Dive Brief:
- Results from the APOLLO Phase 3 study of RNA interference therapeutic patisiran, being developed by Alnylam Pharmaceuticals, Inc. and Sanofi SA, showed that the agent met every primary and secondary endpoint with statistical and clinical significance in patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy.
- The key findings over 18 months were improvements (compared with placebo) in neuropathy impairment score +7 (mNIS+7), and in sensory, motor, and autonomic neuropathy symptoms. There were also improvements in exploratory cardiac endpoints. Patients' quality of life was better, as was their activities of daily living, nutritional status, motor strength, and ability to move around.
- Alnylam is planning to file a New Drug Application in the U.S. by the end of 2017, followed by a submission in Europe in early 2018. It's partner Sanofi Genzyme will make submissions in 2018 in Asia, South America and the rest of the world. The first launch could be by mid- to late-2018, making patisiran the first RNAi therapeutic on the market.
Dive Insight:
Alnylam has put 15 years and over $1.6 billion in R&D investment to show positive evidence of safety and efficacy from a Phase 3 trial of an RNAi drug.
Following on topline data that was released in September, APOLLO showed the success of patisiran when compared to placebo in 225 patients.
"We clearly demonstrate what we believe to be patisiran's transformative potential in patients with Hereditary ATTR amyloidosis," said CEO John Maraganore. "There haven't been any direct comparative studies but we believe that this is the only hATTR drug that can improve quality of life and reduce impairment."
The APOLLO data, while not a direct comparator, clearly trumps data presented by competitor Ionis Pharmaceuticals for its antisense drug inotersen, which was only disease stabilizing and not disease modifying.
This makes Alnylam particularly confident that it can succeed in approval for the breadth of the spectrum of hATTR, and Maraganore sees potential for patisiran in prevention of disease in people who are asymptomatic, or who are carriers.
"Patisiran holds the potential to halt or improve neurological impairment and broader disease features in patients with hATTR amyloidosis. We also view these results as a landmark achievement for the field of RNAi," said Alnylam's head of R&D Akshay Vaishnaw.
"Seeing the comprehensive nature of the effect of the drug, we think we can build a data-driven argument on sensory, motor, autonomic, gut, bladder and cardiac symptoms – we think these should all be built into the label. We are confident that we can make the arguments for this," the exec added.
Sanofi Genzyme and Alnylam also released 36-month data from the open label extension study, in which the clinical activity of patisiran was maintained. There is still a lot of data to come out of APOLLO, according to Vaishnaw.
"Our first priority is to see if we can get regulatory support for cardiomyopathy patients in our initial submission. We can also carve up the APOLLO data further to understand the relationships between outcomes and levels of TTR knockdown. We may be able to use our existing data rather than have to carry out further cardiac studies," said Vaishnaw.
In preparation for launch, Alnylam is raising awareness through education for patients and healthcare professionals, and offers free genetic screening.
"We foresee expanded market opportunity with patisiran over time driven by several variables including potential for additional indications (cardiomyopathy patients and wild-type patients), additional data on survival and duration as a driver, and earlier and broader diagnosis," said Jefferies analyst Maury Raycroft in a note to clients. "Given feedback at the meeting we anticipate patisiran will be used broadly in mixed phenotype patients."
Hereditary ATTR amyloidosis affects around 50,000 people worldwide. It causes amyloid deposits in the nerves, heart and GI tract, and results in death around two to 15 years after onset. Current diagnosis rates vary around the world, and are estimated at around 10% to 50%. By 'dialing down' the mutated protein, patisiran reduces the development of the harmful amyloid deposits, and according to the APOLLO study, appears to – at least to a degree – reverse the disease and improve its symptoms.
Alnylam carried out a specific analysis in a subpopulation with cardiomyopathy, and found an improvement in cardiac markers, including N-terminal pro b-type natriuretic peptide and heart muscle measurements, compared with worsening in the placebo group.
Alnylam has a follow up product in hATTR, ALN-TTRsc02, which has potential for quarterly subcutaneous delivery, compared with the intravenous infusion required for patisiran. Sanofi Genzyme has until the end of 2019 to decide if it will opt into this program as well.
"We are continuing to innovate in RNAI," said Maraganore. "We will look to optimize an agreement with Sanofi Genzyme to avoid any cannibalization of patisiran."