Summary
- Reata Pharmaceuticals has submitted a New Drug Application to the US Food and Drug Administration for omaveloxolone, its experimental drug to treat Friedreich's ataxia. PDUFA date is February 28, 2023.
- The FDA granted the NDA priority review status and conducted a Mid-Cycle Communication Meeting with Reata in Q3 2022, expressing concern about the strength of the efficacy data.
- The FDA is likely concerned about the lack of strong evidence regarding omaveloxolone's ability to bring about clinically significant changes in patients.
- A closer look at the data reveals confounding factors that impact the generalizability of the study results, particularly for FA patients with pes cavus.
- Reata is likely to receive a Complete Response Letter from the FDA and even if omaveloxolone is approved, it is likely to face challenges in the FA market. As a result, Reata is recommended as a "Sell".
Introduction
Reata Pharmaceuticals ( RETA ) is a company in the clinical development stage that specializes in the creation of small-molecule therapeutics with unique mechanisms of action. They focus on treating severe diseases that have few or no approved treatments. Omaveloxolone, which is one of Reata's primary programs, is an experimental drug used to treat Friedreich's ataxia ((FA)).
Recent events: Rolling submission of an NDA for omaveloxolone to the FDA was completed by Reata in March 2022. The NDA was accepted for filing by the FDA in May 2022 and granted Priority Review. In the third quarter of 2022, the FDA conducted a Mid-Cycle Communication Meeting with Reata, stating that it had no significant new concerns but remained worried about the strength of the efficacy evidence. After the meeting, Reata submitted additional data to the FDA. The updated Prescription Drug User Fee Act (PDUFA) date for the application is February 28, 2023.
In this article, we will discuss the pathophysiology of FA, current treatments and limitations, omaveloxolone's mechanism of action, data on omaveloxolone in FA, the concerns regarding the efficacy data, the market for FA, and an analysis of the drug's regulatory/market prospects for FA.
Financials
Let's first review Reata's most recent financials. Reata had cash and cash equivalents of $435.9 million at the end of the third quarter of 2022, which is lower than the $590.3 million at the end of 2021. GAAP and Non-GAAP R&D expenses and GAAP and Non-GAAP G&A expenses increased compared to the same period in the previous year. The GAAP net loss for the third quarter of 2022 was $79.0 million, while the non-GAAP net loss was $53.9 million. Both were higher compared to the same period in the previous year. Reata anticipates its cash reserves to last until EOY 2024.
Understanding Friedreich's Ataxia: Causes, Symptoms, and Treatment Options
Friedreich's ataxia is a rare inherited disease that affects the nervous system and causes progressive damage to the spinal cord, resulting in muscle weakness and problems with movement. FA is caused by mutations in the frataxin ((FXN)) gene, which encodes a protein involved in mitochondrial iron-sulfur cluster biogenesis. As a result, mitochondrial dysfunction, oxidative stress, and inflammation are features of the disease.
It is estimated that around 55% of individuals with FA have pes cavus, a foot deformity characterized by a high arch. Pes cavus is more common among more severely affected individuals, and those with particularly severe foot deformity may be excluded from studies. As a result, pes cavus may identify a subgroup of FA patients with fixed deficits that do not readily reverse, or a subgroup of individuals without abnormalities in functions targeted by potential treatments. Despite the lack of approved therapies for FA, supportive treatment such as physical therapy, speech therapy, and occupational therapy can help maintain or improve mobility and coordination. Additionally, orthopedic procedures such as scoliosis correction, foot surgery, and hand surgery may be necessary. Some medications may also be used to treat symptoms such as tremors or heart problems.
Omaveloxolone: A Potential Treatment for Friedreich's Ataxia by Activating Nrf2 Transcription Factor
Omaveloxolone is a potential treatment for FA that works by activating the transcription factor Nrf2, which is involved in cellular defense mechanisms. Nrf2 is activated in response to oxidative stress and inflammation, and it plays a crucial role in the regulation of mitochondrial function. Omaveloxolone activates Nrf2 by covalently modifying Keap1, a cytoplasmic protein that regulates Nrf2 levels.
A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of Omaveloxolone in the Treatment of Friedreich's Ataxia (MOXIe)
The study focused on evaluating the effectiveness of omaveloxolone in patients diagnosed with FA, with the exclusion of individuals with pes cavus from the full analysis set ((FAS)) utilized for primary efficacy analysis. Safety analyses were conducted on all randomized patients ((ARP)). The objective of the study was to determine the mean difference in the modified Friedreich Ataxia Rating Scale (mFARS) change from baseline, which assesses neurological function including posture, gait, and upper limb coordination, between patients randomized to receive omaveloxolone and those given placebo.
The trial included 103 patients who received either omaveloxolone or a placebo. At 48 weeks, the study observed a statistically significant difference in mFARS score changes between the omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) full analysis set groups. The difference between the two treatment groups was calculated to be -2.40 ± 0.96, with a p-value of 0.014.
In addition, the prespecified sensitivity analyses, which included patients with pes cavus, confirmed the primary analysis results in the FAS population. The difference between the omaveloxolone and placebo groups was -1.93 ± 0.90 (95% CI = -3.7 to -0.15) points, with a statistically significant p-value of 0.034.
Omaveloxolone was generally well-tolerated in the study, with the most commonly reported side effects being fatigue, headache, and gastrointestinal discomfort such as nausea and abdominal pain, which occurred primarily in the early stages of the study. Additionally, there were clinically insignificant increases in liver enzymes observed.
Risks and Uncertainties Associated with Omaveloxolone as a Treatment for Friedreich's Ataxia: Concerns About Efficacy Evidence and FDA's Review
While the MOXIe trial showed a statistically significant improvement in the primary endpoint, some experts have raised concerns about the strength of the efficacy evidence. Additionally, the FDA has expressed concerns about the strength of the data, and it remains to be seen whether additional studies or data will be required before the drug can be approved.
One key concern in the study is the exclusion of patients with pes cavus from the FAS used for primary analysis of efficacy. Excluding patients with pes cavus from the primary analysis set is a reasonable approach to ensure a more homogeneous patient population in clinical trials. However, this exclusion may introduce confounding factors that impact the generalizability of the study results, particularly for patients with pes cavus.
Despite observing a statistically significant difference in mFARS score changes between the omaveloxolone and placebo groups, the study showed that this difference may not be clinically meaningful, as the minimum clinically important difference for mFARS scores is not well established. Moreover, the lack of success in the secondary endpoints echoes this observation. At week 48, patients randomized to receive omaveloxolone showed improvement in their mean scores for Patient Global Impression of Change ((PGIC)) and Clinical Global Impression of Change ((CGIC)) with scores of 3.90 and 3.93, respectively. PGIC and CGIC are standardized assessments used to measure the overall impression of change in patient status over time. These scores are significant for FA patients because they provide a subjective evaluation of treatment efficacy from the patient's and clinician's perspectives, respectively. However, the lack of significant difference in the scores between the groups despite the statistically significant improvement in mFARS scores for the omaveloxolone group suggests that the observed improvement may not be clinically significant.
Overall, while the study provides some evidence of the potential efficacy of omaveloxolone in treating FA, the limitations in the study design and analysis suggest that further research is necessary to confirm and extend these findings.
Addressing the Unmet Need for Effective Treatments for FA: The Potential Market for Omaveloxolone and Hurdles in Marketing for Reata
While the overall FA market is small, with an estimated 5,000 to 10,000 cases in the US, the disease has a significant impact on patients and their families, with a median onset age of 10-15 years and a median life expectancy of 40-50 years. Furthermore, the average annual cost burden for FA patients and their families is estimated as high as $118,000 . As there is a high unmet need for effective treatments for FA, the potential market for omaveloxolone may still be significant if it is shown to be an effective treatment.
However, excluding patients with pes cavus and lack of clinically significant benefits for omaveloxolone may hinder Reata's marketing of the drug for FA. Payers, clinicians, and patients may be less inclined to support the drug if it excludes a significant portion of the patient population or does not demonstrate clear advantages. This may lead to limited patient access and increased out-of-pocket costs.
Reata's Future in Question: FDA Likely to Issue Complete Response Letter for Omaveloxolone Following Discussions and Inadequate Clinical Improvement Data
Based on Reata's discussions with the FDA and the available data, it seems likely that the FDA will issue a Complete Response Letter requiring another trial. While the MOXIe data showed a statistically significant improvement in mFARS score, it may not be clinically significant, which is concerning. In fact, Reata notes the following regarding regulatory guidance:
We are relying on section 115 of the Food and Drug Administration Modernization Act (FDAMA 115) and the December 2019 draft guidance thereunder from FDA on "Substantial Evidence of Effectiveness" as the basis for seeking approval of omaveloxolone in the U.S. The guidance provides that, if a sponsor has not conducted two adequate well-controlled studies, there are two alternative pathways to demonstrate substantial evidence of efficacy for drug approval; either:
(i)
a single adequate and well-controlled clinical study that has demonstrated a clinically meaningful and statistically very persuasive effect; or
(ii)
a single adequate and well-controlled clinical study plus confirmatory evidence.
Reata appears to have done neither in effort towards obtaining FDA approval, according to both their own understanding of regulatory guidance and my analysis of the available data. Even in the event that omaveloxolone is approved by the FDA, its marketability may be restricted due to the absence of substantial clinical progress and the exclusion of FA patients with pes cavus. Consequently, I suggest a "Sell" recommendation for Reata before the FDA's decision.
For further details see:
Reata Pharmaceuticals' Omaveloxolone CRL Appears Imminent