With phase III vaccine trials nearly enrolled and data expected soon, a half-year of expedited development efforts, plus massive government funding may soon provide the ammunition needed to effectively stop the SARS-CoV-2 scourge of 2020.

A total of 763 vaccines and therapeutics are in development for the COVID-19 pandemic, with about half in clinical trials. Most of the development has emerged since March when the virus began its global spread. The U.S. government’s Operation Warp Speed (OWS) has supported vaccine development with more than $10 billion in contracts.

As of Oct. 1, the World Health Organization (WHO) reports 33.7 million global confirmed cases and more than 1 million deaths caused by the novel coronavirus, with the U.S. making up about a fifth of the deaths at 204,642. By population, however, the U.S. is doing better than some other regions at 618 deaths per million. Confirmed U.S. cases are at 7.1 million.

14 vaccines in late-stage clinical trials

There are currently 14 vaccines in the later stages of development for COVID-19, including two approved by Russia and China. Sputnik V, developed by the Gamaleya Institute in Moscow, gained conditional approval in August, and Cansino Biologics Inc.’s Ad5-nCoV received approval in June for use in China’s military personnel.

The Russian approval was based on two non-randomized phase I/II trials in which both the frozen and freeze-dried formulation induced antibody responses in all 76 participants within 21 days. A phase III trial with 40,000 volunteers began on Sept. 7. The Cansino vaccine entered a phase III trial in Saudi Arabia in August.

In total, BioWorld has tracked 178 vaccines with 48 in clinical trials, 34 of which are phase I/II or earlier. In addition, there are 114 vaccines in preclinical development, 15 in discovery stage and one that is no longer studied as a vaccine, Innovation Pharmaceuticals Inc.’s brilacidin.

A number of COVID-19 vaccine companies reported news in September.

  • Astrazeneca plc paused its phase III trial of its adenoviral vector vaccine AZD-1222 on Sept. 8 following a case of transverse myelitis, but the trial resumed in the U.K. four days later. Pfizer Inc. and Biontech SE upped trial enrollment from 30,000 to 44,000 to include patients as young as 16 and those with HIV or hepatitis C or B infections.
  • Curevac AG’s mRNA vaccine, CVnCoV, treated the first of 690 participants in the CV-NCOV-OO2 phase II study.
  • Sinovac Biotech Ltd. started a phase III study in Turkey of Coronavac, its inactivated vaccine, enrolling 1,300 health care workers and 12,000 others.
  • Moderna Therapeutics Inc.’s phase III COVE study of mRNA-1273 enrolled more than 75% of its 30,000 participants by mid-September. Interim phase I data released Sept. 30 suggested the vaccine could generate neutralizing antibodies in elderly adults at levels comparable to younger adults.
  • Johnson & Johnson’s Janssen Pharmaceuticals began enrolling up to 60,000 adults in a phase III study of JNJ-78436735 (Ad26.COV2.S), a recombinant adenoviral vector vaccine. An interim phase I/IIa study analysis showed a single dose induced a strong neutralizing antibody response in nearly all participants, including older adults.
  • Biontech and Pfizer’s BNT-162b2 phase II/III trial had recruited 23,000 of 30,000 subjects early in September. The companies later amended protocol to raise enrollment to 44,000 to include patients as young as 16 and those with HIV and hepatitis C and B infections.

Other vaccines in late-stage development include Novavax Inc.’s protein subunit vaccine, NVX-CoV2373, which is currently in an interventional phase II trial in South Africa, and Vakzine Projekt Management GmbH’s VPM-1002, a further development of an old Bacillus Calmette-Guérin (BCG) vaccine, which first entered a phase III trial in Germany in June.

Sinopharm subsidiary Wuhan Institute of Biological Products moved its inactive viral vaccine into a phase III trial in July in Abu Dhabi, and a phase III trial began Sept. 4 to evaluate Merck & Co. Inc.’s live attenuated measles/mumps/rubella (MMR) vaccine. In phase IV trials are Merck’s BCG vaccine and Bandim Health Project’s oral polio vaccine.

Inovio Pharmaceuticals Inc. had planned to move its DNA vaccine candidate, INO-4800, into a phase II/III trial in September, but the FDA placed a partial clinical hold for undisclosed reasons on the study.

While the U.S. led the world with OWS vaccine supply contracts, other countries continue to secure access to the vaccines.

The U.K. government signed a €1.4 billion (US$1.7 billion) advance purchase agreement with Valneva SE for up to 190 million doses of the attenuated whole virus vaccine, VLA-2001, which is expected to enter phase I/II development in December. The European Union is creating its own unit in order to more quickly secure advance purchase orders for vaccines.

Brazil has a $360 million deal for Astrazeneca’s AZD-1222, while states in the northeast and south have agreements for Russia’s Sputnik V vaccine. The Russian Direct Investment Fund (RDIF) in Moscow and Pharco Pharmaceuticals, of Alexandria, Egypt, agreed to secure the supply of 25 million doses to Sputnik V.

113 therapeutics are phase II/III or later

As for therapeutics, BioWorld has tracked 585 in which 332 are in clinical testing, including 43 in phase II/III trials, 53 in phase III trials, and 17 in phase IV trials. A total of 203 therapeutics for COVID-19 are in preclinical development, while 49 are at the discovery stage and one – the IL-6 receptor inhibitor Kevzara (sarilumab, Regeneron Pharmaceuticals Inc. and Sanofi SA) – is no longer studied.

Only two treatments, remdesivir (Veklury, Gilead Sciences Inc.) and convalescent plasma, hold emergency use authorizations (EUA) in the U.S. The remdesivir EUA was expanded in September to include all hospitalized patients, not just those with severe disease, following data from three randomized controlled trials. The therapy is now allowed for use in 50 countries.

The convalescent plasma EUA is not based on randomized controlled trials, but on past use during previous pandemics, as well as data pulled from 90,000 patients enrolled in a national expanded access protocol sponsored by the Mayo Clinic. Democrats on the Senate Health, Education, Labor and Pensions (HELP) Committee have questioned whether political influence by President Donald Trump, who is up for re-election, came into play. A randomized controlled trial in moderately ill patients conducted in India found no association between convalescent plasma and reduced mortality or progression to severe disease, although the donors appeared to have low titers of detectable neutralizing antibody, as opposed to the higher titers recommended in FDA guidance.

Genentech Inc.’s IL-6 inhibitor, Actemra (tocilizumab), hit its phase III endpoint in September with only 12.2% of patients progressing to mechanical ventilation over 28 days, compared with 19.3% of those in the control arm. The mortality rate, however, while not statistically significant, was higher with Actemra (10.4%) over placebo (8.6%), and the drug failed to hit secondary endpoints of reducing time to hospital discharge and time to clinical failure.

Several other companies developing COVID-19 therapeutics reported news in September.

  • A meta-analysis of seven randomized trials evaluating dexamethasone, hydrocortisone and prednisolone supported the U.K. Recovery trial finding that corticosteroids reduce mortality in the sickest COVID-19 patients, specifically showing eight fewer deaths for every 100 patients.
  • More inhalation therapies began appearing in the BioWorld list of therapeutics, including Auris Medical Holding Ltd.’s AM-301, Parnell Pharmaceuticals Holdings’ Novomid and Ena Respiratory Pty Ltd.’s INNA-051. Starpharma Holdings Ltd., which is developing its SPL-7013 COVID-19 antiviral nasal spray, gained $32 million through a private placement.
  • The U.K. Recovery randomized phase III trial will test Regeneron’s antibody cocktail REGN-COV2 with standard of care in hospitalized patients, assessing all-cause mortality at 28 days and its ability to reduce hospital stays and ventilation. Initial data reported Sept. 29 from a seamless phase I/II/III trial showed the cocktail reduced viral load and the time to alleviate symptoms in non-hospitalized patients.
  • Eli Lilly and Co. and Incyte Corp.’s JAK1/JAK2 inhibitor, baricitinib, achieved in a phase III trial a median time to recovery that was one day shorter than that achieved by remdesivir.
  • Innovation’s brilacidin showed that overall viral load was reduced by 99.85% when used with remdesivir, according to data from a U.S. regional biocontainment laboratory.
  • A study in Japan showed those who received Fujifilm Holdings Corp.’s Avigan (favipiravir) recovered from symptoms an average of 2.8 days earlier than the control group.
  • Top-line phase III results of Oncoimmune Ltd.’s immunomodulator, Saccovid (CD24Fc), showed a 60% better chance over placebo in achieving clinical recovery (p=0.005), with median time to recovery of six days vs. 10 days for placebo.
  • Eiger Biopharmaceuticals Inc. reported that peginterferon lambda-1a in 120 outpatients with mild and uncomplicated infection showed no difference vs. placebo in duration of SARS-CoV-2 viral shedding, but the company is still waiting for results in hospitalized and more advanced patients.

Supply, storage, compliance and politics

Although therapeutics have an important role in helping those already infected, vaccines are still seen as the answer to stopping the COVID-19 pandemic; yet, there are significant challenges ahead with storing and supplying them.

The National Academies of Sciences, Engineering and Medicine released a discussion draft suggesting a four-phase approach for delivering the vaccine, with those on the front lines and most vulnerable receiving it first, followed by school staff and those with moderate co-morbidities, and then young adults, children and essential workers. The final phase opens the vaccine to anyone who wants it. The academies, however, received comments that certain ethnic groups contract COVID-19 at a much higher rate and should receive the vaccine earlier, as should those with mental health issues, which is not listed as a co-morbidity.

Another large, looming issue concerns vaccine storage requirements, with the six candidates under development as part of the U.S. government’s OWS all requiring something different. Pfizer and Biontech’s vaccine, for example, must be stored at negative-94 degrees Fahrenheit.

The CDC posted its vaccine distribution plan on Sept. 16 with director Robert Redfield saying sufficient vaccine quantities to cover everyone in the U.S. might not be available until the third quarter of 2021.

Authorities also are worried that large portions of the U.S. population will not get the vaccine. Surgeon General Jerome Adams said 60% to 80% of the population is needed for herd immunity, but polls show many Americans mistrust the data. Herd immunity, however, could be achieved not only through a vaccine, but also through natural immunity of those previously infected.

The U.S. is just one month away from a presidential election and COVID-19 has become a contentious subject of debate. Whether the research is moving too fast or too slow and whether leaders are making science-based decisions are issues that are central to the battle.

As for the speed of research, NIH Director Francis Collins testified Sept. 9 at a HELP committee hearing that in a randomized trial with 30,000 participants, only 150 incidents of infection are needed to show if the vaccine is at least 50% effective. Adams pointed out that the FDA generally recommends 3,000 participants for vaccine trials.

And although FDA Commissioner Stephen Hahn suggested the agency could grant an EUA to a COVID-19 vaccine prior to having complete phase III data, top biopharma CEOs declared that they would not submit a filing until the complete data are in hand. Democratic leadership of the U.S. House Energy and Commerce Committee said their pledge was not enough, and asked for more transparency.

The FDA plans to hold a public advisory committee meeting before authorizing anything, but President Trump said FDA guidance would have to be approved by the White House as it may cause a delay in vaccine availability.