Omicron thwarts all but one monoclonal antibody; demand for Sotrovimab spikes

Omicron thwarts all but one monoclonal antibody; demand for Sotrovimab spikes

By Stephen Ditmore

Vir Biotechnologies, brainchild of former Biogen CEO George Scangos and located adjacent to the University of California at San Francisco, developed a monoclonal antibody treatment for SARS-CoV-1, then adapted it to treating SARS-CoV-2 by targeting a conserved portion of the spike protein to create VIR-7831. Their supposition was that this antibody would be broadly effective against future variants, and they were right. According to Stanford University VIR-7831, now called Sotrovimab and trade named Xevudy, is 4.9-fold less effective against the Omicron variant than against original wild-type SARS-CoV-2. That compares with the other major monoclonals being 100 to over 1000-fold less effective against Omicron, with two new candidates from China in double digits (where low is better). Far from standing still, Vir’s next antibody, VIR-7832, has completed a study in hamsters, and is, like Sotrovimab, effective against Omicron. The question is whether Vir’s production partner, GlaxoSmithKline, is up to the challenge of quickly supplying the world with their product. One must wonder, with the need being so urgent, what the impediment would be to switching facilities currently making other monoclonal antibodies to making Sotrovimab? Could threatening an invocation of the Defense Production Act make that happen, or would companies collaborate if promised some simple exemptions from anti-trust provisions?

While there’s nothing as effective against the Omicron variant as Sotrovimab (except Vir’s newer VIR-7832) among existing monoclonal antibodies, there is in a competing category, antivirals, in which the hands-down winner is Pfizer’s protease inhibitor cocktail, Paxlovid.

Paxlovid comes in packets of 3 pills, a major advantage over intravenous infusion for a therapy that must be administered early in the disease, pre-hospitalization.  The two pinkish tablets are nirmatrelvir, which inhibits 3CLpro enzyme inside the cell, blocking viral proteins needed by SARS-CoV-2 to replicate.  The white tablet, ritonavir, prevents enzymes in the liver from breaking down nirmatrelvir before it has a chance to disable the coronavirus.

Like anything that inhibits certain liver functions, ritonavir, a component of some HIV treatment cocktails, can affect how other medications are metabolized by the body.  These drug-drug interactions are spelled out by NIH in The COVID-19 Treatment Guidelines Panel’s Statement on Potential Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications. A wide range of drugs should not be given with ritonavir, including some that are commonly used to treat heart conditions, suppress the immune system, and reduce pain.  While this is problematic, ritonavir is similarly employed in existing HIV treatments, so physicians who treat AIDS are already experienced with managing these challenges.

For those who cannot take Paxlovid due to interactions or its lack of supply, the use of Merck’s Molnupiravir can be considered. For most, though, Molnupiravir appears to be significantly less effective, having fallen short of expectations in clinical trials. Considering the need for drug efficacy against the Omicron variant there is a single standout pharmaceutical in each category, monoclonal antibodies, and antiviral drugs. Because each has drawbacks, patients and physicians need both Sotrovimab and Paxlovid as treatment options. The need is for rapid scaling of production of these two drugs, both of which already have emergency use authorization from the FDA in the United States.

There are consultancies and companies in place that can help make it happen: contract development and manufacturing organizations (CDMO’s). Even Pfizer, a giant company that can do a great deal in-house, has turned to them from time-to-time, and did so in producing its COVID-19 vaccine. Lonza, CordenPharma, Patheon, and Catalent are four examples. Turning to them for aspects of Sotrovimab production and packaging is an option for Vir+GSK, and for any government agency looking at this issue.

Within the U.S. government, defense-related health agencies including BARDA and DARPA have a reputation for expediency. Involving them is an option for the Biden Administration, especially as specific bottlenecks are identified that interfere with efficient production and distribution. While there are issues of distribution, equity, and price, there will be no access without adequate supply. Until we have that, physicians must have the latitude to employ repurposed medicines to treat emerging variants of COVID-19, learning as they treat.

References

https://www.biorxiv.org/content/10.1101/2021.12.14.472630v1.full.pdf

https://covdb.stanford.edu/page/susceptibility-data/  (A low value is good.)

https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-paxlovid-drug-drug-interactions/

https://cen.acs.org/business/outsourcing/Pfizer-Moderna-ready-vaccine-manufacturing/98/i46

Remdesivir references from This Week in Virology

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009929

https://www.nature.com/articles/s41467-020-20542-0

https://www.jbc.org/article/S0021-9258(17)50437-8/fulltext

Movie of polymerase stalling (Nat Comm)