On 11/23/2020 AstraZeneca announced interim data from two trials involving 22,690 patients after 131 cases of COVID-19 developed in the population. The COV002 trial (NCT04400838) enrolled 12,390 volunteers in the U.K., and the COV003 trial (NCT04536051) enrolled 10,300 participants in Brazil. An analysis of two trials by the independent Data Safety Monitoring Committee found the average efficacy for both dosing regimen of the vaccine to be 70% in preventing COVID-19, two weeks after the second dose of the vaccine. Giving a half dose as the first immunization and a full dose four weeks later resulted in 90% efficacy (n=2,741), while giving a full dose at both immunizations resulted in 62% efficacy (n=8,895). The vaccine can be stored, transported and handled at 2-8 degrees Celsius for at least six months.
The FDA approved an Emergency Use Authorization (EUA) for the combination of casirivimab (REGN10933) and imdevimab (REGN10987)(REGEN-COV2, Regenron) on 11/21/2020, for the treatment of patients, 12 and older and weighting at least 40 kg, with mild or moderate COVID-19, who are at high risk of progressing to a severe infection and who do not require hospitalization. Casirivimab and imdevimab are administered as a one-time intravenous dose. The FDA advised against using the drug in hospitalized patients, because a benefit has not been demonstrated. Healthcare providers should review the Fact Sheet for information on the authorized use of casirivimab and imdevimab and mandatory requirements of the EUA. Please see the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients, Parents, and Caregivers. Regeneron has an agreement with Roche to increase manufacturing capacity and distribution of REGN-COV2. Regeneron will distribute the drug in the U.S. and Roche will handle distribution outside the U.S. The combined manufacturing capacity will increase production to at least 2 million doses per year. Regeneron has 80,000 doses available and forecasts 200,000 by the beginning of the 2021 and 300,000 by the end of January 2021. The U.S. government has purchased 300,000 doses that will be distributed at no charge.
The FDA plans to post their reviews and data supporting an Emergency Use Authorization for COVID-19 vaccines. The FDA is working on a meeting during second week of December for its vaccines advisory committee to discuss COVID-19 vaccines from Pfizer-BioNTech and Moderna. Peter Marks, the head of the FDA’s Center for Biologics Evaluation and Research said the FDA review may takes weeks.
Pfizer and BioNTech are evaluating BNT162b2 in a Pfizer funded, 44,000 patient, Phase II/III trial (NCT04368728) BNT162b2 will be administered as two 30 mcg immunizations given 21-days apart. The trial was expanded from its original 30,000 patients, in September 2020, to allow the vaccine to be tested in a larger more diverse population, including adolescents as young as 16 years of age and people with HIV, Hepatitis C, and Hepatitis B. Pfizer and BioNTech announced final efficacy results from the Phase III trial on 11/18/2020. BNT162b2 efficacy was found to be 95% in 43,661 patients 28 days after the first dose, 7 days after the second dose. A total of 170 cases of COVID-19 developed in the study population with eight in the vaccine group and 164 in the placebo group. There were ten cases of serious COVID-19 with one in the vaccine group and nine in the placebo group. About 42% of participants have diverse backgrounds, and 41% are 56-85 years of age. Efficacy was consistent across age, gender, race and ethnicity demographics. The observed efficacy in adults over 65 years of age was over 94%. The only ADR that were Grade 3 (severe) and occurred in at least 2% of patients was fatigue (3.8%) and headache (2%). Older adults reported fewer and milder adverse events following vaccination. Pfizer and BioNtech requested an emergency use authorization (EUA) for BNT162b2 to prevent COVID-19 on 11/20/2020 and will have 50 million vaccine doses available in 2020 and up to 1.3 billion doses in 2021.
Results from the 500 patient, Phase II portion of a 12,390 patient, Phase II/III trial found that AZ’s AZD1222 elicited similar antibody titers in all age groups. The vaccine was well tolerated and older patients had fewer adverse reaction than younger patients.
In a 743 patient Phase I/II trial (NCT04352608), Sinovac COVID-19 vaccine, CoronaVac, elicited neutralizing antibodies four weeks after two doses of the vaccine given 14 days apart. Based on results from the trial a 3 mcg dose was chosen for Phase III trials.
COVID-19 Monoclonal Antibodies
NIH did not find enough evidence to recommend for or against use of bamlanivimab for the treatment of outpatients with mild to moderate COVID-19. Due to the limited supply, use of the drug should be restricted to patients at the highest risk to progress to severe COVID-19. Hospitalized patients should not receive bamlanivimab outside of a clinical trial.
COVID-19 Antiviral and Anti-inflammatory
The FDA granted an EUA for the combination of baricitinib (Olumiant. Lilly) plus remdesivir (Veklury, Gilead) to treat hospitalized adults and pediatric patients two years of age or older, with COVID-19 and who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The approval was based on the 29-day, 1,034 patient, Phase III, ACTT 2 trial (NCT04401579), where baricitinib added to remdesivir reduced the time to hospital discharge by one day (7 vs 8 days) compared to remdesivir alone in hospitalized patients with COVID-19. ACTT 2 was sponsored by NIAID. The largest effect was seen in patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation.
Moderna and NIAID initiated an NIAID funded, 30,000 patient, Phase III, COVE trial (NCT04470427) for COVID-19 vaccine candidate mRNA-1273 on July 27. The vaccine is administered as two 100 mcg immunizations given 28 days apart. Moderna announced the 30,000 patient goal was met on 10/22/2020. On 11/16/2020, interim data was announced based on over 30,000 patients, from an analysis by the independent NIH-appointed, Data Safety Monitoring Committee, after 95 cases of COVID-19 developed in the population. The vaccine achieved 94.5% efficacy in preventing COVID-19, two weeks after the second dose of the vaccine was given. No severe cases of COVID-19 developed in the vaccine group, compared to 11 cases in the placebo group. The study population included 42% over the age of 65 or who were at increased risk for severe COVID-19. The study population also included 37% with diverse backgrounds. If no safety issues are identified after the two-month safety data is available, Moderna will request an emergency use authorization (EUA) and have 20 million vaccine doses available in 2020 and up to 1 billion doses in 2021. Moderna said that based on data from the interim report, the most common adverse events with mRNA-1273 are injection site pain and redness, fatigue, myalgia, arthralgia, headache and general pain. Adverse effects have been mild to moderate. Moderna announced that mRNA-1273 is stable for 30 days at 2 to 8 C and for six-months at -20 C. This will make the vaccine easier to ship and use in pharmacies, clinics and small hospitals.
BioNTech announced that the COVID-19 vaccine it is developing with Pfizer, BNT162b2, can be stored for up to five-days at 2 to 8 C. The shipping container will keep the vaccine viable for up to ten days if stored at 15 to 25 C without opening and up to 15 days if opened and then re-iced with dry ice. The vaccine is stable for up to six months at -70 C.
Johnson and Johnson is initiating a 30,000 patient, Phase III, ENSEMBLE 2 trial (NCT04614948), to evaluate a two doses of JNJ-78436735 given 57 days apart compared to placebo. BARDA is giving J&J an additional $454 million and J&J is providing $604 million, for the ENSEMBLE Phase III program. The Phase III, ENSEMBLE trial (NCT04505722) is evaluating a single dose of JNJ-78436735 in a 60,000 patient trial.
An unpublished report describes interim data from a 248 patient, Phase I dose ranging trial (NCT04449276), where two 12 mcg doses of CureVac’s COVID-19 vaccine, CVnCoV, elicited antibody levels similar to levels seen in a group of recovered COVID-19 patients. In the Phase I trial, healthy patients were randomized to doses of 2, 4, 6, 8 and 12 mcg on days 1 and 29. The 12 mcg dose was chosen for future trials. Most adverse events were mild or moderate. The most common were headache and fatigue, myalgia, chills and fever.
The FDA granted Novavax’s COVID-19 vaccine, NVX-CoV2373, a Fast Track Designation for the prevention of COVID-19.
Once approved Pfizer will ship initial supplies of their vaccine directly to hospitals, clinics, pharmacies and other points of vaccination, rather than distribute it through McKesson. The extreme temperature required for the vaccine caused Pfizer to decide on direct shipments. The vaccine must be kept at -70 to -80 C. Pfizer will ship the vaccine in boxes that can keep the vials at -70 C for 10 days. The dry ice in the shipping container can be refilled with dry ice to keep the vaccine cold for facilities that do not have freezers that can maintain a -70 to -80 C temperature. Healthcare facilities that plan to use the cold-pack shipping containers to store the vaccines should make sure they have a reliable source for replacement dry ice.
Medicago is developing a virus-like particle vaccine (CoVLP). The virus-like particles are created in genetically modified plant cells. Medicago has signed an agreement to provide 76 million doses to Canada.
The Russian National Research Center for Epidemiology and Microbiology claims the Sputnik V vaccine is 92% effective, based on the distribution of 20 cases of COVID-19 among 16,000 volunteers (Note: Pfizer based their 90% effectiveness on 94 cases distributed among 39,000 patients, other vaccine manufacturers are waiting until there are at least 50 cases).
COVID-19 Monoclonal Antibodies
HHS announced plans for distribution of bamlanivimab. Like the earlier program for remdesivir, weekly supplies of bamlanivimab will be distributed to states based on reported COVID-19 cases. Each state health department will determine where and how much bamlanivimab to send to individual health care facilities.
A retrospective review of 280 COVID-19 patients from four Florida hospitals found lower mortality in patients treated with ivermectin compared to patients not treated with the drug (15.0% vs 25.2%). Most patients were receiving hydroxychloroquine, azithromycin, or both.
In a 28-day, 101 patient, Phase II trial (NCT04385095), patients treated with nebulized interferon beta-1a were twice as likely to have improved their WHO Ordinal Scale for Clinical Improvement by day 15-16 and three times as likely by day 28 in hospitalized British patients with COVID-19.
In an 89 patient trial in Oman, favipiravir and nebulized interferon beta-1b did not improve time to recovery, decrease in inflammatory markers nor improvement in oxygenations compared to hydroxychloroquine in hospitalized patients with moderate to severe COVID-19 pneumonia. Almost all patients also received antibiotics, one-third received tocilizumab, two-thirds received a corticosteroid and over half received convalescent plasma.
Pfizer and BioNTech are evaluating BNT162b2 in a Pfizer funded, 44,000 patient, Phase II/III trial (NCT04368728) BNT162b2 will be administered as two 30 mcg immunizations given 21-days apart. The trial was expanded from its original 30,000 patients, in September 2020, to allow the vaccine to be tested in a larger more diverse population, including adolescents as young as 16 years of age and people with HIV, Hepatitis C, and Hepatitis B. Pfizer announced that as of 11/9/2020, 43,538 patients had been enrolled in the Phase III trial with 42% overall having diverse backgrounds. Interim data, from an analysis by the independent Data Monitoring Committee after 94 cases of COVID-19 developed in the population, found the vaccine to be 90% effective in preventing COVID-19. A final analysis of the vaccine’s efficacy is planned when 164 confirmed COVID-19 cases have accrued in the trial population. Pfizer estimates that two months of safety data will be available in the third week of November. If no safety issues are identified, Pfizer and BioNtech will request an emergency use authorization (EUA) and have 50 million vaccine doses available in 2020 and up to 1.3 billion doses in 2021. Pfizer also announced unblinded, interim data in September 2020, suggesting the most common adverse events with BNT162b2 are fatigue, headache, diarrhea, muscle pain, joint pain and chills. Adverse effects have been mild to moderate.
COVID-19 Monoclonal Antibodies
The FDA approved an Emergency Use Authorization (EUA) for bamlanivimab on 11/9/2020 for the treatment of patients, 12 and older with mild or moderate COVID-19, who are at high risk of progressing to a severe infection and who do not require hospitalization. Bamlanivimab is administered as a one-time intravenous dose. The FDA advised against using the drug in hospitalized patients, because a benefit has not been demonstrated.
Bamlanivimab will be distributed through an allocation program through AmerisourceBergen. The U.S. government has purchased 300,000 doses that will be distributed at no charge.
Healthcare providers should review the Fact Sheet for information on the authorized use of bamlanivimab and mandatory requirements of the EUA. Please see the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients, Parents, and Caregivers (English) (Spanish).
Novartis announced interim data from the 29-day, 454 patient, CAN-COVID trial (NCT04362813), where treatment with canakinumab did not decrease mortality without the need for invasive mechanical ventilation, compared with placebo in hospitalized patients with COVID-19 pneumonia and cytokine release syndrome.
Humanigen announced interim data from 257 patients enrolled in a 28-day, 515 patient, Phase III trial, where treatment with lenzilumab reduced time to recovery compared to placebo in hospitalized COVID-19 patients not requiring ventilation. To improve the chance of the patient population experiencing 402 recoveries as recommended by the independent data monitoring board, Humanigen increased the patient population from 300 patients to 515. BARDA is funding consultants to assist in submitting an EUA and BLA for lenzilumab.
Novavax had enrolled 5.500 patients by the end of October 2020 in a Phase III British trial and increased the total number in the trial to 15,000. The company expects to complete enrollment by the end of November 2020. Novavax plans to enroll 30,000 patients in a Phase III, Operation Warp Speed sponsored trial, in the U.S. and Mexico. Due to delays in scaling up vaccine manufacturing, the initiation of the trail is expected to begin at the end of November.
CureVac reported that in a 250 patient, Phase I dose ranging trial (NCT04449276), a 12 mcg dose of its COVID-19 vaccine, CVnCoV, elicited antibody levels similar to levels seen in a group of recovered COVID-19 patients after a second dose of the vaccine. In the Phase I trial, healthy patients were randomized to doses of 2, 4, 6, 8 and 12 mcg on days 1 and 29. The 12 mcg dose was chosen for future trials.
Interim results from 452 patients enrolled in the Phase II, dose-ranging BLAZE-1 trial (NCT04427501), found that on day 11, there was a significant decrease in viral load with bamlanivimab 2,800 mg, but non-significant decreases with 700 mg and 7,000 mg. Among secondary endpoints, COVID-19 symptoms from days 2 through 6 were less severe with bamlanivimab than placebo and hospitalizations on day 29 were also significantly lower (1.6% vs. 6.3%).
The U.S. government will pay Lilly $375 million for 300,000 doses of bamlanivimab for the treatment of mild to moderate COVID-19 in high-risk patients. The doses are to be delivered after an EUA is granted. There is an option to purchase up to 650,000 vials through June 30, 2021, which would correspond to an additional $812 million. Lilly set WAC at $1,250 per vial for bamlanivimab. The number of doses available for bamlanivimab will depend on the approved dose. The current calculation is based on a 700 mg dose, but if a 2,800 mg dose is used, the number of doses will significantly lower.
Regeneron provided an update from the first 799 patients enrolled in a 1,300 patient, adaptative Phase I/II/III trial (NCT04425629), where treatment with REGN-COV2 lowered viral levels through day 7 to a greater extent at increasing viral loads. The monoclonal antibody appeared to be more efficacious in patients that had not produced antibodies and/or had higher viral loads. Treatment with REGN-COV2 reduced COVID-19 related medical visits compared to placebo (2.8% vs 6.5%).
Regeneron held enrollment of hospitalized COVID-19 patients requiring high-flow oxygen or mechanical ventilation on 10/30/2020 at the recommendation of the independent data monitoring committee (IDMC) due to a potential safety signal and an unfavorable risk/benefit profile. The IDMC recommended continuing enrollment of hospitalized patients requiring either no or low-flow oxygen. The Phase I/II trial is evaluating REGN-COV2 in the treatment of COVID-19 in 1,860 hospitalized patients (NCT04426695).