Friedreich's failure highlights thinning pipeline

Another failure in Friedreich’s ataxia, this time with Reata Pharmaceuticals’ omaveloxolone, has exposed a dearth of late-stage candidates for this indication.

After Horizon Pharma’s stumble with Actimmune last year there are no projects in phase III development and just five in phase II – and some of these seem to have stalled, providing another reminder of how tricky rare disease drug development can be (see table below).

The pipeline has thinned since the last time EP Vantage carried out this analysis – as well as Actimmune, two phase I projects have fallen by the wayside (Therapy focus – Clinging to options in Friedreich’s ataxia, September 1, 2016). 

Commercial projects for Friedriech’s ataxia in phase II
Product Company Pharmacological class Trial ID
Omaveloxolone AbbVie/Reata Pharmaceuticals Nuclear factor erythroid derived 2 (Nrf2) activator NCT02255435 (Moxie) – part 1 failed
RT001 Retrotope Free radical scavenger NCT02445794 – hit, extension trial ongoing
Epicatechin Cardero Therapeutics Mitochondria targeted therapy NCT02660112 – results expected 2018
EPI-743 Edison Pharmaceuticals NADPH quinone oxidoreductase (NQO) 1 modulator NCT01962363 – concluded 2016, no results reported
NCT01728064 – concluded 2015, no results reported
JOT101 Jupiter Orphan Therapeutics CNS agent NCT01339884 – concluded 2012, mixed results
Source: EvaluatePharma.

Reata’s omaveloxolone could be next for the scrapheap. The first part of the phase II Moxie trial failed to meet its primary and secondary endpoints. The group said that there was a significant improvement on the modified Friedreich’s Ataxia Rating Scale (mFARS) over baseline. This scale was used as the secondary endpoint – but versus placebo, and here the drug did not show a significant benefit.

The trial also missed its primary endpoint, peak work during maximal exercise testing. Reata tried to talk up the positives by pointing to analysis in a subgroup of patients without a foot deformity associated with Friedreich’s called pes cavus, which causes high arched feet.

According to the company, this deformity can affect patients’ ability to walk and perform neurological and exercise testing. It said the exercise endpoint was scuppered because patients with pes cavus were not able to reach peak muscle exhaustion because of pain associated with their foot deformity.

Investors initially seemed convinced by the positive message, sending Reata’s stock up 6% yesterday; however, shares opened down 8% this morning.

The group plans to push ahead with the second part of the Moxie trial, which is due to start in the second half and will enrol around 100 patients who will receive either 150mg of omaveloxolone or placebo. The proposed primary endpoint is change from baseline in mFARS with omaveloxolone versus placebo at 24 weeks, with peak work during maximal exercise testing relegated to a secondary endpoint.

In another bid to improve its chances, Reata says it plans to limit the number of patients with pes cavus.

A positive result is far from assured, but last year’s approval of Sarepta’s Exondys 51 shows that the FDA can be lenient when it comes to rare diseases with no approved treatments.


But even assuming that omaveloxolone – or one of the other phase II candidates – manages to clear the clinical hurdles, it will be some time before a Friedreich’s ataxia therapy reaches the market.

Horizon had hoped to be the first, but it announced last December that the phase III Steadfast trial of Actimmune had not met its primary endpoint – the FARS-mNeuro score – and that it was discontinuing the programme.

Also still in play are Retrotope’s RT001, which has succeeded in a phase I/II trial, albeit one only designed to show safety and tolerability; and Cardero Therapeutics’ Epicatechin, which is expecting phase II results next year. The 10-patient trial of Cardero’s project does have an efficacy endpoint, change from baseline in the FARS score at 24 weeks. 

With the pipeline so sparse, perhaps it is not surprising that Reata is persevering in the hope that even a glimmer of efficacy will be enough for approval.

To contact the writer of this story email Madeleine Armstrong or Elizabeth Cairns in London at [email protected] or follow @ByMadeleineA or @LizVantage on Twitter

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