Alnylam confirms amyloidosis advantage

Ionis Pharmaceuticals has put on a brave face, but the verdict appears to be in: inotersen will not be able to match the efficacy of Alynlam’s patisiran in what is likely to be a hotly contested hereditary ATTR amyloidosis space.

One of the few advantages Ionis may have is an earlier launch, as a European application went in today and a US application will be going in the next week. Investors’ reactions to data released yesterday matched the conclusions of sellside analysts who are already giving the crown to patisiran – Alnylam finished the day with a 10% boost to share prices, while Ionis sank the same amount.

Beating expectations

Patisiran’s edge had been largely presumed since topline data disclosed that it not only arrested disease progression but actually reversed neuropathic impairment and improved quality of life (Alnylam celebrates a successful Apollo mission, September 20, 2017).

Full data released at the 1st European ATTR Amlyoidosis Meeting – a conference that seemed to be tailor-made for only two companies – exceeded these expectations. The study found improvement of six points from baseline on the modified neuropathy impairment score (mNIS+7), the primary endpoint, with patisiran, and a difference over placebo of 34 points. On the secondary endpoint, the Norfolk quality of life questionnaire – diabetic neuropathy, patisiran showed an improvement over baseline of 6.7 points and over placebo by 21.1 points.

This compares with inotersen’s mNIS+7 decline of around five points – which, while a nearly 20-point improvement over placebo, still represented disease progression – and a near standstill on the quality of life battery, which was an improvement over placebo of more than 11 points.

Alnylam vs Ionis – round two
Patisiran in Apollo (NCT01960348)  Inotersen in Neuro-TTR (NCT01737398) 
mNIS+7 (primary endpoint)
Result  Mean 6-point improvement vs baseline; mean 34-point benefit over placebo ~5-point deterioration vs baseline; mean 19.73-point benefit over placebo
Norfolk QoL (secondary in Apollo; co-primary in Neuro-TTR) 
Result Mean 6.7-point improvement vs baseline; mean 21.1-point benefit over placebo <1-point deterioration vs baseline; mean 11.68-point benefit over placebo
Note: Apollo measured 18-month improvements, Neuro-TTR 15-month. 

Where can Ionis win?

Safety does not look to be a differentiator for either drug, with thrombocytopenia an adverse event of note with inotersen and peripheral oedema with patisiran. More patients taking inotersen died than those in its placebo arm – five versus zero. Ionis said four were because of disease progression and “unrelated to treatment,” and one a case of intracranial haemorrhage resulting from thrombocytopaenia which had been previously reported (Investors scent blood after death in Ionis trial, May 15, 2017).

This leaves Ionis with the best hope of appealing to those patisiran patients who discontinue because of peripheral oedema or infusion reactions. Inotersen is administered subcutaneously, and does not require steroid pre-treatment.

The outlook in hereditary ATTR amyloidosis
WW sales ($m)
Project Company 2018 2019 2020 2021 2022
Patisiran Alnylam/Sanofi 96 309 560 799 973
Inotersen Ionis 8 48 120 188 290
Source: EvaluatePharma

Forecasts for the two agents already reflect the belief that patisiran will dominate this space. By 2022, sales for Alnylam and partner will be pushing blockbuster numbers while Ionis will approach $300m.

Ionis is seeking a partner as it approaches the market – Glaxosmithkline backed out of a collaboration in August. Attracting a strong replacement will be challenging given the phase III results, and it may be that Ionis will face a tough choice of going it alone or signing a deal that gives away a larger chunk of the cash than it prefers.

To contact the writer of this story email Jonathan Gardner or Madeleine Armstrong at [email protected] or follow @ByJonGardner or @ByMadeleineA on Twitter

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