Gene therapies have long been thought to be the next frontier in treatments for hemophilia. After 20 years without new innovation for the debilitating blood disorder, long-acting therapies came to market several years ago, changing the treatment landscape for patients. However, those new long-acting therapies only increased the time between treatments from daily to weekly; by contrast, gene therapies promise to increase the time between treatments to years, and could even be a cure for the bleeding disorder.

While most gene therapies for hemophilia are still in early stages, the promise for patients (and company’s bottom lines) means these therapies are being closely watched. Gene therapies (and a few other promising medicines) took center stage this week at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress in Berlin this week.

Lofty goals

BioMarin presented data from its open-label Phase 1/2 study of its hemophilia A gene therapy BMN 270, which was conducted in 15 severely sick patients. These patients had less than 1% of the clotting Factor VIII in their blood.

Hemophilia A patients have a defective gene that results in a deficiency of clotting Factor VIII, while hemophilia B patients — a smaller percentage of the population — have a deficiency in clotting Factor IX. Healthy individuals have between 50% to 150%

Patients in the BioMarin study received either a dose of 6e13 vg/kg or 4v13 vg/kg. As of the end of May, those patients receiving the 6v13 vg/kg dose had reached 52 weeks of follow-up. At one year after treatment with BMN 270, all of these patients had retained mean and median Factor VIII levels above 50%. Meanwhile, by week 24, all patients on the lower dose had gone from severe hemophilia to mild cases of the bleeding disorder.

Of those patients on the higher dose, five out of six had zero bleeds, and none required Factor VIII infusions after they reached levels of 5% or greater.

While both doses of the gene therapy showed positive data, BioMarin has the lofty goal of providing a cure for these severely ill patients and is moving the higher dose (6v13 vg/kg) into a Phase 3 registrational study in the fourth quarter of this year. The study design is still being determined, but the trial will likely have 100 patients and last less than a year with a year follow-up, the company said. Analysts believe that BMN 270 could hit he market as early as 2019 and be the first gene therapy for hemophilia A.

Spark Therapeutics and Sangamo Therapeutics are also both developing gene therapies for hemophilia A. Both companies had strong preclinical data for their respective candidates and are currently enrolling Phase 1 studies.

Sparking enthusiasm

Ahead of data for its hemophilia A treatment, investors are keeping a close watch on Spark’s hemophilia B gene therapy in hopes it will shed some light on the A therapy, which has a broader market potential.

Spark is already a pioneer in the field, with its gene therapy for a rare form of blindness currently being reviewed by the Food and Drug Administration — it could be the first gene therapy to hit the U.S. market. And how Spark handles issues such as pricing will be keenly observed.

While the biotech has already announced early data for its hemophilia B treatment, SPK-9001, it provided an update at ISTH. Ten patients have been given the treatment as of June 5, with five currently more than a year out from administration, and one having been administered the gene therapy more than 18 months ago.

Nine of the 10 patients haven’t experienced a bleed since receiving SPK-9001, and the infusion rate has been reduced by 99%.

The one patient that was infused 18 months ago now has a steady-state Factor IX level of about 33% of normal, a major improvement for the patient. In the year prior to the gene therapy, the patient had 98 infusions of Factor IX and experienced four breakthrough bleeds.

What makes this therapy especially exciting: it has partnered with Pfizer (although the big pharma recently partnered with Sangamo on its hemophilia A treatment).

Interesting competitors

While the gene therapies are certainly the most exciting and life-altering therapies in the pipeline, there are a few later-stage hemophilia drugs that could have blockbuster potential once they hit the market.

One of those is from Alnylam Pharmaceuticals, in partnership with Sanofi’s Genzyme unit. Fitusiran is a late-stage ready RNA-interference (RNAi) therapy that targets antithrombin, a protein made in the liver that blocks clotting. RNAi drugs alter snippets of genetic code that are the building blocks of proteins.

The companies presented further data from an open label extension of a Phase 2 study showing the drug was both safe and effective in hemophilia A and B patients. Of the 33 patients in the study, nearly half have not experienced a bleed during the 11 months on the drug. While the monthly dosed drug doesn't cure the disease like gene therapies could, it can reduce the bleeding events that patients experience. One of the only adverse events was the presence of elevated liver enzymes, which could be an indicator of liver toxicity. The company has proposed excluding patients with hepatitis C from further studies to avoid the complication.

The companies are potentially targeting patients with inhibitors — those that have developed an immune response to other treatments. “We also believe that the Phase 3 ATLAS program assessing fitusiran directly in the prophylactic setting as well as in the inhibitor and non-inhibitor settings will confirm that fitusiran is indeed positioned for broad use in hemophilia and potentially other blood-related disorders,” wrote Jefferies analyst Maury Raycroft in a note to clients.

Fitusiran’s biggest near-term competition is Roche’s Phase 3 emicizumab. The big pharma presented further data from the HAVEN 1 and HAVEN 2 studies, which are the underpinnings of its new drug application filings with both the FDA and EMA. Emicizumab is being studied in hemophilia patients with inhibitors, and analysts expect the drug to have peak sales of as much as $5 billion.

While the drug has had impressive reduction in bleeding, there has been some safety signals – though Roche argues that all of those patients that had adverse events were also treated with Shire’s Feiba. Shire isn’t happy about the implication and filed an injunction in a German court calling the claims “misleading.”

Even though the hemophilia market has remained stagnant for decades, highly innovative technologies promise to make this one of the hottest markets to watch over the next five years. Stay tuned.