On World Hemophilia Day, Some of the Top Advances

scientist examining blood vials with word hemophilia on screen

April 17, 2019, is the 29th World Hemophilia Day, a designated day to create awareness of the disease. Hemophilia is one of a number of bleeding disorders. The blood of people with hemophilia does not clot normally as the result of insufficient clotting factor. As a result, they can bleed for a longer time.

The most common form of hemophilia is hemophilia A, caused by insufficient amounts of clotting Factor VIII. Hemophilia B is less common, caused by insufficient clotting Factor IX. The overall result, however, is the same, they bleed for longer than normal. In the most severe cases, spontaneous bleeding can occur, often into joints and muscle. Almost all people with hemophilia have prolonged bleeding after injury, and women with hemophilia often experience menorrhagia, heavy menstrual periods, and may hemorrhage after childbirth.

According to the U.S. Centers for Disease Control and Prevention (CDC), hemophilia occurs in about 1 in 5,000 live births. In the U.S. about 20,000 people have hemophilia. Hemophilia A is four times more common than hemophilia B. More than half of people with hemophilia A have the severe form of the disease.

The primary treatment for hemophilia A is a concentrated FVIII product. About 75% of patients with hemophilia A receive an FVIII product developed using recombination DNA technology, with about 25% using FVIII product derived from human donor plasma.

However, a number of biopharma companies are making progress in developing treatments, therapies, and potentially even cures. Let’s take a look.

Takeda’s Adynovate in Hemophilia A

On February 6, 2019, Takeda Pharmaceutical released data from its Phase IIIb/IV clinical trial for Adynovate at the 12th Annual Congress of the European Association of Haemophilia and Allied Disorders (EAHAD).

The data released from the PROPEL study compared the safety and efficacy of Adynovate after PK-guided prophylaxis targeting two different FVIII trough levels in patients with severe hemophilia A. The bottom line was the data suggested that optimizing FVIII profiles via PK-driven dosing that targets trough levels 8 to 12 percent was consistently achievable and that a personalized medicine approach for treating hemophilia A should be considered.

“The study reiterates the importance of personalized prophylaxis for those living with hemophilia,” stated Robert Klamroth, Head of the Department of Internal Medicine Angiology and Coagulation Disorders and Director of the Comprehensive Care Haemophilia Treatment Center and the Haemostasis and Thrombosis Unit at the Vivantes Klinikum in Berlin, Germany.

Kamroth added, “The findings suggest the need to measure actual FVIII levels and show a clear trend that if we’re able to keep FVIII levels in a higher range, there may be better patient outcomes, including enhanced bleed protection that could help more patients reach zero bleeds.”

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uniQure’s Hemophilia B Therapy Showed Promise in Phase IIb Clinical Trial

On February 8, 2019, Lexington, Mass. and Amsterdam, the Netherlands-based uniQure updated its Phase IIb trial of AMT-061 in hemophilia B. AMT-061 is an AAV5-based gene therapy that contains an FIX-Padua variant, meaning a patent-protected form of Factor IX, the missing or insufficient protein that results in the disease.

In this segment of the trial, three patients with severe hemophilia, whose FIX activity was less than 1 percent, were enrolled. They received a single intravenous dose of the therapy. Before receiving AMT-061, all three patients were tested and found to have low levels of pre-existing antibodies to AAV5, but that did not exclude them from the trial.

Earlier data showed that all three patients had increasing and sustained levels of FIX after the one-time administration. Mean FIX activity at 12 weeks increased to 38 percent of normal, which exceeds threshold FIX levels clinical considered sufficient to prevent or at least significantly decrease the risk of bleeding events.

At 16 weeks, the first patient had 48 percent of normal levels. FIX activity in the second patient was 25 percent at Week 14, and the third patient had 51 percent of normal at 12 weeks. The second and third patients were excluded from another gene therapy earlier because of pre-existing neutralizing antibodies to a different AAV vector.

“We are extremely pleased with these updated data,” stated Robert Gut, chief medical officer of uniQure. “The study demonstrates AMT-061 has the potential to increase FIX activity into the normal range and continues to be very well tolerated, with no serious adverse events reported and no patients requiring any immunosuppression therapy. We look forward to providing further updates on these patients later in the year at other academic conferences.”

Roche Acquired Spark Therapeutics

In February 2019, Roche acquired Philadelphia-based Spark Therapeutics for about $4.8 billion. In 2018, the U.S. Food and Drug Administration (FDA) approved Spark’s Luxturna (voretigene neparvovec), a gene therapy for a rare, genetic form of blindness. But also of interest is Spark’s gene therapy for hemophilia A. In August 2018, Spark released mid-stage clinical data showing a one-time treatment yielded a 97% response rate in reduced bleeding events. Additional data provided at the American Society of Hematology meeting in December 2018 also showed a strong response from patients in addition to a strong safety profile.

Severin Schwan, Roche’s chief executive officer, indicated that the hemophilia trial is one of the primary drivers of the acquisition. The therapy will complement Roche’s hemophilia treatment Hemlibra. A 2018 approval for a second indication made Hemlibra the only prophylactic treatment for people with hemophilia A and without Factor VIII inhibitors that can be administered subcutaneously.

BioMarin Prepares to Submit Valrox for Hemophilia A to Regulators

Although no official announcement has been made yet, BioMarin Pharmaceutical has projected since mid-2018 that it would submit its Valrox (valoctocogene roxaparvovec) to regulators for hemophilia A. In a development pipeline R&D Day presentation on November 1, 2018, the company discussed the possibility the gene therapy might benefit from new FDA guidelines that might accelerate approval. Valrox is a gene therapy that uses a viral vector to deliver a functional gene for factor VIII.

At the update, Geoff Nichol, BioMarin’s chief medical officer, stated, “Valrox Phase I/II data conforms to regulatory requirements for expedited registration.” He also indicated that by the time they file the company should have three-and-a-half years of data from the Phase I/II trial.

On May 22, 2018, the company updated the Valrox trial information. The gene therapy appeared to decrease a need for factor VIII infusions by 97% after a single dose of the therapy. In a one-year follow-up, 71% had zero bleeds, and in two years, 86% had zero bleeds that required factor VIII infusions.

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