With a biologics license application (BLA) for BAX 111 (vonicog alfa) already pending at the FDA, investigators for the phase III study of the Baxalta Inc. therapy, branded Vonvendi, reported that 100 percent of patients treated with the recombinant, glycosylated von Willebrand factor (PSA-rvWF) achieved success in controlling bleeding. The data, which were presented in April at the Scientific Symposium of the Hemostasis and Thrombosis Research Society in New Orleans, were published Monday in Blood.

Vonvendi would become the first recombinant replacement treatment designed to manage bleeding episodes for von Willebrand patients, also representing a potential first approval for the recent spinout from Baxter International Inc. and an opportunity to extend Baxalta's hematology franchise in bleeding disorders beyond hemophilia.

Although von Willebrand disease is the most common hereditary bleeding disorder, much of the attention in the space has focused on hemophilia. Treatment options in von Willebrand, which has no cure, primarily include transfusion therapy and plasma-derived vWF concentrates. According to Cortellis Competitive Intelligence, products targeting the disorder are marketed by companies that include CSL Behring, Octapharma AG, LFB SA with partner Swedish Orphan Biovitrum AB, and Alpha Therapeutic Corp. with partner Grifols SA.

The field of von Willebrand therapeutics generated a bit of controversy a few years back, when the FDA took the first-ever step of rescinding orphan drug exclusivity for Octapharma's Wilate (vWF/coagulation factor VIII complex), saying it made a mistake two years earlier in determining the treatment was superior to CSL's previously approved Humate-P (human factor VIII/vWF complex). As a result, Wilate kept its orphan drug designation but lost its seven years of exclusivity, retroactive to its approval in December 2009 to treat spontaneous and trauma-induced bleeding episodes in certain patients with von Willebrand disease. (See BioWorld Today, Aug. 10, 2012.)

A year later, the FDA codified its action, drawing a line between orphan drug designation and exclusivity in a final rule that amended regulations issued in 1992 to implement the Orphan Drug Act. (See BioWorld Today, June 13, 2013.)

Vonvendi poses no such concerns. Unlike earlier vWF concentrates, the recombinant technology results in a more consistent concentration of ultra-large molecular weight multimers, which were shown in the lab to enhance platelet aggregation, explained John Orloff, Baxalta's head of research and development and chief scientific officer at Baxalta, based in Deerfield, Ill. The therapy was developed using a plasma- and albumin-free manufacturing method.

"This is really a differentiated product," Orloff told BioWorld Today. In addition to being the first recombinant product in von Willebrand, Vonvendi would become only the second product for the indication that is not combined with factor VIII. The recombinant nature of the product reduces the risk of viral contamination, Orloff said, while the separation from factor VIII reduces the risk of dosing-related thrombosis.

"This gives a lot more flexibility to physicians to individualize treatment," he pointed out, noting that only patients with low factor VIII level would typically need factor VIII in their initial infusion. Subsequent infusions, if needed, could be restricted to Vonvendi.

'PEAK SALES OF AT LEAST $500 MILLION'

Successive infusions might be rare, according to data from the open-label phase III trial of BAX 111, which assessed safety, efficacy and pharmacokinetics in the on-demand treatment of 37 patients with severe von Willebrand disease at sites in the U.S., Europe, Australia, Japan, Russia and India. The primary endpoint was the number of patients experiencing successful treatment for bleeding episodes, measured at 12 months. Secondary endpoints included additional efficacy measures, pharmacokinetics, the number of infusions and the number of units administered per bleeding episode.

Study participants reported a mean efficacy rating of <2.5 on a four-point scale, where one equaled excellent control and four equaled no bleeding control. Data indicated that one infusion was sufficient to control 81.8 percent of bleeds, with a median of two infusions required to treat major bleeds. No thrombotic events or severe allergic reactions were observed, and none of the participants developed anti-vWF binding or neutralizing antibodies to vWF.

"Most patients required only one infusion, and the half-life of this product is also longer than the other products, which is also a potential advantage," Orloff said.

The most common adverse events (AE) in the study were headache, vomiting/nausea and anemia, which were not considered treatment-related. One patient experienced two simultaneous serious AEs related to treatment, which were characterized by chest discomfort and increased heart rate during infusion. These resolved within three hours without further symptoms, according to the company.

The FDA and EMA granted orphan drug designation to the product in November 2010. Baxalta filed the BLA in December 2014. The company completed its midcycle review with the FDA "and there were no red flags," Orloff said, suggesting Vonvendi is on track for year-end approval. Launch is planned for mid-2016, since Baxalta wants to ensure sufficient product supply for the commercial market as well as continued studies. The company has a phase III of BAX 111 underway in patients with severe von Willebrand undergoing surgery and plans to initiate studies next year in prophylaxis use in adults and in pediatric use.

The phase III surgery study, due to report next year, will serve as the basis for a marketing authorization application with the EMA, which Baxalta expects to file in the first half of 2017, according to Orloff.

With an eye to the finish line in the U.S., the company is "working through" its approach to advancing and commercializing BAX 111 in the rest of the world, he added.

Sales figures for approved von Willebrand products were not broken out by the companies, but in Morningstar's most recent report on the hemophilia market in January 2013, analyst Karen Andersen projected the von Willebrand segment would account for approximately $389 million this year, representing approximately 3.6 percent of the estimated $10.8 billion therapeutic market for bleeding disorders. Those market figures are projected to grow to $436 million and $11.4 billion, respectively, in 2016.

In an update on the plasma market published in January, Andersen said products such as Alphanate from Grifols and Wilate from Octapharma are "most vulnerable to the introduction of Baxter's recombinant product," as "BAX 111 is likely to rapidly gain share."

Andersen also was bullish on Baxalta's second quarter results, reported last week, writing that "we continue to think that Baxalta's plasma leadership and hemophilia franchise warrant a narrow moat. Baxalta has an aggressive goal for 20 new drug approvals by 2020, and we now think upcoming approvals including Obizur in Europe, Adynovate (BAX 855) in the U.S., Vonvendi (BAX 111) in the U.S., and a 20 percent immunoglobulin (filed in Europe and filing in the U.S. this year) will help support 8 percent sales and adjusted EPS growth from 2015 to 2019."

Although Baxalta's initial focus on patients with severe von Willebrand – type 3 and certain type 2 patients – represents only about 1 percent of the von Willebrand patient population, "there are a lot of opportunities" even in this group, Orloff said. An estimated 700,000 patients worldwide fall into this category, but only 16,000 are currently on treatment.

Indeed, Baxalta CEO Ludwig Hantson said on the earnings call that, with Vonvendi, "we're branching out into new bleeding disorders," and predicted the von Willebrand treatment would serve "a significantly underdeveloped segment and [offer] potential for peak sales of at least $500 million."