 689

ATLANTA – Voxelotor, an investigational inhibitor of hemoglobin polymerization, demonstrated consistent and sustained improvements in hemoglobin levels in adolescents with sickle cell disease (SCD), according to first results of a phase 2b study.

A hemoglobin response of at least 1 g/dL was achieved in 55% of patients (6 of 11) at 16 weeks, in results of the ongoing open-label, 24-week study presented at the annual meeting of the American Society of Hematology.

The treatment was well tolerated, associated with mostly grade 1-2 adverse events, and also improved patient-reported symptoms, according to Carolyn C. Hoppe, MD, of University of California, San Francisco, Benioff Children’s Hospital.

“These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with sickle cell disease,” Dr. Hoppe said at a press conference. “We need therapies to treat this disease and prevent the complications.”

Dr. Hoppe presented data on the first 12 patients in a study designed to assess the safety, pharmacokinetics, and efficacy of voxelotor in adolescent patients with homozygous hemoglobin SS or hemoglobin S beta-0 thalassemia.

All patients except one were already receiving standard care with hydroxyurea, suggesting that the two drugs may provide additive effects, according to investigators.

Treatment with voxelotor was associated with improvements in hemoglobin at 16 weeks, along with improvements in clinical measures of hemolysis – a 34% median reductions in reticulocytes and a 27% reduction in indirect bilirubin, Dr. Hoppe reported.

Patient-reported symptoms improved in 10 of 12 patients, with a median reduction of 94% in total symptom scores (TSS) at week 16, including 5 subjects with a mean TSS of 0.

Voxelotor is designed to address the cause of sickle cell disease, according to Dr. Hoppe, by modulating hemoglobin’s affinity for oxygen, which in turn inhibits hemoglobin polymerization.

“If we can interrupt that early on, we can hopefully disrupt or interrupt the biologic pathways that lead to the consequences of the disease,” she said.

The study is ongoing, as is a phase 3 clinical trial evaluating voxelotor in patients aged 12 years and older with SCD.

Voxelotor was previously known as GBT440

The study was sponsored by Global Blood Therapeutics. Dr. Hoppe reported research funding from and advisory relationships with Global Blood Therapeutics. Several coauthors are employees of the company.

SOURCE: Hoppe C et al. ASH 2017. Abstract 689

ATLANTA – Voxelotor, an investigational inhibitor of hemoglobin polymerization, demonstrated consistent and sustained improvements in hemoglobin levels in adolescents with sickle cell disease (SCD), according to first results of a phase 2b study.

A hemoglobin response of at least 1 g/dL was achieved in 55% of patients (6 of 11) at 16 weeks, in results of the ongoing open-label, 24-week study presented at the annual meeting of the American Society of Hematology.

The treatment was well tolerated, associated with mostly grade 1-2 adverse events, and also improved patient-reported symptoms, according to Carolyn C. Hoppe, MD, of University of California, San Francisco, Benioff Children’s Hospital.

“These interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with sickle cell disease,” Dr. Hoppe said at a press conference. “We need therapies to treat this disease and prevent the complications.”

Dr. Hoppe presented data on the first 12 patients in a study designed to assess the safety, pharmacokinetics, and efficacy of voxelotor in adolescent patients with homozygous hemoglobin SS or hemoglobin S beta-0 thalassemia.

All patients except one were already receiving standard care with hydroxyurea, suggesting that the two drugs may provide additive effects, according to investigators.

Treatment with voxelotor was associated with improvements in hemoglobin at 16 weeks, along with improvements in clinical measures of hemolysis – a 34% median reductions in reticulocytes and a 27% reduction in indirect bilirubin, Dr. Hoppe reported.

Patient-reported symptoms improved in 10 of 12 patients, with a median reduction of 94% in total symptom scores (TSS) at week 16, including 5 subjects with a mean TSS of 0.

Voxelotor is designed to address the cause of sickle cell disease, according to Dr. Hoppe, by modulating hemoglobin’s affinity for oxygen, which in turn inhibits hemoglobin polymerization.

“If we can interrupt that early on, we can hopefully disrupt or interrupt the biologic pathways that lead to the consequences of the disease,” she said.

The study is ongoing, as is a phase 3 clinical trial evaluating voxelotor in patients aged 12 years and older with SCD.

Voxelotor was previously known as GBT440

The study was sponsored by Global Blood Therapeutics. Dr. Hoppe reported research funding from and advisory relationships with Global Blood Therapeutics. Several coauthors are employees of the company.

SOURCE: Hoppe C et al. ASH 2017. Abstract 689

ATLANTA – Matching red cell products to sickle-cell disease (SCD) patients with rare Rh antibodies can be accomplished with a little fancy stem cell footwork and some genetic legerdemain, investigators report.

With the help of CRISPR/Cas9 gene-editing, Stella T. Chou, MD, from Children’s Hospital of Philadelphia and her colleagues have created a panel of red cell reagents customized from induced pluripotent stem cells (iPSCs) to produce a renewable source of red cell reagents and potentially universal infusion products for patients with SCD.

“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” Dr. Chou said in a statement. “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”

Up to half of all patients with SCD who require chronic transfusions may develop antibodies to allogeneic blood products, but identifying inactivating antibodies in a given patient can be both challenging and time consuming, due to a paucity of the appropriate reagent red cells, Dr. Chou and her colleagues reported.

The investigators previously reported that despite receiving transfusions from Rh-matched minority donors, patients with SCD have a high prevalence of red blood cell alloimmunization, and that Rh antibodies are the most common type of antibody in SCD patients, with about 33% of Rh antibodies associated with delayed transfusion reactions (Blood. 2013 Aug 8;122:1062-71; doi: 10.1182/blood-2013-03-490623).

It is both costly and time consuming to genotype donated blood for Rh antigens in order to match a low-antigen product to a specific patient. Instead, the investigators identified a workaround involving reprogramming or genetically engineering iPSCs from donors with rare antigen profiles, with the goal of creating a standard panel of red cell reagents that could reliably and quickly identify SCD patients with complex antibodies.

They used CRISPR/Cas9 gene-editing techniques to modify existing iPSCs to include Rh null cells, other cells lacking all or part of certain high-prevalence Rh antigens, and low prevalence novel antigens.

The investigators then showed that they could induce hematopoietic differentiation of their customized iPSCs through a three-step process and demonstrated that, as they had expected, the engineered antibodies were able to more accurately type Rh in gel card assays than did off-the-shelf commercial assays.

“We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents,” Dr. Chou said.

They also asserted that iPSC-derived red blood cells (iRBCs) produced from their customized iPSCs could be used with standard blood bank assays as a potential means of streamlining and standardizing the antibody identification process in alloimmunized patients with complex antibody specificities.

“In the future, when technology for scale-up is available, Rh null iRBCs could be used as ‘universal’ donor cells for future therapeutic applications,” the reseachers wrote.

The study was supported by the National Institutes of Health/National Heart Lung and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Chou S et al. ASH 2017 Abstract 3

ATLANTA – Matching red cell products to sickle-cell disease (SCD) patients with rare Rh antibodies can be accomplished with a little fancy stem cell footwork and some genetic legerdemain, investigators report.

With the help of CRISPR/Cas9 gene-editing, Stella T. Chou, MD, from Children’s Hospital of Philadelphia and her colleagues have created a panel of red cell reagents customized from induced pluripotent stem cells (iPSCs) to produce a renewable source of red cell reagents and potentially universal infusion products for patients with SCD.

“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” Dr. Chou said in a statement. “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”

Up to half of all patients with SCD who require chronic transfusions may develop antibodies to allogeneic blood products, but identifying inactivating antibodies in a given patient can be both challenging and time consuming, due to a paucity of the appropriate reagent red cells, Dr. Chou and her colleagues reported.

The investigators previously reported that despite receiving transfusions from Rh-matched minority donors, patients with SCD have a high prevalence of red blood cell alloimmunization, and that Rh antibodies are the most common type of antibody in SCD patients, with about 33% of Rh antibodies associated with delayed transfusion reactions (Blood. 2013 Aug 8;122:1062-71; doi: 10.1182/blood-2013-03-490623).

It is both costly and time consuming to genotype donated blood for Rh antigens in order to match a low-antigen product to a specific patient. Instead, the investigators identified a workaround involving reprogramming or genetically engineering iPSCs from donors with rare antigen profiles, with the goal of creating a standard panel of red cell reagents that could reliably and quickly identify SCD patients with complex antibodies.

They used CRISPR/Cas9 gene-editing techniques to modify existing iPSCs to include Rh null cells, other cells lacking all or part of certain high-prevalence Rh antigens, and low prevalence novel antigens.

The investigators then showed that they could induce hematopoietic differentiation of their customized iPSCs through a three-step process and demonstrated that, as they had expected, the engineered antibodies were able to more accurately type Rh in gel card assays than did off-the-shelf commercial assays.

“We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents,” Dr. Chou said.

They also asserted that iPSC-derived red blood cells (iRBCs) produced from their customized iPSCs could be used with standard blood bank assays as a potential means of streamlining and standardizing the antibody identification process in alloimmunized patients with complex antibody specificities.

“In the future, when technology for scale-up is available, Rh null iRBCs could be used as ‘universal’ donor cells for future therapeutic applications,” the reseachers wrote.

The study was supported by the National Institutes of Health/National Heart Lung and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Chou S et al. ASH 2017 Abstract 3

ATLANTA – Matching red cell products to sickle-cell disease (SCD) patients with rare Rh antibodies can be accomplished with a little fancy stem cell footwork and some genetic legerdemain, investigators report.

With the help of CRISPR/Cas9 gene-editing, Stella T. Chou, MD, from Children’s Hospital of Philadelphia and her colleagues have created a panel of red cell reagents customized from induced pluripotent stem cells (iPSCs) to produce a renewable source of red cell reagents and potentially universal infusion products for patients with SCD.

“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” Dr. Chou said in a statement. “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”

Up to half of all patients with SCD who require chronic transfusions may develop antibodies to allogeneic blood products, but identifying inactivating antibodies in a given patient can be both challenging and time consuming, due to a paucity of the appropriate reagent red cells, Dr. Chou and her colleagues reported.

The investigators previously reported that despite receiving transfusions from Rh-matched minority donors, patients with SCD have a high prevalence of red blood cell alloimmunization, and that Rh antibodies are the most common type of antibody in SCD patients, with about 33% of Rh antibodies associated with delayed transfusion reactions (Blood. 2013 Aug 8;122:1062-71; doi: 10.1182/blood-2013-03-490623).

It is both costly and time consuming to genotype donated blood for Rh antigens in order to match a low-antigen product to a specific patient. Instead, the investigators identified a workaround involving reprogramming or genetically engineering iPSCs from donors with rare antigen profiles, with the goal of creating a standard panel of red cell reagents that could reliably and quickly identify SCD patients with complex antibodies.

They used CRISPR/Cas9 gene-editing techniques to modify existing iPSCs to include Rh null cells, other cells lacking all or part of certain high-prevalence Rh antigens, and low prevalence novel antigens.

The investigators then showed that they could induce hematopoietic differentiation of their customized iPSCs through a three-step process and demonstrated that, as they had expected, the engineered antibodies were able to more accurately type Rh in gel card assays than did off-the-shelf commercial assays.

“We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents,” Dr. Chou said.

They also asserted that iPSC-derived red blood cells (iRBCs) produced from their customized iPSCs could be used with standard blood bank assays as a potential means of streamlining and standardizing the antibody identification process in alloimmunized patients with complex antibody specificities.

“In the future, when technology for scale-up is available, Rh null iRBCs could be used as ‘universal’ donor cells for future therapeutic applications,” the reseachers wrote.

The study was supported by the National Institutes of Health/National Heart Lung and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Chou S et al. ASH 2017 Abstract 3

Image by Spencer Phillips

The gene therapy SPK-9001 has produced positive results in a phase 1/2 trial of adults with hemophilia B, according to researchers.

SPK-9001 produced sustained factor IX (FIX) activity and allowed all 10 patients in this study to stop FIX prophylaxis.

Eight patients had no further FIX treatment after SPK-9001, and 9 patients had 0 bleeds.

There were no serious adverse events, and none of the patients had thrombotic events or developed FIX inhibitors.

“A one-time therapy sufficient to prevent bleeding without further medical intervention is the ideal treatment goal for patients with hemophilia,” said Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia in Pennsylvania.

“This cohort of 10 patients all safely experienced sustained clinical benefit after one infusion.”

Dr George and her colleagues reported these results in NEJM. The trial was sponsored by Spark Therapeutics and Pfizer.

SPK-9001 is an investigational vector that contains a bio-engineered adeno-associated virus capsid and a codon-optimized, high-activity human FIX gene enabling endogenous production of FIX.

The researchers tested SPK-9001 in 10 males with hemophilia B.

With a cumulative follow-up of 492 weeks, the mean steady-state FIX activity was 34% of normal (range, 14% to 81%) after a single administration of SPK-9001.

The annualized bleeding rate was reduced 97%, from a mean rate of 11.1 events per year before SPK-9001 administration to 0.4 events per year after (P=0.02).

Nine patients had 0 bleeds after SPK-9001, and 1 patient had 4 bleeds.

Use of FIX treatment was reduced 99% during this study, from a mean dose of 2908 IU/kg (range, 0 to 8090) before SPK-9001 to a mean dose of 49.3 IU/kg (range, 0 to 376) after SPK-9001 (P=0.004).

Two patients did receive FIX treatment after SPK-9001, but none of the patients received FIX prophylaxis.

The researchers noted that the patient who required FIX treatment for bleeding (4 events) had significant baseline joint damage. However, this patient still used 91% less FIX than before he received SPK-9001.

There were a total of 40 adverse events in this study, but none were serious. There were no deaths, no thrombotic events, and no cases of inhibitor development.

The only adverse events thought to be related to SPK-9001 were asymptomatic and transient increases in liver enzymes in 2 patients. These events resolved with a tapering dose of oral corticosteroids.

“People who live with hemophilia face a life-long need for vigilant monitoring and recurrent factor concentrate infusions to prevent spontaneous, potentially life-threatening bleeds and to protect their joints,” said study author Katherine High, MD, president and head of Research and Development at Spark Therapeutics.

“The data suggest a one-time infusion of SPK-9001 has the potential to safely sustain factor IX coagulant activity level that may result in the termination of baseline prophylaxis factor infusions, significantly reduce bleeding, and nearly eliminate the need for exogenous factor IX concentrate infusions.”

Image by Spencer Phillips

The gene therapy SPK-9001 has produced positive results in a phase 1/2 trial of adults with hemophilia B, according to researchers.

SPK-9001 produced sustained factor IX (FIX) activity and allowed all 10 patients in this study to stop FIX prophylaxis.

Eight patients had no further FIX treatment after SPK-9001, and 9 patients had 0 bleeds.

There were no serious adverse events, and none of the patients had thrombotic events or developed FIX inhibitors.

“A one-time therapy sufficient to prevent bleeding without further medical intervention is the ideal treatment goal for patients with hemophilia,” said Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia in Pennsylvania.

“This cohort of 10 patients all safely experienced sustained clinical benefit after one infusion.”

Dr George and her colleagues reported these results in NEJM. The trial was sponsored by Spark Therapeutics and Pfizer.

SPK-9001 is an investigational vector that contains a bio-engineered adeno-associated virus capsid and a codon-optimized, high-activity human FIX gene enabling endogenous production of FIX.

The researchers tested SPK-9001 in 10 males with hemophilia B.

With a cumulative follow-up of 492 weeks, the mean steady-state FIX activity was 34% of normal (range, 14% to 81%) after a single administration of SPK-9001.

The annualized bleeding rate was reduced 97%, from a mean rate of 11.1 events per year before SPK-9001 administration to 0.4 events per year after (P=0.02).

Nine patients had 0 bleeds after SPK-9001, and 1 patient had 4 bleeds.

Use of FIX treatment was reduced 99% during this study, from a mean dose of 2908 IU/kg (range, 0 to 8090) before SPK-9001 to a mean dose of 49.3 IU/kg (range, 0 to 376) after SPK-9001 (P=0.004).

Two patients did receive FIX treatment after SPK-9001, but none of the patients received FIX prophylaxis.

The researchers noted that the patient who required FIX treatment for bleeding (4 events) had significant baseline joint damage. However, this patient still used 91% less FIX than before he received SPK-9001.

There were a total of 40 adverse events in this study, but none were serious. There were no deaths, no thrombotic events, and no cases of inhibitor development.

The only adverse events thought to be related to SPK-9001 were asymptomatic and transient increases in liver enzymes in 2 patients. These events resolved with a tapering dose of oral corticosteroids.

“People who live with hemophilia face a life-long need for vigilant monitoring and recurrent factor concentrate infusions to prevent spontaneous, potentially life-threatening bleeds and to protect their joints,” said study author Katherine High, MD, president and head of Research and Development at Spark Therapeutics.

“The data suggest a one-time infusion of SPK-9001 has the potential to safely sustain factor IX coagulant activity level that may result in the termination of baseline prophylaxis factor infusions, significantly reduce bleeding, and nearly eliminate the need for exogenous factor IX concentrate infusions.”

Image by Spencer Phillips

The gene therapy SPK-9001 has produced positive results in a phase 1/2 trial of adults with hemophilia B, according to researchers.

SPK-9001 produced sustained factor IX (FIX) activity and allowed all 10 patients in this study to stop FIX prophylaxis.

Eight patients had no further FIX treatment after SPK-9001, and 9 patients had 0 bleeds.

There were no serious adverse events, and none of the patients had thrombotic events or developed FIX inhibitors.

“A one-time therapy sufficient to prevent bleeding without further medical intervention is the ideal treatment goal for patients with hemophilia,” said Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia in Pennsylvania.

“This cohort of 10 patients all safely experienced sustained clinical benefit after one infusion.”

Dr George and her colleagues reported these results in NEJM. The trial was sponsored by Spark Therapeutics and Pfizer.

SPK-9001 is an investigational vector that contains a bio-engineered adeno-associated virus capsid and a codon-optimized, high-activity human FIX gene enabling endogenous production of FIX.

The researchers tested SPK-9001 in 10 males with hemophilia B.

With a cumulative follow-up of 492 weeks, the mean steady-state FIX activity was 34% of normal (range, 14% to 81%) after a single administration of SPK-9001.

The annualized bleeding rate was reduced 97%, from a mean rate of 11.1 events per year before SPK-9001 administration to 0.4 events per year after (P=0.02).

Nine patients had 0 bleeds after SPK-9001, and 1 patient had 4 bleeds.

Use of FIX treatment was reduced 99% during this study, from a mean dose of 2908 IU/kg (range, 0 to 8090) before SPK-9001 to a mean dose of 49.3 IU/kg (range, 0 to 376) after SPK-9001 (P=0.004).

Two patients did receive FIX treatment after SPK-9001, but none of the patients received FIX prophylaxis.

The researchers noted that the patient who required FIX treatment for bleeding (4 events) had significant baseline joint damage. However, this patient still used 91% less FIX than before he received SPK-9001.

There were a total of 40 adverse events in this study, but none were serious. There were no deaths, no thrombotic events, and no cases of inhibitor development.

The only adverse events thought to be related to SPK-9001 were asymptomatic and transient increases in liver enzymes in 2 patients. These events resolved with a tapering dose of oral corticosteroids.

“People who live with hemophilia face a life-long need for vigilant monitoring and recurrent factor concentrate infusions to prevent spontaneous, potentially life-threatening bleeds and to protect their joints,” said study author Katherine High, MD, president and head of Research and Development at Spark Therapeutics.

“The data suggest a one-time infusion of SPK-9001 has the potential to safely sustain factor IX coagulant activity level that may result in the termination of baseline prophylaxis factor infusions, significantly reduce bleeding, and nearly eliminate the need for exogenous factor IX concentrate infusions.”