Agios strengthens the case for mitapivat

A filing in pyruvate kinase deficiency beckons, but bigger indications could be trickier.

Trial Results

Agios, now fully focused on rare diseases, has taken another step towards the first approval of its lead pipeline project, mitapivat, in pyruvate kinase deficiency (PKD).

The phase III Activate-T trial, in PKD patients dependent on regular transfusions, showed a benefit in terms of transfusion reduction. However, PKD is a small indication and, to justify its $3bn market cap, Agios will also need results in more common disorders like sickle cell disease – and here mitapivat is going up against some fierce competition.

There are also a couple of reasons to be cautious about the Activate-T data: first, the trial was small, enrolling just 27 patients. And it was a single-arm study, with a comparison being run not against placebo but patients’ own historical control data.

Notwithstanding these issues, Activate-T was a success. Agios said after hours yesterday that 37% of patients achieved the primary endpoint, a 33% or greater reduction in transfusion burden versus historical control. And 22% were transfusion free. Both endpoints were measured over a 24-week period during which patients received a fixed dose of mitapivat; before this there had been a dose-escalation phase of up to 16 weeks.

Small population

A spokesperson for Agios told Evaluate Vantage that transfusion-dependent patients accounted for just 15-20% of those with PKD, a disease that itself only affects 3,000-8,000 in the US and EU.

Given this tiny population, the FDA and EMA “were comfortable” with the size and design of Activate-T, he added, particularly as a supplement to the randomised, placebo-controlled Activate trial in non-transfusion-dependent PKD patients, which read out positively in December (Agios gets a pre-Ash boost, December 1, 2020).

The spokesperson also said Activate-T was not powered to show a specific response, despite Agios’s press release giving a one-sided p value of 0.0002 for the transfusion burden endpoint. The spokesperson pointed out that a lack of powering does not preclude prespecifying a test for statistical significance.

Still, overall the data in PKD should be enough for approval of the pyruvate kinase R activator, given the lack of approved therapies for this genetic disease, which leads to red blood cell destruction and anaemia. Agios plans to file mitapivat with the US FDA in the second quarter, and with the EU’s EMA in mid-2021.

Full results from both Activate and Activate-T are slated for the EHA meeting in June. Safety will be closely watched, especially given previous reports of vaso-occlusive crises in a trial of mitapivat in sickle cell disease.

Agios merely said that, in Activate-T, mitapivat’s safety profile was “consistent with previously reported data”.

As expected

The market reaction to the latest data this morning was muted, which Leerink analysts put down to the fact a win had been anticipated by investors following the Activate success, and that the focus would now shift to the commercial opportunity in PKD, which is unlikely to become clear until mitapivant’s launch.

They reckon the project’s peak sales in PKD will hit $425m. However, in sickle cell disease Leerink more than halved its peak forecast to $466m after the Ash meeting, during which mitapivat looked relatively unimpressive versus Forma Therapeutics’ rival project FT-4202 in a cross-trial comparison.

FT-4202 is not in clinical development for PKD; however, competition for mitapivat here could come from Rocket Pharmaceuticals, which has a gene therapy, RP-L301, in phase I.

Sellside consensus compiled by EvaluatePharma forecasts mitapivat sales of $593m in 2026 across all indications.

Agios is set to start pivotal trials in sickle cell disease and thalassaemia this year. Since the group offloaded its cancer portfolio to Servier the pressure on mitapivat has only increased, and with little else in the pipeline Agios now needs these studies to deliver.

Mitapivat's pivotal trial programme
Indication Trial name Detail
PKD (non-transfusion-dependent) Activate Topline win Dec 2020
PKD (transfusion-dependent) Activate-T Topline win Jan 2021
Thalassaemia (non-transfusion dependent) Energize To start H2 2021
Thalassaemia (transfusion dependent) Energize-T To start H2 2021
Sickle cell disease TBD To start YE 2021
Source: EvaluatePharma, clinicaltrials.gov & company release.

This story has been updated to include comments from Agios on the powering of the Activate-T trial.

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