Dangerous blood clots and thrombocytopenia, rare simultaneous side effects seen with two adenoviral vector vaccines from Astrazeneca plc and Johnson & Johnson, as well as a worldwide spike in COVID-19 cases and deaths, primarily in India, has set the stage for what could soon become the next big vaccine option, a protein subunit candidate from Gaithersburg, Md.-based Novavax Inc.

While both mRNA vaccines from Pfizer Inc./Biontech SE and Moderna Inc. also have shown clotting in rare instances, thrombocytopenia (low blood platelets) appears absent in those cases. Nevertheless, global access to a fifth vaccine, another that was part of the U.S. government’s Operation Warp Speed (OWS) effort, could reduce increasing pressures on global supply, following a contamination issue at Emergent Biosolutions Inc. that resulted in the loss of 15 million doses of the J&J vaccine.

According to Johns Hopkins University data, global cases and deaths rose between April 1 and May 1 by 12% and 6%, respectively, while U.S. cases have dropped 43% and deaths are down 35%. In contrast, data show cases in India have skyrocketed by 456% over the last month, reaching 401,993 cases on April 30, the most for a single day since the pandemic started. Deaths in the country reached a high of 3,679 on May 1, a 684% increase over the prior month.

Four vaccines are approved in India: Bharat Biotech International Ltd.’s Covaxin, Astrazeneca’s Vaxzevria (AZD-1222), Serum Institute of India’s Covishield (AZD-1222), and the Gamaleya National Centre of Epidemiology and Microbiology’s Sputnik V.

For its part, Novavax has a license agreement with Serum Institute to provide NVX-CoV2373 to India. The U.K. phase III trial demonstrated 89.7% efficacy against mild, moderate and severe disease, including the U.K. B.1.1.7. variant. In the original strain, it showed 96.4% efficacy, placing it competitively with the mRNA vaccines.

Novavax received $1.6 billion in OWS funding last July in a contract to supply 100 million doses in the U.S. The two-dose vaccine, which consists of a full-length spike protein produced in insect cells and administered with the Matrix-M adjuvant, is under rolling review in the U.S., Europe, the U.K. and Canada. The company’s stock (NASDAQ:NVAX) dropped by 18% on May 3 and continued to fall May 4, possibly due to a report that raw material scarcity has bumped vaccine delivery for Europe to the end of the year. Shares closed May 4 at $180.67, down $14.45.

An additional two-dose regimen is being offered in the U.S. phase III, which also is expanding into 3,000 12- to 17-year-olds. An emergency use authorization (EUA) for the U.S. could come as early as this month.

The World Health Organization (WHO) reported that, cumulatively, global cases have reached 152.4 million and deaths are at 3.2 million, while U.S. cases and deaths are at 32 million and 570,000, respectively. A total of 1.01 billion vaccine doses have been administered, a near doubling of the number administered by the beginning of April.

BioWorld has tracked 921 therapeutics and vaccines in development for the SARS-CoV-2 virus. Johns Hopkins also reported that more than 436.3 million COVID-19 tests have been given in the U.S. Well over 300 diagnostic tests, including antibody, antigen and molecular, currently have EUAs in the country.

Hurdles for J&J and Astrazeneca

Both Pfizer/Biontech and Moderna gained EUAs for Comirnaty and mRNA-1273 in the U.S. in December, while J&J’s vaccine, JNJ-78436735, was authorized in February. Astrazeneca has not yet filed for an EUA in the U.S. for Vaxzevria, although it is authorized in nearly 100 countries.

April was a rough month for both J&J and Astrazeneca.

At its Baltimore facility, manufacturing partner Emergent found that drug substance for J&J’s vaccine was mixed with ingredients from Astrazeneca’s vaccine. Blamed on human error, doses from both companies had to be destroyed. FDA investigators conducted a nine-day inspection, and Emergent agreed to pause production to work on quality issues. J&J had committed 100 million doses to the U.S. government for the first half of 2021.

J&J also faced a temporary pause to its vaccine rollout in the U.S., following the blood clot and thrombocytopenia cases that grew from six mid-month to 15 a week later, out of nearly 7 million single-shot vaccinations given. All cases, with one fatality, involved women, with only two over the age of 50. The J&J vaccine is based on an adenovirus 26 vector, which is also employed in the Sputnik V vaccine. The FDA determined that the benefit outweighs the risk and lifted the pause, suggesting that doctors avoid heparin therapy and patients be on guard for severe headache and abdominal pain. The EMA’s safety committee agreed.

A retrospective analysis found that SARS-CoV-2 infection placed the risk of central venous thrombosis at 39 per million, much greater than the risk with either the J&J or Astrazeneca vaccines. U.K. and EMA authorities decided that Vaxzevria outweighs the risks, although the label will now list the rare side effects. Denmark, the Netherlands, Latvia and Norway stopped using the vaccine, while others restricted its use. The Australian government recommended that those under 50 take Comirnaty instead of Vaxzevria, as 11 of the 19 people who have died were under 50.

Another hurdle faced by Astrazeneca was the legal action begun by the European Commission (EC) for failure to deliver contracted doses. The company informed the EC in January of manufacturing problems at its Belgian plant.

In other vaccine news:

  • Phase III data showed Comirnaty was 91.3% effective from seven days to six months after the second dose, positioning the company to file a BLA in the U.S. Pfizer and Biontech also are seeking to expand the EUA to include adolescents 12 to 15.
  • Moderna’s mRNA-1273 received authorization in the U.K., and phase I data indicate antibody persistence six months after the second dose. Moderna is investing its cash to increase 2022 manufacturing capacity to up to 3 billion doses.
  • The director of China’s Centers for Disease Control acknowledged that the Chinese vaccines require improvements, as Sinovac Biotech Ltd.’s vaccine reached only 50.4% efficacy.
  • Bharat Biotech reported phase III data of inactivated vaccine Covaxin (Ocugen Inc.), showing 78% efficacy against mild, moderate and severe infection.
  • A U.K. study showed symptomatic infections fell by 74% and asymptomatic infections by 57%, 21 days after receiving the first dose of Vaxzevria or Comirnaty. The U.K. also is studying mixed dosing schedules of AZD-1222, Comirnaty, mRNA-1273 and NVX-CoV2373.
  • Cuban researchers have started phase III trials of Abdala (CIGB-66), a three-dose subunit vaccine.
  • Valneva SE reported that 90% of people receiving its inactivated, adjuvanted vaccine candidate, VLA-2001, developed significant levels of antibodies. The company started a phase III trial in 4,000 participants.
  • Inovio Inc.’s DNA vaccine, INO-4800, induced neutralizing antibodies and T-cell responses against all spike protein variants tested in a phase I study, but performed about the same as other available vaccines. The company’s shares (NASDAQ:INO) dropped 25% on April 23 after the U.S. Department of Defense pulled funding for the phase III portion of an ongoing trial.

Therapeutics failures aplenty

Of 921 development candidates for COVID-19, 219 are vaccines and 702 are therapeutics. About a dozen therapeutics companies reported disappointing news throughout April.

Emergent’s hyperimmunoglobulin (COVID-HIG) did not provide clinical benefit in a phase III trial when added to Gilead Sciences Inc.’s Veklury (remdesivir) in hospitalized patients. Olumiant (baricitinib), an oral JAK inhibitor from Eli Lilly and Co. and Incyte Corp., which received a U.S. EUA last November, missed its phase III Cov-Barrier primary endpoint of progression to non-invasive or mechanical ventilation or death. Beigene Ltd.’s Brukinsa (zanubrutinib), an oral BTK inhibitor, also failed in a phase II trial in patients hospitalized with COVID-19 respiratory symptoms.

Takeda Pharmaceutical Co. Ltd.’s hyperimmune immunoglobulin Covig-19, a polyclonal antibody, did not show meaningful improvement in the clinical status of hospitalized, adult COVID-19 patients, and Astrazeneca’s Farxiga (dapagliflozin), an SGLT2 inhibitor, also failed in the phase III DARE-19 trial. Finally, Covis Pharma Group’s corticosteroid drug, ciclesonide, missed its phase III endpoint in non-hospitalized symptomatic patients.

Problems with enrollment or futility led some companies to shift focus or terminate development.

  • Merck & Co. Inc. stopped its phase II/III Move-in study of hospitalized patients due to a lack of clinical benefit with oral molnupiravir (Ridgeback Biotherapeutics LP). The trial will continue studying outpatients.
  • Merck also discontinued development of fusion protein MK-7110 for hospitalized patients after the FDA said more data would be needed to support an EUA. The product was part of the $425 million November acquisition of Oncoimmune Inc.
  • Due to data to date and the therapeutic environment, Fera Pharmaceuticals LLC will no longer develop Nicox SA’s naproxcinod, a cyclooxygenase-inhibiting nitric oxide-donating naproxen.
  • A phase II study of Fibrogen Inc.’s pamrevlumab, an antibody inhibiting CTGF, in hospitalized patients was terminated due to low enrollment.

While positive data reported throughout the month was slim, it included news from Kiniksa Pharmaceuticals Inc., Mesoblast Ltd. and the University of Oxford.

Kiniksa’s monoclonal antibody, mavrilimumab, showed in phase II that COVID-19 pneumonia and hyperinflammation patients who received the drug vs. placebo had a 12.3% higher likelihood of surviving and being free of mechanical ventilation at day 29 (p=0.1224), a 65% reduction in risk of mechanical ventilation/death (p=0.0175), and a 61% reduction in risk of death (p=0.0726). A phase III trial is currently enrolling patients.

Mesoblast’s remestemcel-L reduced mortality through day 60 by 46% in those under age 65 in a phase III trial. When added to dexamethasone, it reduced mortality by 75%. And the University of Oxford’s inhaled corticosteroid, budesonide, shortened the recovery time of COVID-19 patients older than 50 by a median of three days.

On the regulatory front, following a request from Eli Lilly, the FDA revoked the EUA for bamlanivimab. Romark Laboratories LC filed for an EUA for its orally administered NT-300 (nitazoxanide extended release) after phase III data showed an 85% reduction in progression to severe illness in a secondary endpoint analysis. And the U.S. NIH recommended Regeneron Pharmaceuticals Inc.’s REGEN-COV (casirivimab with imdevimab) be used in non-hospitalized patients at high risk of clinical progression.

Entering late-stage trials are Implicit Bioscience Ltd.’s anti-CD14 antibody, IC-14; Brii Biosciences Ltd.’s antibodies BRII-196 and BRII-198; and Atea Pharmaceuticals Inc.’s antiviral AT-527.

Surge causes global tailspin

Countries around the world are battling a surge in COVID-19 cases. With only 13% of the population vaccinated with one dose, Europe accounts for about a third of the global deaths. The EU optioned for another 100 million Comirnaty doses, bringing the total to 600 million.

The variant B.1617 is to blame for the rise in India cases, and biopharma companies and the Biden administration have offered help. Gilead is donating active pharmaceutical ingredient, as well as 450,000 vials, and it will provide technical support to voluntary licensors, to help address shortages of remdesivir in the country. U.S. lawmakers continue to demand a march-in on the remdesivir patents. Merck also formed voluntary licensing agreements with several Indian generics manufacturers to provide molnupiravir. The U.S. expects to share 60 million Vaxzevria doses with India and other countries, and WHO is establishing a technology transfer hub.

Finally, the U.K. is studying vaccine failures, and Oxford University researchers found that one in three COVID-19 survivors was diagnosed with a neurological or psychiatric condition within six months.