Could the new COVID pill become the next Tamiflu saga?
By Maryanne Demasi, PhD
This week we witnessed breathless media coverage of molnupiravir, a new antiviral drug for the treatment of COVID-19. Science.org, for example, stated it was “unquestionably a game changer!” based on claims made by the manufacturer.
It not only raised hopes that COVID-19 could be treated simply with a course of pills (like it was claimed of Tamiflu for influenza) but it also sent the company’s share price soaring.
Once again, we relied on science by press release.
The buy up
The Australian Government secured the purchase of 300,000 courses of molnupiravir from Merck (co-partner Ridgeback Biotherapeutics), pending the drug’s provisional registration with the Australian Register of Therapeutic Goods (ARTG). Delivery to the National Medical Stockpile may occur in early 2022.
Similarly, the Biden Administration has procured 1.7 million courses pending emergency use authorisation or approval from the FDA. If authorised, molnupiravir will be the first oral antiviral drug for COVID-19 (an oral formulation of remdesivir is in the pipeline).
Merck seized the opportunity, early in the pandemic, to commence testing molnupiravir as a potential COVID-19 treatment. The company already had ivermectin in its stable of drugs, which also has antiviral properties and is approved by the FDA for treating worms.
But when Merck publicly discredited the use of ivermectin for COVID-19, despite some early trials demonstrating its effectiveness, many suggested it was a strategic move by the company to sideline ivermectin (which is cheap & off-patent), to make way for its new, highly profitable drug.
Molnupiravir will cost around US$700 per course and is reported to earn the drug company up to US$7 billion by the end of this year.
Merck has secured various agreements with governments and entered into licensing agreements with multiple Indian companies that manufacture generic drugs. Indian companies are planning to price the drug much cheaper though, ~ $12 for a five-day course, according to reports.
Molnupiravir – which is still investigational - can inhibit the production of RNA viruses like SARS-CoV-2. It is given early in the course of the disease as a pill for a duration of five days.
In the press release, Merck published the “interim analysis” of its Phase 3 MOVe-OUT trial in 775 ‘at-risk’ people. Impressively, the drug halved hospitalisations (7% vs 14% on placebo, p=0.001) in the first 29 days, and no deaths were reported in patients who received molnupiravir, compared to 8 deaths in the placebo group.
Overall, molnupiravir appears to be less effective than ‘monoclonal antibodies,’ which reduce hospitalisation or death by 79% in adults with mild-to-moderate COVID-19 symptoms, but these need to be administered by injection.
At this stage, Merck says its drug is effective against the variants gamma, delta, and mu, but its long-term effectiveness is unknown since, like all antiviral drugs, the ability to target constantly mutating viruses may diminish over time.
There is minimal information publicly available about the harms of molnupiravir.
Merck’s press release says the incidence of molnupiravir-related harms in its Phase 3 interim-analysis was “comparable” between the drug and placebo groups (12% and 11%, respectively).
A recent study published in Nature stated that molnupiravir is “mutagenic”, that is, it increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans.
Mutagenic drugs can cause birth defects or cancer, which is why males in the trial were asked to refrain from donating sperm and agree to abstain from sex or use contraception. Females were not allowed to be pregnant or breastfeeding.
Another study published in the Journal of Infectious Diseases reported that the initial metabolite of molnupiravir caused mutations in animal cell cultures and could pose a risk to the host.
But Merck said there is nothing to worry about. “The totality of the data from these studies indicates that molnupiravir is not mutagenic or genotoxic in in-vivo mammalian systems,” said the company's spokesperson.
Is this déjà vu?
The excitement over new, but unproven COVID-19 therapies, appears to be a reoccurring event.
In May 2020, remdesivir was touted as a “miracle drug” after preliminary data from a placebo-controlled trial involving 1063 patients hospitalised with COVID-19, was published in the New England Journal of Medicine.
The unbridled enthusiasm led governments in many countries to immediately declare that they would make remdesivir available for the treatment of COVID-19 in those requiring hospitalisation.
However, when remdesivir was tested by the WHO (Solidarity trial) involving 405 hospitals in 30 countries, the results, published several months later, showed it had no effect on overall mortality, initiation of ventilation or duration of hospital stay.
In light of the findings, the WHO released a statement recommending against the use of remdesivir, however, many hospital physicians still use the drug to treat COVID-19.
Merck’s missing trial data?
Merck's Phase 3 trial was terminated early. The interim analysis only included data on 775 subjects, even though they had recruited 90% of the total number intended (1850 subjects). The data from the remaining subjects are unpublished.
An independent safety monitoring board, together with the FDA, determined that the interim results were so “compelling” that it was probably unethical to deny treatment to people taking the placebo.
According to Clinicaltrials.gov, Merck had also registered another trial to investigate the effectiveness of molnupiravir in people hospitalised with COVID-19. However, on 9 Sept 2021, leading up to its most recent announcement, the trial was terminated ‘for business reasons’.
A press release by Merck explained that “following an interim analysis of data, it was concluded that the study was unlikely to demonstrate a clinical benefit in hospitalised patients. The decision was made to discontinue the study.”
These data also remain unpublished, including the harms of the drug in hospitalised patients.
Could this become the next Tamiflu saga?
Tamiflu, an antiviral drug touted as a saviour for influenza sufferers, led governments around the world to stockpile the drug in the event of a pandemic, which was worth billions to the manufacturer, Roche.
At the time, knowledge of the drug’s benefits and harms was based on published trials in medical journals. However, there were unpublished trials that had never seen the light of day.
It took the heroic efforts of several researchers, together with a BMJ campaign, to pressure Roche into releasing the underlying clinical trial data for independent scrutiny.
Once all the unpublished data were subjected to independent analysis, it was revealed that Tamiflu could not reduce hospital admissions, secondary complications, or lower respiratory tract infections, as originally claimed by Roche.
In fact, the only benefit the researchers found was that Tamiflu could reduce the time to first alleviation of symptoms by 17 hours – a trivial effect for an expensive drug.
According to the BMJ:
The WHO recommended Tamiflu but had not vetted the underlying data.
The European Medicines Agency approved Tamiflu but had not vetted the underlying data.
The CDC encouraged the use and stockpiling of Tamiflu on the basis of the 6-page manufacturer funded pooled analysis of 10 clinical trials but had not vetted the underlying data.
The majority of Roche's Phase 3 trials were unpublished a decade after completion.
Since then, one of the researchers involved in exposing the scandal, Prof Tom Jefferson, launched legal action against Roche in the US, claiming the company defrauded the federal and state governments by falsely claiming that Tamiflu could be a powerful tool in mitigating a flu pandemic.
The lawsuit sought reimbursement of taxpayer funds in excess of US$4.5 billion for “falsified scientific conclusions” and for mounting “a high-powered marketing and lobbying campaign to deceive the government about the effectiveness of Tamiflu for fighting a flu pandemic.”
Lessons from Tamiflu
Uncovering trials that had been buried by the drug company for over a decade was ultimately successful and it helped galvanise a movement towards increased transparency of clinical trial data and improved access.
Watching the media hype over molnupiravir, Prof Jefferson reflects on what lessons can be learned from the Tamiflu scandal.
“When all data relevant to the benefits and harms of a drug are available, we can start making clinical decisions,” says Prof Jefferson.
“History is littered with very costly ‘wonder-drugs’ which, in the long run, have shown not to be so. The media and those who fuel frenzies in times of crisis should be made accountable for their actions. Let's hope the lessons have been learned," he added.