BREAKING NEWS

For Immunocompromised Patients and their Physicians

In January of 2023, the FDA revoked the Emergency Use Authorization (EUA) for tixagevimab-cilgavimab (Evusheld), the only prophylactic measure to prevent severe COVID-19 in immunocompromised patients, particularly those that don’t make adequate antibody responses to vaccines due to primary immunodeficiencies or due to immune suppression caused by underlying diseases and their treatments. Evusheld consisted of long-lasting monoclonal antibodies that could be administered twice yearly to protect this vulnerable population, but due to uncontrolled transmission among the general population, the SARS-CoV-2 virus had progressively mutated to the point that it was able to evade the neutralizing effect of these monoclonal antibodies and Evusheld lost its protective effect.

Yesterday (March 22, 2024), the FDA issued an EUA for a new monoclonal antibody (human IgG1) pre-exposure prophylaxis for these immunocompromised individuals.

This new preparation goes by the generic name Pemivibart and the brand name of Pemgarda. It is authorized for use in patients aged 12 years and older, so long as they weigh at least 40kg (88 lbs.) who have moderate-to-severe immune compromise such that they would not be expected to mount a sufficient (protective) immune response after COVID-19 vaccination. Pemivibart is not authorized for use in post-exposure prophylaxis or in treating COVID-19. Pemgarda is made by a company named Invivyd (Nasdaq: IVVD), formerly Adagio Therapeutics, (Nasdaq: ADGI).

Clinical trials (named CANOPY) began almost exactly one year ago. The interim data justified the granting of the EUA in the judgment of the FDA reviewers and advisors. The study was conducted with two arms. The first included an open label arm in which 300 participants (median age 59) with moderate-to-severe states of immunocompromise received 4,500 mg intravenously on day 1 and were re-dosed at day 90. The primary endpoints were safety, tolerability and 28-day post-infusion neutralizing antibody tiers against JN.1, the primary globally circulating SARS-CoV-2 variant.

The second arm (control group – median age 48) included 450 participants not known to be immunocompromised, but who were at high-risk of exposure to SARS-CoV-2 due to frequent unmasked indoor contacts with others. Of these 450 participants, 300 were randomized (double-blinded) to receive the same dosing of Pemgarda as the first arm participants and the remaining 150 received a placebo intravenously.

The first arm also consisted of individuals at higher risk for severe disease progression apart from their significant states of immunocompromise due to higher percentages of participants with significant comorbidities compared to the second arm, including diabetes, chronic kidney disease, chronic lung disease and underlying cardiac disease.

Of those that received Pemgarda, 623 participants for which data was available were reviewed. Four individuals (0.6%) experienced anaphylaxis (all in the first arm participants – half occurred with the first dose and the other half occurred after the second). Nine percent had systemic infusion-related reactions and hypersensitivity reactions, 6% experienced an upper respiratory infection other than COVID-19, 5% experienced infusion site infiltration/extravasation/vein rupture, 3% developed fatigue, 2% experienced headache, 2% developed nausea, and 2% developed local infusion site reactions.

As to the primary endpoint of neutralizing antibody titers, based on a prior study for a previous monoclonal antibody (and prior variants), a target neutralizing antibody titer of 8944 at 28 days post-infusion and 3514 at 90 days was used. [This is one limitation of the study in that we don’t know whether the same antibody titers are sufficient for more recent variants.] For those in the first arm (moderate-to-severely immunocompromised), the geometric mean titer at 28 days was 7365 and at 90 days (prior to re-dosing) was 3199. By using the antibody titer curves, it was projected that patients who receive Pemgarda would maintain neutralizing antibody titers above 3514 for approximately 77 days. It was estimated that neutralizing antibody titers would be approximately 33% higher on average following the first two doses if subsequent doses were administered on an every-three-month schedule.

Pemgarda is for intravenous administration only. It is dispensed in 500mg (4 cc) vials. The vials must be refrigerated and should not be shaken. It is dosed at 4500 mg IV every 3 months. The infusion should be administered over a period of at least one hour, and patients should be observed for two hours post-infusion. Due to the risk for anaphylaxis, Pemgarda must be infused under medical supervision in a setting where the resources are available to treat anaphylaxis and resuscitate a patient, and where emergency medical services can be activated and accessed.

Pemgarda is not renally excreted, so there is no recommendation to reduce the dose for renal insufficiency or patients on dialysis. The effect of hepatic insufficiency on the metabolism and clearance of Pemgarda is unknown, however, Pemgarda is not metabolized by cytochrome P450 enzymes, thus, it is not expected that coadministration of medications that are inducers or inhibitors of cytochrome P450 enzymes would affect the dosing or clearance of Pemgarda.