As expected, the FDA cleared Biocryst Pharmaceuticals Inc.’s oral, once-daily Orladeyo (berotralstat, formerly known as BCX-7353) for the prevention of hereditary angioedema (HAE) attacks.

Last month, Research Triangle Park, N.C.-based Biocryst, as part of its earnings report, said approvals of the compound, a kallikrein inhibitor evaluated by U.S. regulators without an advisory committee meeting, could come in Japan this month and in the EU by the first half of next year.

Wainwright analyst Andrew Fein said in a Nov. 6 report that he “continue[s] to believe that an approved oral treatment option can represent a significant advancement for HAE patients otherwise reliant on conventional injection, with the platform to be evaluated based on its execution post-approval and post-launch, in our view.”

Fein added that he was “encouraged by the U.K.’s Medicines and Healthcare Products Regulatory Agency providing a positive scientific opinion” in October of this year for Orladeyo, available through an early access program. He forecasted total revenue of about $60.6 million in 2021 and about $141.5 million in 2022, “assuming modest traction at launch and moderate pricing of approximately $380,000 per year,” though he said such estimates “could prove to be conservative.” His price estimate was: Biocryst set the wholesale acquisition cost at $485,004 annually, or $37,308 per 28-day pack of either 150-mg or 110-mg capsules.

The cost of Orladeyo proved higher than Jefferies’ Maury Raycroft had guessed, too, by about 40%. “Though a proportion of patients will want to switch their HAE medications to try an oral treatment, the responder analysis [included in the label] should be a key selling point,” he wrote in a report. A responder was defined as having at least a 50% relative reduction in HAE attacks during treatment vs. baseline. Biocryst said 58% of patients on 150 mg of the drug and 51% on 110 mg exceeded the bar.

In a Nov. 23 report when she started coverage of Biocryst, Evercore ISI analyst Liisa Bayko highlighted the debate over the use of Orladeyo, which works significantly less well than market leader Takhzyro (lanadelumab), also a kallikrein inhibitor, from Takeda Pharmaceutical Co. Ltd., of Tokyo. Takhzyro is self-injected every two weeks. “Bears ask why would anyone take this drug where there are more efficacious options,” she wrote. “Bulls wonder why anyone would not take Orladeyo since it’s oral. But what do the patients want? They want oral therapies.”

Bayko’s firm polled 25 allergists and immunologists actively seeing ≥10 HAE patients in their clinics. About 31% of prescriptions are written for Takhzyro now; with the approval, about 34% of doctors are expected to use Orladeyo, based on the Evercore ISI survey. In first-line therapy, the Biocryst drug could take 56% of prescriptions, in second line 48%, and in third line 4%. “Many of my patients are quite interested in this drug and have inquired,” she quoted one doctor as saying. The compound was deemed welcome because it delivers an option for patients “unwilling or unable to start parenteral therapy.” Other approved therapies in the space include Haegarda, the plasma-derived C1 esterase inhibitor from CSL Behring LLC, of King of Prussia, Pa.; Cinryze, also a C1 esterase inhibitor, from Tokyo-based Takeda Pharmaceutical Co. Ltd.; and the synthetic androgen danazol.

In the pivotal, phase III APeX-2 trial, Orladeyo significantly reduced attacks at 24 weeks, and the benefit held through 48 weeks. HAE patients who completed 48 weeks of treatment at 150 mg saw reductions in their HAE attack rates, from a mean of 2.9 per month at baseline to a mean of one per month after 48 weeks of therapy. In the long-term open-label APeX-S trial, patients completing 48 weeks of therapy at 150 mg recorded a mean attack rate of 0.8 per month.

Kalvista in play with oral therapy

The compound proved safe and well-tolerated in both trials. The most frequently reported adverse reactions in patients on drug compared with placebo were gastrointestinal reactions, which generally turned up early after the start of treatment. They became less frequent as time went on, and typically self-resolved.

J.P. Morgan analyst Jessica Fye welcomed the “clearly positive” green light for Orladeyo. “We had a chance to catch up with the company which said they are ‘thrilled with the label,’” she wrote in a report. The language includes no boxed warnings and no contraindications. “Importantly, we see this news enabling potential royalty-backed funding options (the terms of which should be better with approval in hand) which could help address concerns around cash runway,” in her view.

Biocryst ended the third quarter with $148.5 million in cash and investments, and Fye projected about $116 million at the end of the year with no additional funding. “We will listen for more details on the launch at the J.P. Morgan Healthcare Conference [in January], and expect execution on that in addition to cash runway to be important drivers of stock performance going forward.” Although she expects “some debate around the opportunity for Orladeyo will persist, we see upside over time from current depressed levels and see an interesting entry point in the stock with the launch for Orladeyo in HAE ahead.” Shares of Biocryst (NASDAQ:BCRX) closed Dec. 4 at $6.10, up 96 cents, or 18.8%.

Also on the horizon with an oral kallikrein inhibitor strategy in HAE is Kalvista Pharmaceuticals Inc., of Cambridge, Mass., which in October gave Wall Street an update on the program testing KVD-900. Phase II recruitment was declared complete, with data due before the end of this year. Another candidate, KVD-824, achieved targeted exposure levels for HAE prophylaxis and an IND is due in the first quarter of next year. SVB Leerink analyst Joseph Schwartz likes the setup, and wrote in a Nov. 16 report that he believes KVD-900 is poised to be the “first sufficiently effective oral on-demand therapy, and the company's chemistry expertise has strong potential to extend to KVD-824, [its] twice-daily oral plasma kallikrein inhibitor for the prevention of attacks.” Kalvista said “optimization work has yielded a formulation that maintains the concentrations required to compete with approved injectable prophylactic therapies,” he noted.

In October 2014, Biocryst gained approval of the injected neuraminidase inhibitor Rapivab (peramivir) to treat influenza in adults. The label was expanded in September 2017 to include the treatment of acute uncomplicated flu in pediatric patients two years and older who have been symptomatic for no more than two days.