Blueprint for disappointment

Ayvakit hits in its pivotal indolent systemic mastocytosis trial, but a dwindling effect size reignites commercial concerns.

Sometimes statistical significance is not enough. Long-awaited data from part 2 of the Pioneer study of Blueprint’s Ayvakit in indolent systemic mastocytosis showed hits across the board, but the extent of the treatment effect has failed to impress.

The data leave investors unconvinced of whether Ayvakit, should it be approved in indolent disease, can command the kind of rare disease pricing – more than $350,000 per year – it carries in the aggressive form of systemic mastocytosis. Blueprint’s shares were down 20% so far today.

Ayvakit is a selective inhibitor of D816V mutant KIT, the driver of almost all systemic mastocytosis cases. The rare disease, which affects one in 10,000-20,000 people, according to key opinion leaders cited by Wells Fargo, can cause debilitating skin, gastrointestinal and neurocognitive symptoms, as well as anaphylaxis.

Although Ayvakit is already marketed for advanced systemic mastocytosis, the non-advanced or indolent form is a much bigger prize; the latter accounts for 90% of patients, Wells Fargo recently wrote. 

Pioneer tested Ayvakit 25mg against placebo on a background of best supportive care. Part one of the study was dose-finding and part three is an extension trial; part 2 is the pivotal efficacy analysis. 

The part 2 data hit significance on the primary endpoint, mean change in total symptom score, and on all the secondaries. But the placebo-adjusted improvement in the symptom score was just 6.4 points, a deterioration from the 19.7-point decline seen in Ayvakit's phase 1 study. 

Ayvakit's declining efficacy in indolent systemic mastocytosis
  improvement from baseline in total symptom score  
Trial Ayvakit Placebo Placebo-adjusted
Pioneer (phase 2) 15.6% 9.2% 6.4 points
Phase 1 19.7% 3.2% 16.5 points
Source: company releases.

SVB analysts write that, assuming a similar symptom score baseline as in the phase 1 study, this represents an improvement of around 30% with Ayvakit, compared with 20% in the control group. Previously, Blueprint had touted a 30-point delta as clinically meaningful.

At least Ayvakit's safety profile raised no eyebrows, given worries about cognitive side effects and intracranial haemorrhage seen with the higher 200mg dose used in advanced systemic mastocytosis.  

In Pioneer there were fewer adverse events in the treatment group than with control, with no bleeding events; a fatal brain bleed had marred the otherwise impressive phase 1 data.

Overall, Ayvakit looks approvable, and Blueprint plans to file it with the FDA for indolent disease in the fourth quarter. But it seems likely that payers will baulk at phenomenally high rare-disease pricing for a chronically used therapy with a limited treatment effect.

Stifel analysts today wrote that Ayvakit’s penetration in indolent disease had been expected to reach up to 30%, which would have propelled the drug to blockbuster status. But that was under the phase 1 data assumptions.

While Blueprint's investors were disappointed, the result was read as a positive for a systemic mastocytosis rival, Cogent Biosciences, whose shares climbed 16% today.

Pioneer safety data
  Ayvakit Placebo
Adverse events (%) 90.8 93.0
Discontinuations (%) 0.7 0.0
Cognitive adverse events (%) 2.8 4.2
Intracranial haemorrhage (%) 0.0 0.0
Headache (%) 7.8 -
Nausea (%) 6.4 -
Periopheral oedema (%) 6.4 -
Periorbital oedema (%) 6.4 -
Source: company release.

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