ISTH 2019 Highlights: Novo Nordisk, Takeda, BioMarin and Others Showcase Advances in Hemophilia Therapies

Recently, the 27th Congress of the International Society on Thrombosis and Haemostasis (ISTH) was held in Melbourne, Australia, where the latest therapies and research advances in hemophilia were presented.

I. BioMarin Plans to Submit Marketing Application for Hemophilia Gene Therapy in the Fourth Quarter

BioMarin Pharmaceutical Announces Plans to Submit Marketing Authorization Applications for Investigational Gene Therapy Valoctocogene Roxaparvovec to Regulatory Authorities in the United States and Europe for the Treatment of Patients with Severe Hemophilia A. The submission is based on updated three-year Phase 1/2 data and interim analysis from a recently completed Phase 3 study of commercial manufacturing material, with results presented at ISTH 2019.

In the Phase 1/2 study, the 3-year update for the 6e13 vg/kg dose cohort demonstrated that bleeding control and reduced factor VIII usage persisted for three years following a single administration of Valoccogene roxaparvovec. In the year prior to enrollment, the annualized bleeding rate (ABR) had a mean of 16.3 and a median of 16.5. After three years, the ABR decreased to a mean of 0.6 and a median of 0. This represents a 96% reduction in mean ABR, with 100% resolution of target joints. Over the three-year period, the mean annualized factor VIII usage also decreased by 96%, and all participants remained off factor VIII prophylaxis. Factor VIII levels maintained over the three-year period were sufficient to achieve significant hemostatic efficacy. Factor VIII expression has entered a plateau phase, with a markedly slowed rate of decline, suggesting durable, long-term expression.

Dr. John Pasi, Principal Investigator for the Phase 1/2 study and Lead Investigator for the Phase 3 study, stated, “Valoctocogene roxaparvovec represents a potentially transformative therapy that can improve patients’ quality of life.”

II. Novo Nordisk N9-GP Can Effectively Prevent/Treat Bleeding in Pediatric Patients with Hemophilia B

Novo Nordisk presented new interim analyses of the PARADIGM5 and PARADIGM6 clinical studies in pediatric patients with hemophilia at the ISTH 2019 Congress: Nonacog beta pegol (N9-GP) demonstrated a low annualized bleeding rate and was well tolerated in pediatric patients with hemophilia B, reinforcing the long-term safety and efficacy established in prior trials.

In the interim analyses of Paradigm 5 and Paradigm 6, previously treated pediatric patients (≤12 years) with hemophilia B exhibited low bleeding rates (overall annualized bleeding rate [ABR] of 0.66, spontaneous ABR of 0.07, and trauma-related ABR of 0.47). Twenty percent of patients experienced no bleeds, and 64% had no spontaneous bleeds throughout the trial. Furthermore, no patients developed inhibitory antibodies, and no safety signals were identified.

III. Takeda Highlights the Potential Benefits of Individualized Prophylaxis in Patients with Severe Hemophilia A Treated with ADYNOVATE

At the ISTH 2019 Congress, Takeda Pharmaceutical Company Limited announced the latest results from the PROPEL Phase IIIb/IV clinical trial of ADYNOVATE® [Antihemophilic Factor (Recombinant), PEGylated]. This was a randomized, multicenter study comparing the safety and efficacy of pharmacokinetic-guided prophylaxis with ADYNOVATE in patients with severe hemophilia A, targeting two different trough activity levels of factor VIII (FVIII).

Recent study results indicate that in patients with severe hemophilia A, prophylaxis with ADYNOVATE can enhance pharmacokinetic (PK) profiles by increasing FVIII trough levels from 1–3% to 8–12%. This represents a clinically meaningful trend, with a higher proportion of patients achieving zero bleeding episodes (62% in the elevated level group [ELE] vs. 42% in the reference group [REF]; p=0.0545). In patients randomized to the 8–12% target trough level group, reductions were observed in the mean annualized total bleeding rate (ABR) (1.6 for ELE vs. 3.6 for REF) and the mean annualized spontaneous joint ABR (0.5 for ELE vs. 2.0 for REF).

Data confirm the pivotal role of FVIII replacement therapy and demonstrate that PK-guided prophylaxis with ADYNOVATE can reliably achieve individualized FVIII levels of 8–12%, thereby improving outcomes in certain patients.

IV. Elocta® Achieves a Median Tolerability Duration of 11.7 Weeks in Patients with Severe Hemophilia A

At ISTH 2019, Sobi and Sanofi presented the interim results of the prospective Phase 4 verITI-8 study, which evaluated the efficacy of Elocta (efmoroctocog alfa) for first-line immune tolerance induction (ITI) in patients with severe hemophilia A with inhibitors.

VerITI-8 is an ongoing, prospective, open-label study that evaluates Elocta for immune tolerance induction (ITI) for the first time in subjects with severe hemophilia A and high-titer inhibitors (historical peak ≥5 BU/mL). The primary endpoint is the time to tolerance of Elocta, and secondary endpoints include the annualized bleeding rate, the number of subjects achieving successful ITI, and adverse events.

In the study, ITI tolerance (success) was defined as having a negative Bethesda titer at two consecutive visits, normal recovery (incremental recovery ≥66% at two consecutive visits), and pharmacokinetics (Elocta half-life ≥7 hours).

In the interim analysis, 15 patients with a history of high-titer inhibitors who had not previously undergone immune tolerance induction (ITI) received ITI therapy, which involved the administration of Elocta at a dose of 200 IU/kg/day until tolerance was achieved or for up to 48 weeks. As of January 23, 2019, six patients had successfully achieved tolerance, with a median time to tolerance of 11.7 weeks. Eight subjects in the study continued to receive Elocta ITI therapy, and one patient failed treatment. No adverse events related to rFVIIIFc were reported.

V. Concizumab Shows Promise in Preventing Bleeding in Patients with Hemophilia

At the 27th ISTH Congress, Professor Astermark presented that Concizumab demonstrated favorable safety and clinical efficacy in preventing bleeding episodes in patients with hemophilia A (Explorer5) and hemophilia A/B (Explorer4).

Concizumab is a high-affinity, humanized recombinant monoclonal antibody that inhibits TFPI by binding to the Kunitz-2 domain, allowing the FVIIa–tissue factor complex to generate sufficient activated factor X to restore hemostatic potential in patients with hemophilia. Due to its unique mechanism of action, concizumab may be equally effective in both hemophilia A and B. Furthermore, its subcutaneous administration helps improve adherence, thereby leading to better outcomes.

Explorer4 is a randomized, controlled Phase 2 study involving 26 patients with hemophilia A or B and inhibitors, while Explorer5 is a Phase 2 study enrolling 36 patients with hemophilia A. In Explorer4, patients were randomized in a 2:1 ratio to receive either concizumab or on-demand prophylactic treatment with activated eptacog alfa (recombinant activated factor VII [rFVIIa]). The results demonstrated that concizumab was well tolerated, with no discontinuations due to adverse events and no thromboembolic events reported.

References:

1.BioMarin Plans Regulatory Submissions for Marketing Authorization of Valoctocogene Roxaparvovec to Treat Severe Hemophilia A in 4Q 2019 in both U.S. and Europe

2.Interim Data Evaluating Elocta for Immune Tolerance Induction in People With Inhibitors and Severe Haemophilia A Shared at ISTH 2019

3.Concizumab phase 2 data demonstrate its potential as a safe and efficacious subcutaneous prophylaxis treatment for all patients with haemophilia

4.Takeda Unveil New Data from the PROPEL Study at ISTH 2019, Reinforcing the Potential Benefit for Personalized Prophylaxis with ADYNOVATE in Severe Hemophilia A

5.New data show nonacog beta pegol (N9-GP) is effective and well tolerated for the prevention and treatment of bleeding in children with haemophilia B