With Reata Pharmaceuticals’ investors focused on the group’s upcoming pivotal readout with bardoxolone, its second most advanced project, omaveloxolone, has understandably received relatively little attention.
There is another good reason for this: the chances of the asset getting a positive result in a mid-stage trial in Friedreich’s ataxia look slim after a previous flop in this rare neurological disease. Still, the company is adamant that changes it has made to its phase II Moxie study will pay off.
If the Reata manages to succeed against the odds in Friedreich’s it hopes to expand omaveloxolone into other neurological disorders, mirroring the approach it has taken with bardoxolone methyl in rare kidney diseases. This plan hinges on part two of Moxie, results from which are due in the second half of this year.
|NPV as % market cap||1%|
|Event||Data from part two of phase II Moxie trial in Friedreich's ataxia|
The signs are not auspicious: the first part of the same study did not show a benefit with omaveloxolone on the primary endpoint, peak work during maximal exercise testing, or its secondary endpoint, change versus placebo on the modified Friedreich’s ataxia rating scale (mFARS), when it reported two years ago (Friedreich's failure highlights thinning pipeline, 2 June 2017).
Despite this, Reata claimed that the data were positive, and Vinny Jindal, the group’s vice-president of strategy, told Vantage: “I wouldn’t classify part one of Moxie as a failure.” He added that the study had found a “meaningful” effect on patients, as measured by mFARS, a 100-point scale on which a higher score represents more severe disease.
Mr Jindal pointed to a 2.3-point placebo-corrected reduction on mFARS after 12 weeks' treatment with omaveloxolone 160mg, the best-performing dose in part one. This missed statistical significance with a p value of 0.06.
Nevertheless, Mr Jindal maintained: “Patients typically progress 1-2 points per year, so that improvement [could save patients] more than a year of progression.”
mFARS to go
One reason for Mr Jindal’s optimism around part two of Moxie, which is testing a 150mg dose, is that Reata has switched to mFARS as the primary endpoint. He described this as a more validated outcome than peak work, adding that the US FDA has said that a win on mFARS could allow either accelerated or full approval of omaveloxolone in Friedreich’s ataxia, a disease with no approved therapies.
When asked why the company had chosen to focus on peak work instead of mFARS in part one, Mr Jindal replied that Reata had wanted to test whether omaveloxolone’s mechanism of action, Nrf2 activation, restored mitochondrial functioning and energy production as intended. “That could be picked up in something like the peak work test.”
This was not in fact proven in part one, but Reata put the failure down to a high number of patients with a foot deformity called pes cavus, which causes high arched feet and can affect patients’ ability to walk. Around 66% of patients in the 160mg arm had pes cavus; in part two this has been capped at 20%.
Another reason he believes part two can succeed is the longer treatment period: the first portion of the study tested 12 weeks of omaveloxolone, whereas part two is evaluating 48 weeks. “At 12 weeks mFARS looked like it was continuing to decline, so longer dosing could allow for a greater effect.”
This could also minimise the placebo response, which tends to peak at the beginning of therapy but washes out after around six months, Mr Jindal said. “The more motivated you are, the better your mFARS score could be. But placebo ultimately doesn’t have an effect on a fast-moving neurodegenerative disorder like Friedreich’s ataxia.”
Overall, the second part of Moxie is powered to meet significance at an improvement of 1.2 mFARS points over placebo. If the trial succeeds Reata will have another issue to address: the involvement of Abbvie, which struck an agreement over omaveloxolone in 2011 but later ceased development, retaining a future right to opt in.
|Friedreich's ataxia projects in active clinical trials|
|Project||Company||Mechanism of action||Note|
|Omaveloxolone||Reata Pharmaceuticals||Nrf2 stimulant||Moxie part two data due H2 2019 (NCT02255435)|
|MIN-102||Minoryx Therapeutics||PPAR-gamma agonist||Phase II Frames trial to read out in 2020 (NCT03917225)|