Gilead announced interim results from 397 patients enrolled in a 6,000 patient, Phase III, SIMPLE trial (NCT04292899). There was no difference in efficacy, measured on a seven-point scale that runs from death to not hospitalized, between a 5-day course of remdesivir and a 10-day course in hospitalized patients with severe COVID-19. The data suggested that earlier treatment was more efficacious than later treatment.
NIAID announced preliminary data from a 29-day, 1,063 patient, Phase III, Adaptive COVID-19 Treatment Trial (ACTT) trial (NCT04280705), where patients treated with remdesivir for up to ten days had a median time of recovery (hospital discharge or returning to normal activity level) of 11 days compared to 15 days with placebo in patients with severe COVID-19. There was a non-significant difference in the mortality rate of 8% with remdesivir compared to 11.6% with placebo. The ACTT trial was closed to enrollment on April 19.
In a 28-day, 237 patient, Phase III, Chinese trial, treatment with remdesivir for ten days was not associated with a clinical benefit compared to placebo (non-significant 20 days vs 23 days) in hospitalized patients with severe COVID-19 infection (NCT04257656). Due to a decrease in patients with COVID-19 infections in China, enrollment was suspended after 237 patients entered the study instead of the target of 450 patients, which reduced the statistical power from 80% to 58%. The researchers noted they “could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters". Confounders in this study included 54% of the patients in the remdesivir group receiving the drug more than 10-days after developing symptoms compared to 40% of placebo patients. Almost 30% of remdesivir patients received interferon and/or lopinavir–ritonavir. While use of lopinavir–ritonavir was similar in both groups, 38% of patients received interferon. The placebo group was 65% male compared to 56% in the remdesivir group. These differences could have been due to the final population not reaching the target total.
The New York Times reported the FDA will likely issue an emergency authorization for remdesivir.
Sanofi and Regeneron announced interim results from a Phase II/III trial, where treatment with sarilumab did not improve clinical outcomes in severe and critical COVID-19 patients. Though not statistically significant, patients requiring oxygen supplementation, but not ventilation (severe infections), had a trend toward a worse outcome with sarilumab, but those requiring ventilation had a trend toward a benefit. Due to the trend of worsening in patients requiring oxygen supplementation, but not ventilation (severe infections), the researchers are discontinuing enrollment of severe COVID-19 patients, but since there was a trend toward a better outcome in patients requiring ventilation (critical infection), patients with critical COVID-19 infections will continue to be enrolled.
The Infectious Diseases Society of America (IDSA) has published guidelines for preventing infection in health care professionals (HCP) caring for suspected or known COVID-19 patients. The guidelines provide eight recommendations on the use of personal protective equipment (PPE) in conventional, contingency and crisis capacity settings.
BioNTech is developing an mRNA vaccine for the COVID-19 virus. While mRNA vaccines can be designed, manufactured and tested faster than typical vaccines, they have not been proven to be efficacious or safe. BioNTech expects to begin clinical testing by the end of April 2020. Forsum Pharma will market BNT162 in China. Pfizer will co-develop and market BNT162 outside of China. BioNTech and Pfizer initiated a 200 patient, Phase I/II trial in Germany in April. The trial is expected to begin enrolling patients in the U.S. in May. Four vaccine candidates are being tested. Three require two doses, while the fourth contains self-amplifying mRNA and requires a single dose. Pfizer expects data from the first trial to be available in May or June with a successful vaccine candidate moving to larger trials and possibly emergency use or accelerated approval in the 4Q20.
The journal Nature provided a graphical description of the different types of methods to create a vaccine that are currently being used to work on a vaccine for COVID-19.
The data currently available for COVID-19 treatments is very preliminary and does not demonstrate or disprove efficacy. Current guidelines (NIH, CDC, WHO, IDSA, SCCM) have not found enough evidence to recommend using or not using any drug for the treatment of COVID-19 regardless of severity. This should be kept in mind as news reports from unreviewed, unedited articles are leaked. These studies may have design flaws, inaccurate or incomplete descriptions of results or missing information. The published trials are small and have not adequately controlled for confounders, so the true effect of the intervention is not clear. Most often the problem involves several drugs that may have antiviral properties included in the supportive care of the patient. Therefore, it is unclear which treatment(s) produced an effect. Another problem is when the drug is not given until 1-2 weeks after the patient develops symptoms, which may be too late to have a full effect. So, review the most recent guideline from a major medical group, optimize supportive care according to their recommendations and consider an investigative treatment as a shared decision with the patient and in the context of a clinical trial.
Preliminary results from the Chinese Phase III COVID-19 trials in patients with severe infections (NCT04257656) were posted on the WHO web site and then taken down. STAT reported on the data and posted a screen shot of the data before it was taken down. The single paragraph reported no benefit with remdesivir. These reports are too preliminary, since at this point, we do not know what other treatments were given to the patients. It should also be noted that patients could receive the drug up to 12 days after developing symptoms, which may be beyond the window for effective use of the drug. At this time, it would be better to wait until the results are published in a reviewed article.
Hydroxychloroquine and Chloroquine
A posted retrospective review of 368 patients hospitalized with confirmed CPVOD-19 at a U.S. Veterans Health Administration medical centers found that hydroxychloroquine alone or with azithromycin did not decrease the need for mechanical ventilation compared to supportive care, and patients treated with hydroxychloroquine alone had higher mortality. However, patients in the study that received hydroxychloroquine alone or with azithromycin were more likely to have more severe disease, so as the authors note it is expected there will be higher mortality in the group that received the drugs. The authors used propensity score to control for characteristics/covariates, but in its current form, the study does not provide enough details to assess their conclusions, so please wait until the final published article is available before using the data in this article for patient care decisions.
The Department of Justice approved AmerisourceBergen to distribute hydroxychloroquine from the U.S. Strategic National Stockpile based on volumes and ship-to destinations identified by the government. Hydroxychloroquine is being provided at no cost to health care providers as part of the COVID-19 emergency efforts lead by FEMA and HHS.
General COVID-19 Research News
The National Institutes of Health (NIH) published guidelines on treating patients with COVID-19. The guidelines do not recommend any pre- or post-exposure pharmacotherapy prophylaxis outside of clinical trials. The guideline panel did not find enough evidence to recommend using or not using any drug for the treatment of COVID-19 regardless of severity.
The Society of Critical Care Medicine has provided Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) as an expansion of their Surviving Sepsis Campaign. The guideline focuses on critically ill patients and provides guidance in four areas with 50 recommendations to recommend for or against an option or if there is insufficient evidence to make a recommendation.
The American Thoracic Society has published COVID‐19: Interim Guidance on Management Pending Empirical Evidence that focuses specifically on drug therapies and ventilation. The guidelines also include the results of voting by the panel on interventions. An intervention required a minimum of 70% of the panel to vote for the intervention for it be included as a recommendation.
Enrollment in NCT04292899 has increased from 2,400 to 6,000 patients with severe COVID-19 infections. Just 2 weeks ago, Gilead had increased the trial size from 400 to 2,400. The trial is still projected to be completed in May 2020 with a primary endpoint of improvement on day 14 as measured on a seven-point scale that runs from death to not hospitalized. Data from the first 400 patients in the 2,400 patient trial was locked on 4/16/2020 and may be announced by the end of April.
The result from the Gilead sponsored trial in patients with mild-to-moderate COVID-19 (NCT04292730) is estimated to be available in May 2020. Results from the NIAID sponsored placebo-controlled trial (NCT04280705) are also expected to be available in May.
An unreviewed, unedited article described an animal trial sponsored by Gilead and NIH, where early treatment with remdesivir reduced pulmonary disease and viral titers in rhesus macaques.
Hydroxychloroquine and Chloroquine
Novartis will compare hydroxychloroquine and hydroxychloroquine plus azithromycin to placebo in 450 hospitalized patients with moderate-to-severe COVID-19 that are not on ventilators.
University of Massachusetts researchers are comparing favipiravir to standard of care in a 50 COVID-19 patient trial and Stanford researchers are evaluating the drug in a 120 patient trial of mixed severity COVID-19.
General COVID-19 Research News
NIH has formed the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership with HHS, FDA, CDC, EMA and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Evotec, GlaxoSmithKline, J&J, KSQ Therapeutics, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda and Vir. ACTIV will coordinate and prioritize trials to optimize vaccine and treatment development for COVID-19 through a steering committee of representatives of members. In mid-April, there were 657 COVID-19 trials with 304 of the trials being listed as active or recruiting. It is hoped that by coordinating trials, research centers will not be overwhelmed, and patient recruitment will be improved. The steering committee will also prioritize research on the most promising candidates.
A researcher at the University of Chicago announced results from 113 patients that had participated in a trial comparing high dose and low dose remdesivir in patients with severe COVID-19 (NCT04292899). Most patients had a reduction of fever and were discharged after six days, suggesting 10 days of therapy is not required. Patients on ventilators were weaned off ventilators after one day of therapy. Data from the first 400 patients in the 2,400 patient trial was locked on 4/16/2020 and expected to be announced before the end of the month.
Chinese researchers were evaluating remdesivir in two placebo controlled Phase III COVID-19 trials in patients with severe infections (NCT04257656) and mild-to-moderate infections (NCT04252664). Recruitment for the trials was slowed due to a requirement that patients had not been treated with another therapy within 30-days before entering the trial and a decrease in available patients. Many patients have already self-treated based on information they found on the Internet. The severe COVID-19 trial was terminated on 3/30/2020; 237 patients were enrolled in the trial and the study was completed on 4/10/2020. The mild-to-moderate infection trial was suspended on 4/10/2020 with 308 patients enrolled. The mild-to-moderate study is estimated to be completed on 4/27/2020. Gilead has stated it is up to the Chinese researchers on when the trial data will be presented or published.
The result from the Gilead sponsored trial in patients with severe COVID-19 infections are estimated to be available in late April, while results from the mild-to-moderate trial is estimated to be available in May 2020. Results from the NAID sponsored trial are also expected to be available in May.
Hydroxychloroquine and Chloroquine
FEMA shipped 19 million hydroxychloroquine tablets in early April 2020 from the Federal stockpile. This would be enough to treat 1.3 to 1.6 million patients.
An unreviewed, unedited article provided a retrospective review of 181 French patients hospitalized with hypoxemic pneumonia due to COVID-19; the addition of hydroxychloroquine to standard of care treatment did not reduce ICU admission or death by day seven after hospital admission compared to standard of care. Patients were excluded if they had received an antiviral during their hospitalization.
In an unreviewed, unedited report of a 150 patient, Chinese trial, the addition of hydroxychloroquine to standard of care treatment did not result in a higher negative conversion rate compared to standard of care in patients hospitalized with COVID-19. Standard of care included antivirals in an unspecified number of patients. The authors stated the negative conversion was not improved when excluding patients that received an antiviral, but they did not specify the number of patients with or without another antiviral. Hydroxychloroquine did alleviate more symptoms when only patients that did not receive an antiviral were considered.
In an unreviewed, unedited abstract, French researchers provided data on 1,061 patients not previously included in their initial reports of outcomes with 80 patients. There was no randomization or comparative group. Patients were treated with hydroxychloroquine and azithromycin for at least 3-days and followed for at least 9-days. The clinicians report a good clinical outcome and virological cure in 91.7% of patients.
Brazilian researchers (NCT04323527) are evaluating two dosages of chloroquine plus azithromycin in 440 hospitalized patients with COVID-19 in a Phase IIb trial that began in March 2020. After an analysis of the first 81 patients (unreviewed, unedited report) revealed an increase in mortality in the high dose population due to QTc prolongation, recruitment for the higher dose was halted. Most patients in the trial (89.6%) were also receiving oseltamivir for suspected influenza. Both azithromycin and oseltamivir can also increase the QTc interval.
Prescribe Right COVID-19 Drug Tracker
We have added galidesivir to the tracker. Galidesivir is being evaluated by BioCryst (NCT03891420) in the treatment of COVID-19 or Yellow Fever in a 66 patient, Phase I, placebo-controlled, Brazilian trial that began in April 2020 and is expected to be completed at the end of May 2020.
Our COVID-19 Drug Tracker is now monitoring 30 drugs and adding more each week. The drugs we track include:
But we are also staying atop developments with non-COVID-19 investigational drugs. We currently track 841 drugs, supported by 1,342 PubMed citations. This week we added vutrisiran, an RNAi Therapy for the treatment of TTR amyloidosis, and tozuleristide, a tumor-targeting optical imaging agent for use in fluorescence-guided surgery for pediatric central nervous system tumors. We’re making sure our subscribers can stay up to date with investigational drug therapies. See our subscription page for our latest offers.
A case study described a mechanically ventilated 40-year-old patient with severe COVID-19 that was treated with delayed initiation of remdesivir. Because remedesivir was not readily available, the patient was initiated on hydroxychloroquine. After five days, hydroxychloroquine was discontinued due to an increase in ALT and AST. Remdesivir was obtained through a compassionate use program and started on day 13 (it took 9-days to obtain the drug supply). The patient improved and was extubated on the third day of remdesivir treatment.
The Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network of NIH is evaluating hydroxychloroquine compared to standard of care in a Phase III, ORCHID trial involving 500 adult, hospitalized patients with COVID-19. The study began in April 2020.
Johns Hopkins, Stanford, Columbia, Mayo Clinic, Washington University and others have published a review of the evidence for the use of convalescent plasma to treat COVID-19 and step-by-step instructions for how to collect, process, store and administer transfusions.
General Treatment Guidelines
JAMA published a review of drugs to treat COVID-19. The review is current as of articles published March 25, 2020. The authors found that most evidence was from case studies and case series. They warn of confounding and selection bias along with shifting demographics of patients, testing, and treatment approaches.
AHA, ACC and HRS published Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 19) Treatment to provide guidance on the arrythmia potential of hydroxychloroquine, chloroquine, azithromycin and lopinavir/ritonivir in the treatment of COVID-19. The review includes a table rating potential adverse cardiac events of the medications.
Sanofi and GlaxoSmithKline have agreed to work together to develop a vaccine for COVID-19. The companies will use Sanofi’s S-protein COVID-19 antigen based on the company’s recombinant DNA tech in combination with GSK’s pandemic adjuvant technology. The recombinant DNA platform is the same one used to create the quadrivalent influenza vaccine FluBlok. GSK’s vaccine adjuvant reduces the amount of antigen required for a dose enabling a quicker way to scale up production. Both companies have the capacity to manufacture vaccines on a global scale. The companies forecast clinical trials beginning in the second half of 2020 and a BLA filed in the second half of 2021.
Data from 53 patients hospitalized for severe COVID-19 pneumonia and treated with remdesivir through a compassionate use program demonstrated clinical improvement in 68% of patients 18 days after treatment initiation, with 47% discharged and 7% died. At 28 days there was clinical improvement or discharge from the hospital in 84% of patients. Adverse reactions were reported in 60% of patients with the most common being increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension.
The FDA has provided guidance to health care providers and investigators on the administration and study of convalescent plasma collected from individuals who have recovered from COVID-19.
General Treatment Guidelines
The Infectious Diseases Society of America (IDSA) has published treatment guidelines for COVID-19. The guideline reviews data for hydroxychloroquine/chloroquine with and without azithromycin, lopinavir/ritonavir, corticosteroids, tocilizumab, and convalescent plasma. The writing panel rated available data to provide a low level of certainty on use as treatments, and recommended that use should be done in the context of a clinical trial. When clinical trials are not feasible, IDSA recommends that registries be established to help in the evaluation of the efficacy and safety of the drugs.
Prescribe Right COVID-19 Drug Tracker
We have added 3 drugs to the tracker:
Gilead is expanding the size of two remdesivir trials.
An alliance of plasma-derived drug manufacturers that include Takeda, CSL Behring, Biotest, Bio Products Laboratory, Octapharma and LFB have banded together to develop and manufacture a non-branded hyperimmune immunoglobulin. The group formed in order to speed development. The product will be an anti-COVID-19 polyclonal hyperimmune globulin (HIG). Because HIGs have been shown to be effective in the treatment of severe acute viral respiratory infections they are being tested as a treatment option for COVID-19. HIGs require plasma from patients that have recovered from COVID-19 or have been vaccinated (when a vaccine is available) to harvest COVID-19 antibodies that could potentially reduce illness severity or possibly prevent it.
In a ten patient Chinese case series, one 200 ml infusion of convalescent plasma infused 16.5 days after hospital admission improved or resolved symptoms within three days. All patients had severe pneumonia and confirmed to have a COVID-19 infection. All patients received antivirals and eight out of ten were receiving antibiotics and six out of ten were receiving methylprednisolone.
Massachusetts General Hospital researchers are comparing favipiravir to standard of care in a 60 COVID-19 patient trial.
Inovio began clinical testing of INO-4800 in a 28-week, 40 volunteer, Phase I trial (NCT04336410) in April 2020. Healthy volunteers will receive two doses of the COVID-19 vaccine 4 weeks apart. Inovio anticipates having initial data available from the trial in late summer 2020.
Novavax is developing a COVID-19 vaccine based on recombinant protein nanoparticle technology to generate coronavirus spike (S) protein antigens. The company is using its saponin-based Matrix-M adjuvant to enhance immune responses. Novavax plans to initiate a 130 patient, Phase I trial for NVX-CoV2373 in mid-May 2020, with initial results expected in July 2020.
Gilead implemented an expanded access program for remdesivir in late March for severe COVID-19 patients, over 18, requiring ventilation through NCT04323761. Contact: Gilead Clinical Study Information Center, 1-833-445-3230, GileadClinicalTrials@gilead.com
Remdesivir has been used to treat 1,700 patients through expanded access, compassionate use and clinical trials. Gilead has 1.5 million doses of remdesivir available and will donate the supply for to treat patients at no cost through expanded access, compassionate use and clinical trials. It is estimated the supply would be enough to treat 140,000 patients. Gilead is ramping up manufacturing and plans to have a drug supply large enough to treat 500,00 patients by the end of October and 1,000,000 by the end of 2020 with larger amounts available in 2021 if needed.
The European Medical Agency (EMA) released recommendations on use of remdesivir through compassionate use programs in Europe. The recommendations include a summary of dosing, administration, monitoring and management of patients receiving remdesivir.
Chloroquine and Hydroxychloroquine
In a 62 patient, Chinese trial, the addition of hydroxychloroquine to oxygen therapy, unspecified antiviral and antibacterial agents and immunoglobulin with or without corticosteroids reduced the time to remission, resolved cough, normalized temperature and improved pneumonia compared to placebo in patients hospitalized with COVID-19. (Note: the posted article is on an editorial server and has not been peer reviewed)
The EMA restricted use of chloroquine and hydroxychloroquine to already approved indications to treat malaria and autoimmune diseases, but the drugs can be used by COVID-19 patients through nationally established protocols or through clinical trials.
Chloroquine and hydroxychloroquine are in short supply. The FDA declared a shortage of both drugs in in late March 2020. ASHP has issued recommendations for stewardship of these drugs.
Three Chinese trial are evaluating favipiravir in the treatment of COVID-19.
Moderna estimates it will be able to initiate a Phase II trial for the mRNA-1273 vaccine in late spring or early summer.
Stay informed, subscribe to the Prescribe Right Pharmaceutical Pipeline Tracker