WHAT HAPPENED

Pemgarda (pemivibart) is a new drug indicated for pre-exposure prophylaxis (PrEP) of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus in adults and adolescents (12 years and older weighing at least 40 kg).

Pemgarda is only authorized for use if the individual is, first, not currently infected with SARS-CoV-2 and has not had contact with infected SARS-CoV-2 persons in the recent past and, second, is characterized by moderate-to-severe immune compromise due to a medical condition, immunosuppressive medication, or any treatment and is therefore unlikely to mount an adequate immune response to COVID-19 vaccination.

This includes, but is not limited to, people with certain autoimmune or genetic diseases, those with organ transplants, and some cancer patients.

Pemivibart, developed by Invivyd, is approved by the U.S. Food and Drug Administration (FDA) in mid-March 2024 under the Emergency Use Authorization (EUA) [1].

Pemgarda should be administered every three months to provide reliable protection against COVID-19. The drug is administered by intravenous infusions of at least 60 minutes duration.

Pemgarda confidently prevents COVID-19 development caused by currently circulating variants of SARS-CoV-2, all of which are Omicron lineages variants.

Because SARS-CoV-2 is continuously evolving, its subsequent genetic changes could potentially lead to SARS-CoV-2 variants against which Pemgarda would be powerless.

Nexsheld: Updated Evusheld for Effective Vaccine-Free COVID-19 Protection

Sipavibart injection every six months for reliable prevention of COVID-19.

 

IMPORTANT NOTES

Pemgarda (pemivibart) is not authorized for the treatment of COVID-19 or its post-exposure prophylaxis (PEP) after contact with SARS-CoV-2 infected individuals.

COVID-19 PrEP with Pemgarda does not replace vaccination of those individuals to whom it is recommended.

If COVID-19 vaccination is recommended, even with moderate-to-severe immune compromise, the choice should be made in favor of the vaccine rather than Pemgarda.

For persons previously vaccinated against COVID-19 who are indicated for Pemgarda, it should be administered at least two weeks after vaccination.

If there has been a history of severe allergic reaction to COVID-19 vaccine, Pemgarda may be alternatively administered if suitability criteria are met.

If COVID-19 still develops after receiving Pemgarda, it is not prohibited to treat it with antiviral drugs such as Paxlovid (nirmatrelvir + ritonavir), Veklury (remdesivir), and Lagevrio (molnupiravir).

 

THE SUITABILITY

PrEP-protection provided by Pemgarda (pemivibart) is suitable for people who meet the following criteria with moderate-to-severe immune compromise [1]:

  • Active treatment for solid tumor and hematologic malignancies
  • Hematologic malignancies associated with poor responses to COVID-19 vaccines regardless of current treatment status (e.g., chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, acute leukemia)
  • Receipt of solid-organ transplant or an islet transplant and taking immunosuppressive therapy
  • Receipt of chimeric antigen receptor (CAR)-T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
  • Moderate or severe primary immunodeficiency (e.g., common variable immunodeficiency disease, severe combined immunodeficiency, DiGeorge syndrome, Wiskott–Aldrich syndrome
  • Advanced or untreated HIV infection (people with HIV and CD4+ T cell counts < 200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
  • Active treatment with high-dose corticosteroids (i.e., ≥ 20 mg prednisone or equivalent per day when administered for ≥ 2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, and biologic agents that are immunosuppressive or immunomodulatory (e.g., B-cell depleting agents).

 

WHY IT MATTERS

In early December 2021, Evusheld (tixagevimab + cilgavimab), a monoclonal antibody combination by AstraZeneca, became the first (and only) PrEP for prevention of COVID-19 in those who are ineligible or contraindicated for vaccination.

The emergence of Evusheld was a significant event, listed by Time magazine as one of the best inventions of 2022 [1] [2].

However, at the end of January 2023, the FDA canceled the Evusheld authorization. Due to the abundance of new Omicron variants of SARS-CoV-2, which it is unable to cope with, this method of protection against infection no longer works [3].

Evusheld: First Drug for Strong and Long-Lasting Protection Against Coronavirus

One dose of AstraZeneca’s monoclonal antibody cocktail protects against COVID-19 for six months or longer.

Other pharmaceutical developers have failed to provide an alternative to Evusheld, leaving tens of millions of people in desperate need of passive immunization against COVID-19 for over a year, instead of active immunization through vaccination. The introduction of Pemgarda (pemivibart) aims to fill the gap in effective preventive measures against COVID-19.

 

AWARENESS AND ENLIGHTENMENT

Despite Evusheld’s impressive protective efficacy prior to the era of the Omicron variants of SARS-CoV-2, its uptake has been incredibly stagnant. Even eight months after Evusheld’s introduction in the U.S., only a small fraction of the millions of immunocompromised American citizens who needed it had received it. Either physicians did not know about this possibility or chose not to pursue it, or patients themselves were not informed of this new method of COVID-19 protection, which is an alternative to the traditional vaccination. Meanwhile, hundreds of thousands of doses of Evusheld, which the government had purchased, continued to gather dust in warehouses [1].

The limited popularity of Evusheld can be attributed to several factors, including a lack of awareness, absence of a large-scale social advertising campaign, fear of using new drugs, and bureaucratic red tape. These factors have hindered the drug’s potential to save more lives.

 

THE COST

Invivyd has not yet announced the cost of Pemgarda (pemivibart), but it is expected to be substantial. First, there are no alternatives to pemivibart on the market.

Second, the drug is sold commercially rather than under a subsidized government order [1].

Third, in order to overcome the mutation resistance of SARS-CoV-2, significantly higher dose of monoclonal antibody (4500 mg) are required compared to Evusheld (600 mg), which understandably increases production costs.

Fourth, Invivyd asserts that Pemgarda costs more than $2,000, which is a typical price for anti-SARS-CoV-2 monoclonal antibodies [2] [3] [4] [5] [6]. This cost is justified by the drug’s confirmed benefits, as evaluated through pharmacoeconomic analysis [7] [8] [9].

If we’re talking about the desire of Invivyd’s owners and shareholders to enrich themselves, the prospects are quite pleasing. In 2022, the only full year that Evusheld was present in all of the top pharmaceutical sales markets, it earned AstraZeneca a respectable $2.19 billion.

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Similarly, Xevudy (sotrovimab), backed by GlaxoSmithKline and Vir Biotechnology, generated $2.86 billion in 2022.

Invivyd estimates that there are 9 million immunocompromised individuals in the U.S. However, the primary commercial focus will be on the 485,000 individuals who are in dire need of Pemgarda, including those who have undergone stem cell transplants, organ donor recipients, and ones with hematologic malignancies. It is feasible to earn $1 billion.

 

WHAT IT FOUND OUT

In mid-December 2022, the FDA and the European Medicines Agency (EMA) held a joint online workshop, “Efficacy of Monoclonal Antibodies in the Context of Rapidly Evolving SARS-CoV-2 Variants,” during which they laid out an alternative strategy for accelerating the development of novel anti-SARS-CoV-2 monoclonal antibody therapies based on prototypes that have previously demonstrated safety and efficacy in clinical trials and using neutralizing antibody titers as a surrogate measure of clinical efficacy or as a correlate of protection under prophylactic conditions [1].

A little later, there was a corresponding scientific publication supporting this idea [2].

The ongoing CANOPY (NCT06039449) phase 3 immunobridging clinical trial found that 28 days after administration of Pemgarda (pemivibart), the geometric mean titer (GMT) of serum neutralizing antibodies (NAbs) against JN.1, now the dominant Omicron lineages variant of SARS-CoV-2 in the U.S. [3], was no worse than the GMT of serum NAbs against the Delta variant (B.1.617.2) provided in the EVADE (NCT04859517) phase 2/3 clinical trial on day 28 after administration of adintrevimab, the prototypical monoclonal antibody for pemivibart [4].

According to additional analysis, the GMT range of serum NAbs against JN.1 conferred by pemivibart at 3 months post-injection was consistent with that following the administration of three third-party anti-SARS-CoV-2 monoclonal antibodies, which in their own clinical trials have demonstrated efficacy in protecting against time-relevant variants of SARS-CoV-2.

In vitro, pemivibart provides sufficient neutralizing activity against all currently circulating SARS-CoV-2 Omicron lineages variants that the World Health Organization (WHO) has classified as of variants of interest (VOIs), including XBB.1.5 (23A), XBB.1.16 (23B), EG.5, BA.2.86 (23I), and JN.1 [5].

At 67 and 90 days after Pemgarda administration to subjects without moderate-to-severe immune compromise, confirmed symptomatic COVID-19 occurred in 0% (n=0/322) and 0.3% (n=1/314) of individuals — versus 3% (n=5/162) and 5% (n=8/159) in the placebo group [6].

At 35 and 90 days after Pemgarda administration, 0% (n=0/306) and 1% (n=3/298) of participants with moderate-to-severe immune compromise experienced confirmed symptomatic COVID-19.

The prescribing information for Pemgarda (pemivibart) includes a boxed warning regarding the risks of anaphylaxis with life-threatening potential. According to a study, 0.6% (n=4/623) of subjects experienced this adverse reaction [7].

 

HOW IT WORKS

It all started when Invivyd, an out of the walls Adimab startup launched in mid-July 2020 and then still called Adagio Therapeutics [1], was developing adintrevimab (ADG20), a fully human IgG1 monoclonal antibody that target a highly conserved epitope on the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein.

When adintrevimab binds to RBD, it prevents the interaction between RBD and angiotensin-converting enzyme 2 (ACE2), a receptor that SARS-CoV-2 uses to attach to the host cell membrane and enter the cell.

Passive immunization with adintrevimab against COVID-19, assuming neutralization of SARS-CoV-2, provides temporary protection against infection, and if infection does occur, a slowing of disease progression and accelerated recovery should be expected.

Adintrevimab is an antibody derived from memory B cells of a patient who recovered from severe acute respiratory syndrome (SARS) caused by the 2003 SARS-CoV-1 coronavirus.

In vitro, adintrevimab exhibits broad neutralizing activity against not only SARS-CoV-2 in its various variants, but also against other SARS-like coronaviruses of the Sarbecovirus subgenus, which enter host cells by high affinity to ACE2 and are characterized by pandemic potential [2] [3] [4] [5] [6].

Adintrevimab has an extended half-life due to amino acid substitutions in the Fc region, enabling its use every three months [7].

Adintrevimab does not induce antibody-dependent enhancement (ADE) of infection, but exhibits undesirable Fc effector functions such as antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD).

Adintrevimab: Cure for All Mutant Variants of SARS-CoV-2

Adagio Therapeutics’ monoclonal antibody will help fight all strains of the coronavirus.

In late March 2022, adintrevimab demonstrated adequate efficacy and safety in pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) and treatment of COVID-19 during the global spread of Delta variant and the just-begun Omicron era (BA.1 and BA.1.1.1 variants), after successfully completing the phase 2/3 pivotal clinical trials EVADE (NCT04859517) and STAMP (NCT04805671) [8] [9] [10]

Invivyd had intended to submit adintrevimab for FDA authorization in Q2 2022. However, in mid-April, they abandoned their plans because adintrevimab lost its in vitro neutralizing activity against other Omicron variants, including BA.2, which were gaining momentum [11].

After desperate attempts to find the best solution, accompanied by a series of top management changes and layoffs, including co-founders, Invivyd finally made up its mind in early March 2023, selecting pemivibart (VYD222) as the lead drug candidate [12].

Pemivibart is a version of adintrevimab modified to include current SARS-CoV-2 variants. Pemivibart, which differs from adintrevimab by only eight amino acids in the variable region, has retained the high neutralizing activity of its prototype and all the characteristics described above, while adding the ability to counteract emerging SARS-CoV-2 variants.

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THE FLIPSIDE

In contrast to the United States [1], several territories, including Europe, the UK, Canada, Australia, and Russia, continue to incorporate Evusheld and/or other anti-SARS-CoV-2 monoclonal antibodies and combinations thereof into their clinical guidelines for the prevention and/or treatment of COVID-19 [2] [3] [4] [5] [6].

Remarkably, regulators themselves have long issued numerous warnings about the lack of efficacy of monoclonal antibodies against new SARS-CoV-2 variants in the Omicron lineages era, however have not yet revoked their marketing authorizations [7] [8] [9] [10]. It is possible that industry watchdogs are adopting a wait-and-see approach: What if the coronavirus mutates so that monoclonal antibodies become effective again?

Authoritative medical agencies have spoken out strongly against any anti-SARS-CoV-2 monoclonal antibodies because of their complete lack of proper efficacy: SARS-CoV-2 has mutated too deeply and severely for these drugs, which previously worked, to continue to provide the necessary antiviral neutralizing activity [11] [12] [13].

According to a database maintained by Stanford University that tracks the decreasing susceptibility of SARS-CoV-2 variants to monoclonal antibodies targeting the virus’s spike protein, the outlook is grim. These drugs are not at all suitable for the war against COVID-19 with its current set of mutations [14].

Apart from Pemgarda (pemivibart), none of the ever formally authorized anti-SARS-CoV-2 monoclonal antibodies, even if previously relatively successful in the prevention (pre- and post-exposure) and treatment of COVID-19, make any sense to use now. Currently, the following drugs are considered completely useless [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]:

  • amubarvimab (BRII-196, P2C-1F11) + romlusevimab (BRII-198, P2B-1G5)
  • bamlanivimab (LY3819253, LY-CoV555) + etesevimab (LY3832479, LY-CoV016, JS016, CB6)
  • bebtelovimab (LY-CoV1404, LY3853113)
  • casirivimab (REGN10933) + imdevimab (REGN10987) — marketed under the brand name REGEN-COV/Ronapreve
  • regdanvimab (CT-P59) — Regkirona
  • sotrovimab (VIR-7831, GSK4182136) — Xevudy
  • tixagevimab (AZD8895, COV2-2196) + cilgavimab (AZD1061, COV2-2130) — Evusheld (AZD7442).

The position of evidence-based medicine is clear: Do not spend money on absolutely worthless drugs drugs while falsely reassuring people that they are protected against COVID-19.

 

MEANWHILE

The development of anti-SARS-CoV-2 monoclonal antibodies by other pharmaceutical companies is carried out without much enthusiasm. Bitterly experienced drug developers realize that any drug, having passed through the complicated and costly path of regulatory approval, will eventually lose its effectiveness due to the high mutational nature of SARS-CoV-2, and it is hardly possible to come up with a monoclonal antibody that is highly resistant to resistance mutations.

Thus, AstraZeneca is finalizing Nexsheld (sipavibart), indicated for pre-exposure prophylaxis (PrEP) of COVID-19 in adults and adolescents. Nexsheld, which replaces Evusheld, is administered intramuscularly once every six months.

Nexsheld: Updated Evusheld for Effective Vaccine-Free COVID-19 Protection

Sipavibart injection every six months for reliable prevention of COVID-19.

Swiss biotech startup Aerium Therapeutics, launched at the end of March 2022 [1], is investigating combinations of anti-SARS-CoV-2 monoclonal antibodies [2] and has already made some progress [3].

Canada’s Immune Biosolutions has chosen a curious approach to treating mild-to-moderate COVID-19 with the experimental IBIO123. This mixture of three fully human monoclonal antibodies targets different RBD epitopes of the spike protein and is inhaled for several minutes via a mesh nebulizer. This approach has shown effectiveness in the early stages of the disease when SARS-CoV-2 is primarily present in the lungs. The clinical trial results indicate that on day 6 after treatment, COVID-19 symptoms resolved in 42% and 35% of subjects in the entire population and high-risk persons who received IBIO123, respectively, compared to 17% and 14% in the placebo group (p=0.017 and p=0.083) [4].

 

EXTRAS

Pemgarda (pemivibart). Emergency use authorization (EUA): Fact sheet for healthcare providers. [PDF]

Pemgarda (pemivibart). Emergency use authorization (EUA): FAQ. [PDF]

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