DUBLIN – Try as they might, management at Alnylam Pharmaceuticals Inc. was unable to shake off investor concerns that the company's RNAi drug, givosiran, may have a problematic safety profile, despite hitting the primary endpoint of the Envision phase III trial in acute hepatic porphyria (AHP) with a very robust level of significance.

Imbalances between the drug treatment (n=48) and the placebo (n=46) arms in terms of serious adverse events (20.8 percent vs. 8.7 percent), liver enzyme elevations (14.6 percent vs. 2.2%) and the occurrence of chronic kidney disease (10.4 percent vs. 0 percent) all contributed to perceptions that givosiran could increase the risk of damage to the very organs whose function is already compromised by the normal course of the disease.

None of those events had a major impact on patient treatment, however.

Just one participant discontinued the study due to having alanine aminotransferase (ALT) elevations over eight times higher than the upper limit of normal. That precaution was predefined in the study protocol – and the problem subsequently resolved. Of the other six patients on givosiran who had elevated ALT, five resolved after continued drug dosing, and one resumed treatment after a brief pause.

"What we look for are adverse events leading to discontinuations," Akin Akinc, general manager of the givosiran program at Cambridge, Mass.-based Alnylam, told BioWorld.

Tellingly, all eligible patients (93/94) opted to enroll in an ongoing open-label extension (OLE) study. "I think we're definitely encouraged by that." An earlier OLE study that followed its phase I/II trial, provides Alnylam with some additional comfort on the safety side, even if it involves small numbers. "We have patients out there who've been on therapy for two years now," Akinc said.

The drug, moreover, aced the composite primary endpoint, which comprised reductions in the annualized rate of acute intermittent porphyria (AIP) attacks requiring hospitalization, an urgent health care visit or administration of hemin, the current standard of care, with a high level of statistical significance (p=6.04 x 10-9).

"On the whole, the robust significance across all components of the primary endpoint in the population should enable approval," Piper Jaffray analyst Edward Tenthoff wrote in an investor note.

Givosiran would be the first preventive therapy to gain approval in AHP. Hemin, a decades old blood product, is administered three to four times daily during hospital stays. "It is a pretty involved and intensive therapy," Akinc said.

The company has yet to disclose the actual level of reduction of AIP attacks. It plans to do so next month at the International Liver Congress in Vienna. At the same event last year, it reported a mean decrease of more than 75 percent in annualized attacks vs. placebo in a phase I study. Repeating that feat in the larger study would be a home run. Moreover, that metric improved even further, to more than 90 percent, after longer dosing during a phase I/II OLE study. (See BioWorld, April 16, 2018.)

Acute hepatic porphyria (AHP) comprises a set of rare genetic conditions caused by mutations in one of eight enzymes involved in heme biosynthesis. The most common subtype, acute intermittent porphyria (AIP), arises from mutations in the gene encoding hydroxymethylbilane synthase, which catalyzes the third step in the pathway. Eighty-nine of the 94 patients enrolled in Envision had genetically confirmed AIP. The condition leads to an accumulation of two toxic intermediates, delta aminolevulinic acid (ALA) and porphobilinogen (PBG), which are generated by the first two steps in the pathway. Givosiran is designed to shut down ALA and PBG production, by targeting translation of the mRNA encoding aminolevulinic acid synthase 1 (ALAS1), which catalyzes the first step in the pathway.

According to Alnylam's top-line Envision data, givosiran reduced synthesis of ALA at three and six months and of PBG at six months with high levels of statistical significance (p=8.74x10-14; p=6.24x10-7, p=8.80x10-7, respectively). It also hit its mark on two other secondary endpoints, reduction at six months of annualized days of hemin administration and reduction in annualized rate of attack of any AHP.

It failed to reach significance on four other secondary endpoints, however, including pain, fatigue, nausea and a health-related quality of life, although it demonstrated positive trends on all of those measures. "These benefits may become more significant once longer one-year data is revealed," Evercore ISI analyst Josh Schimmer wrote in an investor note.

"This was a small, short-term study," Alnylam R&D president Akshay Vaishnaw said on an analyst call Wednesday. "It's a matter of power in all likelihood."

The OLE study will have a 12-month readout on those endpoints, but Alnylam CEO John Maraganore emphasized that "the primary endpoint is what matters from a regulatory perspective."

Aiming for 2020 launch

Alnylam aims to complete a rolling NDA for the drug around midyear and to file a marketing authorization application in Europe shortly afterward. With breakthrough therapy designation in the U.S. and Prime status in Europe, the drug will receive accelerated assessment in each jurisdiction.

"Assuming regulatory approval, we expect to launch givosiran in early 2020," said Alnylam President Barry Greene.

The company plans to implement an expanded access program to allow patients to get on drug in advance of its launch. It is also ramping up disease awareness and physician education initiatives in advance of a potential approval. A free genetic testing service, which is currently available in the U.S. and Canada only, picked up 31 new diagnoses from 305 submitted samples. If scaled up further, that could widen what is currently a limited opportunity for Alnylam. AHP is very often confused with other conditions, and a correct diagnosis can take more than a decade.

Envision represents the first phase III readout of an RNAi drug based on the N-acetylgalactosamine (GalNAc) conjugation technology, which offers far more efficient delivery to liver cells than the lipid nanoparticle formulation used with Alnylam's first approved drug, Onpattro (patisiran), cleared for hereditary transthyretin-mediated amyloidosis. The safety issues seen in the study "do not appear to read through to [the] rest of [the] platform given totality of data in other settings," Schimmer noted.

Evercore upped its price target on the stock, from $87 to $110, on the strength of its RNAi platform and the lack of competition compared with other biotechnology segments.

Cowen & Co. is even more bullish with a share price target of $147

The company's stock (NASDAQ:ALNY) slid as much as 8 percent downwards during pre-market trading Wednesday, although it recovered some of that ground later in the day, to close at $84.75, down $3.56.