Pemgarda and Paxlovid

Background

Pemgarda and Ensitrelvir are two promising agents being explored in the fight against long COVID. Pemgarda is a long-acting monoclonal antibody, primarily designed for immunocompromised patients unable to mount an adequate antibody response. This drug aims to provide prolonged antiviral pressure, potentially helpful for patients with lingering SARS-CoV-2 reservoirs. Ensitrelvir is a novel antiviral that inhibits the main protease of SARS-CoV-2, preventing the virus from replicating in the body. Together, these agents could form a powerful combination against persistent viral infection.

Mechanism of action

1. Pemgarda

FDA Factsheet [1]

Long-acting monoclonal antibody initially designed for immune-compromised patients who cannot mount their own antibody response. These human-derived antibodies are tweaked to allow them to remain in the body for longer periods of time than typical antibodies (half-life: 44 days, FDA Factsheet). For Long COVID patients, the mechanism of action is clearing persistent virus by directly binding with virus, along with (seemingly) effector functions (ref [7]).

The idea here is to provide long-acting pressure against the virus in many viral reservoirs. It's unclear whether these relatively large molecules are able to pass the blood brain barrier (BBB), but some experts believe there is limited uptake. There is also evidence [8] of impaired BBB in Long COVID with increased permeability.

2. Paxlovid

FDA Factsheet [2]

Paxlovid is a viral replication inhibitor consisting of nirmatrelvir, which inhibits the SARS-CoV-2 main protease,and ritonavir, which is a CYP3A inhibitor that slows the break-down of nirmatrelvir by the body. The mechanism of action is slowing viral replication by not allowing viral proteins to properly assemble into new virions.

Risks

Pemgarda had an anaphylaxis rate of 0.6% in clinical trials (see FDA factsheet). It needs to be administered via IV in a setting with emergency procedures in place for anaphylaxis.

Paxlovid has a lot of drug-drug interactions, and people taking certain other drugs may have to discontinue them while on Paxlovid. For some folks, this will not be tenable.

Why combination treatments

Combination therapeutics are used to avoid creating drug-resistant strains of viruses. There is some evidence it may be happening in Long COVID / SARS-CoV-2 as well.

Using two drugs with different mechanisms of action reduces the chance of developing drug-resistant viral strains.

Other notes

Pemgarda is the only long-acting monoclonal antibody currently available in the U.S., and Paxlovid is widely available in the U.S. One of the biggest advantages of this treatment candidate is that we can start trying it immediately.

Pemgarda requires an IV administration, which limits accessibility to patients who can access IV infusions. Perhaps we can partner with IV infusion clinics offered Pemgarda here [6].

UCSF is currently doing a long-acting monoclonal antibody study [3] of AER002 for Long COVID, but this drug is not FDA approved and will be harder to access for decentralized trials.

u/rd_108 [5] used a similar treatment combination (Evusheld and Paxlovid) in 2022, in three treatments over 3 months, with 100% symptom reduction (LC score

References

[1] FDA Factsheet, Pemgarda (pemivibart). https://www.fda.gov/media/177067/download

[2] FDA Factsheet, Paxlovid. https://www.fda.gov/media/155050/download

[3] UCSF AER002 monoclonal antibody study for Long COVID. https://clinicaltrials.ucsf.edu/trial/NCT05877508

[4] Recent Invivyd presentation screenshots framing their drug Pemgarda. https://x.com/atranscendedman/status/1848863615841145238

[5] u/rd_108 un-published case study on long-acting monoclonals in combination with Paxlovid. https://x.com/bioprotocol/status/1843726799039082754

[6] Pemgarda infusion clinics. https://www.pemgarda.com/patient/infusion-center-locator/

[7] Non-peer reviewed pharma industry analysis of Pemgarda. https://biopharma.media/pemgarda-for-covid-19-protection-instead-of-vaccines-11602/

[8] Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. https://www.nature.com/articles/s41593-024-01576-9