HIV Treatment: Less (Often) Is More (Desirable)

Once-daily oral tablet regimens are the current standard of care for HIV treatment. The daily tablets were a leap forward from earlier regimens that required taking multiple pills a day.

But now many people living with HIV want treatments that are even less frequent than a daily pill, and drug developers are competing to meet the demand.

The interest and investment in longer-term HIV treatment got a major boost early last year when the FDA approved Cabenuva (cabotegravir and rilpivirine), an injectable treatment that is administered monthly.

Brii Biosciences, a biotech company with offices in China and the United States, is one of the HIV drug developers vying for spot in the HIV treatment market. The company is developing two, once-weekly HIV treatment pills, provisionally named BRII0778 and BRII-732.

BRII-778 is an extended-release formulation of Edurant (rilpivirine hydrochloride), a nonnucleoside reverse transcriptase inhibitor (NNTRI).

“Edurant, an instant-release formulation of rilpivirine, has exhibited antiviral activity against a broad panel of HIV’s most common strains,” says David Margolis, M.D., Ph.D., vice president, head of infectious diseases at Brii Biosciences. “BRII-778, like all NNRTIs, binds to the NNRTI binding site which is a flexible allosteric pocket located at a site adjacent to the deoxyribonucleic acid polymerizing processing site, resulting in conformational changes and altered function of reverse transcriptase.”

Last year, Brii Bio completed the phase 1 SAD/MAD study of BRII-778 in the U.S. and selected one of the formulations for further development and evaluation in clinical trials. The data readout of phase 1 SAD/MAD trial for BRII-778 is expected to be presented at a scientific conference in the second half of 2022.

BRII-732 is a new chemical entity that is metabolized upon oral administration into EFdA (4'-Ethynyl-2-fluoro-2'-deoxyadenosine), which is also known as islatravir.

“EFdA functions not only as a potent chain-terminator like other NRTIs (nucleoside reverse transcription translocation inhibitors), but also as a potent HIV reverse transcriptase translocation inhibitor, with high binding affinity to the active site of RT, that inhibits HIV reverse transcriptase by blocking translocation of nascently synthesized strand for the next nucleotide incorporation,” Margolis says.

In April 2021, Brii Bio received clearance from the FDA for an investigational new drug (IND) application for BRII-732. The next month, a phase 1 trial that involved giving the drug to human patients got started.

However, in December 2021, the FDA placed a temporary hold on all islatravir-based clinical trials sponsored by Merck due to a decline in CD4 cell count in some subjects. BRII-732 is a prodrug of islatravir and was also placed on clinical hold out of abundance of caution and pending additional safety evaluations.

Based on the published data and information disclosed by Merck in December 2021, the safety finding of CD4 cell count decrease is both dose and time dependent. Brii Bio believes a safe dose of BRII-732 may be selected based on the Phase 1 study and will be efficacious for patients. The company plans to meet with the FDA to discuss plans to further investigate and develop BRII-732.

“Top-line data from the completed Phase 1 SAD/MAD study for BRII-732 showed that the therapeutic candidate is well tolerated without any CD4 cell count decrease observed,” notes Margolis.

Margolis says that HIV treatment has continued to evolve in important ways, to meet the priorities and preferences of people living with HIV.

Several safe and highly effective treatments have been developed in the past decade, the standard of care has always required daily dosing for life, to maintain viral suppression. However, daily oral dosing can complicate medication compliance and heightens the stressors of living with HIV, for some patients.

“Within just the past year, the first ever long-acting regimen, Cabenuva, was approved in the U.S. enabling injectable dosing every 4-8 weeks, freeing some patients for the first time ever from taking daily therapies,” says Margolis. “Research into additional long-acting approaches is being conducted in experimental clinical trials, including the potential for once-weekly oral options and self-administered injectable options, aiming to further reduce the medication burden and psychological burden of living with HIV.”