IDMC Observes Some Safety Signals in Regeneron’s Study of REGN-COV2 in Hospitalized Patients: Recommendations Made to Modify

IDMC Observes Some Safety Signals in Regeneron’s Study of REGN-COV2 in Hospitalized Patients Recommendations Made to Modify TrialsiteN

Regeneron’s monoclonal antibody investigational product known as REGN-COV2 has been touted by trial site’s all over the United States, almost in a marketing like manner due to the explicit promotion of the drug by POTUS during the stay at Walter Reed Medical Center. Referring to the advanced but highly investigational therapy as a cure, even implying the divine original of the investigational product, now there’s some possible issues. Recently, the independent data monitoring committee (IDMC) overseeing the overall program and its multiple clinical trials recommended that the current hospitalized patient trial be modified. With the detection of an apparent safety signal, Regeneron recently identified in its press release that due to “an unfavorable risk/benefit profile the IDMC recommends further enrollment of patients requiring high-flow oxygen or mechanical ventilation be placed on hold pending collection and analysis of further data on patients already enrolled.” However, the IDMC does recommend that the clinical trial continue for all other patient cohorts so overall this event is certainly an indicator that the FDA/GcP process is healthy in the Regeneron REGN-COV2 program.  TrialSite however has observed trial sites around the nation using the fact that POTUS was treated with this experimental drug as a means of differentiation and almost marketing like purpose. This practice touches a gray area and trial sites should probably refrain from such tactics.

TrialSite breaks down this most recent update from the company.

What is REGN-COV2?

This combination of two monoclonal antibodies (REGN10933 and REGN10987) was designed specifically to block infectivity of SARS-CoV-2 as declared in Regeneron’s recent press release. The New York region-based biotech has developed impressive life science-based technological advances including their VelociSuite® technology platform including VelociGene® and VelociMouse® for superior disease modeling and drug target exploration. 

The company developed REGN-CoV2 using VelocImmune® mice, which have been genetically modified to have a human immune system as well as antibodies identified from humans who have recovered from COVID-19. As the company positions  these two potent, virus neutralizing antibodies actually bind in a complimentary manner to the critical receptor binding domain of the SARS-CoV-2 spike protein, thereby diminishing the ability of the mutant viruses to escape treatment and also protect against spike variants manifesting in the human population as reported in Science

What is the trial at hand?

The clinical trial (NCT04426695), a Phase 3 study to evaluate the safety and tolerability of the combined monoclonal antibody cocktail as compared to the placebo as well as A) evaluate the virologic efficacy compared to placebo in reducing viral shedding of COVID-19 B) evaluate the virologic efficacy of the investigational product compared to placebo in reducing viral shedding of COVID-19 C) evaluate the investigational product compared to placebo in improving clinical status Phase 3 and D) evaluate and confirm the clinical efficacy of the investigational product compared to placebo in improving clinical status. Note Regeneron hasn’t updated still registered the trial as Phase 1/2 however a Regeneron spokesperson informed TrialSite it was progressing to Phase 3.

The trial is designed to enroll patients in four independently randomized cohorts:

  • Cohort 1: patients on low-flow oxygen
  • Cohort 1A: patients not requiring oxygen
  • Cohort 2: patients on high-flow oxygen
  • Cohort 3: patients on mechanical ventilation

What happened to trigger the IDMC recommendation?

It’s not clear as the company didn’t disclose what safety signal the IDMC detected. Clearly there was some safety issue, whether a serious adverse reaction (SAR) or Suspected Unexpected Serious Adverse Event (SUSAR) or something else because the IDMC recommended that based on whatever happened now there is an unfavorable risk/benefit profile for those hospitalized patients requiring either high-flow oxygen or mechanical ventilation in this clinical trial. So clearly something at least somewhat material occurred.

Now whatever happened could have a different medical root cause, it’s not clear what happened and if it is certainly related to REGN-COV2. That’s why the company declared the incident must be assessed.

Is this evidence that overall the clinical trials process is healthy?

Yes the IDMC is clearly monitoring this trial very carefully and employing risk-based analyses continuously to ensure that first and foremost patient safety is the number one priority.

Does this recommendation impact the rest of the study or other studies?

No. The IDMC recommends continuing enrollment of hospitalized patients requiring either no or low-flow oxygen as the risk/benefit remains acceptable in these cohorts. Moreover, they recommended to keep the outpatient trial going without modification hence implying low risk to patients.

Is the study data still “blinded”?

Yes. The IDMC still monitors the data that is blinded to all those  involved. This means that no one but the IDMC has access to the study data.

What is Regeneron’s goal with this program?

They are seeking to have the monoclonal antibody cocktail evaluated by the FDA for a potential Emergency Use Authorization in mild-to-moderate outpatients in high-risk scenarios.

Will Regeneron share these findings with regulators?

Yes they are sharing with the FDA as well as regulators in the UK which is hosting a trial to evaluate REGN-COV2 in hospitalized patients.

Is this an example of why not to promote investigational drugs?

Yes. Because investigational drugs are experimental—that is they have not been proven to be safe and effective. Especially when it comes to safety profile there is no track record whatsoever with such a new, advanced and experimental drug. Hence why it was a mistake by POTUS to tout these drugs by name and by company. 

Since then, TrialSite has noticed media has picked up on what happened and now positions these Regeneron trials across the nation as the drug that POTUS was given.

Is there additional sensitivity to this study?

Yes. TrialSite has introduced in past articles how this particular study’s origin is somewhat unorthodox in nature. There was no formal completion of a Phase 1 study to kick off even Phase 2 and 3 trials. Rather, as Regeneron disclosed to TrialSite, the company and FDA entered into an agreement that sentinel cohort population can be used for initial safety signal data. See the link for more information. 

Why did this study start in such an unorthodox way?

Probably due to the pandemic. With so many people infected and the horrific death count at the time regulators, NIH/NIAID government supporters and the company sought to get studies moving in an agile and accelerated manner.

Has Regeneron been responsive for questions?

Yes. TrialSite can report that Regeneron has responded to any and all questions sent to them. In fact, they are the most responsive biotech thus far observed in the brief two year history of TrialSite

Has Regeneron received public (taxpayer funding) for this research and development effort?

Yes. The development and manufacturing of REGN-COV2 has been funded in part with use of federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services under OT number: HHSO100201700020C.

Has Regeneron partnered with Roche to increase global supply of this product?

Yes, they have put a deal together to increase the global supply of REGN-COV2 starting in 2021. They have carved out the following market territory: Regeneron makes the product for the U.S. and Roche the rest of the world.

Does this product show potential?

Yes. Of course, its highly experimental and considerable risk is associated with such a class of product but data thus far appears promising. But no one can be certain until comprehensive data from clinical trials and post-market surveillance can be accumulated, organized and analyzed.