Study read-across and biotech bull market help Alnylam climb

Probably the most important thing about yesterday’s phase II analysis of Alnylam’s lead project, patisiran, is that it bodes well for the primary efficacy endpoint of its ongoing 200-patient pivotal study.

That said, the trial in question is a small, open-label one, and the positive result has come from a comparison against historical data. Alnylam probably would not have risen 19%, and neither would it be worth $6.6bn on the strength of just four clinical-stage assets, were it not for the biotech bull market.

The phase II study also backs the mechanistic rationale behind patisiran, an RNAi project for treating the rare disease transthyretin-mediated amyloidosis (TMA) in patients with familial amyloidotic polyneuropathy. Alnylam already claimed to have solved the problem of RNAi delivery, so this provides a key endorsement.

TMA results from mutations in the transthyretin gene, and primarily affects the liver. This makes the condition a logical one for targeting with RNAi, which naturally goes to the liver; thus while effective targeting of RNAi has long been a problem, conditions like TMA and hepatitis B have provided glimmers of hope.

The open-label phase II trial was an extension of a safety study, and enrolled just 27 patients, 19 of whom were evaluable. Patisiran treatment resulted in mean serum transthyretin knockdown – a secondary endpoint – of 80% over nine months, with an up to 89.6% knockdown between doses, Alnylam said.

Leerink analysts said this rationale strongly backed patisiran mechanistically versus drugs like diflunisal and tafamidis – the only options for early-stage TMA, thought to work by preventing transthyretin from being converted to amyloid.

Neuropathy stabilisation

But it was patisiran’s effect on patients’ modified neuropathy impairment score (mNIS+7), an outcome not specified in the phase II protocol, that might give even greater cause for celebration. This is because it is the primary endpoint in Apollo, patisiran’s double-blind, placebo-controlled phase III trial, due to read out in 2016.

In the 19 phase II patients there was a mean 0.95-point decrease in mNIS+7 at six months, Alnylam said; this slight decrease in neuropathy progression implies disease improvement. As a comparison the company presented historical data from familial amyloidotic polyneuropathy studies suggesting 6-month increases in mNIS+7 – implying disease worsening – of 6.9 to 10.3 points.

Obviously such a comparison has to be treated carefully. Historical controls are scientifically dubious, and some of the figures presented by Alnylam are themselves extrapolations or estimates. Nevertheless, Leerink reckons that repetition of this result in phase III “would be a home run scenario”.

The analysts apply a 75% risk adjustment to patisiran and attribute $2bn of value to it. The consensus view, as computed by EvaluatePharma, is even more bullish, seeing $634m in 2020 sales, which extrapolates to a 75% risk-adjusted NPV of $5.1bn.

Whether this is at all realistic, it cannot be denied that Alnylam has already secured a vital endorsement for patisiran and its RNAi technology from Sanofi (Alnylam lives the biotech dream as big pharma returns to RNAi, January 13, 2014).

Next up are open-label phase II data for Alnylam’s ALN-TTRsc in familial amyloidotic cardiomyopathy, and the possible start of phase III by the year end. Like familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy is a clinical manifestation of TMA.

If Alnylam really has cracked the RNAi delivery problem then the phase II data probably bode well for ALN-TTRsc too.

Study Design Trial ID
Phase II 27 TMA patients, single-arm NCT01961921
Phase III (Apollo) 200 TMA patients, double-blind, vs placebo NCT01960348

To contact the writer of this story email Jacob Plieth in London at or follow @JacobEPVantage on Twitter

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