Nearly a year after the SARS-CoV-2 virus first appeared in Wuhan, China, a ray of hope is shining on the world with high efficacy reported for four vaccines and U.S. emergency use authorizations granted to three more therapeutics.
The month of November was a beacon in a dark storm, providing scientific evidence that it is possible to emerge from the COVID-19 pandemic much sooner than expected, after months of societal lockdowns, economic devastation and political division.
As of Dec. 1, the World Health Organization reported 62.8 million cases and 1.47 million deaths worldwide, while U.S. numbers show 13.23 million cases and 264,808 deaths. The number of candidates in development continue to climb and is currently at 821, including 634 therapeutics and 187 vaccines.
With upbeat news in recent weeks of some real therapeutic and vaccine options, RBC Capital Market’s analyst Brian Abrahams now expects herd immunity around June 2021 “when roughly 45% of the U.S. population has been vaccinated or infected,” but that outcome is dependent on “continued behavioral modifications and care.” When that threshold reaches 60%, “transmission will slow substantially regardless of behavior and we could see a fuller return to normalcy” by early fall 2021, he said.
The RBC model, however, still predicts an additional 270,000 deaths in the U.S. “for a total of just over half a million.”
High efficacy for four vaccines
Efficacy jumped to 95% from the 90% found in the interim analysis and placed Biontech SE and Pfizer Inc.’s mRNA vaccine, BNT-162b2, as a frontrunner for preventing COVID-19 infection at seven days following the second dose. The vaccine also hit its safety milestone, so the companies submitted an emergency use authorization (EUA) application to the FDA on Nov. 20, and an agency committee will meet Dec. 10 to discuss the request.
According to Geoffrey Porges and team at SVB Leerink Research, the vaccine will likely “be approved within days of the Dec. 10 advisory meeting, given the urgent and paramount need to deploy the vaccine ideally ahead of the Christmas holiday and before the inevitable surge in cases from the Thanksgiving holiday becomes overwhelming.”
The U.K. granted conditional approval of BNT-162b2 this week, and rolling submissions are underway in Australia, Canada, Europe and Japan. The vaccine needs to be kept at minus 70 degrees Celsius, which could complicate some distribution plans. Pfizer and Biontech have a deal for 200 million doses for the European Union, with an option for 100 million additional doses, as well as a $1.95 billion U.S. government Operation Warp Speed contract signed in July for 100 million doses, with an option for 500 million additional doses. The two-dose vaccine will be provided for free to U.S. citizens.
The second vaccine to show efficacy in an interim phase III analysis is Russia’s Sputnik V, a two-shot human adenovirus-based vaccine, which hit 92% efficacy. The vaccine, which was developed by the Gamaleya National Center of Epidemiology and Microbiology and funded by the Russian Direct Investment Fund, gained emergency use authorization in Russia on Aug. 11, and 1.2 billion doses-plus are on order from more than 50 countries. Sputnik V comes in a freeze-dried formulation. The vaccine demonstrated 91.4% efficacy in the second interim analysis.
“If the first two very different vaccines are about 90% effective, then it does suggest that several effective vaccines will reach market in the coming months,” said Paul Hunter, a professor in medicine at the University of East Anglia, U.K.
In addition to BNT-162b2 and Sputnik V, a second mRNA option and the third vaccine to show high efficacy in November is Moderna Inc.’s mRNA-1273. The company filed for an EUA with the FDA, and an agency advisory meeting is set for Dec. 17, following data confirming the vaccine to be 94.1% effective in preventing symptomatic cases of the disease and 100% effective in preventing severe cases. The efficacy was consistent across age, race, ethnicity and gender. The Cambridge, Mass.-based company also applied for conditional marketing authorization with the EMA. By the end of 2020, Moderna expects to have about 20 million doses available in the U.S. and it remains on track to manufacture 500 million to 1 billion doses globally in 2021. As of Nov. 25, Moderna granted an option to the European Commission to buy up to 80 million additional doses of mRNA-1273 and could ship the doses beginning in December. The vaccine remains stable at 2-degrees to 8-degrees Celsius (36-degrees to 46-degrees Fahrenheit) and could be kept in a standard refrigerator for 30 days.
The data for both BNT-162b2 and mRNA-1273 “validate and support the potential approval of the first vaccines based on mRNA technology,” said Piper Sandler analyst Edward Tenthoff in a research note. “We see potential for wider distribution of mRNA-1273, which remains stable at conventional refrigeration temperatures for 30 days and requiring no dilution, easier administration.”
Another potential vaccine is Astrazeneca plc’s AZD-1222, a chimpanzee adenovirus vectored vaccine, which demonstrated an average of 70.4% efficacy across two dose regimens, well above the 50% threshold needed, but significantly down from what was seen with the mRNA vaccines. Efficacy of AZD-1222, however, increased to 90% in the prime-boost arm of the trial, in which volunteers received half a dose, followed by a full dose.
“Despite apparent inferiority vs. the mRNA drugs, we think there are some attributes of the program that are important, especially during the first wave of vaccines at the height of the pandemic, where demand will significantly outstrip supply,” said SVB’s Andrew Berens.
AZD-1222 trials were paused in September due to an unexplained illness in the U.K., but the studies later resumed when the event appeared to be unrelated to the vaccine. The vaccine can be stored in regular vaccine refrigerators and could be delivered worldwide using existing cold chain infrastructure, “which we believe could help the company gain initial traction in geographical locations where the vaccine will be approved,” Berens said.
A significant advantage with AZD-1222 is that it demonstrated the same immune response in healthy people aged 70 as was seen in those ages 18 to 55, and the older people had fewer side effects, in a phase II trial. Moderna’s mRNA-1273 also showed a similar advantage, whereas lower responses in older adults were seen with the Pfizer/Biontech vaccine, as well as with two others developed by Chinese firms: Cansino Biologic Inc.’s single-dose human adenovirus vaccine, Ad5-nCoV, and Sinopharm Group Co. Ltd.’s inactivated virus vaccine, both of which are in phase III trials.
A third Chinese developer stumbled in November when Brazil’s health care surveillance agency, Anvisa, halted the trials of Beijing-based Sinovac Biotech Ltd.’s Coronavac after a serious adverse event occurred on Oct. 29. The phase III trials restarted a few days later and any possible relationship between the adverse event and vaccine is being monitored. Phase I/II data indicate Coronavac, a traditional inactivated whole virus vaccine, is safe and induces an antibody response in healthy volunteers, but the mean neutralizing antibody titers are lower than levels in recovered COVID-19 patients. Coronavac can be kept in a standard refrigerator for up to three years.
Several other potential vaccines continue to move forward in development.
- Novavax Inc.’s NVX-CoV2373, a protein subunit vaccine which is set to enter a phase III with 30,000 participants in the U.S., received fast track designation from the FDA. A phase IIb in South Africa and a pivotal trial in the U.K. fully enrolled 4,422 and 15,000 participants, respectively. Interim efficacy data are expected in the first quarter of 2021.
- Curevac NV’s mRNA candidate, CVnCoV, is entering a pivotal phase IIb/III trial with 35,000-plus volunteers, initially at sites in Europe and South America, with an interim analysis also expected sometime in the first quarter.
- Janssen Pharmaceuticals, a unit of Johnson & Johnson, started a second phase III trial of its recombinant adenoviral vector vaccine JNJ-78436735 in the U.K., over concerns that the availability of competing vaccines may deter volunteers from participating. J&J expanded the partnership with the U.S. Biomedical Advanced Research and Development Authority (BARDA), with Janssen committing $604 million and BARDA committing about $454 million to support the ongoing phase III Ensemble trial evaluating the single-dose candidate in up to 60,000 participants worldwide. The Ensemble trial was stopped in October following a serious adverse event, but resumed when it could not be determined that the event was caused by the vaccine. The EMA has initiated a rolling review.
- Medicago Inc. entered a phase II/III program with Covlp, a plant-derived virus-like particle vaccine, in combination with Glaxosmithkline plc’s pandemic adjuvant. The phase III portion with 30,000 participants is expected to begin by year-end 2020.
- Arcturus Therapeutics Holdings Inc.’s LUNAR-COV19, another mRNA vaccine candidate, will advance into later-stage trials with a single 7.5-ug dose and prime-boost regimen following interim phase I/II results. The vaccine showed neutralizing antibodies comparable to that of convalescent plasma, and dose-dependent anti-spike immunoglobulin G titers increased over time through about day 43.
- CEPI, the Coalition for Epidemic Preparedness Innovations, is funding development of Sichuan Clover Biopharmaceuticals Inc.’s protein-based S-Trimer COVID-19 vaccine candidate through a global pivotal phase II/III efficacy trial, investing up to $328 million, including previously announced commitments of $69.5 million.
Three EUAs granted for therapeutics
Up until now, those infected with COVID-19 have had few options, limited in the U.S. to only three therapeutics that received EUAs: hydroxychloroquine, for which an EUA was granted in March and revoked in June following the Recovery trial failure; Gilead Sciences Inc.’s Veklury (remdesivir), which gained an EUA on May 1 and then an FDA approval on Oct. 22; and convalescent plasma, which was granted an EUA on Aug. 23. The outlook became significantly brighter in November with three new U.S. EUAs announced for therapeutics.
Eli Lilly and Co. received one for bamlanivimab (LY-CoV555), a neutralizing IgG1 monoclonal antibody, on Nov. 9 to treat mild to moderate COVID-19 in adults and pediatric patients, 12 and older, with a positive COVID-19 test, who are at risk for progressing to severe COVID-19 and/or hospitalization. Lilly plans to manufacture up to 1 million doses in early 2021. The U.S. government purchased 300,000 doses for $375 million and could pay as much as $1.19 billion for 950,000 doses. An NIH-sponsored phase III trial, ACTIV-3, testing bamlanivimab and Veklury in hospitalized COVID-19 patients was paused and then halted after data showed it was unlikely to help advanced patients.
Lilly’s baricitinib (Olumiant), a JAK inhibitor, in combination with Veklury, received an EUA on Nov. 19 after showing a one-day reduction in median recovery time for the overall patient population when compared with those treated only with Veklury. The EUA targets suspected or laboratory-confirmed COVID-19 in hospitalized adults and pediatric patients ages 2 or older who require supplemental oxygen, invasive mechanical ventilation or extracorporeal membrane oxygenation.
And Regeneron Pharmaceuticals Inc. was granted an EUA on Nov. 21 for its antibody cocktail, a combination of casirivimab and imdevimab, also known as REGN-CoV2, to treat mild to moderate COVID-19 in adults and pediatric patients ages 12 and older and weighing at least 40 kg and who are at high risk of progressing to severe COVID-19. The therapy was part of a $450 million manufacturing and supply contract through the U.S. government’s Operation Warp Speed.
Another potential therapeutic to report positive news in November is Humanigen Inc.’s lenzilumab, a granulocyte macrophage-colony stimulating factor ligand inhibitor, which showed 37% more recoveries compared with the placebo arm, according to interim phase III data. The company signed a $20 million deal granting Telcon RF Pharmaceuticals Inc. and KPM Tech Co. Ltd. development and commercialization rights in South Korea and the Philippines.
Three other once-promising therapeutic options for COVID-19 hit roadblocks in November.
Novartis AG is stopping development of canakinumab, a monoclonal antibody targeting interleukin-1 beta, for COVID-19, as it did not meet its primary endpoint of improved survival without the need for invasive mechanical ventilation in a phase III trial in hospitalized COVID-19 patients with pneumonia and cytokine release syndrome. The drug also failed on a key secondary endpoint, reduction in COVID-19-related death within four weeks after the treatment period.
Astrazeneca’s Calquence (acalabrutinib) missed the primary efficacy endpoint of increasing proportion of those alive and free of respiratory failure when added to best supportive care in hospitalized patients with respiratory symptoms of infection. The company has said it will instead focus on its AZD-1222 vaccine and its long-acting antibody combination, AZD-7442.
And just in case clinical data presented to date were not already clear, the U.S. NIH concluded the malaria drug hydroxychloroquine provides no clinical benefit to hospitalized patients. The drug is still being studied in combination treatments targeting different patient populations.
Other noteworthy COVID-19 therapeutic news in November:
- Recently-completed phase I studies showed that treating patients with Celltrion Inc.’s monoclonal antibody CT-P59 resulted in at least a 44% faster recovery time when compared with a placebo. It was also well-tolerated with no clinically significant safety issues.
- An exclusive, global licensing deal worth $1.3 billion was signed by Mesoblast Ltd. for its mesenchymal stromal cell product remestemcel-L, which is in phase II/III for acute respiratory distress syndrome related to COVID-19, granting development, manufacturing and commercialization rights to Novartis AG.
- Even though Gilead’s Veklury is approved for COVID-19 in the U.S., the World Health Organization’s Guideline Development Group panel has advised against use of the drug due to a lack of evidence that it has an effect on mortality, the need for mechanical ventilation or the time to clinical improvement.
Mapping the way forward
Understanding the virus remains a top priority in protecting the world from future coronavirus pandemics. Beyond the development of therapeutics and vaccines, researchers are studying everything from the origins of the virus to its potential mutations and genetic markers.
Although the virus is believed to have originated in bats, evidence that minks are harboring a variant of SARS-CoV-2 with mutations in the spike protein led to the Danish government ordering a mass cull of 15 million mink. In addition, researchers from Erasmus Medical Center reported that 68% of tested mink farm residents, employees and/or contacts had evidence of SARS-CoV-2 infection, including data from 16 Dutch mink farms.
Research done by Vir Biotechnology Inc. and the MRC-University of Glasgow Centre for Virus Research showed that the receptor binding motif (RBM) is the least conserved region in the SARS-CoV-2 spike protein, and that a variant in the RBM, N439K, showed resistance to human neutralizing monoclonal antibodies. The research highlights the importance of watching for immune evasion mutations when developing antibodies and vaccines. None of the mutations documented thus far appear to increase the virus transmissibility in humans, according to a study published online in the Nov. 25 issue of Nature Communications.
And a research team from the American Museum of Natural History identified the ORF3d gene in SARS-CoV-2, which can encode a protein that is longer than expected by chance alone, possibly contributing to the virus’ unique biology and pandemic potential.
On a final note, U.S. President-Elect Joe Biden put together a board of scientists and public health experts in preparation for his leadership and his seven-point plan for addressing the pandemic, which includes a national mask mandate, vaccine and therapeutic distribution efforts, and protection from price gouging. In addition, FDA Commissioner Stephen Hahn highlighted the need for greater diversity in clinical trials due to differences in how the virus is affecting various populations in the U.S.