Less than a month after Shire plc finished its $5.9 billion buyout of kallikrein player Dyax Corp., Biocryst Pharmaceuticals Inc.'s unhappy phase IIb data with an oral, liquid-filled soft-gel candidate avoralstat in the same class for hereditary angioedema (HAE) hobbled the firm on Wall Street and turned investor hopes toward the same drug's solid form, which has shown better, dose-dependent exposure for longer in preclinical models, along with a next-generation prospect.

"All of those features would be very helpful to have, and we'll know the answer pretty soon, because we're about to start a pharmacokinetics [PK] study in healthy subjects," chief medical officer William Sheridan said in a conference call with investors.

Research Triangle Park, N.C.-based Biocryst's shares (NASDAQ:BCRX) closed Monday at $1.78, down $4.36, or 71 percent.

The OPuS-2 (Oral ProphylaxiS-2) study with kallikrein inhibitor avoralstat given three times daily for the prophylactic treatment of HAE failed to show a benefit on the primary endpoint of preventing attacks. Thirty-eight subjects were given avoralstat 500 mg, 36 subjects got 300 mg, and 36 subjects received placebo. Treatment with 500 mg and 300 mg of the drug three times daily failed to demonstrate a statistically significantly lower mean attack rate versus placebo. The mean (standard deviation) attack rates per week were 0.63 (0.57) on avoralstat 500mg, 0.71 (0.66) on avoralstat 300mg, compared to 0.61 (0.41) on placebo, Biocryst said.

"I think the most telling data to explain the failure to meet the primary endpoint is the drug-exposure story," principal trial investigator Marc Riedl said. The hitch can be partly explained by variances in bioavailability, but there was also a problem with dosing intervals. "While the study makes every effort to have subjects stick with the compliance of every eight hours, that didn't happen in every case in this study," he said, adding that the placebo effect turned out pretty big. Although "it's certainly a known entity with parallel-group designs," and "doesn't explain the failure of the study," the 30 percent placebo rate was an issue, he said. "The overwhelming scientific and clinical evidence is that this target is correct," he add, and an oral kallikrein inhibitor is "highly anticipated among HAE specialists around the globe and [by] the patient community."

Dublin-based Shire in November agreed to buy Dyax, of Burlington, Mass., at the $5.9 billion price tag, and threw in the promise of $646 million more if the FDA approves DX-2930, a subcutaneously administered, kallikrein-targeting prophylactic antibody treatment for HAE set to enter phase III trials. Shire, Dyax, and Biocryst had been in a three-way kallikrein skirmish. (See BioWorld Today, April 2, 2015, and Nov. 3, 2015.)

J.P. Morgan analyst Jessica Fye called the OPuS-2 data "disappointing" and "a surprise," but Piper Jaffray's Charles Duncan said they are "not entirely unexpected, given that management has pointed to a second dosage form of avoralstat, or even second-generation compound BCX7353, as most likely to move forward." Pending more data, "and given increased execution risk that we perceive for its HAE program, as well as decreased visibility on the development path forward," Duncan was less than optimistic in a research report. "We are also pushing out first sales [of an oral kallikrein inhibitor] from 2019 to 2020 in the U.S. and 2021 in Europe, based on guidance on the company call today," he wrote. "These changes result in our new $5 price target, down from $15." He added that his firm is "unsure which development candidate will move forward" – the solid avoralstat or BCX7353.

CEO Jon Stonehouse said on the call that the solid form of avoralstat is dosed twice daily and BCX7353 once daily. PK data with the former should be available mid-year and phase II results with the latter are expected by the end of the year. Biocryst began 2016 with $100 million in cash and investments, so it's well-enough capitalized to get past both milestones, he said.


The company filed an 8-K a month ago with the SEC that provided more color on BCX7353, and Jefferies analyst Brian Abrahams found it encouraging. PK/pharmacodynamics data in healthy volunteers in Japan came from testing single doses of 100 mg and 500 mg, and seven days of dosing at 250 mg. The firm reported that patients on multiple doses "indeed experienced good inhibition of kallikrein, which if anything was actually greater than in the previously reported, non-Japanese volunteers (comparable to the prior 350 mg to 500 mg doses) – not surprising, given drug exposures are often higher in Japanese subjects," he wrote in a research report that detected a small cloud on the horizon. "With the additional 10 Japanese patients receiving multiple doses, it appears only one additional grade 2 adverse event was seen, and there were no concerning laboratory abnormalities or new safety issues. The grade 2 toxicity was a maculopapular rash, developing after completion of dosing and reversing with antihistamine. Taking this with the prior report of the grade 3 hypersensitivity reaction, and our discussion with the company suggesting that the temporal pattern appears similar for the two cases, it does appear more likely BCX7353 has an association with skin reactions/hypersensitivity, which had been a concern after the original data was reported and particularly given the very high safety bar set by competitor Dyax's HAE program."

On the upside with BCX7353, in Abraham's view, "the rates of skin reactions appear low (4 percent), perhaps more associated with higher exposures which may not be necessary for efficacy, and the new case was also less severe (less irritating, with less skin coverage); additionally, there has not been any mucosal involvement. Overall, if BCX7353 can improve upon avoralstat's efficacy meaningfully and the rash continues to be non-severe, reversible, and occurring at a low rate, [it] should remain commercially viable."