Treatment with Minoryx Therapeutics’ leriglitazone in a Phase 2/3 clinical trial was found to improve motor function in people with early symptomatic adrenomyeloneuropathy (AMN), one of the most common types of adrenoleukodystrophy (ALD).
“On the basis of the overall results from this clinical trial, Minoryx is now preparing for discussions with regulatory authorities for defining a path forward for registration of leriglitazone for AMN sufferers,” Marc Martinell, CEO of Minoryx, said in a press release.
Leriglitazone, also called MIN-102, works by activating the protein PPAR-gamma in the brain. That, in turn, is expected to prevent the biological processes that drive disease progression in AMN, including lessening inflammation and normalizing cellular metabolism.
The Phase 2/3 clinical trial (NCT03231878), called ADVANCE, enrolled 116 men with AMN, who were given either leriglitazone or a placebo for 96 weeks (nearly two years). The trial was conducted in North America and Europe and was sponsored by Minoryx.
Of those enrolled, 96 completed the trial, with about 90% of the participants electing to continue into an open-label extension study, which will continue to collect long-term data.
The trial’s primary endpoint — its main measurement of efficacy — was a change from the start of the trial (baseline) in the six-minute walk test (6MWT). As the name suggests, the 6MWT measures the distance an individual can walk in six minutes; it is commonly used as a measure of physical function in ambulatory people.
Among the entire study population, changes in the 6MWT from baseline were not statistically significant. However, a statistically significant and clinically meaningful difference was observed among participants who had early symptomatic AMN.
“Neurodegeneration for AMN patients is more pronounced in the earlier stages of the disease, leveling off for those with a longer disease duration,” said Wolfgang Koehler, MD, coordinator principal investigator for ADVANCE at the University of Leipzig Medical Center, in Germany.
“For the primary endpoint of this clinical trial, clear differences versus placebo were observed only for those patients with a shorter disease duration [early symptomatic disease], implicating the urgent need of an early treatment onset,” Koehler said.
Compared with a placebo, leriglitazone significantly improved measurements of body sway, which is reflective of the biological systems most impacted in AMN, such as balance and body posture, the data showed. There also were trends toward a decrease in measurements of disability and progressive myelopathy, or spinal cord injury, though these were not statistically significant.
Based on imaging data, treatment with leriglitazone significantly lessened the development of brain lesions. Specifically, eight of the 39 participants in the placebo group showed new or progressing lesions, as compared with three of 77 participants given leriglitazone. Other measurements showed generally consistent results, suggesting that leriglitazone has a protective effect against brain tissue damage.
“Occurrence of cerebral inflammatory brain involvement in AMN patients is life-threatening. Our data suggest that this risk can be reduced significantly,” Koehler said.
The investigational treatment was generally safe and well-tolerated during the trial period. The most common adverse events were weight gain and edema (swelling). These are consistent with what is known about leriglitazone’s mechanism of action, according to Minoryx. Of note, there were no data indicating an increased risk to heart health with leriglitazone treatment.
“Leriglitazone demonstrated significant clinical benefits in multiple endpoints in patients suffering from AMN, although results of the primary endpoint were inconclusive in the overall population,” said Uwe Meya, chief medical officer at Minoryx.
“These clinical outcomes, together with those showing reduction of cerebral lesion progression, hold promise for patients suffering from AMN who currently have no available therapeutic options,” Meya said.
According to Meya, ADVANCE is a landmark study in AMN.
“It is the first large, robust and definitive study with protocol outcomes endorsed by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA),” Meya said.
Both the EMA and the FDA have designated leriglitazone an orphan drug. That designation gives companies researching cures for rare diseases various tax reductions and market exclusivity.
The FDA also has granted the investigational therapy fast track and rare pediatric disease designations. Fast track status is designed to support the development, and speed the review and approval process, for therapies for serious conditions with an unmet medical need.
Minoryx also is conducting a Phase 2 clinical trial (2019-000654-59) called NEXUS in the EU to assess the safety and efficacy of leriglitazone in children with childhood cerebral ALD (cALD).
