October brought another burgeoning swell of pandemic news with the U.S. granting its first FDA approval for a COVID-19 therapy, a promising vaccine candidate reaching full enrollment in phase III, and the stoppage of several trials due to safety signals.

Interspersed, amid the ongoing research of 619 therapeutics and 182 vaccines tracked by BioWorld, is a highly contested U.S. presidential election in which the handling of the coronavirus has become a sore issue. The World Health Organization (WHO) currently reports 228,998 U.S. deaths and 9 million confirmed cases. Globally, it has tallied 1.2 million deaths and 46.4 million cases.

The disruption to local economies and livelihoods, as well as the ripple effects of SARS-CoV-2’s impact on education and overall well-being, has indisputably led to one pressing question: When will it all end?

Scientists continuously work to understand the selective nature of COVID-19, concluding that widespread immunity is necessary before the world will be completely rid of the worst infectious attack in a century.

RBC Capital Markets’ analyst Brian Abrahams and team have suggested that without a vaccine, “the U.S. should achieve sufficient effective immunity to meaningfully slow transmission and restore societal ‘normalcy’ by the first quarter of 2023.” With a vaccine in coming months, there should be “a meaningful slowing of transmission” by the third quarter of 2021.

Large-scale population surveys indicated in late October that SARS-CoV-2 antibodies in England declined by 26.5% over three months, suggesting that “we are a long, long way from the population being protected,” said Imperial College professor Helen Ward.

There have been five cases of reinfection worldwide, including one in the U.S., confirmed by viral DNA sequencing. “It might prove to be a rare phenomenon,” said Simon Clarke, associate professor of cellular microbiology at Reading University, but if it is not, “the implications of more widespread reinfection are that herd immunity would not work.”

Nevertheless, Abrahams pointed out the unknowns, “including the degree that other forms of immunity like T cells may still confer protection.” In fact, a U.K. study published Nov. 2 showed T cells against SARS-CoV-2 were found in subjects six months post infection.

And undetectable antibody levels does not mean “there are no memory B cells readily available to differentiate into plasma cells and prevent a second infection on stimulation with antigen,” Abrahams added, “but nonetheless it does raise some questions about the extent and duration in which asymptomatic patients can contribute to herd immunity.”

As scientists work to answer these questions, biopharma companies are lining up to provide effective therapeutics, with Gilead Sciences Inc.’s Veklury (remdesivir) becoming the first U.S.-approved treatment after being used under emergency use authorization for months.

U.S. President Donald Trump received the therapy at Walter Reed Army Medical Center after testing positive in early October. He also received Regeneron Inc.’s antibody cocktail under compassionate use, and the steroid dexamethasone, before his hospital release. The 74-year-old president returned to campaigning against his opponent, former Vice President Joe Biden, by mid-October, only weeks prior to the Nov. 3 general election.

Aside from the election itself, U.S. political discussions throughout October have focused on phase III data readouts for COVID-19 vaccines. During a fireside chat at a recent med-tech conference, FDA Commissioner Stephen Hahn said approval of a vaccine will be insulated from political pressures. The FDA delivered promised Emergency Use Authorization (EUA) guidance for COVID-19 vaccines, requiring manufacturing information ensuring quality and consistency, demonstrated safety with follow-up of two months, and efficacy of at least 50% from a phase III trial. Japan released similar guidelines.

“Ideally, you’d like to have longer-term safety follow-up, but the duration of safety data has to be balanced against the cost of waiting as more people die every day from COVID-19,” said Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research. The guidance is meant to instill trust so citizens feel confident in taking the vaccine.

Therapeutics on the front lines

Until a vaccine is ready, therapeutics are the first line of defense. Of the 619 therapeutics in development, a total of 354 are in clinical trials, 135 of which are phase II/III or later.

Safety was a key factor in a halted trial studying advanced patients with Eli Lilly and Co.’s antibody, LY-COV555. Likewise, an independent data monitoring committee recommended that Regeneron place on hold enrollment of patients requiring high-flow oxygen or mechanical ventilation, due to a safety signal and an unfavorable risk-to-benefit profile, in its REGN-CoV2 trial.

Phase II therapies no longer developed for COVID-19 include Biosig Technologies Inc.’s antiviral, merimepodib, and Phasebio Pharmaceuticals Inc.’s vasoactive intestinal peptide analogue, pemziviptadil, following less-than-impressive interim data.

Other news reported in October include:

  • Humanigen Inc.’s lenzilumab appeared to rescue a 77-year-old man with co-morbidities who deteriorated in the hospital for 12 weeks until being discharged 16 days after lenzilumab treatment. A separate Mayo Clinic study showed an 80% reduction in relative risk of invasive mechanical ventilation and/or death for treated patients. The U.S. National Institute of Allergy and Infectious Diseases launched the ACTIV-5 Big Effect Trial testing lenzilumab and risankizumab (Boehringer Ingelheim GmbH and Abbvie Inc.) in combination with remdesivir.
  • Gilead’s now FDA-approved Veklury (remdesivir) had a median time to recovery of 10 days vs. 15 days for placebo (p<0.001) in the ACTT-1 trial. Time to recovery was 11 days vs. 18 days, respectively, for those requiring oxygen support at baseline. Mortality rate was 6.7% vs. 11.9% at 15 days.
  • Regeneron’s antibody cocktail, REGN-CoV2, was added to the Recovery trial, and the company submitted an EUA filing with the FDA. In an overall study population of 799 patients, REGN-COV2 reduced COVID-19-related medical visits by 57% through day 29.
  • Eli Lilly filed for an EUA for LY-CoV555 (bamlanivimab) and plans to soon request an EUA for LY-CoV555’s combination with LY-CoV016. Blaze-1 phase II data of the combination showed a 99.99% clearance of virus in the placebo group over 11 days, but both monotherapy and combination therapy showed a more rapid decrease in viral load. Evercore ISI analyst Umer Raffat pointed out that "remdesivir was unable to show a benefit on viral load." An NIH-sponsored phase III trial, ACTIV-3, testing LY-CoV555 and Veklury in hospitalized COVID-19 patients, however, was paused and later halted after data showed it was unlikely to help advanced patients. Three other studies remain ongoing in milder cases of disease.
  • Full results of the randomized U.K. Recovery study showed Abbvie Inc.’s lopinavir-ritonavir demonstrated no significant difference in the primary endpoint of 28-day mortality, at 22.1% in the treatment arm vs. 21.3% for standard of care (p=0.58). WHO has halted lopinavir-ritonavir treatment groups in its Solidarity trial and reported that the interim results are in line with the U.K. data.
  • In addition to lopinavir-ritonavir, interim data from Solidarity showed remdesivir, hydroxychloroquine and subcutaneously administered interferon regimens apparently “have little or no effect” on 28-day mortality in hospitalized patients. Synairgen plc and Faron Pharmaceuticals Oy are moving forward with their inhaled and intravenous interferon candidates.

A large $486 million contract was received in October by Astrazeneca plc from the U.S. government to support the long-acting antibody combination AZD-7442, which just entered phase III with more than 6,000 participants. Roche Holding AG and Atea Pharmaceuticals Inc. also signed a significant deal, worth $350 million in cash up front to Atea, for exclusive rights to research, develop and distribute its oral antiviral candidate, AT-527, to treat COVID-19 outside of the U.S.

Some earlier-stage clinical candidates also are moving forward:

  • Corvus Pharmaceuticals Inc.’s CPI-006, when administered at very low doses in a phase I, appears to boost antibody responses in a dose-dependent fashion.
  • Research showed a 29% reduction in recovery time in 100 outpatients who received standard of care and nutritional protocol with Chromadex Corp.’s Niagen.
  • Phase II data showed the survival rate beyond 60 days was 81% for those taking Neurorx Inc.’s RLF-100 (aviptadil) and 17% for control patients.
  • Taiwan Liposome Co. Ltd.’s stock (NASDAQ:TLC) rose 36% on news that it is starting a phase I trial of TLC-19, its hydroxychloroquine liposome inhalation suspension, which may overcome the toxicity limitations of oral hydroxychloroquine.
  • Mild to moderate patients treated in the Iliad study of Eiger Biopharmaceuticals Inc.’s Peginterferon Lambda were 4.1-fold more likely to clear their viral load by day seven (p=0.029).
  • Pharmamar SA’s Aplidin (plitidepsin) yielded an average drop in viral load of 50% on day seven and 70% on day 15.
  • Ana Therapeutics Inc.’s oral niclosamide formulation, ANA-001, moved into a phase II/III trial to treat moderate COVID-19.
  • The University of Maryland School of Medicine released findings that aspirin use reduced the risk of being placed on mechanical ventilation by 44%, the risk of ICU admission by 43% and the risk of dying in the hospital by 47%.
  • Nitric Oxide Innovations LLC is moving its sodium nitrite therapy, Noviricid, into a phase IIb/IIIa trial with 840 African American COVID-19 patients. CDC statistics indicate that African Americans are hospitalized with COVID-19 at a rate that is 4.7 times higher than that of white people.
  • Celltrion Inc.’s monoclonal antibody, CT-P59, for asymptomatic COVID-19 patients and close contacts is moving into phase III trials in South Korea.
  • Direct Biologics Inc.’s Exoflo gained expanded access from the U.S. FDA to use it for severe COVID-19 patients.

Vaccines to end the war

While therapeutics play an important role in treating COVID-19, vaccine development has long been the focus for providing global immunity. Several candidates will have data soon and some are starting the regulatory filing processes. Of the 182 vaccines in development for COVID-19, 50 are in clinical trials, 14 of which are late-stage.

In the U.S., the Centers for Medicare & Medicaid Services, and the Departments of Labor and the Treasury, issued a federal rule on Oct. 28 that the price for any vaccine licensed by the FDA or granted an EUA will be covered for most Americans.

Moderna Inc. completed phase III enrollment of 30,000 participants for mRNA-1273 on Oct. 22, and the company has initiated a rolling submission with Health Canada. It also has received written confirmation from the EMA that it can submit a marketing authorization application (MAA).

Biontech SE and Pfizer Inc. started a rolling MAA submission for the mRNA-based vaccine BNT-162b2 after having enrolled more than 42,000 participants in the phase II/III trial. Initial data are expected by the third week of November.

Following a global halt of trials after one volunteer developed symptoms of transverse myelitis, Astrazeneca resumed phase I/II studies in Japan of AZD-1222, and also received FDA authorization to restart the phase III trial in the U.S.

However, another phase III trial of a COVID-19 vaccine, Johnson & Johnson’s JNJ-78436735, was placed on hold in October due to an unexplained illness. J&J’s Janssen Pharmaceuticals unit entered an advance purchase agreement to supply 200 million doses of the vaccine to European Union Member States, with an option for 200 million additional doses.

Other COVID-19 vaccine news reported in October:

  • The Lancet Infectious Diseases has published the first phase I/II data on BBIBP-CorV, an inactivated whole virus vaccine adjuvanted with aluminum hydroxide and developed by a Sinopharma subsidiary, Beijing Institute of Biological Products Co. Ltd., showing that all vaccine recipients out of 540 health volunteers seroconverted by day 28, with older recipients requiring higher doses.
  • The Russian Direct Investment Fund submitted applications to WHO for accelerated registration (emergency use listing) and prequalification of Sputnik V, a vaccine approved in Russia and developed at the Gamaleya Research Institute of Epidemiology and Microbiology.
  • The U.K. has plans to start in 2021 a human challenge study with $42.5 million in funding. The government will test COVID-19 vaccines by infecting patients with the SARS-CoV-2 virus one month after inoculation.
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