As solid efficacy data are reported for at least four more front-runner vaccines, and while biopharma companies join arms with combination antibodies, SARS-CoV-2 variants continue to spread and countries are racing to vaccinate.

None of the research is slowing, and governments are determined to make sure another COVID-19 pandemic never again takes the world by surprise.

Global deaths are up to 2.2 million, with 102.9 million confirmed cases, according to the World Health Organization. At least 865 therapeutics and vaccines to fight the virus have entered development in the last year.

In the U.S., about 25.9 million cases and 437,964 deaths represent 25% and 20%, respectively, of the global totals. U.S. President Joe Biden signed an executive order to strengthen American manufacturing, and also ordered a review of scientific integrity policies. His efforts came at a time when the U.S. Government Accountability Office reported critical gaps in pandemic response, and the U.S. Office of Special Counsel laid out findings of an investigation that the U.S. Department of Health and Human Services (HHS) was using the “Bank of BARDA” as a slush-fund, even though it was earmarked for public health threats such as COVID-19.

Making the most of the vaccine supply, the EMA recommended a label update for Comirnaty (Pfizer Inc., Biontech SE), clarifying that each vial may contain six doses instead of five. U.S. lawmakers also are concerned about vaccine supplies, with some expiring because administrators are limiting those who get them first. The U.K. decided to prioritize the dosing of Comirnaty and Covishield (Astrazeneca plc, Oxford University), giving one shot to a larger pool of people and pushing the second shot out by 12 weeks, instead of the recommended three or four weeks.

Celebrating more vaccine options

Biopharma researchers continue their fervent work throughout January to find solutions to the disruptive pandemic. Vaccine data from four companies offered more optimism that herd immunity is around the corner.

  • NVX-CoV2373 from Novavax Inc. was 89.3% effective based on interim phase III U.K. data. The B 1.1.7 variant was detected in more than 50% of confirmed symptomatic cases, and the vaccine was 95.6% effective against the reference strain and 85.6% effective against the variant. It showed 60% efficacy in preventing mild, moderate and severe COVID-19 in a phase IIb study in South Africa, suggesting it is also effective against the 501Y.V2 variant.
  • A potential single-shot option, Johnson & Johnson’s JNJ-78436735 (Ad26.COV2-S), through interim phase III data, showed it was 85% effective overall in preventing severe disease, and provided complete protection against hospitalization and death. The global results also showed it was 66% effective against the South Africa variant. The company intends to file for U.S. emergency use authorization (EUA) this month.

Two others that released promising phase III data in the last month include Sinovac Biotech Ltd. and the Gamaleya National Center of Epidemiology and Microbiology.

  • Sinovac’s Coronavac showed 50.4% efficacy against very mild disease, 77.9% against mild disease leading to a person seeking medical assistance, and 100% for severe disease, based on a phase III trial in Brazil with 12,476 participants. Data released Jan. 7 showed it was 78% effective in mild cases, but that was later clarified to account for those with very mild disease.
  • Gamaleya’s Sputnik V, which now has approval in Russia, Bolivia, Palestine, Paraguay, Argentina, Venezuela, Algeria, Serbia, Belarus, the United Arab Emirates and the Republic of Guinea, was validated by The Lancet on Feb. 2, with a peer-reviewed paper confirming 91% efficacy, making it the third vaccine to show efficacy above 90%. Authorization was rejected in Brazil, but Dr. Reddy’s Laboratories Inc. received approval in India to conduct a phase III trial. Development of Sputnik V was initially criticized as the original approval in Russia on Aug. 11, 2020, the first in the world, was based on early studies with only 76 volunteers.

In addition to Sputnik V, several other vaccines have continued to gain global EUAs since the start of the new year.

Australia granted provisional approval for Comirnaty for those 16 and older. Hong Kong also approved it for emergency use.

Moderna Inc. gained approvals in Israel, the European Union, the U.K. and Switzerland for mRNA-1273, while its partner, Takeda Pharmaceutical Co. Ltd., dosed the first of 200 healthy adults in a phase I/II study in Japan.

India conditionally approved Bharat Biotech International Ltd.’s COVID-19 vaccine, Covaxin, and Astrazeneca/Oxford’s COVID-19 Vaccine Astrazeneca (also called Covishield, or AZN-1222) for emergency use and was criticized for rushing the approvals without full efficacy data. In addition to India, the Astrazeneca vaccine was granted emergency use in Argentina, Dominican Republic, El Salvador, Mexico, Morocco and Brazil, where Sinovac’s Coronavac also gained an EUA.

The EMA recommended approval of COVID-19 Vaccine Astrazeneca, following the U.K.’s lead in late December, as a two-dose regimen at a four- to 12-week interval, assessing the efficacy at 59.5% in preventing symptomatic disease, after excluding a pool of participants that received half the standard dose followed by the standard dose. Including the protocol deviation boosted efficacy of the vaccine to 90%.

Three other items of COVID-19 vaccine news to note:

  • Curevac AG has entered a global alliance with Bayer AG to accelerate its efforts with mRNA vaccine CVnCoV, which entered a pivotal phase IIb/III trial on Dec. 14.
  • Initial phase III data of Regeneron Pharmaceuticals Inc.’s antibody cocktail, REGEN-COV (casirivimab and imdevimab), for use as a passive vaccine to prevent COVID-19 in high-risk individuals, showed 100% efficacy in preventing symptomatic infection and about 50% lower overall rates of symptomatic and asymptomatic infection. The cocktail has an EUA in the U.S. as a treatment.
  • After phase I data failed to show efficacy, Merck & Co. Inc. terminated development of its recombinant viral vector technologies, V-591, which was acquired through the buyout of Vienna-based Themis Bioscience GmbH, and V-590, which was part of a collaboration with the International AIDS Vaccine Initiative.

Variants break up the party

With more vaccines nearing availability, the sense of relief they provide has been short-lived, as emerging variants, first found in the U.K. (B 1.1.7), South Africa (501.V2 or B 1.351) and Brazil (B 1.1.248), continue to spread. Research seems to indicate that the N501Y mutation found in the emerging U.K. and South Africa variants does not create resistance to Comirnaty’s induced immune responses. The U.K. variant has spread to more than 60 countries, and researchers from the National Institute for Communicable Diseases in South Africa say 501Y.V2 escapes neutralization by both monoclonal antibodies and convalescent plasma. Unlike B 1.1.7., both 501Y.V2 and B 1.1.248 have E484K and K417N mutations.

Moderna also announced results showing no significant impact on neutralizing titers against B 1.1.7 relative to prior variants, whereas there was a sixfold reduction in the case of B 1.351. The company is testing whether adding a third dose increases neutralizing antibodies against emerging variants, and it will start early development of a version designed to be effective against B 1.351. The first cases in the U.S. of the variant were found in South Carolina, according to the CDC on Jan. 28.

The U.K. started a consortium of virologists, G2P-UK (Genotype to Phenotype-UK), to assess how mutations play a role in the effectiveness of vaccines and therapeutics, as well as the severity of COVID-19 and transmissibility of the virus. And scientists on the U.K.’s New and Emerging Respiratory Virus Threats Advisory Group (Nervtag) suggest the B 1.1.7 variant is associated with a 30% to 40% increased risk of death compared to earlier variants.

Antibody combinations to counter mutations

Some of the most compelling data from the last month for therapeutics involved bamlanivimab (Eli Lilly and Co., Abcellera Biologics Inc.), which already has an EUA in the U.S. for mild to moderate disease in high-risk patients.

Blaze-2 phase III study results showed bamlanivimab (LY-CoV-555) reduced nursing home residents’ risk of contracting symptomatic COVID-19 by 80%. An antibody cocktail of bamlanivimab and etesevimab met its primary and key secondary endpoints in a phase III Blaze-1 trial, decreasing the risk of hospitalizations or death by 70%. It also produced improvement in the change from baseline to day seven in SARS-CoV-2 viral load, time to sustained symptom resolution and COVID-related hospitalization. All 10 deaths involved patients taking placebo.

Lilly’s bamlanivimab also joined with Vir Biotechnology Inc.’s VIR-7831 in a deal to combine the antibodies in the ongoing phase II BLAZE-4 study, enrolling about 200 low-risk COVID-19 patients with mild to moderate disease. The collaboration follows research showing bamlanivimab, as well as Regeneron’s casirivimab, have reduced potency against the B 1.351 variant. That was not the case for the parent monoclonal antibody for VIR-7831. Bamlanivimab binds to the receptor binding motif (RBM), while VIR-7831 binds to a different area of the receptor binding domain.

Other significant therapeutic news reported in January:

  • ATYR-1923 met the primary safety endpoint in a phase II trial in patients with severe respiratory complications who do not require mechanical ventilation. A single dose of 3 mg/kg resulted in a median time to recovery of five and a half days (vs. six days on placebo), with 83% of patients achieving recovery in less than a week (vs. 56% placebo).
  • A phase II trial of CERC-002 showed improvement in patients hospitalized with COVID-19-associated pneumonia and mild to moderate acute respiratory distress syndrome, demonstrating a trend toward statistical significance for the primary endpoint, the proportion of patients alive and free of respiratory failure over the 28-day study period compared to placebo. A subgroup of 60-year-old enrollees showed treatment led to a greater than threefold increase in the likelihood of avoiding respiratory failure and death vs. placebo.
  • The U.K. placed interleukin-6 inhibitors as the standard of care for critical COVID-19 patients after the Remap-Cap study showed they reduced mortality by 8.5% and improved recovery, discharging intensive care patients a week earlier than controls. The data relate to 353 patients treated with Actemra (tocilizumab, Roche Holding AG), 48 who received Kevzara (sarilumab, Regeneron Inc. and Sanofi SA), and 402 controls. Mortality was 27.3% for those treated with IL-6 inhibitors, compared with 35.8% for the control group. The data are in stark contrast to clinical results released last summer when Regeneron stopped development of Kevzara for COVID-19 in July 2020 after it failed to show a significant benefit in phase III trials. Actemra also failed to hit its primary endpoint in the Covacata study, but later showed a positive signal by reducing hospitalized patients from requiring mechanical ventilation by 44%.
  • Interim results of Kintor Pharmaceutical Ltd.’s proxalutamide, an androgen receptor antagonist, showed the percentage of hospitalization was 1.7% vs. 17.1% for placebo, admission to ICU was 0% vs. 8.6%, mechanical ventilation requirement was 0% vs. 5.7%, and death was 0% vs. 2.9%. Final data are expected by March.
  • Celltrion Inc.’s CT-P59 showed in a phase II/III trial that it reduced progression rates to severe COVID-19 by 54% for mild to moderate patients and 68% for moderate patients 50 and older, compared to placebo. Those treated with CT-P59 recovered in 5.4 days on average compared with 8.8 days for placebo.
  • Interim data from a study of Kaleido Biosciences Inc.’s microbiome metabolic therapy, KB-109, in patients with COVID-19 showed there was no difference in median time to resolution of 13 overall COVID-19-related symptoms for KB-109 plus supportive self-care (SSC), but for patients with one or more co-morbidities, median time to resolution was 18 days for KB-109 plus SSC compared to 27 days for SSC alone.
  • None of the patients treated with MGC Pharma Ltd.’s anti-inflammatory Artemic (artemisinin, curcumin, frankincense and vitamin C), required additional oxygen, mechanical ventilation or intensive care, compared to 23.4% of patients treated with placebo in a phase II trial.

Recruiting and efficacy problems left some therapeutics on the sidelines.

Sorrento Therapeutics Inc. withdrew its study in hospitalized patients with moderate disease testing COVI-Guard, a COVID-19 spike glycoprotein inhibitor, due to difficulty recruiting patients. Caladrius Biosciences Inc. stopped development of CLBS-119, a CD34+ cell therapy, withdrawing its study due to a lack of patients with long-term hypoxia.

Alexion Pharmaceuticals Inc. paused further enrollment in a global phase III trial of complement inhibitor Ultomiris (ravulizumab) to treat patients hospitalized with severe COVID-19 due to lack of efficacy. While the trial is continuing for those already enrolled, the move indicates the complement inhibitor will likely become another therapeutic that is no longer developed for COVID-19.

Finally, Dr Reddy’s Laboratories Ltd. reported that Avigan (favipiravir) failed to show statistical significance in a phase III study in moderate to severe COVID-19 cases in Kuwait. The trial was terminated after data showed patients taking Avigan took seven days for sustained hypoxia resolution compared to eight days for placebo (p>0.05). The study of outpatient mild to moderate cases continues in North America.