Alnylam's hemophilia candidate reduces levels of anticoagulant in PhI study

RNAi specialist Alnylam ($ALNY) said that development of its early-stage, subcutaneous compound for hemophilia and rare bleeding will be accelerated following ongoing Phase I trial results, which indicated that the candidate can knock down levels of the anticoagulant known as antithrombin (AT) by up to 86%. Pivotal trials for FDA approval are slated to begin in mid-2016.

The company's stock fell 7% following the news on June 23, when the data dump occurred at the Toronto's International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress. But Deutsche Bank analyst Alethia Young told Benzinga, "We don't see anything related to the data presentation" in the stock price decline. "Everything is on track."

Indeed, the sell-off has continued since then, indicating that investors probably reacted to something else, not a generally positive trial of an early-stage candidate.

The data from 12 patients with severe hemophilia who participated in the open-label, multidose, dose-escalation study found durable signals of a reduction in AT. The subjects received three weekly subcutaneous doses of the candidate (ALN-AT3) at doses of 15, 45, or 75 mcg/kg with a volume per injection ranging from 0.2 to 0.7 mL, according to the release.

At the maximum dose of 75 mcg/kg (as opposed to 15 or 45 mcg/kg), the mean maximum AT knockdown was 59%, Alnylam said. In addition, the knockdown lasted more than two months after the last dose.

On the safety side, the company reported that candidate was well tolerated and generated no serious adverse events.

Alnylam Chief Medical Officer Akshay Vaishnaw

"With the potential for infrequent subcutaneous dose administration and possible correction of disease phenotype, we believe that ALN-AT3 represents an innovative investigational medicine for the treatment of hemophilia and rare bleeding disorders. We regard these new results from our ongoing Phase I study as very promising, as they demonstrate clinical activity for ALN-AT3 toward AT knockdown and a re-balancing of hemostasis with a normalization of thrombin generation and improved whole blood clot formation," said Alynlam Chief Medical Officer Dr. Akshay Vaishnaw in a statement, adding, "We also look forward to presenting additional data from our ongoing Phase I study, including results from hemophilia subjects receiving a once-monthly subcutaneous dose regimen, later this year."

The initial dose cohort received the candidate at a dose of 225 mcg/kg, equivalent to three dosages of the maximum dosage in the just-completed round of patients dosed weekly.

In addition, an exploratory post hoc analysis demonstrated signs that the candidate's AT knockdown was associated with a reduction in bleeding events.

Alnylam believes the long-acting subcutaneous candidate could become a viable option for patients who receive "on demand" therapy or those who have developed inhibitory antibodies to other hemophilia meds.

Alnylam accomplishes gene silencing using novel RNAi drug delivery techniques. Alnylam's GalNAc-siRNA platform uses the sugar molecule GalNAc conjugated to the RNA molecule to enable subcutaneous delivery.

Alnylam COO Barry Greene

"When we say delivery, we're talking about getting the siRNA [small interfering RNA], which is the drug that intermediates RNAi into the cytoplasm of the cell, which is where the RNAi machinery works," Alnylam COO Barry Greene said in a previous interview with FierceDrugDelivery.

The naturally occurring RNAi paradigm's discovery in 1998 earned scientists Andrew Fire and Craig Mello a Nobel Prize in 2006. But no RNAi compounds have been commercialized so far. Alnylam is one of the leaders in the scramble to the end zone thanks to its two Phase III candidate for TTR-mediated amyloidosis.

- read the release

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