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The press release from Pfizer states that their novel COVID-19 oral antiviral candidate PAXLOVID™ reduced the risk of hospitalisation or death by 89% compared to placebo in non-hospitalized adult patients with COVID-19 who are at high risk of progressing to severe illness
Prof Penny Ward, Independent Pharmaceutical Physician, Visiting Professor in Pharmaceutical Medicine at King’s College London, said:
“Good news is coming in twos this week with today’s results (announced by press release) of an 89% reduction in rate of hospitalisations and deaths from an interim analysis of the ongoing PIII trial with PF-07321332 plus ritonivir combination which has now been christened with its tradename, Paxlovid.
“Of interest is the focus on the primary analysis from patients starting treatment within the first 3 days of onset of illness. In the trial as a whole efficacy was slightly (but not hugely) lower and, if my math is correct, for patients starting treatment on days 4/5 post symptom onset, overall efficacy in preventing hospitalisation/death was about 84% (reduced from ~8.8% in placebo recipients to ~1.4% in patients given the antiviral therapy) which is still a benefit worth having but reinforces the general principle that earlier rather than later treatment is more beneficial when treating respiratory viral disease.
“The overall rate of hospitalisations/deaths reported in the placebo group in this study is notably lower (6.7%) than reported for the molnupiravir study (14.3%). This may reflect differences in the populations recruited into these two trials. Because ritonavir is a highly potent inhibitor of CYP 3A4, high risk patients taking other medicines metabolised by this enzyme were excluded from the trial. This could have included a substantive number of older patients with heart disease/hyperlipedemia/diabetes who are at higher risk of serious complicated disease than younger patients eligible because of obesity.
“To be able to fully interpret both this and the molnupiravir trial we need to see the detailed study data so that clinicians can interpret the benefit risk of each product for individual patients.
“We also need to see data on potential for emergent resistant viruses in treated patients. A priori resistance may be less likely to follow use of molnupiravir, based on its mechanism of action, but we know little about the resistance potential of PF-07321332 and this is an important consideration for use in immunecompromised patients where risk of emergent resistant virus is likely to be greater.
“Lastly, we are told nothing about the adverse effect profile of this combination is in the treated patient population. This is another important consideration for future prescribers likely to be faced with a choice of options for their patients.
“I look forward to seeing the detailed data as soon as possible.”
Dr Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said:
“The news that Pfizer’s SARS-CoV2 3Cl protease inhibitor drug, Paxlovid, is having such profound success during preliminary analysis is welcome indeed. Hospitalisations were significantly reduced (almost 90%) and deaths were absent from the large >1000+ cohort, even though therapy was only started up to three or five days after a positive test. Adverse effects and treatment discontinuations were similar or lower in the treatment compared to placebo patients, and side effects were generally mild.
“Combined with the recent announcement that Molnupiravir (Merck) also shows promise in the early treatment of SARS-CoV2, these newly developed antiviral drugs mark an important addition to our arsenal. They both demonstrate that, with appropriate investment, the development of bespoke direct-acting antiviral drugs targeting SARS-CoV2 was eminently feasible and has ultimately proven far more successful than repurposing other drugs with questionable antiviral effects.
“However, much like vaccines, there is a need to protect these vital therapies such that their benefits can endure for the longer term. It would be fantastic to see data on how the virus declines in the bodies of treated patients, as well as sequences for those in which the decline is slower or absent, with a view to identifying the potential for future drug resistance. Ideally, we would start to use these drugs as combination therapies to mitigate against such an eventuality, plus their use ought to retain clinical oversight rather than being left to self-administration.
“Regardless, the success of these antivirals potentially marks a new era in our ability to prevent the severe consequences of SARS-CoV2 infection, and is also a vital element for the care of clinically vulnerable people who may be unable to either receive or respond to vaccines.”
Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“As with previous such reports, comments must be caveated on the basis that we are seeing a press release, not a formal scientific presentation on the trial’s findings.
“I have commented previously on another antiviral drug, molnupiravir1.
“Very similar comments apply to ritonavir.
“As I explained previously, antivirals are of little or no use once serious starts: this phase of illness is due to an immune system over-reaction, triggered by the virus, but by the time the problems kick in the virus has almost invariably been eliminated.
“We know with other antivirals – such as oseltamivir for influenza – that virals are most effective if given very early on. Within 48 hours of symptom onset; preferably before. Indeed, oseltamivir is probably most valuable when given prophylactically (as a preventive treatment), e.g. in care homes with vulnerable residents. In that context it is given before exposure or symptom onset; and it has the added benefit that people who become infected while on antiviral chemoprophylaxis secrete less virus, and do so for a shorter time, so they are less likely to transmit the disease to others. (“Chemoprophylaxis” refers to the use of antimicrobial agents such as antibiotics and antivirals to prevent infection and/or illness.)
“The press releases for molnupiravir and ritonavir are all we have to go on at present – no doubt the regulators will have seen far more detailed data. According to the Pfizer press release, the inclusion criteria required ritonavir to have been started within 3 days of symptom onset; whereas the Merck press release say inclusion criteria required molnupiravir to have been started within 5 days of symptom onset.
“If these drugs behave like oseltamivir, then efficacy will fall off quickly if the interval between symptom onset and starting treatment exceeds 48 hours.
“The press releases do not contain sufficient information to know if that is the case; or even, since different inclusion criteria were used, to compare the two antivirals. If my informed speculation is correct, patients in whom molnupiravir was started after a greater interval than three days would not have benefited. Such patients would not have been included in the ritonavir trial.
“Either way, I can see a lot of practical problems in using such drugs. It is logistically difficult to give a treatment within three days of symptom onset. After all:
“If these treatments are to be used successfully – and we can assume that requires them to be initiated very early – we will require systems for identifying patients who might benefit extremely early, and for getting the treatments to them very quickly indeed.
“This will inevitably mean giving the drugs before you’ve confirmed the diagnosis, to many people, some of whom will have Covid-19, but would never have become seriously ill; and some of whom will not have had Covid-19 at all. This will mean giving out a lot of the drugs, so the costs (both financial and in terms of adverse reactions) will be very high.
“I note that both press releases suggest that the drugs should be used for high risk patients. Many patients who become seriously ill do not have known risk factors; the key one is age. Which suggests that the drugs might best be used in a way that is very similar to the way we use oseltamivir in care homes – giving them to people who are at high risk by virtue of their age and the relatively high probability of transmission in the care home, after a case is identified, and before most of them develop symptoms.
“There may be some other contexts – like some hospital wards – where a similar approach would work. Outside this sort of context, I doubt that these drugs use, in time to be of benefit, will be practicable.”
1 English PMB. Getting molnupiravir to patients in a timely way is likely to be problematic. BMJ 2021;375:n2648. (https://www.bmj.com/content/375/bmj.n2648.full).
All our previous output on this subject can be seen at this weblink:
www.sciencemediacentre.org/tag/covid-19
Declared interests
Prof Penny Ward: “I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”
Dr Stephen Griffin: “My laboratory is undertaking research into SARS-CoV2 antivirals, and is very much at the preclinical stage of development. The work is funded by locally administered research council translational grants (EPSRC EIAA, MRC CiC) and we receive no support from industry. Our target of interest is unrelated to those involved with the recently announced Pfizer or Merck antivirals.”
Dr Peter English: “Dr English is on the editorial board of Vaccines Today: an unpaid, voluntary, position. While he is also a member of the BMA’s Public Health Medicine Committee, this comment is made in a personal capacity. Dr English sometimes receives honoraria for acting as a consultant to various vaccine manufacturers, most recently to Seqirus.”