Encouraging results for RDV in compassionate use
On April 10, the NEJM published Compassionate Use of Remdesivir for Patients with Severe Covid-19 by Grein et al. (I believe there is no firewall). The abstract's conclusions read as follows:
In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.)
Context for the above numbers is relevant for the STAT article, and especially for the ongoing severe COVID trial which has no placebo group. Grein et al. summarize prior data in their wrap-up (discussion) section. Relevant points include the following (emphasis added by me):
In a recent randomized, controlled trial of lopinavir–ritonavir in patients hospitalized for Covid-19, the 28-day mortality was 22%.10 It is important to note that only 1 of 199 patients in that trial were receiving invasive ventilation at baseline.
...among 201 patients hospitalized in Wuhan, China, mortality was 22% overall and 66% (44 of 67) among patients receiving invasive mechanical ventilation.
The authors thus had favorable thoughts about RDV, saying:
... the 13% mortality observed in this remdesivir compassionate-use cohort is noteworthy...
No new safety signals were detected during short-term remdesivir therapy in this compassionate-use cohort.
... comparisons with contemporaneous cohorts from the literature, in whom general care is expected to be consistent with that of our cohort, suggest that remdesivir may have clinical benefit in patients with severe Covid-19.
That's about as much as an author would want to conclude, or be allowed by NEJM's editors, about a retrospective study of a drug in compassionate use settings. That said, the data were indeed encouraging to me, but even if valid, not clearly a game-changer for society's strategy against COVID or for GILD's stock.
Because of the length of the article, and the various additional hedging and explanatory comments, the above excerpts are incomplete. Please consider reviewing the actual article to get a fuller story than could be presented here.
Now to a brief set of quotes and comments on the STAT article.
Chicago data impressive; can it be so?
I am writing this on Saturday, nearly 24 hours after the story ran. So far, I have not seen the basic authenticity of the article being challenged. So I trust that, for example, when the head of the UCM arm of this multi-center trial, Dr. Mullane, is quoted by the article as having "confirmed the authenticity of the footage," that this is correct.
According to the audio-video recording of a conference within UCM last week, very encouraging data was presented. From the article, quotes from the video conference, apparently all from Dr. Mullane, included several points, among them the following, each with a brief comment from me:
We’ve only had two patients perish...
My comment: Amazing given 113 severe patients; better than expected given the compassionate use data.
Next quote:
... when patients do come in with high fevers, they do [reduce] quite quickly. We have seen people come off ventilators a day after starting therapy.
My comment: Impressive; consistent with a fast-acting "magic bullet." Note, this appears to prove that any commentary floating around the internet that none of these patients were on ventilators is incorrect.
The final quote to present:
Most of our patients are severe and most of them are leaving at six days, so that tells us duration of therapy doesn’t have to be 10 days. We have very few that went out to 10 days, maybe three...
My comment: The idea that severely ill COVID patients, some on mechanical ventilation, got better in several days is very surprising.
What to make of all this, first medically, then for GILD stock, and then for the big picture?
The stars could be lining up just right for RDV, GILD... and thus all of us
Sometimes a series of good things happen, and begin to look inexorable. This just might, and I emphasize might, be happening with RDV. For example, the NIH had this media release on Friday (my emphasis):
Antiviral remdesivir prevents disease progression in monkeys with COVID-19
Study supports clinical testing under way across U.S.
... The investigators note that the data supports initiating remdesivir treatment in COVID-19 patients as early as possible to achieve maximum treatment effect. The authors, from NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, also note that while remdesivir helped prevent pneumonia, it did not reduce virus shedding by the animals. “This finding is of great significance for patient management, where a clinical improvement should not be interpreted as a lack of infectiousness,” they write.
The article on which the above reports is Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Its conclusion was cogent:
Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.
I did not expect to see the NIAID, which is headed by Dr. Fauci, segue from monkey data to clinical treatment of COVID in people with RDV. My optimistic interpretation of the STAT article was therefore enhanced when I saw the above comments.
Also helpful is that in February, researchers elucidated the mechanism by which RDV works to block replication of viral RNA in the coronavirus that causes MERS. The link to the abstract may interest some readers.
Interim conclusion
My observation is that the news out of UCM does not exist in a vacuum. Rather, there is now a proposed molecular mechanism of action of RDV, an animal model which NIAID interprets favorably, and encouraging data from compassionate use. The Chicago data, assuming it is valid, strikes me as unexpectedly strong. From a medical standpoint, of course, more data is needed, both from UCM and from all other sites. A further straw in the wind may be that apparently the UCM data was locked Thursday (and that of other sites?), and by Friday, it appears to me that GILD increased the size of the study in severely ill patients to 6,000 from 2,400. I cannot see GILD doing this if the drug did not work and work well.
Thus, my working hypothesis is that RDV will be the first drug approved for severe COVID.
While there is little data around in moderately severe COVID, i.e., the placebo-controlled smaller study of RDV, my understanding of treatment of infectious diseases in general and viral infections in specific is that if a drug works for advanced cases, it will work for less advanced or severe cases.
In putting together a matrix of probabilities of what will happen - and only one thing will happen with RDV - I have shifted the curve to the bullish side of the playing field.
In the next sections, I will briefly speculate on a new fair value for GILD, then make some comments on the general market environment if RDV actually does get marketed for RDV with strong clinical data backing up the approval.