FDA Approves Skyclarys (omaveloxolone) for the Treatment of Friedreich’s Ataxia

In continuation of my update on omaveloxolone

Reata Pharmaceuticals, Inc. (Nasdaq: RETA) announced   the U.S. Food and Drug Administration (“FDA”) approval of  Skyclarys™ (omaveloxolone) for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older. With this approval, the FDA granted a rare pediatric disease priority review voucher.

"The approval of Skyclarys, the first therapy specifically indicated for the treatment of Friedreich’s ataxia, is an important milestone for patients affected by this disease as well as their families and caregivers," said Warren Huff, Reata's Chief Executive Officer. "We are grateful to Friedreich’s ataxia patients, investigators, U.S. regulators, and our scientists and employees who made this approval possible. As a company, this is a transformative milestone that highlights our commitment to developing and commercializing novel therapies for patients with severe diseases with few or no approved therapies. We look forward to delivering Skyclarys to eligible patients as quickly as possible."

Friedreich’s ataxia is an ultra-rare, inherited neurodegenerative disorder that is typically diagnosed during adolescence. Patients with Friedreich’s ataxia experience progressive loss of coordination, muscle weakness, and fatigue, which commonly progresses to motor incapacitation and wheelchair reliance by their teens or early twenties, and eventually death. Friedreich’s ataxia affects approximately 5,000 diagnosed patients in the U.S.

“Friedreich's ataxia is a debilitating neuromuscular disease that progressively robs patients of their mobility and independence,” said Susan Perlman, MD, Clinical Professor, Department of Neurology, David Geffen School of Medicine, UCLA. “The approval of Skyclarys represents an important step forward in the treatment of Friedreich's ataxia, providing physicians with the first disease-specific treatment option approved for patients living with this ultra-rare and progressive disease.”

"Today’s approval of Skyclarys represents a significant milestone in our effort to advance research and achieve treatments for Friedreich’s ataxia," said Jen Farmer, Chief Executive Officer at Friedreich's Ataxia Research Alliance. "The entire Friedreich's ataxia community including patients, clinicians, scientists, pharmaceutical companies, government agencies, and others have worked collaboratively for decades to enable therapeutic development for this debilitating disease. Today, we celebrate the impact of an engaged patient community, and we are grateful to the FDA and Reata for working together on the approval of Skyclarys, the first therapy approved in the United States for adult and adolescent patients aged 16 years and older with Friedreich's ataxia.”

The approval of Skyclarys is supported by the efficacy and safety data from the MOXIe Part 2 trial and a post hoc Propensity-Matched Analysis of the open-label MOXIe Extension trial.

MOXIe Part 2 was a randomized, double-blind, placebo-controlled study. Patients with genetically confirmed Friedreich’s ataxia and baseline modified Friedreich’s Ataxia Rating Scale (“mFARS”) scores between 20 and 80 were randomized 1:1 to receive placebo or 150 mg of Skyclarys daily. The primary endpoint was change from baseline in mFARS score compared to placebo at Week 48 in the Full Analysis Population of patients without severe pes cavus (n=82). The mFARS is a clinical assessment tool to assess patient function and is used in clinical trials to assess the efficacy of investigational products for use in Friedreich’s ataxia. Treatment with Skyclarys resulted in statistically significant lower mFARS scores (less impairment) relative to placebo at Week 48. The placebo-corrected difference between the two groups was -2.41 points with a p-value of 0.0138. The most common adverse reactions in MOXIe Part 2 (≥20% and greater than placebo) were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.

Further, in a post hoc Propensity-Matched Analysis, mFARS progression of patients treated with 150 mg of Skyclarys daily in the open-label MOXIe Extension trial was compared to the progression of propensity score-matched untreated patients in the largest natural history study of Friedreich’s ataxia, Clinical Outcome Measures in Friedreich’s ataxia (“FA-COMS”). All patients enrolled in the MOXIe Extension study with at least one post-baseline assessment (n=136) were matched one to one with patients from the FA-COMS study (n=136). Lower (improved) mFARS scores were observed in patients treated with Skyclarys after 3 years relative to the matched set of untreated patients from the FA-COMS natural history study. These exploratory analyses should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.

FDA Approves Skyclarys (omaveloxolone) for the Treatment of Friedreich’s Ataxia

Novel compound along with checkpoint inhibitors may enhance immune response in melanoma patients

A novel compound may restore immune response in patients with melanoma, according to a study presented at the ESMO Immuno Oncology Congress 2017.

"Checkpoint inhibitors are a standard of care immunotherapy for metastatic melanoma," said lead author Dr Sapna Patel, Assistant Professor, Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, US. "However, many patients do not respond because myeloid derived suppressor cells (MDSCs), a type of inhibitory cell, are present in the tumor microenvironment."

"In animal studies, omaveloxolone inhibited MDSCs and restored immune activity," she continued. "Myeloid-derived suppressor cells (MDSCs) produce reactive nitrogen radicals that alter the receptors on the surface of the tumor to hide it from cytotoxic lymphocytes that kill tumor cells. Omaveloxolone inhibits MDSC activity, suppresses reactive nitrogen radicals, and restores anti-tumor immune responses. Administering omaveloxolone with checkpoint inhibitors may improve the antitumor response of these immunotherapies."

This open label, multicenter, phase 1B trial investigated the safety and efficacy of omaveloxolone in combination with the checkpoint inhibitors ipilimumab or nivolumab. The study included 30 patients with unresectable or metastatic melanoma, of whom seven were naïve to checkpoint inhibitors and 23 had prior checkpoint inhibitor treatment.

The overall response rate was 57% in checkpoint inhibitor naïve patients and 17% in those with prior exposure. Median time to response was 19 weeks. There were no serious adverse events related to omaveloxolone and it was well tolerated in combination with ipilimumab or nivolumab.

Dr Patel said: "Our findings suggest that omaveloxolone may overcome resistance to checkpoint inhibitors. Omaveloxolone in combination with checkpoint blockade had activity in both naïve and checkpoint inhibitor refractory melanoma patients."

She added: "This is one of the first studies to demonstrate a meaningful response rate in the checkpoint inhibitor refractory melanoma population. Further dose escalation and dose expansion studies are underway as well as translational tissue-based experiments to clarify the impact of this treatment combination."

Commenting on the study for ESMO, Dr Olivier Michielin, head of Personalised Analytical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, said: "Omaveloxolone's novel mechanism of action is to block MDSCs, cells known to suppress the immune response. This study tested a new combination therapy in immuno oncology and found encouraging response rates with omaveloxolone plus ipilimumab or nivolumab in patients who were checkpoint inhibitor naïve or resistant. The combination was well tolerated and may address some of the immune escape mechanisms that limit the activity of current checkpoint blockade therapies."

Michielin added: "More data is needed before we can make a final call on whether there is a place, and where would the place be, for this combination in the current treatment portfolio. The next step should be a randomized trial to investigate whether omaveloxolone provides additional benefit when combined with the checkpoint blockade backbone, for example, comparing the efficacy of PD-1 blockade alone versus PD-1 blockade plus omaveloxolone."

Novel compound along with checkpoint inhibitors may enhance immune response in melanoma patients