As COVID-19 vaccinations continue to roll out, momentum builds with strong phase III data for what could become the fourth and fifth walls of defense in the U.S.

With three vaccines already authorized, research reported in March offers hope for a second adenovirus vector vaccine candidate with Astrazeneca plc’s AZD-1222, as well as for the first protein subunit vaccine option with Novavax Inc.’s NVX-CoV2373.

More therapeutics may also be on the way. Vir Biotechnology Inc. and Glaxosmithkline plc (GSK) filed an emergency use authorization (EUA) for antibody VIR-7831, and EUA filings for Humanigen Inc.’s antibody, lenzilumab, and Neurorx Inc.’s vasoactive intestinal polypeptide, Zyesami (intravenous aviptadil), are expected soon.

The month was not without its disappointments, however. Several therapeutics failed to hit endpoints, and both Russia and China appear to be casting doubt on vaccines developed outside their countries. Another challenge: Biopharma leaders are facing demands for intellectual property waivers.

Although daily cases and deaths from COVID-19 dropped last month, they rose by 123% and 70%, respectively, from March 1 to March 31, according to Johns Hopkins University data. The U.S. also has shown a rise in cases month-over-month of about 14%, while daily deaths have dropped by 30%.

According to the World Health Organization (WHO), global cases have reached 127.6 million and deaths are at 2.79 million, with U.S. cases and deaths reaching 30 million and 545,000, respectively. A total of 520.5 million vaccine doses have been administered, and BioWorld has tracked 904 candidates in development. Johns Hopkins reports that more than 392 million COVID-19 tests have been given in the U.S., and 318 diagnostics currently have EUAs.

AZ dominates headlines; NVAX efficacy strong

Despite positive phase III data, AZD-1222 traveled a bumpy road through March with Astrazeneca battling safety concerns and the suggestion that its interim phase III data were outdated. The company is preparing for an EUA filing in the U.S.

Five cases of cerebral venous sinus thrombosis (CVST) in those who received AZD-1222 are under investigation, but European authorities determined the benefits of the vaccine outweigh the risks. A total of 18 cases of CVST and seven cases of disseminated intravascular coagulation, from which nine people have died, have led several countries to suspend the vaccine, which is also known as ChAdOx1 or COVID-19 Vaccine Astrazeneca. There were no cases of CVST found in the U.S. phase III study, which was part of a $1.2 billion U.S. government Operation Warp Speed contract.

Phase III interim data showed 79% efficacy in preventing symptomatic infection and 100% efficacy in preventing serious disease and hospitalization. The outdated data concern, raised by the U.S. National Institute of Allergy and Infectious Diseases, led Astrazeneca to quickly publish the full analysis showing 76% efficacy in preventing symptomatic disease and 85% efficacy in those over 65.

Canada authorized AZD-1222 in March, but it later required a risk-benefit assessment of the vaccine to determine if certain people have a higher risk of blood clots. Astrazeneca is supplying hundreds of millions of doses to low- and middle-income countries, and Australia approved the manufacture of 50 million doses. AZD-1222, which can be stored in a normal refrigerator for at least six months, will likely be the vaccine that most Australians receive. It is authorized in more than 80 countries and has WHO’s emergency use listing.

Another potential U.S. EUA candidate is NVX-CoV2373 from Novavax. Although the company will not have data from the U.S./Mexico phase III trial until the second half of 2021, the vaccine demonstrated 89.7% efficacy against mild, moderate and severe disease in the U.K. phase III study. Efficacy against the original strain was 96.4%, while efficacy against the B.1.1.7/501Y.V1 U.K variant was 86.3%. A final analysis of a second study in South Africa, where the B1.351 variant is prevalent, showed 55.4% efficacy in HIV-negative trial participants. Novavax has an agreement with the U.K. and GSK to support manufacturing of up to 60 million doses.

Working for and against

In an unprecedented partnership, Johnson & Johnson and Merck & Co. Inc. joined forces to manufacture J&J’s adenoviral vector vaccine, JNJ-78436735 (Ad26.COV2-S), which was granted an EUA in the U.S. on Feb. 27. J&J intends to deliver 100 million doses by the end of June, but with Merck’s help, it will reach its global goal of 1 billion doses by the end of 2021. In March, the J&J vaccine was authorized in Canada and the EU, and WHO issued an emergency use listing.

Russia’s Sputnik V vaccine continues to gain EUAs throughout the world, most recently in Kenya and Mali. The EMA also started a rolling review. U.S. vaccine developers are battling what appears to be a Russian misinformation campaign, according to Jeremy Levin, chair of the Biotechnology Innovation Organization’s executive committee. The social media effort suggests U.S.-developed vaccines are linked to deaths, while Sputnik V is cheaper and easier to transport. Sputnik V has EUAs in 56 countries.

Raising troubling questions about access and the safety of receiving two or more different COVID-19 vaccines, China is requiring foreign visitors to be vaccinated with one of five vaccines developed in China, none of which are authorized in the U.S. or most of Europe.

In other vaccine news:

  • Real-world evidence showed Pfizer/Biontech’s Comirnaty (BNT-162b2) was at least 97% effective in preventing symptomatic disease, severe/critical disease and death two weeks after the second dose. In a phase III of 12- to 15-year-olds, the vaccine was 100% effective, prompting the company to seek an expanded EUA. Comirnaty, the first vaccine to gain an EUA in the U.S., has shown high efficacy up to six months following vaccination.
  • Takeda Pharmaceutical Co. Ltd. submitted an NDA in Japan for Moderna Inc.’s mRNA-1273, the second vaccine to receive an EUA in the U.S., which is now being tested in children. The company also launched development of mRNA-1283, a next-generation, refrigerator-stable version.
  • With limited peer-reviewed data published, the Cuban government approved a phase III trial for Soberana 02, a recombinant dimeric RBD base vaccine candidate developed by the Finlay Institute of Vaccines in Havana.
  • Bharat Biotech International Ltd.’s Covaxin, which has an EUA in India and four other countries, demonstrated efficacy of 80.6% in the first interim analysis.
  • Pivotal data of Curevac AG’s mRNA vaccine, CVnCoV, are expected in the second quarter. Novartis AG is helping to produce up to 50 million doses in 2021.

Of the 904 candidates for COVID-19, 214 are vaccines and 690 are therapeutics.

Therapeutics on deck; eight disappoint

Vir and GSK are seeking an EUA for mild to moderate disease in the U.S. and other countries for VIR-7831 after the phase III showed an 85% reduction in hospitalization or death for those at high risk. VIR-7831 also demonstrated a 70% relative reduction in persistently high SARS-CoV-2 viral load at day seven compared to placebo when used with Eli Lilly and Co.’s bamlanivimab in low-risk adults with mild to moderate COVID-19.

Humanigen raised $92.5 million following its plans to file for an EUA in the U.S. for lenzilumab. Its stock (NASDAQ:HGEN) spiked 54.5% on news that it improved the relative likelihood of survival without mechanical ventilation by 54% in hospitalized COVID-19 patients.

An EUA filing for Neurorx’s Zyesami also is expected after it met its phase II/III primary endpoint of recovery from respiratory failure at days 28 (p=0.014) and 60 (p=0.013) and showed a survival benefit (p<0.001).

Regeneron intends to file a BLA for Regen-Cov (casirivimab with imdevimab), based on phase III data, in high-risk non-hospitalized COVID-19 patients, showing the antibody cocktail reduced the risk of hospitalization or death by 70% and 71% at the 1,200-mg and 2,400-mg doses, respectively, compared to placebo. The company is working to add the 1,200-mg dose to the current EUA.

Blaze-1 data showed the combination of Lilly’s bamlanivimab and etesevimab significantly reduced by 87% (p<0.0001) COVID-19-related hospitalizations and death in high-risk patients. The EMA started a rolling review of the combination and of bamlanivimab alone. Both have EUAs in the U.S.

Kintor Pharmaceutical Ltd.’s proxalutamide, an androgen receptor antagonist, met the primary endpoint at day 14 in a phase III Brazil study, showing a reduction in the WHO COVID-19 ordinal scale, as well as a 92% reduction in mortality risk. It also shortened median hospital length stay by nine days.

Several developers reported mixed news throughout March.

  • Incyte Corp.’s Jakafi (ruxolitinib), a JAK1/JAK2 inhibitor, failed to hit a phase III endpoint, showing mortality through day 29 was 55.2% for Jakafi compared to 74.3% for placebo (p=0.0280) in the 5-mg arm and 51.8% for Jakafi compared to 69.6% for placebo (p=0.0292) in the 15-mg arm.
  • Durect Corp. terminated its phase II study of DUR-928 in organ failure COVID-19 patients due to low enrollment.
  • Apellis Pharmaceuticals Inc. dropped development of APL-9, a targeted C3 therapy, in severe COVID-19 after it phase I/II data showed no meaningful reduction in the overall mortality rate.
  • Paris-based Abivax SA stopped a phase IIb/III Mir-Age trial of ABX-464, a Rev protein modulator, after it failed to show efficacy in high-risk COVID-19 patients.
  • Phase III data showed a 24% reduction in all-cause mortality with Cytodyn Inc.’s Vyrologix (leronlimab) vs. placebo in a subset of invasive mechanical ventilated critically ill patients. The analysis included only 62 of the 384 severe-to-critical participants, sending shares (OTC:CYDY) down by 28.2%.
  • Phase III Remdacta data showed Roche Holding AG’s Actemra/Roactemra (tocilizumab) plus Gilead Sciences Inc.’s antiviral Veklury (remdesivir) missed the primary endpoint in treating hospitalized patients with severe COVID-19 pneumonia. It also failed to meet key secondary endpoints.
  • Apeiron Biologics AG’s APN-01, a recombinant angiotensin converting enzyme 2, failed to hit the primary endpoint of lowering all-cause death or the need for invasive mechanical ventilation in hospitalized severe COVID-19 patients.
  • Boehringer Ingelheim GmbH terminated development of BI-764198, an inhibitor of transient receptor potential canonical type 6, after phase II data showed a lack of benefit in hospitalized patients needing oxygen.

Reaching the developing world

The World Trade Organization (WTO) urged members to work with companies in facilitating technology transfers in order to manufacture COVID-19 vaccines and bring them to developing countries. The world’s 3.5-billion-dose capacity is well under the 10 billion doses needed. Most vaccine doses have been distributed in 75 countries, while 115 others continue to wait, setting up the world for an extended pandemic. Export restrictions and wealthier countries bidding up vaccine prices contribute to the problem.

Advamed, the Biotechnology Innovation Organization and the Pharmaceutical Research and Manufacturers of America authored a letter to top U.S. trade and commerce officials over their opposition to the WTO’s proposal, led by India and South Africa, to waive intellectual property protection for COVID-19 products. Democratic U.S. lawmakers and global research and education organizations are pressing for the waiver, but trade organizations insist that complex manufacturing and supply chain issues are the real barriers, not IP. Biolyse Pharma Corp., of St. Catherines, Ontario, however, wants to manufacture a generic version of J&J’s vaccine and export it to developing countries, but after suggesting a 5% royalty and receiving repeated rejections, the company is threatening to apply for a compulsory license.

Other COVID-19 news of note through March:

  • A large study has identified, in addition to IL-6, the cytokine GM-CSF as a new biomarker of inflammation in severe COVID-19, showing levels 10 times higher in patients who have died. It also distinguishes COVID-19 from influenza.
  • The U.K. Post-Covid hospitalization (Phosp-Covid) study found that 70% of those hospitalized with COVID-19 continued to suffer physical and mental health problems five months later.
  • A BioWorld analysis found that the amount invested in research and development by top biopharma companies in 2020 increased by 23% over the prior year to $44 billion, with a significant amount going toward COVID-19 efforts.