The National Institutes of Health (NIH) initiated the public-private partnership known as the NIH Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV), a mission critical research program set up at the pandemic’s onset to find vaccines and treatments. The program directs billions of taxpayer dollars to fund ongoing clinical trials. TrialSite’s been critical of the program’s focus, overwhelmingly favoring the development of vaccines and novel therapeutics without sufficient emphasis on economical repurposed and generic research aiding the 90% of COVID-19 cases—those with asymptomatic to mild-to-moderate early onset infection. TrialSite profiled ACTIV as heavily favoring industry and academia and has chronicled the billions spent thus far. ACTIV did recently announce ACTIV-6 and the move to finally test therapies for early onset, mild to moderate cases. Now ACTIV has launched another Phase 3 clinical trial testing the safety and efficacy of therapeutics for COVID-19, now enrolling patients hospitalized with life-threatening cases driven by coronavirus infections—including acute respiratory failure. This particular ACTIV-based trial is supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung and Blood Institute (NHLBI). This study, known as ACTIV-3 Critical Care, investigates the use of Zyesami, NeuroRx’s repurposed therapy also known as RLF-100 that showed positive results earlier in the pandemic as well as remdesivir, already approved for the COVID-19 indication. TrialSite notes that NeuroRx licensed this decades old product from Relief Therapeutics of Switzerland as the two jointly agreed to develop the product targeting COVID-19 back in September in a Collaboration Agreement. Zyesami has demonstrated considerable promise yet the Emergency Use Authorization (EUA) filed by NeuroRx in September of 2020 was rejected by the U.S. Food and Drug Administration (FDA) at the end of 2020. The ACTIV-3 study is led by principal investigator Samuel Brown, MD, MS, Intermountain Healthcare, and the University of Utah in Salt Lake City could finally give this drug the chance to help save more lives. But it will take time, and in the meantime, the companies that partnered to develop the drug, both NeuroRx and Relief Therapeutics (Relief) look to be headed to the courts if they don’t resolve their pending disputes soon. As NeuroRx merges into a special purpose acquisition company (SPAC) at a valuation of $500 million, the opportunities for the company open up.
TrialSite provides an introduction to the drug, the clinical timeline, the pending problems between the commercial sponsors, and a brief overview of the ACT-3 study recently announced by the NIH.
Investigational Drug Shows Promise Early On
Of note, most of the sponsors in ACTIV studies have been larger pharmaceutical companies; however, there are some exceptions. In this case, small biotech NeuroRx, which licenses the underlying intellectual property from Switzerland’s Relief Therapeutics, is the beneficiary of public investment now. TrialSite followed this company and the product (RLF-100) for some time. Early on in the pandemic, TrialSite was contacted by a number of family members with very sick loved ones in hospitals. They read about some positive results at Houston Methodist Hospital, for example.
In a recent NIH press release announcing the new study, NIAID Director Dr. Anthony Fauci shared that “We need more treatment options to increase the chances of recovery for people who are extremely sick so they can leave the hospital more quickly, continue their recovery at home, and return to life as usual.” Fauci emphasizes the mission critical importance of supporting the development of effective therapeutics for critically ill COVID-19 patients.
The Study Drug
Zyesami, a formulation of aviptadil acetate, produced by NeuroRx, Wilmington, Delaware, and the antiviral remdesivir (Veklury), developed by Gilead, Foster City, California. Aviptadil is a synthetic version of Vasoactive Intestinal Peptide or VIP, which is made naturally in the human body and appears to have lung-protective antiviral and anti-inflammatory effects. Administered intravenously, it may provide additional protection for lung cells commonly targeted by SARS-CoV-2, the virus that causes COVID-19. It is licensed in the United States for treating hospitalized patients with COVID-19. However, its benefit in patients with more severe COVID-19 is unclear. The trial will test Zyesami and remdesivir (alone and in combination), for their safety and efficacy in hospitalized COVID-19 patients who are experiencing Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition in which the lungs are severely inflamed and may be unable to maintain sufficient oxygen in the blood.
The drug is actually decades old, studied over the decades for a number of treatment uses from erectile dysfunction to pulmonary fibrosis.
The Sponsors & Pending Legal Troubles
RLF-100 (Zyesami) was actually acquired by Switzerland’s Relief Therapeutics (Relief) from Mondo Biotech AG for further study to consider as a potential treatment for ARDS, Acute Lung Injury and Sarcoidosis. Known as Aviptadil, this novel formulation of Vasoactive intestinal Polypeptide (VIP) was first used in combination as a formulation with phentolamine for intracavernous injection authorized in Europe for the treatment of erectile dysfunction, and according to Relief Therapeutics, has a 20-year proven safety track record.
A Timeline of the Partnership
Back in March 2020 during the onset of the pandemic, NeuroRx CEO Johnathan Javitt, MD, MPH, an influential player in the world of drug development and savvy in the ways of securing Fast-Track and Breakthrough Therapy Designations with the U.S. FDA, proposed to Relief that RLF-100 be tested to help treat ARDS in patients infected with COVID-19. It was becoming apparent then that ARDS was the primary cause of death for COVID-19 patients. The two companies subsequently inked a partnership and filed an investigational new drug application (IND) for a phase 2 trial of RLF-100 (Aviptadil) for the treatment of ARDS in patients infected with COVID-19.
With orphan drug status already in place with the FDA and the European Medicines Agency (EMA), the FDA gave the “study may proceed” greenlight on March 29, 2020. This first trial would be overseen by an independent Data Safety Monitoring Board led by prominent academic researchers.
By May 11, NeuroRx filed an investigational protocol with the FDA under the Coronavirus Treatment Acceleration Program (CTAP) to conduct a Phase 2/3 clinical trial investigating the use of inhaled RLH-100 as a treatment for patients with non-acute lung injury caused by COVID-19. This request was granted with a study-may-proceed by August 6, 2020.
A Frantic Summer
By June 11, NeuroRx (and its partner Relief) announced an expansion of the RLP clinical trial to involve more trial sites and patients due to promising results ongoing.
The FDA granted RLF-100 Fast Track Designation by June 24, 2020. During that summer, Relief restructured some debt, agreeing with its single largest shareholder at that time, Gem Global Yield Fund LLC, to an outstanding debt position. Demonstrating the tightening of the relationship between Relief and NeuroRx, Relief announced that CEO Javitt was elected vice chairman of the board of directors of the Swiss company on July 20, 2020. At the same time, the FDA granted NeuroRx in America an expanded access protocol to RLF-100 for respiratory failure in COVID-19 patients. This would allow more patients to access the drug after doctors exhausted all other treatment options.
NeuroRx & Relief Extend Commercial Partnership
The studies ongoing during the summer showed increasing promise as TrialSite before mentioned numerous patients contacted the research information platform for help to access RLF-100 studies or expanded protocol access. Consequently, both companies inked a worldwide commercialization deal. They agreed that the two companies would share all profits from RLF-100 sales for all indications associated with COVID-19 and possibly other respiratory indications on a global basis. Moreover, they agreed that NeuroRX would lead commercialization efforts in the United States, Canada and Israel while Relief would lead commercialization in Europe and the rest of the world. Profits would be allocated to Relief and NeuroRx on a 50/50 basis in the U.S., Canada and Israel and 85/15 (in favor of Relief) in Europe and 80/20 (in favor of Relief in all other market), Relief reported on September 21, 2020.
As part of the deal, the companies shared with investors that they were pursuing a contract “fill/finish” manufacturer as well as a national distribution partner to help provide the sales force should the product get approved. By late September, they forecasted they would have sufficient drug supply to treat 150,000 patients per month with RLF-100. Moreover, the agreement set that NeuroRx would prosecute trademarks for the drug in its designated markets and Relief its corresponding markets. The two partners also clarified later in the month supply chain agreements, along with drug substance orders supporting the treatment of up to 1 million patients.
Emergency Use Authorization Request in Sept 2020
Just days after their commercialization deal, both NeuroRx and Relief shared with the world that they had submitted a request for Emergency Use Authorization (EUA) with the U.S. FDA for the use of RLF-100 in patients who were receiving intensive care and had exhausted all approved treatments.
Progress in Results
By November, both NeuroRx and Relief provided updates on the RLF-100 Expanded Access Protocol endeavor: they had thus far treated 175 patients with critical COVID-19 and respiratory failure also with severe comorbidity. Due to their condition, they couldn’t participate in the Phase 2/3 clinical trial (NCT04311697). The results were promising in what was a rapidly unfolding public health crisis.
Now established as “Zyesami,” RLF-100 was selected by the I-Spy COVID-19 trial by January 11, 2021. TrialSite provided some color on I-Spy back on July 29, 2020. By February, Relief issued a press release acknowledging the partners launched a Phase 2/3 clinical trial investigating RLF-100’s benefits for patients with severe COVID-19 in partnership with UCI Health of the University of California, Irvine. In this study, the sponsors sought to determine if the study drug could be administered at earlier yet severe stages of COVID-19 in a bid to reduce the likelihood of disease progression.
Further good news came on February 24, 2020 when Relief announced that RLF-100 successfully demonstrated ten day accelerated recovery from respiratory failure among critically ill COIVD-19 patients treated with high flow nasal oxygen at 28-day interim endpoint.
By March 30, 2021, Relief announced that NeuroRx reported that the release of 60 day results from the phase 2/3 trial of intravenously administered RLF-100 met the primary endpoint for successful recovery from respiratory failure as well as demonstrated meaningful benefit in survival.
FDA Rejects EUA
By December 30, however, bad news came for the two companies as the U.S. FDA rejected the NeuroRx application for EUA. While this move was criticized, especially considering the FDA’s acceptance of not only the remdesivir EUA after the sponsor, NIAID and Gilead, made last minute changes to the primary endpoint, the FDA even authorized an EUA for convalescent plasma which many criticized. Consequently, Relief’s stock price tanked by 26% at that point. Undoubtedly, this was a great disappointment as both parties were geared up for imminent manufacturing and distribution of the investigational product.
ACTIV Picks Up RLF-100
By April 7 of this year, Relief announced to the world that NeuroRx and RLF-100 was selected by the powerful and prominent ACTIV study known as TESICO (Therapeutics for Severely Ill Inpatients with COVID-19). RLF would be one of the drugs included in the large Phase 3 clinical trial. Success here could lead finally to the EUA milestone but this is many months away still.
Trouble in the Partnership
By the end of December 2020, NeuroRx agreed to merge with a blank check company or a special purpose acquisition company (SPAC) heavily popular now in the life science investment world. Valued at about $500 million, NeuroRx would merge into the entity known as Rock Partners Acquisition Corp. The new legal venture was to be led by Dr. Javitt.
Various tensions that had built up exploded on the news just a few weeks ago in early April when Relief announced the partnership had real problems. First, they noted that NeuroRx wasn’t sharing clinical trials data from its recently completed Phase 2b/3 trial and that such data was contractually to be shared via their “Collaborative Agreement” from September 2020. Moreover, Relief claimed that NeuroRx was not allowing contract partners to share information with Relief. Second, NeuroRx stated publicly as part of their SPAC merger that Relief owes the company $4 million in unpaid invoices.
But Relief counters that “unfortunately, many of these alleged expenses have not been substantiated by valid, verifiable invoices that support that these expenses are reimbursable” under the agreement. Relief noted it has intended to conduct a forensic audit of NeuroRx books. Third, while NeuroRx declared publicly that Relief elected not to fund a recently initiated clinical trial investigating the use of inhaled aviptadil for the treatment of moderate to severe COVID-19 Relief’s position is that because NeuroRx hasn’t shared material information, even after request, that they are not able to move forward.
Fourth, NeuroRx went on the record questioning the profit split rations due to Relief’s failure to fund agreed upon expenses—Relief suggests profit rations not impacted by funding issues per the contract. And fifth, apparently “stability issues” with the investigational product were disclosed in the SPAC deal, Relief arguing now that both the parties understood these clearly going into the Collaboration Agreement back in September 2020.
Moving forward, Relief’s position is that it seeks to resolve the issues “amicably,” however it is prepared to litigate based on its interpretation of the Collaboration Agreement. In the mean time, year to date Relief stock price is way down.
The ACTIV-3 Study
ACTIV-3 Critical Care (NCT04843761) allows for sub-studies of different therapeutics to run concurrently. Each sub-study will enroll approximately 620 participants. Participants will be randomly assigned to receive either the investigational agents in the sub-study or a placebo. In the current version of the study, participants will be randomly assigned to receive one of four treatment regimens in addition to standard of care: both Zyesami and remdesivir, Zyesami and a placebo, remdesivir and placebo, or only placebo. Zyesami is administered for 12 hours daily for three days, with the infusion rate increasing each day. Those randomized to receive remdesivir will receive it for up to 10 days via IV.
“There is a strong body of previous research that supports the use of these agents in ARDS, which is associated with substantial morbidity and mortality,” said Gary H. Gibbons, M.D., director of NHLBI. “Not only is this an important trial, in terms of potential new treatments for COVID-19, but it could open new understanding into the repair of damaged lungs following ARDS.”
The study evaluating Zyesami and remdesivir will enroll hospitalized patients with acute respiratory failure due to COVID-19 who require high-flow supplemental oxygen, delivered by nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation.
Initially, a small cohort of 40 participants will be enrolled at sites in the United States. If no safety concerns are identified, a larger group of participants will be enrolled at additional U.S. and international sites. If necessary, the treatment regimens may be adjusted before additional participants are enrolled.
For the primary analysis of the trial, participants will be assessed on a six-category ordinal scale 90 days after enrollment, and outcomes will be compared among treatment groups. This scale ranges from recovered and living at home without supplemental oxygen within two weeks of enrollment, to death. Following the assessment at the primary endpoint, participants will receive one additional follow-up at 180 days.
During the trial, an independent Data and Safety Monitoring Board (DSMB) will review the data on an ongoing basis. ACTIV-3 Critical Care is part of the overall ACTIV-3 effort, which has been testing new therapeutics in hospitalized patients since Aug. 4, 2020.
The principal investigator of ACTIV-3 Critical Care is Samuel Brown, M.D., M.S., of Intermountain Healthcare and the University of Utah, Salt Lake City. Leaders of the participating networks include James Neaton, Ph.D., of the NIAID-sponsored International Network for Strategic Initiatives in Global HIV Trials network; Taylor Thompson, M.D., of the Prevention and Early Treatment of Acute Lung Injury network, Annetine Gelijns, Ph.D., and Alan Moskowitz, M.D., of the Cardiothoracic Trials Surgical Network, both NHLBI-sponsored networks; and Victoria Davey, Ph.D., M.P.H., of the U.S. Department of Veterans Affairs.