The shake-up caused by convincing phase Ib data from Dyax Corp. with its subcutaneously delivered kallikrein inhibitor DX-2930 for preventing attacks of hereditary angioedema (HAE) left followers of Shire plc mulling the future of that firm's marketed C1-esterase inhibitor Cinryze, given intravenously, and may have sweetened the prospects for Biocryst Pharmaceuticals Inc.'s early stage, oral, kallikrein-targeter BCX-4161.

"We certainly believe that [DX-2930 data] should qualify for breakthrough" status, said Burt Adelman, chief medical officer (CMO) of Dyax, during a conference call with investors, adding that the company is "strongly considering that application." The compound, like Research Triangle Park, N.C.-based Biocryst's, already has fast track designation.

Dyax's stock (NASDAQ:DYAX) closed Wednesday at $25.75, up $9, or 53.7 percent on results from the ongoing study, a multi-center, randomized, double-blind, placebo-controlled, multiple-ascending dose experiment testing the safety, tolerability and pharmacokinetics of DX-2930 in HAE.

Thirty-seven people were randomized 2:1 to get the drug or placebo at doses of 30, 100, 300 or 400 mg. Each was given two doses of DX-2930 or placebo, separated by 14 days, and each was followed for 15 weeks after the second dose. No serious adverse events or dose-limiting toxicities turned up, and DX-2930 proved well tolerated at all dose levels, with no deaths or discontinuations because of an adverse event.

If the results stay at this level in further testing, Burlington, Mass-based Dyax's therapy could carve into the market for much-prescribed Cinryze, the HAE therapy gained by Shire, of Dublin, in its $4.2 billion buyout of Exton, Pa.-based Viropharma Inc. Shire's stock (NASDAQ:SHPG) closed at $232.31, down $6.48. (See BioWorld Today, Nov. 12, 2013.)

RBC Dominion Securities analyst Douglas Miehm noted that although his firm "generally do[es] not assign material value to early stage trial results, we believe the apparent strength of these data calls for some caution." In a research report, he pointed to the primary proof-of-concept analysis done on the 300-mg and 400-mg subgroups given DX-2930, which found that HAE attacks were reduced by 100 percent (p <0.0001) and 88 percent (p = 0.005) respectively, as compared to placebo.

Yung Chyung, vice president of medical research for Dyax, said during the conference call that the firm "will have to go to the data" for a decision on which dose to carry forward. With regard to dosing frequency, "we're going to look to the data again and consider what makes sense from what the right drug levels are and what you have to maintain to prevent attacks. We're still working on that," he said, and the company might "modulate the treatment frequency as well as the actual dose itself" after more closely scrutinizing the results.

Analyst Miehm cited administration upside for DX-2930 over Cinryze as well, with Dyax's drug only administered twice over a 12-week period rather than two times per week for Cinryze in the same time frame. "If all goes as expected, Dyax's pivotal trial for DX-2930 could start by year-end of 2015," Miehm wrote, with data potentially available by late 2016 or early 2017, and a launch in the second half of 2017.

Cinryze sells about $500 million per year for Shire, and is expected to hit about $600 million this year. If the Dyax therapy continues to limit the number of future acute attacks in HAE patients, as suggested in the phase Ib results, Firazyr [icatibant, Shire plc] "could face some risks as well," Miehm noted.

MANUFACTURING IN PLACE

On behalf of Biocryst, Piper Jaffray analyst Charles Duncan was less worried. "Although the [Dyax] data are encouraging from this small, early study and [they] add to the evidence for kallikrein targeting in HAE, consistent with the target for Biocryst's two small-molecule candidates, we note an unclear dose response and differences in patient populations that may make this the point of maximal near-term optimism for the mind-share competitor," Duncan said, adding in a research report that his firm "continue[s] to believe Biocryst is developing a potential 'game-changing' oral candidate with significant potential to become a new standard of care in HAE prophylaxis," no matter what the dosing regimen. (See BioWorld Today, May 24, 2014.)

Biocryst shares (NASDAQ:BCRX) ended Wednesday at $9.99, up 96 cents.

Chyung reminded listeners on the call that much is yet to be learned from the available data. "Not every single one of the 400-mg subjects has gone all the way to day 120, so it will be interesting as their drug levels decline over time, if they start having attacks again," he said. The company still needs "to get better information about when, at what drug level [do the attacks happen]? What biological activity might be associated with attack vulnerability? We'll see what the data show, but we're going to be going through that analysis in the near future."

Analyst Philip Nadeau of Cowen and Co. wanted to know about injection-site reactions with DX-2930, which "seem to be quite transient" but worth taking into account. "To what do you attribute those? Do you think they're due to drug at all, or are those just likely to be reactions to the injection itself?"

That's unclear, too. "We don't know," Chyung said. "There was no apparent safety signal or tolerability signal we could see. As we pointed out, there was no significant difference between the DX-2930-treated patients and the placebo patients. That one [incident of] severe injection-site pain lasted one minute. So we don't know what to make of it. We'll continue to track this, along with regular safety monitoring."

CMO Adelman said the question of how long the next study with DX-2930 should be is also up in the air. "That's a conversation that we're going to have to have with the FDA and with the EMA, and I won't speculate on it," he said. "Whether it's three months or six months, I don't think we're very concerned about that as long as we fully understand what the requirements are and [as long as,] when we get started, we know that if we cross the finish line successfully, it will fulfill the regulatory expectations."

As for manufacturing, "I think we're doing great," Adelman said. "We have both a commercial scale manufacturer for the drug substance and we've recently signed on with a very excellent fill/finish shop. We haven't revealed the names of those places to anyone," but at the moment, the company "[doesn't] believe that there would be any delay in the overall program" while waiting for the commercial manufacturing to reach the needed level.