The Food and Drug Administration (FDA) has approved Altuviiio (antihemophilic factor [recombinant], Fc-VWF-XTEN fusion protein-ehtl), a first-in-class, high-sustained factor VIII (FVIII) replacement therapy.

Altuviiio is indicated for 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 novel recombinant FVIII therapy is designed to extend protection from bleeds by breaking the von Willebrand factor ceiling, which imposes a half-life limitation on current FVIII treatments.

The approval was based on data from the multicenter, open-label, nonrandomized, interventional phase 3 XTEND-1 study (ClinicalTrials.gov Identifier: NCT04161495), which evaluated the efficacy and safety of Altuviiio in patients 12 years of age and older with severe hemophilia A previously treated with FVIII replacement therapy.

The study included 2 parallel treatment arms: the prophylaxis Arm A (n=128), where patients received a weekly prophylactic 50 IU/kg dose of Altuviiio intravenously (IV) for 52 weeks; and the on-demand Arm B (n=26), where patients received on-demand treatment at doses of 50 IU/kg for 26 weeks, followed by weekly prophylaxis for 26 weeks.

Findings showed that weekly prophylactic treatment with Altuviiio resulted in clinically meaningful prevention of bleeds over 52 weeks; the median annualized bleeding rate (ABR) was 0 with a mean ABR of 0.70. An intra-patient comparison demonstrated a significant 77% (95% CI, 58-87) reduction in ABR with Altuviiio vs prior prophylactic FVIII replacement therapy. Additionally, patients with target joints at baseline (defined as ≥3 spontaneous bleeding episodes in a major joint which occurred in a consecutive 6-month period) achieved 100% resolution with 12 months of prophylactic treatment with Altuviiio. 

In XTEND-1, there were a total of 362 bleeding episodes treated with Altuviiio. Bleeding was resolved with a single 50 IU/kg injection in 96.7% of bleeding episodes. Perioperative hemostasis was evaluated in 13 major and 22 minor surgeries. Treatment with Altuviiio was rated as “excellent” in all of these surgeries. As for safety, the most common adverse reactions reported were headache and arthralgia.

The efficacy of weekly Altuviiio as routine prophylaxis was also evaluated in pediatric patients less than 12 years of age (N=67; XTEND-Kids [ClinicalTrials.gov Identifier: NCT04759131]). Patients received Altuviiio 50 IU/kg IV once weekly for 52 weeks. An interim analysis showed that among patients who received routine prophylaxis for 26 weeks (n=23), the mean ABR was 0.5 and the median ABR was 0 for treated bleeds.

“This approval marks an important clinical advancement for the hemophilia community because we have an option that can achieve higher levels of factor activity with a single simplified weekly dose,” said Lynn Malec, MD, Medical Director of Comprehensive Center for Bleeding Disorders and Associate Investigator at The Versiti Blood Research Institute, and Associate Professor of Medicine and Pediatrics at The Medical College of Wisconsin. “By maintaining high levels of factor activity throughout the week, patients can be confident in the bleed protection Altuviiio offers.”

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. The product is expected to be available in April 2023.

References

1. Press release: FDA approves once-weekly Altuviiio, a new class of factor VIII therapy for hemophilia A that offers significant bleed protection. News release. Sanofi-Aventis Groupe. Accessed February 23, 2023. https://www.globenewswire.com/news-release/2023/02/23/2614759/0/en/Press-Release-FDA-approves-once-weekly-ALTUVIIIO-a-new-class-of-factor-VIII-therapy-for-hemophilia-A-that-offers-significant-bleed-protection.html.
2. Altuviiio. Package insert. Sanofi-Aventis Groupe; 2023. Accessed February 23, 2023. https://www.fda.gov/media/165594/download.

Alvaiz is indicated for the treatment of:

• Thrombocytopenia in adult and pediatric patients 6 years and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. It should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
• Thrombocytopenia in adult patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. It should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
• Severe aplastic anemia in adults who have had an insufficient response to immunosuppressive therapy.

The approval was based on efficacy and safety data from clinical studies in adults (ClinicalTrials.gov Identifier: NCT00370331, NCT00102739, NCT00351468) and pediatric patients (ClinicalTrials.gov identifier: NCT01520909, NCT00908037) with persistent and chronic ITP, adults with chronic hepatitis-C associated thrombocytopenia (ClinicalTrials.gov Identifier: NCT00516321), and adults with refractory severe aplastic anemia (ClinicalTrials.gov Identifier: NCT00922883).

Alvaiz is supplied as 9mg, 18mg, 36mg, and 54mg tablets. It is not substitutable with other eltrombopag products on a milligram per milligram basis due to the observed bioavailability in studies conducted on Alvaiz.

AstraZeneca is stopping its phase 4 trial of Andexxa (andexanet alfa) early because the study achieved the prespecified criteria of superior hemostatic efficacy.

Andexxa was granted accelerated approval by the Food and Drug Administration (FDA) in May 2018 for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation was needed due to life-threatening or uncontrolled bleeding. Andexxa exerts its procoagulant effect by binding and sequestering the factor Xa (FXa) inhibitors.

The randomized, open-label, multicenter ANNEXA-I trial (ClinicalTrials.gov Identifier: NCT03661528) included adults 18 years of age and older presenting with an intracranial hemorrhage within 6 hours of symptom onset to baseline scan and within 15 hours of taking an oral factor Xa inhibitor. Patients were randomly assigned to receive either Andexxa or usual care.

The primary endpoint was the rate of effective hemostasis (defined as the change from baseline in the National Institutes of Health Stroke Scale of +6 or less at the 12-hour timepoint and ≤35% increase in hematoma volume compared with baseline on a repeat CT or MRI scan at 12 hours and no rescue therapies administered between 3 hours and 12 hours after randomization).

Following a planned interim assessment of efficacy (n=450), an independent Data and Safety Monitoring Board concluded that Andexxa demonstrated superior hemostatic efficacy after 1 month follow-up compared with usual care. According to the Company, this result was observed earlier than what had originally been anticipated. These confirmatory findings will be submitted to the FDA as the basis for converting to full approval.

“We are pleased that the study has met its efficacy endpoint at the planned interim analysis, showing improved control of bleeding with targeted anticoagulation reversal, compared to usual care,” said Stuart J. Connolly, MD, FRCPC, Senior Scientist at Population Health Research Institute and professor emeritus at McMaster University in Hamilton, Ontario. “We look forward to sharing the full efficacy and safety results after further analysis, with the hope that the data will pave the way for further guidance on the treatment of potentially life-threatening bleeds.”

Beqvez is a one-time AAV-based gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity factor IX variant. The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. A single intravenous (IV) infusion of Beqvez results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

The approval was based on data from the ongoing, open-label, single-arm phase 3 BENEGENE-2 study (ClinicalTrials.gov Identifier: NCT03861273), which evaluated the efficacy and safety of fidanacogene elaparvovec in 45 adult males with moderately severe to severe hemophilia B (defined as factor IX circulating activity of ≤2 IU/dL). 

Eligible patients were required to have completed 6 months of routine factor IX prophylaxis therapy during the lead-in period (ClinicalTrials.gov Identifier: NCT03587116) after which they received a single IV infusion of fidanacogene elaparvovec. Median follow-up was 2 years (range, 0.4-3.2) from the time of infusion.

The primary endpoint was noninferiority in the annualized bleeding rate (ABR) of total bleeds after fidanacogene elaparvovec infusion compared with baseline ABR during the lead-in period.

Results showed a mean ABR of 4.5 bleeds/year (95% CI, 1.9-7.2) during the baseline period and 2.5 bleeds/year (95% CI, 1.0-3.9) after fidanacogene elaparvovec (treatment difference of -2.1 bleeds/year [95% CI, -4.8, 0.7]), meeting the noninferiority success criterion (upper bound of the 95% CI in the difference was less than 3.0 bleeds/year).

Sixty percent of patients had no bleeds during the post-infusion efficacy evaluation period compared with 29% of those in the prophylaxis arm. A median ABR of zero (range, 0-19) was observed during the efficacy evaluation period vs 1.3 (range, 0-53.9) during the lead-in period.

Six patients (13%) resumed routine factor IX prophylaxis after fidanacogene elaparvovec infusion, starting from 0.4 years to 1.7 years after the gene therapy treatment. One patient had intermittent exogenous factor IX use and a higher ABR after fidanacogene elaparvovec infusion (5.0 bleeds/year) compared with baseline (1.2 bleeds/year) with factor IX activity <5% starting at 0.4 years.

The most common adverse reaction reported was an increase in transaminases. The prescribing information for Beqvez includes risks associated with hepatotoxicity, infusion reactions, and malignancy (eg, hepatocellular carcinoma).

Beqvez is supplied as a vial containing a preservative-free suspension for IV infusion. Treatment is provided as a customized kit containing the number of vials required to meet dosing requirements for each patient based on their weight.

Bleeding Disorder Treatments: Hemophilia A

Bleeding Disorder Treatments: Hemophilia B

Bleeding Disorder Treatments: von Willebrand Disease

Cevidoplenib is an investigational spleen tyrosine kinase (SYK) inhibitor, designed to inhibit the downstream signaling of B-cell and Fc receptors resulting in increased platelet counts. The designation is supported by data from a randomized, placebo-controlled phase 2 study (ClinicalTrials.gov Identifier: NCT04056195). 

The trial assessed the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of cevidoplenib in 61 patients with persistent and chronic ITP who failed to respond or relapsed after prior therapy, with a platelet count of less than 30,000/µL. Study participants were randomly assigned to receive cevidoplenib 400mg, cevidoplenib 200mg, or placebo twice daily for 12 weeks.

Results showed 63.6% (14/22) of patients who received cevidoplenib 400mg and 46.2% (12/26) of those who received cevidoplenib 200mg achieved platelet response (primary endpoint; defined as platelet counts ≥30,000/µL and doubling the baseline [average of 2 previous counts] without the use of rescue medication) compared with 33.3% (4/12) of patients who received placebo (P =.151 and P =.504, respectively). 

Additionally, 50% of patients in the higher dose group achieved 2 or more consecutive platelet counts of at least 30,000/µL compared with 8.3% of those who received placebo (P =.015). Achievement of platelet counts of at least 50,000/µL was observed in 40.9% of patients receiving high dose cevidoplenib vs 8.3% of the placebo group (P =.055).

The most common adverse events reported were increased alanine transaminase (8.3%), increased aspartate aminotransferase (6.3%) and nausea (4.2%).

Oscotec is currently seeking partners for further development of cevidoplenib. “Obtaining [Orphan Drug designation] is an important milestone in the development of cevidoplenib and ultimately will benefit patients,” said Dr Taeyoung Yoon, CEO/CSO of Oscotec.