A new way to defend against HIV

A hallmark of successful modern academic institutions is an ability to integrate students, faculty, and alumni within the corporate architecture of local businesses. MIT is known for its ties to General Dynamics and Stanford has attracted many undergraduates hoping to go into business for themselves or with others in Silicon Valley.

New Haven has an illustrious history as the home of many successful businesses that benefitted from their associations with Yale. One of the businesses working together with Yale School of Medicine is a global leader in HIV research named ViiV Healthcare. The company has a facility located in Branford, Connecticut, that focuses on developing a pipeline of novel HIV drugs. One example is a first-of-its-kind investigational medicine called fostemsavir (FTR), which the FDA approved under the brand name "Rukobia" on July 1st. A new antiretroviral agent developed to address the unmet needs of heavily treatment-experienced (HTE) people living with HIV, Rukobia will assist an often-underserved HIV-positive population. Rukobia (FTR) is the prodrug of temsavir, an investigational HIV-1 attachment inhibitor.

Fostemsavir was developed by a team headed by Max Lataillade, DO, MPH, vice president and head of global research strategy for ViiV Healthcare, with collaboration from Michael Kozal, MD, professor of medicine (AIDS), Yale School of Medicine, Associate Dean for Veteran Affairs, and chief of staff, VA Connecticut Healthcare System. Rukobia is intended for patients suffering from late-stage HIV and AIDS who are resistant to multiple antiretroviral treatments and are therefore considered to have multidrug-resistant (MDR) HIV. Many persons living with MDR HIV have strains of the virus that have built up resistance to medical therapy over years of receiving a combination of HIV drugs. Fostemsavir is literally a treatment of last resort for the people who take it—people for whom other treatments are no longer effective. “We have developed Rukobia specifically for heavily treatment-experienced patients—those that have very few options remaining,” said Lataillade.

Kozal’s specialty is tackling HIV strains with mutations associated with resistance to standard HIV medications. The first product he helped develop was an assay for detecting drug resistance mutations in HIV genes, which he referred to as “DNA on a chip.” He and Lataillade formed a close working relationship when Lataillade was a fellow in infectious disease and HIV at Yale and began working in Kozal’s lab. The two researchers’ overlapping interests laid the foundation of a positive long-term collaboration.

“I trained with Mike, and I learned quite a lot about HIV, almost everything I know about HIV resistance, especially how to sequence entire retroviruses, and antiretroviral (ARV) regimens after patients have failed medications,” Lataillade said. Thus it was not surprising that when Lataillade was developing a novel ARV, first at Bristol-Myers Squibb in Wallingford, Connecticut, and later working at ViiV Healthcare for HTE people living with MDR HIV, that he reached out to Kozal to collaborate on the project. The two researchers then chose the Yale HIV Clinical Trial Group as a major site for many Rukobia studies.

The collaboration between the two resulted in a paper published in the New England Journal of Medicine on March 26, 2020, with Kozal as lead author and Lataillade as senior author. “Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection,” part of a global Phase III clinical trial called BRIGHTE, presented primary and week 48 study results, and demonstrated fostemsavir’s effectiveness in combatting MDR HIV infections. ViiV had already submitted a New Drug Application (NDA) to the FDA for fostemsavir in December 2019.

From ViiV’s perspective, the more effective fostemsavir is in treating MDR HIV patients, the better. The team has been working to perfect this drug for more than 20 years; seeing it outperform expectations has been very satisfying. “ViiV is a company that is solely dedicated to the fight against HIV, and we are committed to staying in this fight until the threat of HIV infection doesn’t exist anymore,” said Peter Ackerman, MD, physician project lead at ViiV’s Branford location and one of the paper’s authors. “That means meeting the needs of all persons living with HIV (PLHIV)”.

Developing fostemsavir has implications not only for people living with MDR HIV in the United States, but also for others across the world. “This development program is intended to provide a viable alternative to late-stage patients who have run out of options, and is consistent with our culture, our mission at ViiV to ‘leave no person living with HIV behind,’” said Lataillade. The current Phase III study extends across the world, with 23 participating countries on six continents.

Fostemsavir has shown additional promising characteristics. Many HTE trial participants who had AIDS and very low CD4+ T helper cell counts (a crucial immune system cell and an indicator of immunological health), saw remarkable increases in CD4+ T cell counts, especially in patients whose CD4+ T cells had been virtually annihilated. The drug also reduced overall morbidity and mortality in patients with advanced AIDS.

“We were pleasantly surprised to see the magnitude of CD4+ T cell recovery in the trial, which is especially pronounced in those that started with the lowest strata of CD4+ T cells” said Lataillade. “Although we think this trend is related to Rukobia's unique mechanism of action and are encouraged by such a quick and sustained recovery, further research will be needed to explain the exact mechanism of CD4+ T cell recovery with Rukobia, and how it is helping the immune system in this very advanced patient population.” Lataillade and ViiV Healthcare are already collaborating with Kozal and such other Yale colleagues as Richard Sutton, MD/PhD, professor of medicine, Yale School of Medicine, and chief of infectious diseases, VA Connecticut Healthcare System, to learn more about the immunological benefits of Rukobia and to further elucidate several hypotheses.

Finding the right compound didn’t happen overnight, according to John Kadow, PhD, the senior director of chemistry at ViiV and co-inventor of FTR. “We made over 3,000 compounds to get to fostemsavir, and it went through many, many trials.” According to Kadow and others, fostemsavir’s delivery mechanism is totally innovative for HIV drugs. As he, Kozal, and Lataillade explain, existing drugs work to block the virus after it has already made contact with or entered inside our immune cells, thus preventing further replication of the virus. Fostemsavir has a unique mechanism of action. When Rukobia (FTR) is converted to its active moiety, temsavir, it binds to a large protein (glycoprotein [gp] 120) on the surface of HIV that allows the virus to attach to specific receptors on the surface of CD4+ cells. By binding to gp120, temsavir effectively blocks the HIV virus from attaching to and infecting healthy CD4+ T cells and other immune cells. That is why Rukobia is called an HIV-1 attachment inhibitor; it prevents the very first step of HIV infection. “It’s a totally new way to fight HIV; with Rukobia we are attacking the virus first instead of waiting for HIV to attack our immune cells and immune system,” said Lataillade.

The dedication and commitment of Kozal, Lataillade, and everyone on ViiV’s team helped propel the drug forward over the years. “It’s been a passion project from the start,” said Lataillade. “We’ve always believed in it. To witness the success of this latest trial; to observe firsthand the impact it’s had on the lives of people living with multidrug-resistant HIV; to see hope restored for patients with AIDS—it’s both a humbling and a powerful feeling.”