As 2020 approaches its last quarter, scientists around the globe continue their all-consuming efforts to find effective therapeutics and vaccines to fight the deadly COVID-19 pandemic, which currently has a 3.35% fatality rate and has been plaguing the world for more than half a year.

While the fight rages on, people are growing weary of political posturing and community debates. They face a serious conundrum of how to best protect those vulnerable to the virus, while still considering the psychological and economic impacts of societal lockdowns. In the U.S., where a presidential election is only two months away, public distrust of data and government recommendations has led to a contentious environment.

But that has not stopped biopharma researchers, who are battling beyond the noise. As of Sept. 1, BioWorld has tracked 725 therapeutics and vaccines, as well as 435 diagnostics, for the SARS-CoV-2 virus that causes COVID-19. The U.S. government, through its Operation Warp Speed (OWS) effort, continues to forecast availability of a vaccine by the end of 2020 or early 2021, promising that the speed will not circumvent safety.

As of the end of August, only two therapeutics hold emergency use authorization (EUA) in the U.S. for treating the disease: remdesivir (Veklury, Gilead Sciences Inc.) and convalescent plasma. A third EUA, granted to hydroxychloroquine in March, was revoked three months later following data that showed no benefit.

Russia approves first vaccine

Out of the 170 vaccines in discovery or development, a total of 13 are in late-stage trials.

On Aug. 11, Russia approved the world’s first COVID-19 vaccine, the adenovirus candidate Gam-COVID-Vac (Sputnik V), which was developed at the Gamaleya Research Institute of Epidemiology and Microbiology in Moscow. The approval is based on data from two 38-person phase I/II trials, a sharp contrast from what other regulatory agencies are requiring prior to approval. Late-stage vaccines in the U.S. are enrolling tens of thousands of people, including the elderly and those with co-morbidities.

FDA Commissioner Stephen Hahn recently suggested the possibility of an EUA authorization prior to the completion of phase III vaccine trials. The agency is convening a virtual Vaccine Advisory Committee meeting on Oct. 22.

In a Scientific American editorial, William Haseltine, the founder and former chairman and CEO of Rockville, Md.-based Human Genome Sciences Inc., acquired by Glaxosmithkline plc in 2012 for $3.6 billion, raised concerns of antibody-dependent enhancement, in which a vaccine could make an infection worse, as was seen with Paris-based Sanofi SA’s dengue vaccine, Dengvaxia. “A safe vaccine, effective for all those at risk, is worth the wait, especially when we have other solutions in hand,” he wrote.

Aside from Russia’s Sputnik V, which was set to enter a phase III trial with 40,000 participants at the end of August, at least three other adenoviral vaccines were expected to enter phase III trials during the month. Janssen Pharmaceuticals Inc. planned to enroll 60,000 adults for a study of Ad26.COV2-S, and Astrazeneca plc was moving AZD-1222 into a phase III with 30,000 adults. Likewise, Cansino Biologics Inc. was moving Ad5-nCoV into a phase III trial in Saudi Arabia.

As for mRNA vaccines, Curevac AG said it intends to move CVnCoV into a phase III with 20,000 adults, including those at risk, and Biontech AG and Pfizer Inc. entered a global phase II/III study with 30,000 participants to study BNT-162b2. Moderna Therapeutics Inc., already in a 30,000-participant phase III trial with mRNA-1273, signed an agreement to supply 100 million doses to the U.S. government in an OWS deal worth $1.525 billion.

Companies developing vaccines that use adjuvants also reported news within the last month. Sinovac Biotech Ltd. entered a phase III program for Coronavac, enrolling 9,000 people. And data of Novavax Inc.’s NVX-CoV2373 showed it was well-tolerated and sparked robust antibody responses numerically superior to those seen in human convalescent sera. All participants developed anti-spike IgG antibodies after a single dose, with many also generating wild-type virus neutralizing antibody responses.

Other vaccines in late-stage trials are Merck & Co. Inc.’s Bacillus Calmette-Guerin (BCG) vaccine; Vakzine Projekt Management GmbH’s VPM-1002, a further development of an old BCG vaccine; China National Biotec Group’s inactive viral vaccine; and Merck & Co. Inc.’s live attenuated measles/mumps/rubella (MMR) vaccine.

Notably, a phase I/II-ready recombinant protein-based vaccine was the subject of a $2.1 billion OWS deal in August between the U.S. government and Sanofi and Glaxosmithkline to develop and deliver 100 million doses.

Questions remain as to how long immunity will last following vaccine administration. In August, researchers reported that a Hong Kong man had become infected with two distinct strains of the SARS-CoV-2 virus 142 days apart. The man’s second infection was asymptomatic, suggesting the first case resulted in functional immunity, if not sterilizing immunity. A vaccine with the right adjuvant could provide longer lasting protection than an immune response through direct infection, suggested immunologist Bali Pulendran, a professor of pathology, microbiology and immunology at Stanford University.

Convalescent plasma gains EUA

Of the 554 therapeutics in development for COVID-19, tracked by BioWorld, 111 of them are in late-stage trials.

The most significant news within the last month was the FDA issuing an EUA for convalescent plasma on Aug. 23, as well as a new drug application filing for Gilead’s remdesivir, the only other COVID-19 treatment that holds an EUA in the U.S. Remdesivir’s EUA was expanded in late August to include all hospitalized patients with COVID-19, not just those with severe disease.

Abcellera Biologics Inc.’s LY-CoV555 is entering a phase III trial, as is Revive Therapeutics Ltd.’s Bucillamine, Humanigen Inc.’s lenzilumab and Romark Laboratories LC’s NT-300 (nitazoxanide). Ansun Biopharma Inc. withdrew a phase II/III study of DAS-181 during the month due to trouble recruiting COVID-19 patients in the European Union. However, it’s continuing to test the candidate against the disease in a sub-study of an ongoing phase III parainfluenza trial.

At least two therapeutics companies reported positive data within the past month. An interim analysis of the phase III Odyssey trial of Vanda Pharmaceuticals Inc.’s tradipitant, a neurokinin-1 receptor antagonist, showed it accelerated clinical improvement by day 7 (p=0.0375) and median time to improvement was 10 days for tradipitant and 28 days for placebo (p=0.2254). And despite the Covacta trial missing the primary endpoint in July, IL-6 receptor antagonist tocilizumab (Actemra, Genentech Inc.) showed a statistically significant decrease of about 36% in hospital-related mortality among 210 intensive care unit patients receiving the drug vs. other ICU patients in an observational study at Hackensack Meridian Health hospitals.

Removing one potential therapy from the mix, Sanofi said on Sept. 1 it will not pursue further testing of Kevzara (sarilumab), nor will its partner Regeneron Pharmaceuticals Inc., after the global phase III trial failed to hit primary and key secondary endpoints in critically ill COVID-19 patients who were hospitalized.

Other news to note on therapeutics: An independent data safety monitoring committee recommended a phase III trial continue for Cytodyn Inc.’s PRO-140 (leronlimab); Dr. Reddy’s Laboratories launched favipiravir (Avigan) in India; and the FDA cleared the expanded access program for Pluristem Therapeutics Inc.’s PLX cell product candidate, PLX-PAD cells, to treat acute respiratory distress syndrome caused by COVID-19.

Aside from finding therapeutics to treat COVID-19, researchers are also working to understand the disease and the variability of its symptoms. A U.K. coronavirus immunology consortium (UK-CIC), which includes immunologists from 17 research institutions, is studying 4,000 infected patients at the cellular and molecular level.

Barreling through the noise

Outside of the laboratories where scientists aim to halt the deadly virus, a growing consumption of misinformation has contributed in the U.S. to political polarization and increasing suspicion of drugmakers’ motives.

The virus has created a politicking nightmare, in which “claims, from Democrats and Republicans alike, that the FDA is, or isn’t, authorizing the emergency use of COVID-19 products because of political pressures rather than science do nothing but fuel the public’s distrust of the agency,” opined BioWorld’s regulatory editor Mari Serebrov.

Attorney generals of 31 U.S. states and territories demanded that the federal government march in on the remdesivir patents, under the 1980 Bayh-Dole Act, taking issue with Gilead’s pricing for a five-day treatment course of $2,340 for developed countries and $3,120 for commercial payers in the U.S.

Another area of contention is the conclusions pulled out of COVID-19 numbers, which in some circles show that the U.S. has a large share of COVID-19 cases and deaths, and in other circles show a low fatality rate. Since the World Health Organization declared it a pandemic in March, the FDA has authorized 230 diagnostic tests under EUAs. The U.S. currently has a total of 5.9 million confirmed cases and 182,162 deaths, representing more than 20% of the worldwide totals of 25.3 million and 847,603, respectively. While the global fatality rate is 3.35%, the U.S. fatality rate is at about 3.1%, much lower than rates in other countries. The U.K., for instance, has about a 12% fatality rate. But the rates correlate with the accuracy and the amount of testing. Countries with limited testing capacity, or those only testing symptomatic individuals, would likely show higher fatality rates due to a lower number of confirmed cases. Similarly, countries doing a lot of testing may show a higher percentage of the overall totals.

Regardless of the numbers, experts agree that continued research efforts following the previous SARS outbreak could have prevented the global disruption that COVID-19 has caused.

The first SARS virus infected thousands of people worldwide 17 years ago, but government and industry did not follow through with research and development once the outbreak subsided and recruiting for clinical trials became difficult.

Researchers at Ben-Gurion University (BGU) of the Negev noted that the failure to continue research after the outbreak receded has left the world unprepared for COVID-19. Although SARS and MERS were priority diseases in the WHO’s R&D Blueprint in 2017 and 2018, their research rate did not grow in comparison to other diseases.

“The path to understanding is a marathon, not a sprint,” said Michael Fire, a BGU lecturer.

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