The hemophilia drug market is well established with multiple drugs designed to replace the underlying deficiency: factor VIII for hemophilia A and factor IX for hemophilia B.

The drugs can be used on demand or as prophylactic treatments, but the latter can be draining on patients with multiple infusions each week. Even newer treatments, such as Eloctate (antihemophilic factor [recombinant], Fc fusion protein, Biogen Inc.) only increase the treatment cycle from infusions every two to three days as required by Advate (octocog alfa, Baxter International Inc.) to every three to five days for Eloctate.

And replacement therapy can lead to inhibitory antibodies against factor VIII and factor IX for hemophilia A and hemophilia B patients, respectively. Patients then transition onto bypassing agents, typically Novoseven RT (recombinant coagulation factor VIIa, Novo Nordisk A/S) or FEIBA (factor eight inhibitor bypassing activity), an anti-inhibitor coagulant complex from Baxter, which contains factors II, VII, IX and X derived from plasma.

Because of its short half-life, Novoseven RT can't be given as a prophylactic and is only dosed on demand when a bleed occurs. FEIBA can be given on demand or as a prophylactic, but the latter requires infusions every other day.

"The clear unmet need is prophylaxis to prevent bleeding rather than treat it," Nassim Usman, president and CEO of Catalyst Biosciences Inc., told BioWorld Insight.

EXTENDING AND REINVENTING THE WHEEL

At the International Society on Thrombosis and Haemostasis (ISTH) last week, Catalyst Biosciences presented phase I data on its next-generation and long-acting coagulation factor VIIa, CB 813d, which was called PF-05280602 until New York-based Pfizer Inc. returned rights to the drug earlier this year.

CB 813d shortened two measures of clotting time – activated partial thromboplastin time and prothrombin time – for up to 48 hours after dosing in hemophilia A and B patients in a dose-dependent manner.

Catalyst, of South San Francisco, plans to start a two-part efficacy trial in hemophilia A and B patients who have developed inhibitory antibodies. The first part will test the product as an on-demand treatment to build up more pharmacokinetic and pharmacodynamic data to determine potential schedules for prophylactic treatments. Based on the limited phase I data, Usman said he thinks it'll probably be dosed two to three times a week.

The clinical trial won't start until next year because the manufacturing has to be transferred from Pfizer to Catalyst's contract manufacturer.

"We're going for registration, so the production should be on the level of a commercial-scale protein," Usman said.

Rather than replacing factor proteins involved in the production of thrombin, Alnylam Pharmaceuticals Inc. is taking a different approach, using its RNAi therapeutic ALN-AT3 to knock down an inhibitor of thrombin called antithrombin.

"In hemophilia, the problem is ultimately an inability to make enough thrombin," John Maraganore, CEO of Alnylam, told BioWorld Insight. "ALN-AT3 essentially removes antithrombin from the system as a way of increasing thrombin generation, therefore rebalancing hemostasis."

In a phase I dose-escalation study presented at ISTH, ALN-AT3 was able to produce up to an 86 percent knockdown of antithrombin. As expected, the reduction of antithrombin resulted in thrombin generation with a mean increase of up to 350 percent.

In an exploratory posthoc analysis, Alnylam saw a reduced frequency of bleeding in patients with higher levels of antithrombin knockdown. One patient went 114 days without bleeding.

Alnylam, of Cambridge, Mass., plans to start pivotal studies measuring annualized bleeding rates in mid-2016 after continuing work to determine the best dose. Given the antithrombin knockdown lasted up to two months in the phase I trial, Maraganore said he believes ALN-AT3 could be available as a once-monthly subcutaneous injection.

"Today, subjects with hemophilia have to give intravenous infusions anywhere from two to three times a week, so it could be a game changer," Maraganore said.

CURE?

At ISTH, Baxter's subsidiary Baxalta Inc. gave an update on a phase I/II trial of BAX 335, its gene therapy treatment to replace factor IX in hemophilia B patients.

Seven patients have been treated at three different doses. While the lowest dose produced a modest effect, the two patients that received the middle dose have experienced no bleeds and haven't required regular infusions of factor IX. One of the patients has had factor IX expression levels of 20 percent to 25 percent for 12 months, which would be considered a mild phenotype.

The highest dose of BAX 335 produced peak factor IX expression levels above 50 percent, but the two patients both had an immune response and an elevation in liver enzymes that resulted in a decrease in expression of factor IX. One of the patients has gone back to regular factor IX infusions.

"Durability of effect in some [patients] was questionable and the liver enzyme elevation forces the field to consider several tough questions," Piper Jaffray analyst Joshua Schimmer wrote in a note to clients, pointing out that Deerfield, Ill.-based Baxter might want to try a prophylactic steroid treatment to reduce the likelihood of an immune response.

Gene therapy pioneer Uniqure BV also has a hemophilia B gene therapy program, AMT-060. In an update earlier this month, the Amsterdam-based company said it had commenced screening patients for its first clinical site in Germany and expected to have data from the trial in the second half of the year.

"We believe durable and consistent factor IX expression in hemophilia B patients above the 5 percent factor IX hurdle would be an important de-risking datapoint for Uniqure's AAV5-based liver-targeted gene therapy platform," Leerink analyst Michael Schmidt wrote in a note to clients.

As part of a deal with Chiesi Famaceutici SpA for its already-approved gene therapy Glybera (alipogene tiparvovec), Uniqure licensed the rights to its hemophilia B gene therapy program in Europe and several other territories to Chiesi, of Parma, Italy. (See BioWorld Today, July 10, 2013.)