Solid efficacy and a distinguishing safety profile – so far, anyway – should give Alnylam Pharmaceuticals Inc. and Sanofi SA an edge over competitor Ionis Pharmaceuticals Inc., analysts said, as the partnered pair scored a top-line phase III win testing RNAi therapy patisiran in hereditary transthyretin-mediated amyloidosis (hATTR) with polyneuropathy.

Shares of Cambridge, Mass.-based Alnylam (NASDAQ:ALNY) closed Wednesday at $113.84, up $38.80, or 51.7 percent. Ionis Pharmaceuticals Inc., of Carlsbad, Calif., which in May popped the lid off favorable phase III results marred by safety concerns with the antisense therapy inotersen, saw its stock (NASDAQ:IONS) fall 8.8 percent, or $5.19, ending at $53.88.

Called Apollo, the patisiran study met its primary efficacy endpoint (change from baseline in the modified neuropathy impairment score [mNIS+7] at 18 months) and all secondary endpoints, including the key goal among the latter: improvement in quality of life as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN).

"Although the specific value of mNIS+7 was not provided, both mean and median values were reduced, indicating that disease progression was stabilized and potentially reduced," said Jefferies analyst Maury Raycroft. "We do not know what the mNIS+7 benefit is for the Ionis trial, so it is possible that the mNIS+7 values could end up giving an additional boost to either Alnylam or Ionis," he conceded in a research report. But even if the benefit turns up in favor of Ionis, probably "safety/monitoring issues will negatively outweigh" the advantage, in his view.

The APOLLO trial enrolled 225 patients representing 39 genotypes, at 44 study sites in 19 countries around the world. Patients were randomized 2-to-1 to patisiran or placebo, with patisiran administered intravenously at 0.3 mg/kg once every three weeks for 18 months.

For both the mNIS+7 and Norfolk QOL-DN endpoint measures, a lower score indicates a better clinical result. At 18 months, the mean change from baseline in mNIS+7 was significantly lower in the patisiran group as compared with placebo (p<0.00001). The mean and median changes in mNIS+7 impairment scores for patisiran both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline. Patients in the patisiran arm scored well on the Norfolk QOL-DN (p<0.00001).

All five other secondary endpoints turned up statistically significant favorable differences in the patisiran arm compared to placebo (p<0.001). Those were: NIS-W, the subdomain of mNIS+7 used to assess muscle strength; the Rasch-built Overall Disability Scale (R-ODS), a patient-reported outcome measure of daily living and disability; the 10-meter walk test (10MWT), which shows gait speed; the modified body mass index to determine nutritional status; and COMPASS-31, a questionnaire about autonomic symptoms.

The patisiran and placebo arms had similar frequencies of adverse events (AEs) (96.6 percent and 97.4 percent, respectively) and serious AEs (SAEs, 36.5 percent and 40.3 percent, respectively). Frequency of deaths was similar in the patisiran (4.7 percent) and placebo (7.8 percent) arms. Patisiran treatment was associated with fewer discontinuations compared with placebo (7.4 percent and 37.7 percent, respectively) and discontinuations from treatment due to AEs (4.7 percent and 14.3 percent, respectively).

AEs reported in greater than 10 percent of patients and seen more frequently with patisiran compared with placebo included peripheral edema (29.7 percent vs. 22.1 percent, respectively) and infusion-related reactions (18.9 percent vs. 9.1 percent, respectively), both of which were generally mild to moderate in severity, Alnylam said.

Heart, 10MWT outcomes 'key' for payers

Ionis, when disclosing its phase III data with inotersen, was quick to remind investors that the Alnylam compound comes with a pretreatment regimen that includes steroids, antihistamines and analgesics, yet still garnered a 20 percent rate of infusion reactions in phase II research. Consistent with long-term steroid use, Alnylam reported incidents of osteoporosis, osteonecrosis and bone fractures. (See BioWorld Today, April 22, 2015, and May 16, 2017.)

Those remarks came as Ionis disclosed that its phase III Neuro-TTR study with inotersen, also known as Ionis-TTRRx, in familial amyloid polyneuropathy, or FAP, met both primary endpoints. Specifically, over the 15-month period of the study, inotersen-treated patients achieved statistically significant benefit compared to placebo in the mNIS+7 and the Norfolk QOL-DN (p<0.0001 and p=0.0006, respectively). Statistically significant differences turned up for both endpoints at eight months as well, the company said, but three SAEs of thrombocytopenia were recorded in drug-treated patients. Two recovered and one died from an intracranial hemorrhage. Also, four inotersen patients discontinued the trial due to a renal observation; two met a predefined renal "stopping rule" and two were found having renal SAEs, with one showing chronic renal insufficiency.

Missing from Alnylam's data was information about potential benefit on cardiac function. CEO John Maraganore said during a conference call with investors that those results will be unveiled in November at a scientific meeting. "Fifty-four percent of the Apollo study population has cardiac involvement," he said. "We've excluded class III cardiomyopathy, but we have patients with class II cardiomyopathy. We believe that if we're successful and we hit our primary and secondary endpoints, we should be able to get a label that includes the indication statement for patisiran as a drug that can be used to treat hATTR amyloidosis in patients with polyneuropathy. That allows us to treat patients with cardiac involvement provided they have polyneuropathy," as long as the drug shows benefit there. "We'll have data on the independent effect in neuropathy in those patients," he added, and the company may be able to promote the drug to "a group of patients that probably is defined by 20,000 to 25,000 patients of the total 50,000 population" who fit the phenotype profile.

Analyst Raycroft found cause for optimism. "Some of the secondary endpoints indirectly reflect cardiac function," he pointed out. "Though the company is doing additional analyses on cardiac biomarkers, specifically in patients with baseline cardiomyopathy, we believe commentary around the secondary endpoints implies they are seeing some benefit on cardiac function. We believe these data alone strengthen the case for approval to regulators and payers," though more biomarker results and subset analyses could be helpful, he said. "At this point, we do not foresee the need for an additional study in cardiac patients specifically." An expert consulted by his firm "believes that ATTR cardiomyopathy is underdiagnosed and commented that the number of cases have been increasing over the last decade due to greater awareness and increased diagnostic use of nuclear imaging," he added.

Cowen and Co. analyst Ritu Baral called the Apollo data "remarkably strong despite high expectations." She said in a report that she and her peers "look forward to further detail" at the Paris TTR conference mentioned by Maraganore. Detail on the cardiac subgroup "(including cardiac biomarker data and granularity on [the 10MWT results] and safety [will] be key in future regulatory and payer discussions," she said.

Alnylam expects to submit an NDA for patisiran by the end of this year, with a marketing authorization application in Europe early next year. The FDA awarded the compound fast track status, and the phase III program began in late 2013. (See BioWorld Today, Nov. 12, 2013.)

Geert Cauwenbergh, CEO of RNAi-focused Rxi Pharmaceuticals Corp., of Marlborough, Mass., said Alnylam's phase III outcome "bodes well for the RNAi space" and told BioWorld that he "would expect this to result in a significant step forward in the appreciation" by investors of RNAi efforts.