Kevin Kunzmann

The US Food and Drug Administration (FDA) has revoked the emergency use authorization (EUA) for investigational monoclonal antibody therapy bamlanivimab as a lone therapy for the treatment of mild-to-moderate 

 in adults and indicated pediatric patients.

The decision is based on continued assessment of emerging data—specifically geared toward SARS-CoV-2 variants that show resistance to lone bamlanivimab and reduced likelihood of treatment efficacy—that indicates a change in known and potential benefits of the monoclonal antibody versus the known and potential risks of its emergency use.

The Eli Lilly and Co. investigational therapy was originally granted its EUA on November 9, 2020, for the treatment of COVID-19 in adults and pediatric patients aged ≥12 years old weighing at least 40 kg, with positive SARS-CoV-2, and who are at high risk for progressing to severe COVID-19.

The decision proceeded a request from Eli Lilly to revoke the EUA, as they modified contracts with the federal government to assure adequate supply of etesevimab in combination with bamlanivimab—another available monoclonal antibody regimen from the company. 

"Lilly moved quickly to make bamlanivimab alone available as a potentially lifesaving medicine at a time when Americans were hardest hit by COVID-19," Daniel Skovronsky, MD, PhD, Lilly's chief scientific officer and president of Lilly Research Laboratories, said in a 

. "With the growing prevalence of variants in the US that bamlanivimab alone may not fully neutralize, and with sufficient supply of etesevimab, we believe now is the right time to complete our planned transition and focus on the administration of these two neutralizing antibodies together."

As the FDA stressed in this EUA revocation, monoclonal antibody therapy is still authorized and even approved in some iterations for the very same treatment of COVID-19, including combination casirivimab and imdevimab (REGEN-COV) and combinated bamlanivimab and etesevimab. No emerging data would indicate that the benefit of these combination therapy regimens is compromised significantly by the prevalence of SARS-CoV-2 variants.

Since last month, approximately 1 in 5 sequenced SARS-CoV-2 viruses in the US were reported as variants likely resistant to lone bamlanivimab—a significant jump from the approximate 1 in 20 reported in mid-January this year.

Because no testing technologies are available for healthcare providers to test for SARS-CoV-2 variants prior to monoclonal antibody treatment, the FDA reasoned authorized regimens should entail those known to work broadly against all nationwide-circulating variants.

“While the risk-benefit assessment for using bamlanivimab alone is no longer favorable due to the increased frequency of resistant variants, other monoclonal antibody therapies authorized for emergency use remain appropriate treatment choices when used in accordance with the authorized labeling and can help keep high risk patients with COVID-19 out of the hospital,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement. 

“We urge the American public to seek out these therapies when needed while we continue to use the best data available to provide patients with safe and effective treatments during this pandemic.”

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The decision follows emerging data showing prevalent virus variants are unaffected by the monoclonal antibody.

FDA Revokes COVID-19 Emergency Authorization for Lone Bamlanivimab

A new study from Rwanda indicated that drug-resistant mutations in the malaria parasite are becoming more prevalent, and difficult to mitigate, throughout Africa.

 mutations are associated with delayed parasite clearance—or, the persistence of parasitemia after 3 days of treatment—in a nature first observed in artemisinin-resistant malaria prevalence in Southeast Asia.

The international team of investigators additionally uncovered indications that mutation transmission is likely more prevalent than previously reported in research, and could precede greater geographical spread of treatment-resistant malaria.

Plasmodium falciparum kelch13 (Pfkelch13)

 R561H and P574L have been previously reported in Rwanda as in southeast Asia, but no clinical association to parasite clearance has been established in assessment.

“We aimed to establish the efficacy of artemether–lumefantrine and genetic characterization of 

 alleles and their association with treatment outcomes,” investigators wrote.

The team conducted its open-label, single-arm, multi-center, therapeutic efficacy trial across 3 Rwandan clinical sites in 2018, assessing three-day artemether-lumefantrine in children aged 6-59 months with 

Investigators observed treatment response for 28 days via weekly blood sample microscopy screenings for the malaria-driving parasite. 

multidrug resistance-1 (Pfmdr1) genes were characterized in collected patients’ parasites. The team sought a primary endpoint of PCR-corrected parasitological cure of malaria risk on day 28.

Of the 228 patients enrolled, 224 reached the trial endpoint. Investigators observed PCR-corrected curative treatment efficacies in 97.0% (95% CI, 88 – 100), 93.8% (95% CI, 85 – 98), and 97.2% (95% CI, 91 – 100) of patients from the 3 Rwandan sites.

R561H mutations were observed in 28 (13%) of 218 pre-treatment patient samples; P574L mutations were present in just 2 (1%) samples. A combined 20 participants from 2 of the Rwandan sites were microscopically positive 3 days following treatment initiation, which was associated with pre-treatment presence of 

“Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda,” investigators wrote.

In a statement accompanying the study, lead author Dr. Aline Uwimana, of the Rwanda Biomedical Center in Kigali, noted that mutations can often emerge spontaneously, and in isolated instances of treatment-resistant burden.

“However, our new study shows that resistant isolates are starting to become more common and most importantly, are associated with clinical implications (delayed parasite clearance),” Uwimana said.

Co-author Dr. Naomi Lucci, Centers for Disease Control and Prevention (CDC) Resident Advisor for the US President’s Malaria Initiative did note the positive outcome of 94% overall treatment efficacy of malaria in Rwanda, “but new studies and ongoing monitoring are urgently needed,” she added.

New data indicates failed parasite clearance among Rwandan children is linked to a mutation also observed in southeast Asia.

Resistant Malaria Parasite Mutations Observed in Rwanda

This video was originally published on sister publication HCPLive.

Right now, the Advisory Committee on Immunization Practices (ACIP) is convening an emergency meeting to discuss

 that recently led to thrombotic events in 6 women administered the Johnson & Johnson COVID-19 vaccine in the US.

The committee, meeting following the federal pause of Johnson & Johnson vaccine distribution by the US Food and Drug Administration (FDA), is addressing the matter of cerebral venous thrombosis risk among women aged 18-49 vaccinated with the one-shot prophylaxis.

But what is this concerning side effect—and what is its link to both COVID-19 and adenovirus-based vaccines designed to prevent the pandemic virus?

, Maja Zaric, MD, interventional cardiologist and assistant professor at Zucker Medical School, discussed the risk of thrombotic events now observed in a pair of adenovirus-based COVID-19 vaccines: that from Johnson & Johnson, as well as AstraZeneca.

Per Zaric, the chimpanzee-based adenovirus vector is made inactive, made unable to replicate, and is therefore doses in “large amounts” to vaccinated persons.

“Each vaccine carries somewhere over 50 billion particles,” Zaric explained. “This is a massive amount of adenovirus that has to be injected because it doesn’t replicate in order to achieve the effectiveness.”

What’s being observed in affected patients is the development of PF4 factor antibodies, which inhibits platelet development—a pathology similar to heparin-induced thrombosis (HIT).

“What happens is there is an abrupt cascade of clotting activated in the venous system that is not typically seen in COVID patients, but broader in the vaccine reaction,” Zaric explained.

This commonly occurs in the patient’s brain or cut systems. Symptoms have occurred up to 2 weeks following vaccination—far beyond the standard local site and symptomatic reactions anticipated with COVID-19 vaccines—and include headache, blurry vision, swelling, high temperatures, and shortness of breath.”

Mortality risk with cerebral venous thrombosis is up to 25%, Zaric said.

“The condition rapidly develops and consumes large amounts of coagulation factors and platelets, therefore causing simultaneous clotting,” she explained. “It can be treated early on, when diagnosed."

“We’re just starting to pick and recognize these cases in the US,” Zaric added. “I would be alert on those folks who get the vaccination over the next 2-3 weeks.”

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An interventional cardiologist discusses the observed cases of cerebral venous thrombosis in women administered the Johnson & Johnson COVID-19 vaccine.

Understanding Links Between COVID-19, Vaccines, and Thrombosis

Tomorrow, the Advisory Committee on Immunization Practices (ACIP) will convene an emergency meeting to discuss

 reported among 6 women administered the Johnson & Johnson COVID-19 vaccine in the US.

The committee, in conjunction with the US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC), is tasked with weighing the benefits of the emergency-authorized adenovirus vaccine product from Johnson & Johnson versus the newly observed risks: a half-dozen cases of cerebral venous thrombosis among women aged 18-49 years old.

Whatever their decision, it will likely be reflective of not only unique patient population risks with the vaccine, but the current state of US COVID-19 vaccination rollout—a trend which provides federal agencies the luxury of selectivity.

 on the day of the Johnson & Johnson news, Carlos del Rio, MD, executive associate deanof the Emory School of Medicine & Grady Health System, discussed the benefit of the US more greatly distributing and administering mRNA vaccines from Pfizer-BioNTech and Moderna, particularly as it relates to the Johnson & Johnson vaccine pause.

“I think we have enough vaccines to vaccinate everybody with either Moderna or Pfizer,” del Rio said. “If the decision here in the US is to not use Johnson & Johnson or AstraZeneca, I think we will be fine. I’m more worried about the rest of the world.”

As del Rio noted, the Johnson & Johnson product could currently be better served in the global effort to mitigate COVID-19—particularly in at-need countries, where the benefit of the vaccine versus the pandemic greatly outweighs the newly observed and very rare risk.

“I’m 62,” del Rio said. “If I was scheduled to get a COVID-19 vaccine today and it was Johnson & Johnson, I would still get it. I have a much higher risk of getting and dying from COVID at my age than I do of getting any complications from the vaccine.”

In anticipating federal decision on the availability of the vaccine in the US, del Rio looked to how other agencies responded to similar blood clot-related issues reported with the AstraZeneca vaccine.

“I would not be surprised if the regulators here in the US do something similar to what they did in Europe: say that this vaccine should not be used with people under the age of 50 or 60, then keep this adenovirus vaccine for older populations, where the risk is lower,” he said.

Carlos del Rio, MD, discusses the United States' pandemic situation in assessing the blood clot events observed in 6 Johnson & Johnson vaccine recipients.