As 2020 draws to a close, we asked David Alain Wohl, M.D., a professor of medicine in the Division of Infectious Diseases at the University of North Carolina and a highly respected HIV clinician-researcher, to take stock of the year's most momentous research developments and other critical events. In this exclusive series of articles, Wohl calls attention to 10 such developments that have tremendous short-term implications for our day-to-day efforts to improve HIV prevention, treatment, patient care, and policy in the U.S., and analyzes each development with his trademark wit and clinical savvy.
Can someone tell me when it became OK to announce clinical trial results in a press release well before presentation at a scientific meeting or publication in a peer-reviewed journal?
In the time before COVID-19, the drug development industry was masterful at coordinating podium presentations of clinical trial findings alongside their nearly simultaneous publication in major journals—plus, they then watched as the press digested the story at a press conference with the lead investigators.
Now, companies present data in brief communiques and teleconferences with market analysts. Non-industry investigators are also guilty, taking the short cut of pre-print channels, where they can post their papers prior to any peer review.
While an argument can be made that the COVID-19 crisis demands a much more rapid mechanism to disseminate research findings than the traditional, sloth-paced peer review process, these workarounds lead to confusion, dissemination of incomplete results, and charges of a lack of transparency.
Exhibit A: The reveal of a case of transverse myelitis in one participant in AstraZeneca’s SARS-CoV-2 vaccine trial on an investor call. Exhibit B: This same company’s recent release of murky results from its vaccine trial, particularly related to those inadvertently receiving a low dose of their vaccine. These examples are sonly some of the most recent cases to make against this practice.
Which brings us to lenacapavir, a long-acting inhibitor of the formation of the HIV capsid, that in a Phase 2/3 trial has been found effective at lowering the viral load of patients with multi-drug resistant virus—that is, according to a press release from the company developing it.
A press release is written by press release people, not scientists. It is designed to be succinct, and to only highlight top line and top priority information from the company’s perspective.
In this one, we learn of the CAPELLA trial—which, according to the release, randomized 36 people with multi-class HIV drug resistance while on a failing regimen 2:1 to receive oral lenacapavir or a placebo for 14 days. All participants continued their failing regimen after entering the study, to allow for the researchers to determine the effect of lenacapavir on viremia.
According to the release, a statistically significant greater proportion of the 24 participants receiving lenacapavir met the study’s primary endpoint of a 0.5 log10 copies/mL or greater drop in viral load at 14 days from baseline compared with those receiving placebo (88% vs. 17%, P<0.0001). Additionally, the lenacapavir group achieved a statistically significant greater mean change in viral load versus the placebo group (-1.93 log10 copies/mL vs. -0.29 log10 copies/mL, P<0.0001).
The drug was well-tolerated, although the release includes information about injection site reactions—that’s because a subsequent stage of the trial examines every-six-month subcutaneous (SC) injection of lenacapavir (which, yes, is totally awesome).
A more conventional presentation at the virtual 2020 International AIDS Conference in July provided data on the pharmacokinetics of lenacapavir (previously known as GS-6027) and its impressively long half-life, which supported SC administration once every 24 weeks. A single dose of 900 mg of the drug (administered as three 1.0 mL injections) produced levels well above the inhibitory quotient of the virus out to six months. The slow rise in levels achieved after injection with this formulation necessitates an oral lead-in, as was described in the CAPELLA trial.
The Bottom Line on Lenacapavir as an HIV Drug in Development
Despite my kvetching, the data on lenacapavir we have seen thus far pave the way toward a path that can soon lead to an every-six-month, self-administered antiretroviral injection. Such a therapy can be a powerful tool for treating HIV by increasing convenience and reducing stigma.
The very notion of this type of long-acting agent can spark creative thinking about both HIV treatment and prevention. While the CAPELLA trial is looking at treatment experienced patients, ongoing studies are looking at lenacapavir as first-line therapy using an induction-maintenance approach, during which viral suppression is achieved initially with combination therapy and the drug alone is then used to maintain that suppression.
The likely advent of other long-acting agents, such as islatravir, provides other possibilities. Lenacapavir can also play a major role in HIV prevention; trials with the drug as pre-exposure prophylaxis (PrEP) are being planned.
No doubt, there will be future press releases about lenacapavir and other HIV therapies in development, dangling tantalizing data like bait. But before we bite, let’s demand to see full results presented at major conferences and published in reputable, peer-reviewed journals. Let’s refuse to act on press releases alone. Let’s let science lead again.