FDA Approves BioCryst Drug, First Oral Therapy for Rare Disease HAE

BioCryst logo

Patients who have hereditary angioedema, or HAE, can experience sudden and rapid swelling, often in the feet, hands, and abdomen. These unexpected attacks can also close off airways, potentially becoming fatal. Few treatments are available for this rare disorder but BioCryst Pharmaceuticals can now offer HAE patients another one.

The FDA late Thursday approved berotralstat, a drug the Durham company developed to prevent HAE attacks in adults and children 12 and older. The company will market the capsule under the name Orladeyo.

HAE stems from a mutation to a gene that provides the instructions for making C1-inhibitor, a protein that blocks enzymes associated with inflammation, such as kallikrein. There are two types of HAE. In type I, C1-inhibitor is deficient. In type II, that protein is dysfunctional. The BioCryst drug is a kallikrein inhibitor that comes in capsule form. The once-daily drug is intended to stand in for a patient’s deficient or dysfunctional C1-inhibitor, blocking kallikrein in the blood and preventing the swelling bouts characteristic of HAE.

BioCryst drug Orladeyo
BioCryst drug Orladeyo. -- BioCryst photo

FDA approval of berotralstat is based on results of a Phase 3 study that enrolled 121 patients randomly assigned to receive the drug at either the 110 mg and 150 mg doses, or a placebo. The study’s main goal was showing a reduction in the frequency of HAE attacks. Reduction in attack frequency was observed at 24 weeks, an effect that was sustained through 48 weeks. According to study results released by BioCryst, both doses of the drug showed a reduction in HAE attack rate of 44 percent from baseline, compared to a placebo. Half of the patients who received the high dose had a 70 percent or greater reduction in HAE attacks, compared to 15 percent of those given a placebo. BioCryst said the drug was well tolerated by patients. 

In results of a long-term safety study released a little more than a year ago, BioCryst reported that the most common side effect was the common cold, which it said occurred with similar frequency in both the test groups and the placebo arm. Gastrointestinal problems led 3 percent of patients in the study to stop taking the drug. The company said these reactions generally happened after the start of treatment, became less frequent over time, and in most cases self resolved. Adverse events related to the drug occurred in three of the 342 patients in the study. Those problems were addressed by stopping or interrupting the dosing of the drug, according to the company. 

Berotralstat is now set to join a small group of HAE drugs. All of the others are injectables. Ecallantide, which Takeda Pharmaceutical markets under the name Kalbitor, is a kallikrein inhibitor developed to treat acute HAE attacks. Preventive therapies include two other Takeda products, the antibody drug Takhyzro, and Cinryze, which is composed of functional C1-inhibitor extracted from human plasma. CSL Behring competes with a plasma-derived C1-inhibitor product it markets as Haegarda.  

Takhyrzro and Haegarda boast HAE attack reduction rates of 87 percent and 95 percent respectively, so BioCryst needs to win over patients by touting its drug’s convenience. Berotralstat is the first oral drug approved for the rare disease. BioCryst has set a wholesale price of $485,004 annually, or $37,308 for each 28-day supply of either the 150 mg or 110 mg packs of capsules.

Adds $325M in funding

BioCryst has just secured $325 million in financing from two entities to back the commercialization of berotralstat and to also support additional research and development. The first deal is with Royalty Pharma, a company that strikes financing agreements with biotech companies in exchange for royalties from their drug sales. According to terms of its deal with Royalty Pharma, BioCryst will receive $125 million up front. The royalty translates to 8.75 percent of annual sales of berotralstat up to $350 million. The royalty drops to 2.75 percent on sales between $350 million and $550 million. For sales above $550 million, there is no royalty, but Royalty Pharma is entitled to tiered payments from sales in certain territories that were not specified in the announcement.

The second deal is $200 million in debt financing from a fund managed by Athyrium Capital Management. BioCryst said it will receive $125 million when the deal closes. The biotech company has the option to draw on the rest of the money in two tranches upon reaching revenue milestones that were not disclosed. 

BioCryst plans to use the cash from both deals to support the launch of berotralstat in the U.S. and Europe. The funds will also support another compound in the pipeline, BCX9930. The preclinical compound is a potential treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disease in which the immune system destroys red blood cells. The disorder stems from dysfunction of a part of the immune system called the complement system. The top-selling PNH drug, eculizumab, marketed by Alexion Pharmaceuticals under the name Soliris, blocks a complement system protein called C5. The injectable drug costs about $500,000 annually. 

BioCryst designed BCX9930 to block a different complement system protein called Factor D. The drug comes in pill form, which would be a more convenient formulation for PNH patients. At the annual meeting of the American Society of Hematology, BioCryst released preclinical data showing that the drug blocked the rupturing of red blood cells. A Phase 1 dose-ranging study is currently underway. But BioCryst is still chasing Alexion, which is developing an oral Factor D inhibitor called danicopan. That drug, currently in Phase 3 testing, came to Alexion’s pipeline via the 2019 acquisition of Achillion Pharmaceuticals.

Berotralstat marks BioCryst’s second FDA approval, and its first for a rare disease. The company won FDA approval in 2014 for peramivir, an antiviral for influenza that is marketed as Rapivab. In 2015, BioCryst licensed the rights to that drug to Australian company CSL Limited and turned its focus to developing rare disease drugs, including berotralstat. CSL is the parent company of the world’s second-largest flu vaccine maker Seqirus, which has a newly expanded factory on its 185-acre campus in Holly Springs, to nearly a half million square feet – about the size of nine football fields.

Frank Vinluan, NCBiotech Writer
Sat, 12/05/2020 - 10:15