Alnylam Pharmaceuticals Inc. said the 164-patient Helios-A phase III study with next-generation RNAi drug vutrisiran hit its primary endpoint as well as both secondary goals in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy.

CEO John Maraganore, pointing to the new product’s convenient dosing – once per quarter, subcutaneously – said officials are “quite confident that this will be used increasingly above and beyond even where Onpattro [patisiran] is today in the mixed-phenotype patients for the treatment of polyneuropathy either alone, which happens very frequently, or in combination with TTR stabilizers. It's really that mixed-phenotype segment that is the greatest growth opportunity for the current label of our products in the hATTR polyneuropathy space.”

The primary endpoint was change from baseline in the modified Neuropathy Impairment Score at nine months as compared to historical placebo data from the Apollo phase III study of Alnylam’s Onpattro, cleared by the FDA for ATTR polyneuropathy in August 2018. (Alnylam has provided worldwide sales guidance for 2020 of $295 million to $310 million; Onpattro is infused every three weeks.) The two secondary endpoints in Helios-A were changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and gait speed assessed by the timed 10-meter walk test (10-MWT) compared to historical placebo.

John Maraganore, CEO, Alnylam

Vutrisiran met the primary endpoint (p<0.001) and achieved statistically significant results (p<0.001) for each of the Norfolk QoL-DN and 10-MWT secondary endpoints. The drug showed improvement compared to placebo, too, on the exploratory cardiac biomarker endpoint, NT-proBNP (nominal p <0.05). An encouraging safety and tolerability profile topped off the dataset.

Based on the outcomes, Cambridge, Mass.-based Alnylam plans to submit an NDA to the FDA early this year and follow with regulatory filings in countries such as Brazil and Japan. The company aims to file a marketing authorization application in the EU when results of the 18-month analysis roll in, probably late this year, as previously agreed with the EMA.

The Helios-A study took place at 57 sites in 22 countries. Patients were randomized 3-to-1 to receive either 25 mg of vutrisiran (n=122) via subcutaneous injection once every three months or 0.3 mg/kg of Onpattro (n=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. Additional secondary endpoints at 18 months will be evaluated in the Helios-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index, Rasch-built Overall Disability Scale and serum TTR levels. More exploratory cardiac endpoint data at the 18-month time point will be evaluated as well, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month study period, all patients can opt to stay on vutrisiran for 18 more months as part of an open-label extension study. Full nine-month results will be presented at a medical conference in early 2021, and top-line 18-month results, including the cardiac endpoint data, are expected to be made known in late 2021.

Regarding safety, the experiment had two discontinuations (1.6%) due to adverse events (AEs) in the vutrisiran arm by month nine, both caused by deaths, neither of which was considered related to study drug. There were two serious AEs deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and a urinary tract infection. Treatment-emergent AEs occurring in 10% or more patients included diarrhea, pain in extremity, fall and urinary tract infections, with each of those events occurring at a similar or lower rate as compared with historical placebo. Injection-site reactions were reported in five patients (4.1%); all were mild and transient. There were no clinically significant changes in liver function tests, Alnylam said.

President of R&D Akshay Vaishnaw said during a conference call with investors that “the results are very, very similar to what we saw in Apollo, the original phase III study with Onpattro, in terms of mNIS+7 and in terms of the Norfolk QoL-DN. Of great interest, we saw improvement [in Helios-A], just as we did in that study, with the majority of patients showing improvements in those measures and the overall scores improving. I can assure everybody that the BNP dataset at month nine, the cardiac subgroup, these are all very, very similar. And directionally, I think, as well as the 10-meter walk test.”

SVB analyst Mani Foroohar said in a report that he was not surprised by the Helios-A results. “A clean safety profile with no drug-related discontinuations was consistent with Alnylam’s other GalNAc-conjugated siRNA medicines,” he said. Shares (NASDAQ:ALNY) closed at $139.40, up $12.57. Piper Sandler’s Edward Tenthoff said in his report that vutrisiran should “drive growth in mixed-phenotype [disease],” and might be used in combination with Pfizer's oral Vyndamax (tafamidis), approved in May 2018 for cardiomyopathy in ATTR.

A multisystem, fast-moving and life-threatening condition, hATTR amyloidosis is an autosomal dominant disease caused by one of many possible mutations in the TTR gene. About 50,000 people are living with hATTR amyloidosis worldwide. Also at work in the field is Cambridge, Mass.-based Intellia Therapeutics Inc., which recently dosed the first patient with phase I-stage NTLA-2001, the first systemically delivered CRISPR-based therapy dosed in a patient, which could become the first curative treatment for ATTR. Intellia is continuing to enroll patients in the global experiment testing NTLA-2001 in adults with hATTR polyneuropathy in order to establish an optimal dose. Later this year, the company plans to provide guidance around timing of the first expected data readout, with the goal of demonstrating clinical proof of concept for its modular lipid nanoparticle delivery platform. Intellia in 2016 signed a six-year deal with Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., which paid a $75 million up-front fee, made a $50 million equity investment, and pledged potential milestone payments of up to $320 million per target plus possible royalties. Shares of Intellia (NASDAQ:NTLA) closed at $77.48, up $10.74, or 16.1%.