A Novel Attachment Inhibitor for Individuals who Are Treatment-Experienced Expands Options
by Jay Vithalani
One of the few silver linings of the COVID-19 pandemic is that more people now know how clinical trials work, from preclinical discovery research in the laboratory, to Phase 3 trials involving tens of thousands of people, followed by review by the Food and Drug Administration. The vaccines currently authorized for preventing moderate to serious COVID-19 disease (and possibly for preventing viral transmission as well) were developed in an unprecedentedly short time, just under a year. (They’ve been given what’s known as Emergency Use Approval, or EUA, because of the severity of this global crisis. I cannot emphasize enough, though, that no “corners were cut,” safety and efficacy were thoroughly evaluated.)
But developing a vaccine or new drug usually takes much longer. For example, ibuprofen (the most common brand name is Advil) and fluoxetine (Prozac) took decades to reach the market after discovery and patenting. Now they are commonplace, and the former is in most medicine cabinets. One of the drugs is still used to treat HIV, emtricitabine (FTC), was invented in 1996 and approved by the FDA in 2003. In recent years, the time from preclinical laboratory work to FDA approval has shortened but it still a multi-year process.
Rukobia (fostemsavir) is a newly approved antiretroviral (ARV) from ViiV Healthcare for the treatment of HIV, specifically for people living with HIV/AIDS (PLWHA) who are heavily treatment-experienced (HTE). They are often on their fourth or fifth regimen of ARVs, but whose treatment is failing—CD4 counts declining to dangerously low levels and with unsuppressed or increasing viral loads—because of multidrug resistance and/or safety or tolerance issues. Rukobia is a novel drug: the first within the class of “entry inhibitors” that is also a “post-attachment inhibitor.”
There are approximately 1.2 million people living with HIV in the United States, and about 6% of them are so heavily treatment-experienced that their drug regimens are failing. Rukobia is targeted at the roughly 72,000 people who have no drug recourses left. As such, it is a life-saving medication.
Fostemsavir was granted Breakthrough Therapy Designation by the FDA on July 21, 2015, for the treatment of the heavily treatment-experienced population when used in combination with other antiretroviral agents. Rukobia was approved by the FDA on July 2, 2020, and the European Union is scheduled to grant full, formal approval in February.
The Phase 3 trial of fostemavir that led to its approval was termed BRIGHTE, which had 371 participants from twenty-three countries. Although the primary measure of the trial was determining how participants responded to the drug after the first eight days of administration compared to a placebo, follow-up study was conducted for two years. Rukobia was generally well-tolerated, led to viral suppression and an increase in CD4 counts. The trial also showed that 60% of patients were virally suppressed (that is, undetectable) after 96 weeks. Additionally, the CD4 counts increased by an average of 200 in in one cohort (randomized) of the trial.
Why We Need Options
Some prepared statements provide an overview of why we need options for HIV meds:
Deborah Waterhouse, CEO of ViiV Healthcare: “While incredible strides have been made in treating HIV over the past few decades, a select population of adults with multidrug resistant HIV-1 infections are not able to maintain viral suppression with currently available medication. Without effective new options, this group of people are at risk of progressing to AIDS, so a positive opinion from the CHMP [Committee for Medicinal Products for Human Use in Europe] for fostemsavir, is extremely welcome news and is an important step towards ensuring no one is left behind at any stage of living with HIV. We are committed to pursuing innovative research to meet the diverse needs of the HIV community, and this positive CHMP opinion comes from the culmination of complex research, development and manufacturing. We won’t stop until we have more ways to treat, and hopefully one day cure, HIV.”
Gabriel Maldonado, founder and CEO of an organization, TruEvolution, which fights for health equity and racial justice for LGBTQ people: “Some members of the HIV community face very challenging treatment journeys and do not respond to available therapies for a variety of reasons… The approval of fostemsavir provides a sense of renewed hope for these adults who have few or no viable treatment options left and have been awaiting alternative medicines to control the virus.”
Jacob Lalezari, MD, director of Quest Clinical Research in San Francisco and a BRIGHTE clinical investigator: “As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV. In the BRIGHTE study, fostemsavir in combination with other antiretrovirals effectively achieved and maintained long-term viral suppression and demonstrated clinically meaningful rise in CD4 T cell count even among heavily immunocompromised patients. These are exciting advances for the heavily treatment-experienced population and an advancement the HIV community has long been waiting for.”
The Goal of Improved Health Outcomes
Dr. Lalezari has been an infectious disease physician and researcher since the late 1980s. When I spoke to him last year, I asked how that divide or conjunction—clinical trial investigation as well as treating patients—“works.” The two reinforce each other, he said. The experience of seeing patients suffer and sometimes die reinforces the impatient need for more drug, vaccine, and cure research. Especially for new drug classes for treating HIV, Dr. Lalezari said, seeking new ways to block the virus from attacking the body’s immune system. A large majority of participants in the BRIGHTE trial had had an AIDS diagnosis in the past (CD4 count less than 200) or currently had T-cell counts in the single digits. One participant’s CD4 number, singular, was one: after two years on Rukobia, that number had gone up by over 300 and he had achieved full viral suppression.
As for the name, Rukobia? “I’m the wrong person to ask how ViiV arrived at that! A bunch of people probably sat in a room and somehow translated fostemavir into the brand name Rukobia, but I wasn’t part of that session.”
I also spoke to one of the participants in the BRIGHTE trial, Dennis, a pharmacist who eventually also became a Ryan White Program educator. Dennis had suffered what too many did in the 1980s and 1990s—stigma, lipodystrophy, constant side effects such as nausea, allergy to a component in a drug regimen, multidrug resistance. In 2016, as his viral load was rising and CD4 counts plummeting, he decided to volunteer for the fostemavir trials. Dennis was one of the participants who saw quick and dramatic improvements within just a few weeks. Currently, on Rukobia (600 mg tablets twice a day) and other ARVs, he is undetectable. He described the experience of being in an important drug trial as not only being life-changing (literally) but also as an “OMG!” experience, with the pervasive sense of being part of something, almost akin to a “movement” that could be life-saving for others as well.
I have participated in two clinical trials myself and know full well the satisfaction that comes from being part of something bigger than yourself. Rukobia is not a miracle drug; further work needs to be done, more medicines need to be developed. But its advent has already helped thousands who thought they were beyond hope. HIV is not, does not have to be, a death sentence, even for those who have lived with it for decades.
Thanks for reading. Be well.
Jay Vithalani is a writer and editor. He grew up in Mumbai, and studied English literature, philosophy, and creative nonfiction at Amherst College, Harvard University, and the University of Iowa. Vithalani lives in New York City. He can be reached [email protected].