At the World Federation of Hemophilia (WFH) 2018 World Congress, the old and new guard of companies developing hemophilia treatments presented their plans to change the market.

The incumbents, Novo Nordisk A/S and Bioverativ Inc., are looking to improve on the status quo with their next-generation factor replacement drugs that last longer than current versions.

Bioverativ, of Waltham Mass., presented preliminary data from its ongoing EXTEN-A phase I/IIa trial testing BIVV-001, a fusion protein containing factor VIII, a region of the Fc dimer, von Willebrand factor and XTEN, in patients with severe hemophilia A, defined as having less than 1 percent factor VIII activity.

BIVV-001 builds on Bioverativ's Eloctate (rFVIIIFc), which uses the Fc dimer to increase the half-life of factor VIII. The XTEN polypeptides, licensed from Mountain View, Calif.-based Amunix Inc., help further increase the half-life of the protein. As does the von Willebrand factor, which is normally expressed separately and binds to factor VIII in circulation, extending its half-life.

"Von Willebrand factor has a fairly short half life," John Cox, Bioverativ's CEO, explained to BioWorld Insight. "That von Willebrand factor ceiling is what has made it so difficult – in fact, impossible – for anyone over the last couple of decades to go much further with the half-life of factor VIII."

By adding the region of von Willebrand factor that binds to factor VIII to BIVV-001, which falls off when factor VIII is needed for clotting, Bioverativ has been able to extend the half-life of factor VIII extensively.

"It's the most elegantly engendered recombinant protein I have ever seen," Cox said.

Preliminary data from the EXTEN-A trial showed that a single low dose of BIVV-001 had a half-life of 37 hours, roughly threefold longer than factor VIII. In four patients, the average activity was 13 percent over five days and 5.6 percent over seven days, a solid increase considering moderate hemophilia A is characterized by factor levels of 1 percent to 5 percent.

Bioverativ, which Paris-based Sanofi SA acquired earlier this year, plans to continue the trial with a high-dose cohort before moving on to a phase III trial where it'll look at annualized bleeding rates and other outcomes, including joint deterioration. (See BioWorld, Jan. 23, 2018.)

The increase in half-life is more than just an improvement on convenience with less frequent dosing. "The potential to transform outcomes for these patients and really elevate the standard of care for hemophilia patients with this type of transformative [pharmacokinetics] profile with a factor VIII product is significant," Cox said, noting that even when bleeding is kept to a minimum with the current standard of care, patients' joints still deteriorate over time.

Likewise Novo Nordisk, of Bagsvaerd, Denmark, presented data at WFH showing Refixia, its pegylated long-lasting factor IX, works better than factor-IX-Fc in hemophilia B patients.

In the head-to-head paradigm7 study in 15 patients, Refixia had a half-life of 103.2 hours, significantly longer than the 84.9 hours seen for factor-IX-Fc, which translated into a factor IX exposure that was 4.39-fold greater than factor-IX-Fc. After seven days, the activity of patients treated with Refixia was sixfold greater than for those treated with factor-IX-Fc.

Not only did the activity last longer, but it also started earlier, with total factor IX activity levels 30 minutes after infusion of Refixia that were twofold greater compared to factor-IX-Fc, despite both being given at the same 50-IU/kg dose.

"This is much more than convenience because the key for any hemophilia patient is to keep their factor levels high for as long as possible to prevent bleeds," Christian Kanstrup, senior vice president of biopharm operations at Novo Nordisk, told BioWorld Insight, noting that the high initial level and longer half-life combine to increase both the peaks and troughs of activity between doses.

Gene therapy looks to take over

Meanwhile up-and-comers Biomarin Pharmaceuticals Inc. and Spark Therapeutics Inc. are looking to disrupt the industry with their gene therapies.

Biomarin has already started phase III trials for its factor VIII gene therapy, valoctocogene roxaparvovec (val rox), but WFH gave the San Rafael, Calif.-based company an opportunity to present updated data for patients in its phase I/II trial.

For the higher dose of 6e13 vg/kg, two years after infusion, the mean factor VIII activity level was within the normal range at 59 percent, while the median level was near normal at 46 percent. The values are down from the last update, a year and half after treatment, where the mean and median were 89 percent and 90 percent, respectively.

Biomarin's management wasn't surprised by the decrease because that's what's been seen in preclinical animal studies where initial high expression comes from linear double-stranded DNA monomers, which eventually become circular double-stranded DNA monomers and concatemers, which produce stable expression that persists for years in animals.

"Because the initial peak, leveling out to a sustained durable level of expression in preclinical studies, is similar to that seen in the first two years of our clinical data, it leads us to be optimistic that this is the profile we will see going forward," Stuart Bunting, Biomarin's head of translational biology, explained to investors on a call after the data were presented at WFH.

While the efficacy has come down, Piper Jaffray analyst Christopher Raymond pointed out that the decline in expression has an added benefit of increasing the safety profile. With the average sitting close to 100 percent of normal, there was worry that the higher dose could produce abnormally high levels of factor VIII in some patients. "On safety, with no factor VIII activity above the upper limit of normal in the 6e13 cohort, prior concerns over factor VIII overexpression just evaporated," he wrote in a note to clients.

Importantly, the expression of factor VIII led to a 97 percent reduction in mean annualized bleed rate, with no spontaneous bleeds and elimination of all bleeds in target joints in the second year. The treatment also reduced the mean level of factor VIII usage by 96 percent.

With solid efficacy data, Biomarin decided to increase the enrollment in its pivotal GENEr8-1 phase III trial from 40 patients to 130 patients to power the study to measure superiority of val rox to prophylactic therapy, the current standard of care (SOC).

"While expansion of the GENEr8-1 pivotal trial caught us by surprise, we believe ultimately the superiority claim versus SOC can only strengthen the product profile and the resultant delay is minimal (approximately one quarter)," J.P. Morgan analyst Cory Kasimov wrote in a note to clients.

Spark, which is partnered with New York-based Pfizer for its hemophilia gene therapy program, also presented updated phase I/II data at WFH. The company has enhanced its manufacturing process for SPK-9001, leading to better expression of factor IX to help hemophilia B patients.

The range of steady-state factor IX activity level was 38.1 percent to 54.5 percent for the three patients who had 12 or more weeks of follow-up that were treated with SPK-9001 manufactured using the enhanced process. The first 12 patients treated with the old manufacturing procedure had factor IX activity of 14.3 percent to 76.8 percent from 12 weeks through 52 weeks of follow-up.

"While still early and the patient number is low these results could also indicate that the new process could potentially be less variable than the original manufacturing process – which would be a surprising positive as even more consistent results could alleviate one of the chief concerns that we have heard from [key opinion leaders], which is consistency," Jefferies analyst Michael Yee opined in a note to clients.

While gene therapy has the potential to disrupt the industry, both Novo Nordisk's Kanstrup and Bioverativ's Cox were taking a wait-and-see approach.

"Let's see what the efficacy is relative to the risk," Kanstrup cautioned.

"There is still a lot to be learned," Cox said about gene therapy, noting that factor replacement with protein is predicable and well understood by doctors.