What is positioned as a potential life-saving clinical trial is occurring at the brand new research site called AZ Clinical Trials in Mesa, Arizona. The study, funded by the Department of Health and Human Services and Regeneron, turns out to be part of what is a large Phase 3 clinical trial investigating a novel monoclonal antibody product targeting COVID-19 patients. Nurse practitioner Ann Moore and Dr. Anita Kohli report that this is the first clinical trial, at least in these parts, that focuses on COVID-19 patients who are not currently hospitalized. They have already seen their first five patients according to the news account. Although the news excludes the name of the monoclonal antibody investigational product, TrialSite News identifies the product as REGN10933+REGN10987 also known as REGN-COV-2. Interestingly, although the study has been disclosed, the sites are not named and, again, little information is shared in the recent Arizona news release. Hence, the TrialSite News investigates this clinical trial and finds that there are more questions about this study.
NIH Connections for the Site
As it turns out, Dr. Anita Kohli, Director of Clinical Research, set this new center up just ten days ago specifically to treat COVID-19 patients. Dr. Kohli comes with a good pedigree, a board-certified infectious disease physician who also happened to have trained with Dr. Anthony Fauci at the National Institute for Allergy and Infectious Disease (NIAID), part of the National Institutes of Health (NIH). Dr. Kohli clearly has significant accomplishments and undoubtedly developed valuable relationships which perhaps paved the way for AZ Clinical Trials to become a site for Regeneron.
The study focuses on what is described to the public as a Regeneron monoclonal antibody. Dr. Kohli noted for the local television station ABC 15 that “With this (trial) you are getting a high dosage of COVID-19 specific antibodies given to you and what these antibodies do is they target what we call the S protein of the virus.”
The Monoclonal Antibody Product Background
A recent report authored by Regeneron, et al show that neutralizing antibodies are increasingly considered an valuable approach to treating infectious diseases. The authors introduce a purported recent success story focusing on antibody treatments for Ebola sourced from 1) genetically-humanized mice and 2) a human survivor. Hence, Regeneron took this concept and ran with it, leveraging Regeneron’s proprietary development platform, developing a similar treatment, that is antibodies against the SARS-CoV-2 spike protein originating from both 1) humanized mice and 2) convalescent patients.
This yielded a large collection of fully-human antibodies that were thereafter characterized for binding, neutralization and three dimensional structure. Summarizing what is undoubtedly far more complex, Regeneron and research partners identified a part of “highly-potent individual antibodies that simultaneously blind the receptor-binding domain of the spike protein in what they post equals an ideal partner for “therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single antibody treatment.”
Regeneron was able to secure rapid regulatory approval to launch clinical trials based on the antiviral antibody cocktail. Initiating what they reported were the first Phase 1/2 clinical trials combining the monoclonal antibodies called REGN10933 and REGEN10987 collective known as REGN-CoV2 first in ambulatory and hospitalized adult patients tested positive for COVID-19. According to Regeneron, those studies would retrospectively investigate and compare the two-drug combination versus a placebo in 1,052 and 1,086 patients.
The Phase 3 Clinical Trial
Today the company announced the Phase 3 clinical trial and in a synchronized way, at least the Arizona site was able to secure some air time on the local media evidencing definite planning for the initiative in a bid to enroll participants.
Announcing the evaluation of REGN-COV2, the company’s investigational double antibody cocktail for the treatment and prevention of COVID-19, the Phase 3 trial will evaluate the investigational monoclonal antibody-based cocktail to prevent infection among uninfected people who have had close exposure to a COVID-19 patient (such as a spouse of a housemate) and is being run jointly by the National Institute of Allergy and Infectious Diseases (NIAID), again part of the NIH. REGN-COV2 moved into the Phase 2/3 portion of two adaptive Phase 1/2/3 trials testing the cocktail’s ability to treat hospitalized and non-hospitalized (or “ambulatory”) patients with COVID-19.
As the company reported, this Phase 3 study will be conducted at approximately 100 clinical investigational sites and is expected to enroll 2,000 patients in the United States and this aligns with their Clinicaltrials.gov disclosure. The trial will assess SARS-CoV-2 infection status. Interestingly, the trials are being conducted in the United States, Brazil, Mexico and Chile and seek to evaluate virologic and clinical endpoints, with preliminary data expected later in the summer.
With adaptively designed studies, the number of patients enrolled depend on the trial progress and insights from Phase 2 studies. TrialSite News will pay close attention to primary outcomes measures as the TrialSite Network knows all too well in the Remdesivir trial the primary outcome measure was yanked toward the end of the trial and replaced with one that evidenced results.
Of course, the rush to Phase 3 centers on both the prevention of and treatment of COVID-19 infections, which are resurging. If not put in check, COVID-19 will cause even greater health, social and economic damage. So the imminent imperative is understandable.
Phase I Results & Timing Issues
According to Regeneron’s recent press release, after a positive review from the Independent Data Monitoring Committee of REGN-COV2 Phase I safety results in an initial cohort of 30 hospitalized and non-hospitalized patients with COVID-19, the company was apparently awarded the green light from the federal government to initiate a Phase 3 clinical trial.
Now what needs clarification is where was the Phase 1 clinical trial conducted and disclosed and where are the documented results. Again, their June 11 press release notes the study is just commencing. Dr. Suraj Saggar, Chief of Infectious Disease at Holy Name Medical Center in Teaneck, New Jersey, acknowledges that repurposing existing medicines may not be effective against COVID-19 and that they are excited to “begin studies of REGN-COV2.” Hence the interest in the Phase 1 trial (30 hospitalized and non-hospitalized patients) that was the basis for the IDMC review. That particular Phase 1 wasn’t disclosed on Clinicaltrials.gov as the current ones just published started in mid-June.
What appears to be the case, according to company press releases, is that the Phase 3 study is conducted in parallel as they note, “The first two adaptive Phase 1/2/3 studies are evaluating REGN-COV-2 as a treatment for hospitalized and non-hospitalized patients with COVID-19. The Phase 1 portion will focus on virologic and safety endpoints, and the Phase 2 portion will focus on virologic and clinical endpoints. Data from the Phase 1 and Phase 2 studies will be used to refine the end points and determine size for the Phase 3 studies.”
Now this is where our analysts get confused. According to the Regeneron press release, Phase 3 doesn’t commence until there is sufficient virologic and clinical endpoints. So, the NCT04425629 (COVID19 ambulatory patients Phase 1/2 ) and NCT04426695 (COVID19 hospitalized patients Phase 1/2) are published at the same time as the Phase 3 NCT04452318 (COVID19 health patients Phase 3), which is tagged as not recruiting yet. However, the recent television broadcast clearly highlights this trial (health individuals) has commenced as they (the Arizona site) have already seen five patients. And again, the Phase 3 clinical trial is for healthy patients which dovetails with the Mesa, Arizona site trial study. The sponsors, and for that matter NIAID, could make this a little clearer for the public. In the meantime, TrialSite News investigators are currently reviewing the context and background of this Phase 1 study.
Regeneron scientists evaluated thousands of fully-human antibodies produced by the company’s proprietary VelocImmune® mice, which have been genetically-modified to have a human immune system, as well as antibodies isolated from humans who have recovered from COVID-19. They selected the two most potent, non-competing and virus-neutralizing antibodies to create REGN-COV2 and have scaled up this dual-antibody cocktail for clinical use with the company’s in-house VelociMab® and manufacturing capabilities. REGN-COV2’s two antibodies bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population, as detailed in recent Science publications. More recent research also demonstrates coverage against the now prevalent D614G variant.
For the Mesa, Arizona study site, the Principal Investigator is Dr. Anita Kohli.
Call to Action: TrialSite News‘ investigators are looking deeper into REGN-COV2, which sounds promising but the way this suite of studies have commenced is a bit confusing.