Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using ...

FDA OKs Clinical Testing Of BE-101 As Potential Hemophilia B Treatment

The U.S. Food and Drug Administration (FDA) has cleared clinical testing in adults of BE-101, a B-cell treatment candidate for hemophilia B being developed by Be Biopharma.

The Phase 1/2 trial, called BeCoMe-9, will be a first-in-human study designed to assess the safety and preliminary efficacy of BE-101 in adults with moderately severe to severe hemophilia B. The company said it expects to start dosing patients in the second half of the year.

"The [FDA] clearance is a major milestone in our journey to offer a new, transformative standard of care for people with hemophilia B," Joanne Smith-Farrell, PhD, Be Biopharma's CEO, said in a company press release.

Steven Pipe, MD, from the University of Michigan, said the experimental therapy has the potential to be disease-modifying.

"If proven safe and effective in adults, the ability to treat children and transform the phenotype [disease manifestations] as early as possible would be a game changer," said Pipe, medical director of university's pediatric hemophilia and coagulation disorders program.

BE-101 has 'potential' to be disease-modifying hemophilia B treatment

Hemophilia is mainly caused by mutations that impair the production or activity of certain clotting factors, or proteins that are needed for blood clotting. People with the disorder are highly susceptible to bleeding episodes because the cascade of clotting reactions required to stop bleeding is not functioning properly.

Hemophilia B, the second most common type of hemophilia, is caused by mutations in the F9 gene, which encodes factor IX, known as FIX. Factor replacement therapy, which involves supplying the missing clotting factor to patients, is considered the gold-standard treatment for hemophilia. However, these treatments require patients to receive frequent infusions to maintain clotting factor levels within a therapeutic range to prevent bleeds.

According to Smith-Farrell, "adults and children with hemophilia B have long sought a single dose factor IX replacement therapy with extreme durability while retaining the dosing flexibility of the current standard of care." That's what Be Biopharma is seeking to provide.

BE-101 is an autologous first-in-class B-cell medicine. Being an autologous medicine, it relies on B-cells that are collected from the patient who will then receive treatment.

It works by inserting the human gene encoding factor IX into primary human B-cells, with the aim of sustainably increasing the production and activity of FIX for the treatment of hemophilia B.

Once collected, patient B-cells are engineered in the lab so that a functional F9 gene is inserted into their genome — the entire set of genes found within a cell.

Then, the modified B-cells are expanded and differentiated into plasma cells, which are known to be able to produce thousands of antibodies per second, before being infused back to the patient. At that point, plasma cells are expected to migrate to the bone marrow to produce and release FIX at constant levels.

BE-101 has the potential to be disease-modifying by providing long-lasting FIX protection using the patient's own B cells while providing the option to be [dose-adjusted] and redosable as necessary.

In preclinical studies involving immunodeficient mice, a single dose of BE-101 was able to drive sustained therapeutic FIX activity. The data demonstrated the distribution of FIX-producing cells to the bone marrow, where they survived and expanded over time. The findings also demonstrated that repeated treatment resulted in a predictable increase in FIX levels in the bloodstream.

Moreover, no safety concerns were identified. Similarly, no abnormal clinical observations or mortality were observed in mice receiving treatment.

"BE-101 has the potential to be disease modifying by providing long-lasting FIX protection using the patient's own B cells while providing the option to be [dose-adjusted] and redosable as necessary," Pipe said.

More Pediatric Data Added To Labeling For Hemophilia A Therapy Altuviiio

The Food and Drug Administration (FDA) has approved updated labeling for Altuviiio® (antihemophilic factor [recombinant], Fc-VWF-XTEN Fusion protein-ehtl] to include full results from the phase 3 XTEND-Kids study. 

Altuviiio is a von Willebrand factor independent recombinant DNA-derived, factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for: routine prophylaxis to reduce the frequency of bleeding episodes; on-demand treatment and control of bleeding episodes; and perioperative management of bleeding.

The pediatric approval was supported by interim data from the XTEND-Kids study (ClinicalTrials.Gov Identifier: NCT04759131), in which 74 previously treated patients younger than 12 years of age with severe hemophilia A received Altuviiio 50 IU/kg intravenously once weekly for 52 weeks. The primary endpoint of the trial was the occurrence of inhibitor development (neutralizing antibodies directed against factor VIII). 

Among the 72 evaluable patients, final results showed factor VIII inhibitor development was not detected (0% [95% CI, 0-4.9]). The median and mean annualized bleeding rates (ABRs) were 0.00 (interquartile range: 0.00-1.0) and 0.6 (95% CI, 0.4-0.9), respectively. 

The efficacy of Altuviiio to control bleeding in children less than 12 years old was assessed in the pediatric study. A total of 43 bleeding episodes were treated with Altuviiio. Bleeding was resolved with a single 50 IU/kg dose in 95.3% of bleeding episodes. 

The safety profile of Altuviiio in pediatric patients was similar to that observed in the XTEND-1 trial (ClinicalTrials.Gov Identifier: NCT04161495). The most common adverse reaction was pyrexia. There were no serious allergic reactions or thrombotic/embolic events reported. 

Altuviiio is supplied in kits with a single-dose vial containing 250, 500, 750, 1000, 2000, 3000 or 4000 IU of factor VIII potency, a prefilled syringe, and a sterile vial adapter. 

Switching To Hemlibra Can Control Bleeds Better In Young Patients

In real-world settings, Hemlibra (emicizumab-KXWH) can safely control bleeds in children with hemophilia A better than previous treatment regimens, a study reports.

Hemlibra's improved efficacy was more pronounced among patients with inhibitors, or neutralizing antibodies targeting factor VIII (FVIII), which is the clotting protein missing in people with hemophilia A.

Moreover, the use of FVIII replacement therapies dropped by more than 97% after children started receiving Hemlibra, and no life-threatening bleeds were noted.

"Our data confirms the safety of [Hemlibra] prophylaxis and suggests improved bleeding control among prospectively followed paediatric patients in a large real-world cohort of children with [hemophilia A]," researchers wrote.

The study, "Bleeding control improves after switching to emicizumab: Real-world experience of 177 children in the PedNet registry," was published in the journal Haemophilia.

Hemlibra approved to prevent or reduce frequency of bleeds in hemophilia A

Hemophilia A is caused by genetic mutations that lead to a deficiency or dysfunction of FVIII, a protein involved in blood clotting. Standard hemophilia treatment consists of replacing the missing clotting factor — which in the case of hemophilia A is FVIII — with a lab-made version to prevent or lower the occurrence of bleeding episodes.

However, despite significantly reducing bleeding rates, FVIII replacement therapies are associated with the development of inhibitors that can render treatment ineffective.

Hemlibra is a therapy approved to prevent or reduce the frequency of bleeds in hemophilia A patients. It is an antibody-based therapy that works by binding to clotting factors IX and X, mimicking the action of FVIII. First approved in the U.S. In 2017 for children and adults with hemophilia A with inhibitors, Hemlibra's approval was extended in 2018 to include hemophilia A patients without FVIII inhibitors.

Since its approval, many patients have switched to Hemlibra from standard therapies. Still, real-world data on the treatment's safety and efficacy is limited.

To address this gap, researchers at several European sites examined data extracted from the PedNet Registry (NCT02979119), a multicenter study collecting data from 33 hemophilia treatment centers in 19 countries. Of note, most of the researchers have links to pharmaceutical companies, including Hemlibra's original developer Chugai Pharmaceutical, a Roche subsidiary.

Analysis focused on 177 children with hemophilia A

The analysis focused on 177 children with hemophilia A, with inhibitors or who had been exposed to FVIII replacement therapies for at least 50 days, and who were currently receiving prophylactic or preventive treatment with Hemlibra.

A total of 91 (52%) patients had no history of inhibitors. At the start of treatment with Hemlibra, 64 (36%) had active inhibitors, and 22 (12%) had undergone immune tolerance induction, a treatment to eliminate inhibitors.

Before Hemlibra treatment, patients with FVIII inhibitors had a higher annualized bleeding rate (ABR) (5.08 vs. 2.41 bleeds per year) and a higher joint bleeding rate (1.90 vs. 0.74 bleeds per year) than those without inhibitors. Similar bleeding rates were seen among patients who had undergone induction therapy and those without inhibitors.

During Hemlibra treatment, patients with inhibitors had fewer bleeding episodes in general compared with those without inhibitors (mean ABR of 0.75 vs. 1.11 bleeds per year), but joint bleeding rates were similar.

Accordingly, the most pronounced reduction in ABR was seen among patients with inhibitors, whose ABR dropped from 5.08 to 0.75. Joint ABR also dropped from 1.90 to 0.34. While Hemlibra's efficacy was less pronounced in those without inhibitors, the mean overall ABR significantly dropped from 2.41 to 1.11 and the joint ABR from 0.74 to 0.31.

No life-threatening bleeds reported during Hemlibra treatment

No life-threatening bleeds were reported during Hemlibra treatment, while 10 such events were reported in seven patients before they started on Hemlibra.

Before treatment, nearly half (48%) of the 64 patients with inhibitors received regular prophylactic treatment with bypassing agents, which circumvent the need for conventional clotting factors, and 26 (41%) underwent immune tolerance induction. This amounted to a median of 364 injections per year. After Hemlibra treatment, injection rates significantly dropped to 52 per year, and FVIII consumption by 97.6%.

Most (60%) of those without inhibitors were receiving long-acting FVIII prophylactic treatment before Hemlibra, at a median of 129 injections per year. With Hemlibra, injections were reduced to 35 per year, and replacement therapy consumption by 97.6%.

Five Hemlibra-related adverse events were reported in eight patients. Four patients experienced injection site reactions and one patient stopped Hemlibra treatment after seven months due to the development of antibodies against factors IX and X, even though bleed control was maintained. Inhibitors did not reoccur in the 22 patients who had undergone induction therapy, and no other blood-related events were reported.

"This study showed improved bleeding control compared to previous treatment and a favourable safety profile during [Hemlibra] therapy in paediatric haemophilia A patients," the researchers wrote.

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