This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.
Experts in infectious diseases and investors on Wall Street are honing in on two potential treatments for COVID-19: interleukin inhibitors and remdesivir.
On April 21, NIH published treatment guidelines for COVID-19. The guidelines, which were developed by a panel with representatives from federal agencies, health care and academic organizations, and professional societies, include a review of experimental antivirals, host modifiers, and immunotherapies.
No drug has been proven safe and effective for treating COVID-19, and the panel notes that clinical trial data are insufficient to recommend either for or against any investigational treatment currently available.
The new guidelines include dismissive critiques of some investigational treatments, but remdesivir and two interleukin inhibitors have been spared—at least for now. These agents are in phase III trials.
The guidelines include strong recommendations against using the following therapies in any setting other than clinical trials:
The combination of hydroxychloroquine plus azithromycin, because of the potential for toxicities,
Lopinavir/ritonavir or other HIV protease inhibitors, because of unfavorable pharmacodynamics and negative clinical trial data,
Interferons, because of lack of efficacy in treatment of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and toxicity, and
Janus kinase inhibitors (e.g. baricitinib), because of their broad immunosuppressive effect.
“The NIH’s recommendation is standard from anybody who is in the establishment and understands clinical research,” Don Berry, a professor in the Department of Biostatistics and founding chair of that department at MD Anderson Cancer Center, said to The Cancer Letter. “And the business with HCQ is just horrible. It probably is ineffective, and worse, with cardiovascular issues. It’s a horror, and it’s based on a rumor and innuendo.
“I hate seeing medicine and science politicized. Politicians seem uniquely ignorant of both,” Berry said. “The good politicians are the ones who know they’re ignorant.”
A conversation with Berry appears here.
Therapeutic options that didn’t receive a negative recommendation from the NIH panel are:
Remdesivir, an antiviral drug sponsored by Gilead Sciences,
Interleukin-6 and interleukin-1 inhibitors, agents that are used to regulate pro-inflammatory cytokines,
Convalescent plasma or hyperimmune immunoglobulin, and
Chloroquine or hydroxychloroquine, as single agents.
“Yes, I would agree with [NIH’s evaluation of remdesivir],” said Berry, who is also senior statistical scientist and founder of Berry Consultants, a company that is playing a key role in providing statistical guidance for multiple COVID-19 trials. “I have a probability distribution on the benefits of remdesivir. Thirty-five percent of my probability is on the positive side. But of course, reflecting my uncertainty, as soon as I see some randomized controlled results, this may change dramatically.”
On April 24, FDA issued a safety communication cautioning against the use of hydroxychloroquine or chloroqine for COVID-19 outside the hospital setting or a clinical trial.
“Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT interval prolongation and a dangerously rapid heart rate called ventricular tachycardia,” FDA officials said in the advisory. “These risks may increase when these medicines are combined with other medicines known to prolong the QT interval, including the antibiotic azithromycin, which is also being used in some COVID-19 patients without FDA approval for this condition.
“Patients who also have other health issues such as heart and kidney disease are likely to be at increased risk of these heart problems when receiving these medicines.”
COVID-19 investigators are also in the process of initiating studies focused on other types of antivirals, as well as host-modifying agents that have broad immunosuppressive effects. The NIH guidelines are expected to be continually updated as published data and other authoritative information become available.
Multiple trials for the interleukin inhibitors, especially for IL-6, are underway.
At least three drugs, tocilizumab, sarilumab, and siltuximab, are being assessed in late-stage trials for treatment of acute respiratory distress syndrome (ARDS) caused by immune response to SARS-CoV-2 infection (The Cancer Letter, March 27, 2020).
NCI is finalizing plans to use its clinical trials networks to administer a compassionate use protocol for distribution of tocilizumab to cancer patients (The Cancer Letter, April 10, 2020).
What’s up with remdesivir?
Remdesivir, an investigational nucleotide analog that inhibits RNA-dependent RNA polymerase, is not approved anywhere globally for any use.
The drug, which was found to disrupt replication of RNA viruses, including coronaviruses, was previously tested as an antiviral therapy for the Ebola virus. After encouraging early-stage studies, it underperformed in comparison to several monoclonal antibodies in a multi-arm randomized trial reported in 2019.
Studies and news reports about remdesivir in COVID-19 are closely watched by public health and financial communities.
On April 10, a study published in The New England Journal of Medicine concluded that clinical improvement was observed in 36 of 53 patients (68%) who received remdesivir on a compassionate-use basis. The study was not designed to assess efficacy, which is measured in randomized, placebo-controlled trials.
As data accumulate, Gilead is scaling up production of the drug, with a target of more than 1 million treatment courses by December and, if needed, several million treatment courses in 2021.
While remdesivir is available through several expanded access protocols, phase III randomized trials evaluating the safety and efficacy of the antiviral for treatment of COVID-19 include:
Adaptive COVID-19 Treatment Trial (ACTT), sponsored by the National Institute of Allergy and Infectious Diseases, and
“We expect to share results at the end of this month from our open-label study of remdesivir in patients with severe COVID-19 disease,” Merdad Parsey, Gilead’s chief medical officer, said in a statement April 23. “This randomized clinical trial is fully enrolled and will compare treatment outcomes and safety following five or 10 days of remdesivir treatment.
“We expect data at the end of May from our open-label study in patients with moderate disease that is studying five or 10 days of remdesivir versus standard of care,” Parsey said. “We also anticipate data at the end of May from NIAID’s double-blind, placebo-controlled study of remdesivir in patients across a range of disease severity.”
Two phase III trials of remdesivir in China, sponsored by the Capital Medical University in Beijing—also delineated by moderate or severe COVID-19—have been stopped April 15, citing inability to accrue patients as rationale for terminating or suspending the trials.
On April 23, the results from the China clinical trial for severe COVID-19 were posted, prematurely, on WHO’s website:
“237 patients with laboratory-confirmed COVID-19 underwent randomization (158 remdesivir; 79 control); one patient in the control group withdrew before receiving any study treatment. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1.23, 95% CI 0.87-1.75), mortality at 28 days (13.9% vs. 12.8%, difference 1.1; 95% CI, -8.1, 10.3), or in time to SARS-CoV-2 PCR. :
“In this study of hospitalized adult patients with severe COVID-19 that was terminated prematurely, remdesivir was not associated with clinical or virological benefits. negativity. [sic] Adverse events were reported in 65.2% of remdesvir recipients versus 64.1% in placebo recipients. Remdesivir was stopped early in 19 )11.6%) patients because of adverse effects, compared to 4 (5.1%) in the control group.”
The assessment, which lists the outcome of the trial as “NEGATIVE,” has since been removed from WHO’s website. The apparent slipup, reported by STAT, immediately led to a plunge in share prices for Gilead on April 23.
Gilead officials disputed the assessment of the trial’s results, which were provided to WHO in a draft document by study authors.
“The results of this trial in China, along with those of the compassionate use cohort of more critically ill patients published on April 10, add to a growing but still inconclusive body of evidence for remdesivir,” Merdad Parsey, Gilead’s chief medical officer, said in a statement April 23. “We believe the [WHO] post included inappropriate characterizations of the study.
“The study was terminated early due to low enrollment and, as a result, it was underpowered to enable statistically meaningful conclusions,” Parsey said. “As such, the study results are inconclusive, though trends in the data suggest a potential benefit for remdesivir, particularly among patients treated early in disease.”
The company’s stock price had spiked on April 16 as a result of coverage by STAT, which published preliminary data from the two Gilead-sponsored trials that were accruing at the University of Chicago. In an internal video discussion among UChicago investigators, a researcher characterized early data as encouraging, based on information from her site.
Although “only” two patients died in the UChicago cohort, one of the phase III Gilead trials—for severe COVID-19—does not randomize patients to a control arm, with only placebo or standard of care treatment.
The STAT story quoted a grateful patient, who declared that “remdesivir was a miracle.”
“I’m tied to the conventional wisdom in this regard, because of examples like this. The stuff that we heard about remdesivir from University of Chicago is whim and innuendo and anecdotes,” MD Anderson’s Berry said. “That, of course, was a travesty—as a measure of impact, Gilead’s stock price increased 14% at one point on the basis of this story that came out of the STAT publication.
“To announce trial results prematurely can have grave consequences, including affecting the trial’s integrity. In the case of remdesivir, leaking some of the results was inappropriate,” Berry said. “The investigators are being, and should be, criticized for announcing their narrow experiences in the trial.”
NIAID’s Adaptive COVID-19 Treatment Trial
With 1,063 patients, NIAID’s multicenter ACTT closed to enrollment on April 19. All patients accrued on the trial were randomized to remdesivir vs. placebo (The Cancer Letter, April 17, 2020).
According to ClinicalTrials.gov, the study is conducted in up to approximately 100 sites globally.
“The patients are being randomized approximately 1:1. Randomization is stratified by site and the severity of clinical illness,” NIAID officials said to The Cancer Letter. “Randomization is also done in blocks of participants, so there is not a predictable pattern to the randomization.
“NIAID will share results when they are available, and will also provide an update on plans for the ACTT moving forward.”
The pathogenesis and disease course of COVID-19 in symptomatic patients means that it’s possible to get results rapidly, Berry said.
“The patient’s experience in COVID-19 is not like cancer. It’s over with quickly, one way or the other,” Berry said. “The primary endpoint may be evaluated at 21 days (or sooner in the case of death). So, provided accrual is fast, there’s no reason the trial results can’t be announced in a matter of a few months.”
The primary outcome measure for the NIAID trial is “time to recovery” within 29 days. Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale:
Hospitalized, not requiring supplemental oxygen i.e. no longer requires ongoing medical care;
Not hospitalized, limitation on activities and/or requiring home oxygen; or
Not hospitalized, no limitations on activities.
The Gilead trials use a seven-point ordinal scale to assess primary outcomes, beginning with death. The Norwegian version of WHO’s SOLIDARITY is designed to primarily assess all-cause in-hospital mortality within three weeks, followed by seven secondary outcome measures.
“My own attitude is to focus on death. It’s the easiest endpoint to address and it’s the easiest to understand,” Berry said. “Mortality is not the only possible benefit of a therapy, of course. Generally speaking, most therapies that move patients away from mortality also have a beneficial effect on patients not destined to die. So, you’d look for some sort of movement on that ordinal scale, not just death.
“But especially in view of the high case-fatality rate for COVID-19, death would be quite a reasonable primary endpoint, with an ordinal scale being supportive.”
Like the WHO trial, the ACTT uses adaptive design, which enables investigators to add arms to the trial. While the current version of the ACTT has enrolled patients only for remdesivir vs. placebo, other investigational therapeutic agents may be added if the trial resumes enrollment and interim analyses are conducted.
“All participants in ACTT were given standard of care, and if the standard of care at an institution included other medications, these were allowed in ACTT,” NIAID officials said. “A randomized, placebo-controlled trial is the gold standard for determining if an experimental treatment can benefit patients.
“We can make the protocol available after the trial is complete. Since the protocol may contain proprietary information, there is a process to ensure the protocol is suitable for public dissemination.”
It is typical in many diseases to randomize experimental treatments against the standard of care, Berry said.
“On the other hand, it would be unethical to deprive a patient from receiving a therapy that is known (or widely regarded) to be effective,” Berry said.
The adaptive design of the ACTT allows for early termination of any arm on the basis of futility, efficacy, or safety. On the flip side, if one therapy proves to be efficacious, then the treatment may become the control arm for comparison with new experimental treatments.
“As therapies begin to show that they are better than other therapies, then they are assigned with higher probability to subsequent patients,” Berry said. “This obviously benefits patients in the trial. But it also moves better-performing therapies through the trial faster, graduating them from the trial to general use.
“For me, there is no alternative. Non-adaptive trials are destined for oblivion.”