No Enigma in mid-stage success, Allakos insists

The company’s Enigma study in an orphan digestive tract disease points a way to approval, notwithstanding the company’s statistical analysis method.

A few months ago the immunology-focused group Allakos already stood as the best-performing biotech float of 2018. Today its investors found out that their enthusiasm had been well placed, with the company’s lead asset, AK002, yielding positive results in a small phase II trial in eosinophilic gastritis or gastroenteritis.

Allakos surged 110% in early trade, bringing its market cap near $3bn. The next question for the markets is whether this is an overblown reaction; the data seem strong, with all prespecified primary and secondary measures apparently met, but the use of per-protocol analyses is something investors should always examine closely.

Eosinophilic gastritis and gastroenteritis are rare inflammatory conditions of the stomach and GI tract thought to be driven by mast cells and eosinophils. AK002 is an antibody that activates Siglec-8, an inhibitory receptor on these two cell types, its effect being to deplete eosinophils and inhibit mast cells, thus breaking the inflammatory cascade driving the two diseases.

The study Allakos toplined today, Enigma, had a relatively simple design, testing 1mg/kg or 3mg/kg escalating AK002 doses versus placebo, and measuring as the primary endpoint changes in eosinophil counts. There were two secondary measures, of which change in total symptom score looks to be the more important as far as showing an effect on disease is concerned.

There seems no doubt about the robustness of the primary endpoint, which effectively validates AK002’s mechanism. Importantly, the statistical strength of this readout does not change if considering all 65 subjects recruited, or if the data are cut by just the 59 who complied with the protocol from start to finish.

The question arises as regards the total symptom scores, a metric that reflects AK002’s actual activity on eosinophilic gastritis/gastroenteritis. Here the per-protocol analysis yields a strongly significant result, with a p value of 0.0012, but the p value falls to 0.0359 if considering the intent-to-treat population.

And, within that ITT population, the effect is driven by the high AK002 dose, with the low dose lacking statistical significance (p=0.1556).

Summary of the Enigma trial (NCT03496571) of AK002
  Placebo AK002 (both doses combined)
Eosinophil counts (per protocol)* +10% -95% (p<0.0001)
Eosinophil counts (intent to treat)   p<0.0001
     
Total symptom score (per protocol) -24% -53% (p=0.0012)
Total symptom score (intent to treat)   p=0.0359
Source: Allakos presentation; *primary endpoint.

That said, losing power in a study as small as Enigma is perhaps unsurprising. Moreover, Allakos insisted on a call today that Enigma’s statistical analysis specifically called for a per-protocol assessment, and – crucially – the six non-complying subjects had been excluded before the trial’s blind was broken.

Reasons for non-compliance were receiving only one of four dosing cycles (two subjects), refusal to complete the study questionnaire (one) and altering subjects’ steroid use (three).

Allakos wants to start a phase III eosinophilic gastritis/gastroenteritis study next year, and says just one pivotal trial will suffice for approval. In the meantime, eosinophils and mast cells play a role in numerous inflammatory conditions including conjunctivitis, Crohn’s and some types of asthma, pointing to additional possible AK002 uses.

And some extra cash, which Allakos will doubtless seek to raise on the back of its now strengthened valuation, will not go amiss either.

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