The Positive News
Prohost Biotech’s interest in Reata Pharmaceuticals (RETA) started when we recognized and appreciated the firm’s goals and its scientific capability. Reata Pharmaceuticals’ goal is discovering molecular pathways that regulate cellular metabolism, inflammation and response to stress injury; hence, treat devastating diseases that have yet to find treatments.
Our interest increased with the knowledge that it has already identified new entity therapeutics molecules and has evaluated them in clinical trials for severe progressive life-threatening conditions. We were excited to see these therapeutics navigate preclinical, early clinical and late phase clinical trials without serious problems. The trials have been evaluating the firm’s therapeutics for severe conditions including: Alport syndrome, autosomal dominant polycystic kidney disease (ADPKD), IgA nephropathy, type 1 diabetic chronic kidney disease (CKD), local segmental glomerulosclerosis and Friedreich’s Ataxia (FA).
Our interest in the firms was further compounded when we learned about the severity of the diseases that Reata’s therapeutic molecules could treat as all of these conditions have yet to find treatments. Some of these diseases are chronic, progressive and torturous. Alport syndrome and IgA nephropathy are genetically-related conditions that torture sick children from childhood to adulthood, when the disease becomes life-threatening.
The Therapeutics from Reata Pharmaceuticals
Bardoxolone methyl: This product has been evaluated in clinical trials for the treatment of all the above conditions except Friedreich’s ataxia. We were enthusiastic to learn that this product is an Nrt2 activator – a transcription factor that normalizes the mitochondrial function, restores redox balance and resolves inflammation.
Omaveloxolone: This product is being evaluated in clinical trials for Friedreich’s ataxia. Similar to bardoxolone, this novel molecule is an Nrt2 activator, which also added to our enthusiasm.
We have learned that these treatments are not all the therapeutic molecules Reata has discovered or included in its pipeline. Reata has identified a novel class of proteins that target pathways involved in the cellular stress, the cellular response to misfolded proteins and the mitochondrial protein import.
The lead candidate therapeutics of these proteins is RTA 901 and related analogs. RTA 901 has already demonstrated promising results in animal model trials of neurological diseases without safety or tolerability issues from results from the Phase 1 clinical trial of the product.
Moreover, Reata has also identified a series of potent and selective RORyt inhibitors which block Th17 cell differentiation. The lead product candidate RTA 1701 is orally bioavailable and has already demonstrated significant efficacy in animal models of rheumatoid arthritis and multiple sclerosis. This additional information reinforced our interest in Reata. We decided to invest in this firm by buying a small number of shares all while continuing to follow up on the clinical trial results through the late-Phase trial results when statistically significant positive results of Bardoxolone methyl in the treatment of Alpert Syndrome and other severe diseases was announced.
Successful Trial Results
Alpert Syndrome is the second most common inherited cause of renal failure, affecting 60,000 in the United States.
The condition is caused by a genetic defect in type IV collagen – a component in building the glomerular basement membrane (GBM), the kidney’s filtering system. The mutation of Type IV collagen can alter the GBM’s structure, impair its function and ultimately lead to end-stage renal disease.
With no approved therapies to stop the progressive loss of kidney function, Alport syndrome is presented as a risky disorder with a significant unmet need. As in other forms of chronic kidney diseases, mitochondrial dysfunction and chronic inflammation play important roles in the pathophysiology and progression of Alport Syndrome.
The Product, The Trial and The Results
Bardoxolone methyl has the potential to prevent long-term consequences and improve the symptoms of many diseases by correcting the underlying pathology. Through Nrf2 induction and inhibition of NF-κB, bardoxolone methyl activates molecular pathways that promote the resolution of inflammation by restoring mitochondrial function and redox balance and inhibiting pro-inflammatory signaling. Bardoxolone reverses endothelial dysfunction and chronic, disease-related mesangial cell contraction, resulting in an increased surface area of the glomerulus and increased glomerular filtration rate (GFR).
Furthermore, Bardoxolone methyl inhibits the activation of proinflammatory and profibrotic pathways that lead to structural remodeling and glomerulosclerosis. Thus, bardoxolone methyl targets multiple pathways that contribute to GFR loss in Alport Syndrome.
Phase 3 CARDINAL trial of bardoxolone in patients with Alport Syndrome complicating CKD met its primary and key secondary endpoints at the end of Year 2.
At Week 100 in the intent-to-treat (ITT) population bardoxolone caused statistically significant improvement compared to placebo in mean change from baseline in estimated glomerular filtration rate (eGFR) of 7.7 mL/min/1.73 m2.
In the modified ITT (mITT) analysis bardoxolone demonstrated a statistically significant improvement compared to placebo in mean change from baseline in eGFR at Week 100 of 11.3 mL/min/1.73 m2.
At Week 104 patients in the ITT population treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR of 4.3 mL/min/1.73 m2.
Bardoxolone was generally well-tolerated.
In the long-term extension study, bardoxolone resulted in a mean increase from baseline in eGFR of 11.0 mL/min/1.73 m2.
Based on these results, which are all positive and following a completed pre-New Drug Application meeting with the American FDA, the Company plans to proceed with the submission of an NDA for full marketing approval in the United States in the first quarter of 2021.
Reata will also file for marketing approval in Europe.
This is all good news.
The Perceived Negative News
Friedreich’s Ataxia is an inherited, debilitating and degenerative neuromuscular disorder. This disease is diagnosed during adolescence and can lead to premature death. Patients with FA experience progressive loss of coordination, muscle weakness and fatigue, which commonly progresses to motor incapacitation and wheelchair reliance. The symptoms generally occur in children who will require a wheelchair in their teens or early 20s. FA affects approximately 5,000 children and adults in the United States and 22,000 globally. Currently, there are no treatments approved in the U.S. for FA.
Omaveloxolone for Friedreich’s Ataxia
In November 2020 Reata stated, “As previously announced, at a Type C meeting, the FDA provided us guidance that although it does have no concern with the reliability of the modified Friedreich’s Ataxia (FA) Rating Scale primary endpoint results from the registrational Part 2 of the MOXIe trial of omaveloxolone in FA patients, the agency was not convinced that the results from Part 2 support a single study approval. The FDA stated that we will need to conduct a second pivotal trial that confirms the mFARS results of Part 2 with a similar magnitude of the effect.”
As an alternative, Reata proposed a second study known as the Baseline-Controlled Study, previously called the Crossover Study. The design of the Baseline-Controlled Study was agreed upon by external experts and Reata; the statistical analysis plan was submitted to the FDA prior to conducting the analysis contemplated by the proposed plan.
The FDA acknowledged it would consider the study design but, until the November press release, the agency has not provided its answer.
The Baseline-Controlled Study met its primary endpoint with a statistically significant 3.76 point improvement between the treatment and pre-treatment periods in the primary analysis population. Further, according to the firm, all sensitivity analyses of the primary analysis showed a significant treatment effect which convinced Reata that the Baseline-Controlled Study supports the positive mFARS results of Part 2 and provides additional evidence of the effectiveness of omaveloxolone in FA.
Reata decided to commence the preparations to file for marketing approval in Europe.
On November 24, 2020 Reata informed that the FDA completed its internal review of the Baseline-Controlled Study results of omaveloxolone Friedreich’s Ataxia and concluded that the results do not strengthen the results of Part 2 of the MOXIe study. The FDA proposed some additional exploratory analyses using patients randomized to placebo during the MOXIe Part 2 study but stated that the potential for these analyses to strengthen the study results was questionable due to the small number for analysis. The FDA stated that they remain interested in reviewing the results of the additional patients available exploratory analyses as those may inform the future development program.
The Company plans to submit to the FDA the analyses that they proposed and to request a meeting with the agency to discuss the development program. In addition, based on the FDA’s conclusion, the Company is considering the next steps for the development program, including whether to conduct a second pivotal study in patients with FA.
From the Chairman and CEO of Reata Pharmaceuticals
Warren Huff, Reata’s Chairman, and Chief Executive Officer, said, “Omaveloxolone improved motor function as measured by the modified Friedreich’s Ataxia Rating Scale in both Part 2 of the MOXIe study and the Baseline-Controlled study. We are grateful to the families, physicians, investigators, and advocates who have supported this program to date. Although we are disappointed in the FDA’s feedback on this program, we will carefully consider the potential paths forward for making omaveloxolone available to patients with Friedreich’s Ataxia.”
It is clear why we like Reata. As to the FDA observations and demands regarding Omaveloxolone for Friedreich’s Ataxia, we did not see a rejection anywhere of the drug or its failure. What we did observe is that the FDA believes it is important to cement the statistically significant results with another study.
We believe that the Company’s results from the other products are opening the door for a near term filing for approvals of the firm’s product Bardoxolone for severe life-threatening diseases that have yet to find treatments, including Alport Syndrome, IgA nephropathy and ADPKD.
So, more good news than bad for Reata.
In fact, the FDA’s demands about the FA treatment and trials should not be considered bad news.
To read more about Reata Pharmaceuticals please click here.