Alnylam Pharmaceuticals Inc.'s patisiran seems to be on course to become the standard of care for hereditary ATTR (hATTR) amyloidosis after the full data set from the APOLLO study on the first RNAi therapeutic to succeed in a late-stage trial were unveiled to acclaim at a conference in Paris.
In September, the top-line results from the APOLLO study led to a 52% leap in Alnylam's share price and the full results prompted a 20% jump just during the 20-minute presentation at the European ATTR Amyloidosis meeting in the French capital. The results from the 225-patient trial showed that for the primary endpoint of modified Neuropathy Impairment Score+7 (mNIS+7), treatment with patisiran resulted in a negative 6.0 point change (i.e. improvement) at 18 months compared to a 28.0 mNIS+7 increase (worsening) for those on placebo.
The intravenous drug, which is designed to target and silence specific messenger RNAi, potentially blocking the production of transthyretin (TTR) protein before it is made and restore function in tissues, also showed a negative 6.7 point change (improvement) using the Norfolk-Quality of Life-Diabetic Neuropathy measure at 18 months as compared with a 14.4 point increase (worsening) for the placebo group.
Saying that the data represented the first time a treatment could actually reverse as well as improve hATTR amyloidosis, David Adams of Bicetre Hospital in Paris and principal investigator for APOLLO, told Scrip that he was particularly impressed by the effects seen with patisiran in the cardiac subpopulation, as favorable changes were seen in several measurements, including left ventricular wall thickness and ten meter-walk. He added that he was very pleasantly surprised to see patients who had been struggling to walk unaided returning to clinic with a much-improved gait and feeling better. "The Improvements can be seen not just on a graph."
The disease affects approximately 50,000 people worldwide and hATTR amyloidosis patients have a life expectancy of 2.5 to 15 years from symptom onset. It is often misdiagnosed due to its variety of symptoms that overlap with other more common diseases, Adams noted, and multiple specialists are often seen prior to diagnosis and can lead to ineffective or possibly detrimental treatment. The only approved treatment options for early-stage disease are liver transplantation and Pfizer Inc.’s Vyndaqel (tafamidis), which is available in Europe but is not on the market in the US, and Adams said that both come with considerable limitations.
Now after a 15-year journey, it looks as though a new class of therapy with strong efficacy and safety data (13 deaths were reported but none were the result of patisiran use) may soon be available. Alnylam will start filing with regulatory authorities in late 2017, with the goal of achieving approval in mid-2018.
Adams told Scrip that he expected patisiran to be standard of care very quickly, not least because "at the moment there is no standard of care." He noted that an open-label extension study, in which at least 99% of patients who completed the APOLLO study took part, should hopefully produce more long-term data on the drug's effectiveness.
Ionis' Inotersen Still In The Battle
The Paris conference was billed in some quarters as a head-to-head battle between patisiran and Ionis Pharmaceuticals Inc.'s antisense hATTR therapy inotersen. Full data from the Phase III NEURO-TTR study were presented at the meeting and the study also used the primary endpoints of Norfolk QoL-DN and mNIS+7.
The Ionis study was successful but the data were not as stellar as those from Alnylam's APOLLO trial. In terms of mNIS+7, a 19.73 point benefit was seen from inotersen at 15 months, compared with 34.0 for patisiran, while the Norfolk QoL-DN score was an 11.68-point mean improvement, compared to 21.1 for the Alnylam drug.
There is also some concern about the safety data with the inotersen trial as there were five deaths in the study, all in the inotersen arm. Four were associated with disease progression and considered unrelated to treatment but there was one fatal intracranial hemorrhage in conjunction with serious thrombocytopenia.
Participants at the Paris conference looked more favorably on the patisiran data but when it comes to filings, Ionis is first out of the blocks. The day after the meeting, Nov. 3, the company submitted a marketing authorization application to the European Medicines Agency, which will be reviewed under the latter's Accelerated Assessment program.
Chief business officer Sarah Boyce said in a statement, "We are pleased that we met the last deadline for accelerated assessment in the EU for 2017 [and] next week, we also plan to submit the New Drug Application to the US Food and Drug Administration." She added that "combined with significant efficacy and superior convenience (the Ionis drug is a weekly injection and patisiran is infused every three weeks), we believe inotersen will be the treatment of choice for this patient population."
GlaxoSmithKline PLC recently pulled out of its collaboration with Ionis on inotersen as it moves away from rare diseases but Boyce said that "we are in advanced discussions with potential co-commercialization partners. We believe the right partner can maximize the commercial success of inotersen." Alnylam will market on its own in the US and Europe and has Sanofi on board for the rest of the world. (Also see "Deal Watch: GSK Declines Option As Ionis' Inotersen Nears Finish Line" - Scrip, 11 Aug, 2017.)
Both companies believe they will ultimately be the hATTR winner and pricing as well as safety and efficacy is likely to be a major factor. Obviously, neither company is showing their hand yet but some participants at the Paris meeting told Scrip that they expect inotersen to come in considerably lower.