Herculean task of Choosing Antibody Cocktail

CME INDIA Presentation by Admin.

Casirivimab and Imdevimab in mild to moderate Covid cases.

“Life is a crazy mixture of intoxicating cocktails.” ― Ken Poirot

With the launch of first batch of antibody cocktail against COVID-19 in India, a new hope has emerged for a possible new therapy in mild to moderate cases of Covid.

The Roche’s antibody cocktail was given to then US President Donald Trump when he contracted COVID-19 last year and since then it has become centre of attraction in medical circles.

While in mild to moderate cases, none of the available modalities of treatment have proven any validity till date, NIH Covid-19 Treatment Guidelines interestingly expanded the use of the antibody cocktail. It clearly says:

Specific Therapy for Outpatients with Mild to Moderate COVID-19

Courtesy: https://www.covid19treatmentguidelines.nih.gov

(Rating of Recommendations: A = Strong; B = Moderate; C = Optional)

(Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion)

Silver lining

• “So, NIH allow for the use of the monoclonal antibodies for the treatment of COVID-19 in non-hospitalized adults and children aged ≥12 years and weighing ≥40 kg who are at high risk for progressing to severe COVID-19 and/or hospitalization.”
• The Central Drugs Standards Control Organisation (CDSCO) had recently provided an Emergency Use Authorisation (EUA) for the antibody cocktail (Casirivimab and Imdevimab) in India.
• It has also received a EUA in the US and several EU countries.

Mild to Moderate Covid:

How to know who have high risk for progressing to severe COVID-19 and/or hospitalization

If we see the above list, we will get many patients who will be eligible for this therapy

So, what is the rationale for the Use of Combination Anti-SARS-CoV-2 Monoclonal Antibodies

• The clinical trial data demonstrate the clinical benefit of these anti-SARS-CoV-2 monoclonal antibody combinations for the treatment of outpatients with mild to moderate COVID-19
• It is worth noting that these studies were conducted before the widespread circulation of the variants of concern.

• Clinical Data Bamlanivimab Plus Etesevimab
  • Blocking Viral Attachment and Cell Entry With SARS-CoV-2 Neutralizing Antibodies (BLAZE)-1 and BLAZE-4 trials.
  • Phase 3 BLAZE-1 trial,
  • A randomized trial
  • 1,035 high-risk participants,
  • the primary endpoint -proportion of participants who had a COVID-19-related hospitalization (defined as ≥24 hours of acute care) or who died from any cause by Day 29.
  • Compared to those who received placebo, participants who received bamlanivimab 2,800 mg plus etesevimab 2,800 mg had a 5% absolute reduction and a 70% relative reduction in COVID-19-related hospitalizations or death from any cause.
  •  Endpoint events occurred in 11 of 518 participants (2.1%) in the bamlanivimab plus etesevimab arm and in 36 of 517 participants (7.0%) in the placebo arm (P = 0.0004).
  • There were no deaths in the bamlanivimab plus etesevimab arm, and 10 deaths occurred in the placebo arm.
  • The available data suggest that the antiviral activity of  lower dose is similar to that of bamlanivimab 2,800 mg plus etesevimab 2,800 mg.

•  Casirivimab Plus Imdevimab
  • Phase 3 results from the R10933-10987-COV-2067  trial (no peer-reviewed preprint/Press release only )
  • 1,355 participants who received casirivimab 1,200 mg plus imdevimab 1,200 mg to 1,341 participants who received placebo
  • COVID-19-related hospitalizations or death from any cause were reported in 18 of 1,355 participants (1.3%) in the casirivimab plus imdevimab arm and in 62 of 1,341 participants (4.6%) in the placebo arm (P < 0.0001).
  • This represents a 3.3% absolute reduction and a 71% relative reduction in hospitalization or death in the casirivimab plus imdevimab treatment participants.

Mechanism of action:

• Casirivimab and Imdevimab are human immunoglobulin G-1 (IgG1) monoclonal antibodies produced by recombinant DNA technology in the lab.
• Monoclonal antibodies are proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses.
• Casirivimab and Imdevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells. T
• hanks to its specific engineering of two neutralising antibodies which bind to different parts of the virus spike, the Casirivimab and Imdevimab cocktail remains efficacious against widest spread variants and reduces the risk of losing its neutralisation potency against new emerging variants.

Indian Scenario

• Each of the 1,200mg dose of the drug contains 600 mg of Casirivimab and 600 mg of Imdevimab. The price of each dose will be Rs 59,750.
• The maximum retail price for the multi-dose pack will be Rs 1,19,500. Notably, each pack can treat two patients.
• The drug has been marketed in India by Cipla and the second batch will be made available by mid-June.
• Availability of Antibody Cocktail (Casirivimab and Imdevimab) in India can help in minimizing hospitalization and play a key role in the treatment of high-risk patients before their condition worsens.

What the Roche literature say

• The antibody cocktail (Casirivimab and Imdevimab) is to be administered for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age or older, weighing at least 40 kg) who are confirmed to be infected with SARS-COV2 and who are at high risk*of developing severe COVID-19 disease and do not require oxygen.
• It has been shown to help these high-risk patients before their condition worsens, reducing the risk of hospitalisation and fatality by 70% and shortening the duration of symptoms by four days.

How to administer

• Each pack of Antibody Cocktail (Casirivimab and Imdevimab) contains one vial of Casirivimab and one vial of Imdevimab totaling 2400 mg of the antibody cocktail (one vial of Casirivimab (1200 mg) and one vial of Imdevimab (1200 mg)).
• Each pack can treat two patients as the dosage per patient is a combined dose of 1200 mg (600 mg of Casirivimab and 600 mg of Imdevimab) administered by intravenous infusion or subcutaneous route.
• The vials need to be stored at 2°C to 8°C. If opened for the first patients’ dose, a vial can be used for the second patients’ dose within 48 hours if stored at 2°C to 8°C.

Points to Ponder

• There are no comparative data to determine whether there are differences in clinical efficacy or safety between bamlanivimab plus etesevimab and casirivimab plus imdevimab.
• There are SARS-CoV-2 variants, particularly those that contain the mutation E484K, that reduce the virus’ susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known.

CME INDIA Learning points

By Dr SK Gupta, MD(Med) FICP, CFM((France), Visiting Consultant, Max Hospital, Delhi.

Roche’s antibody cocktail (Casirivimab 1200mg and Imdevimab 1200mg ) launched in India at ₹59,750/dose developed by pharmaceutical giants Roche and Regeneron. Cipla will distribute the product across the country.

Former US president Donald Trump was one of the early patients on whom this experimental therapy was used.

Why a cocktail of two monoclonal antibodies in one?

• Cocktail of two antibodies is directed against two subunits of Spike protein S1 and S2 of Sars Cov 2.
• Giving only one antibody may lead to escape of Virus rendering treatment ineffective.

When should one start treatment with Monoclonal Antibodies?

• Treatment should be started as soon as possible after the patient receives a positive report of Covid RTPCR or Rapid Antigen and within 10 days of symptom onset

Why such expensive drug, so early in mild disease?!

• Because it is Virus neutralizing therapy. Virus replication occurs early in disease. Once Virus has invaded the lungs and caused damage, this therapy may not be able to reverse it.

Why within 10days of onset of symptoms?

• Because effective viral replication stops after 10 days and monoclonal antibody is targeted against virus.
• Many individuals with COVID-19 produce neutralizing antibodies to SARS-CoV-2 about 10 days after disease onset. So, preformed antibodies will be helpful in initial phase only.

Do monoclonal Antibodies relieve symptoms?

• Yes, Monoclonal antibodies have the potential to alleviate symptoms and limit progression to severe disease.
• It has been shown to help these high-risk patients before their condition worsens, reducing the risk of hospitalisation and fatality by 70% and shortening the duration of symptoms by four days.

Who are the candidates for Monoclonal antibody treatment?

• Monoclonal antibody combinations are used  to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression to severe disease and/or hospitalization, who meet at least one of the following criteria:

• Obese with Body mass index (BMI) ≥35
• Chronic kidney disease
• Diabetes mellitus
• Immunocompromising condition
• Currently receiving immunosuppressive treatment
• Aged ≥65 years
• Aged ≥55 years and have:
  • CAD Cardiovascular disease, or
  • HT Hypertension, or
  • COPD (Chronic obstructive pulmonary disease) or
  • Some other chronic respiratory disease like ILD

Will it be helpful in serious patients admitted in Hospital?

• No. Anti-SARS-CoV-2 monoclonal antibodies are not beneficial in hospitalized patients with severe COVID-19.

Which other companies developed Monoclonal antibodies?

• Combo of Bamlanivimab 700 mg plus etesevimab 1400 mg developed by Lilly.

Why Antibodies made by Lilly not approved in India?

• Because of an increasing number of reports of SARS-CoV-2 variants that are resistant to bamlanivimab alone, FDA recently revoked the EUA for bamlanivimab.

CME INDIA Tail Piece

• Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen test or a nucleic acid amplification test and within 10 days of symptom onset.
• It is emphasised that physicians need to intelligently access the HIGH-RISK mild to moderate cases as per EUA criteria (See above Table).
• Its high cost will prohibit its use widely.
• In laboratory studies, some SARS-CoV-2 variants of concern or interest that harbor certain mutations have markedly reduced susceptibility to bamlanivimab and may have lower sensitivity to etesevimab and casirivimab.
• Vaccination with a COVID-19 vaccine should be deferred for at least 90 days in those who have received anti-SARS-CoV-2 monoclonal antibodies. This is a precautionary measure, as the antibody treatment may interfere with vaccine-induced immune responses.
• In people who are vaccinated and then develop COVID-19, prior receipt of vaccine should not affect treatment decisions, including the use of and timing of treatment with monoclonal antibodies.

Reference:

1. https://investor.regeneron.com/news-releases/news-release-details/phase-3-trial-showsregen-covtm-casirivimab-imdevimab-antibody
2. https://www.covid19treatmentguidelines.nih.gov/whats-new/

Discover CME INDIA

• Explore CME INDIA Repository
• Examine CME INDIA Case Study
• Read History Today in Medicine
• Register for Future CMEs

Get CME INDIA Highlights

Curated articles in your inbox.

SUBSCRIBE!

You have Successfully Subscribed!