Combination Inhibitor BMS-986197 Demonstrates Good Anti-HIV Activity in Early Study

A long-acting bioengineered "combinectin" molecule with a triple mechanism of action demonstrated potent antiviral activity and worked against HIV that developed resistance to any of the 3 separate mechanisms in a laboratory study, and lowered viral load in humanized mice, according to research presented at theConference on Retroviruses and Opportunistic Infections (CROI 2016)last month in Boston.

Modern antiretroviral therapy is highly safe and effective for most people with HIV, but there is still room for more convenient agents that could help improve adherence, as well as drugs for people with highly resistant virus.

BMS-986197 is an injectable biologic agent which investigators think could potentially be self-administered as a long-acting subcutaneous injection; combining different modes of action in a single agent could avoid the need for multiple injections.

Mark Krystal, formerly of Bristol-Myers Squibb and now at ViiV Healthcare, presented findings from early laboratory and animal studies of BMS-986197, which is part of the portfolio of Bristol-Myers Squibb's investigational HIV agents recently acquired by ViiV.

BMS-986197 is made up of adnectins, small proteins with modifiable binding loops resembling certain antibody regions. Researchers combined adnectins targeting the CD4 cell surface receptor and HIV's gp41 protein subunit, along with a peptide fusion inhibitor, to build a so-called combinectin inhibitor that uses independent mechanisms to interfere with 3 routes of HIV entry. Finally, this combinectin was attached to human serum albumin to improve its pharmacokinetics.

The anti-CD4 adnectin appears to allow HIV's gp120 envelope protein to bind to the receptor, but prevents conformational changes needed for binding to co-receptors (CCR5 or CXCR4). The second adnectin attacks the N17 sequence of the HIV gp41 envelope protein subunit. The fusion inhibitor component works similarly to enfuvirtide (T20 or Fuzeon).

The EC50, or 50% effective concentration, of the anti-CD4 adnectin, the anti-gp41 adnectin, and the fusion inhibitor peptide were 8.5, 5.4, and 0.4 nM (nanoMolar), respectively. Linking these 3 inhibitors into a single molecule led to synergistic effects greater than the sum of the parts. The optimal combination of the 2 adnectins increased potency by more than 100-fold, while adding the fusion inhibitor appeared to increase the barrier to resistance. The addition of human serum albumin decreased potency but made the combinectin last longer in the body.

In the laboratory BMS-986197 demonstrated antiviral activity against a wide range of clinical virus isolates of different subtypes obtained from people with HIV. It retained potency against viruses that were resistant to any 1 of the 3 separate entry inhibition mechanisms and it showed no loss of potency in human blood serum.

In bio-engineered mice with humanized immune systems BMS-986197 produced dose-dependent decreases in viral load, and at the highest dose most became undetectable. Cell receptors remained occupied and pharmacokinetics were consistent over 36 days. In cynomologous monkeys a subcutaneous injection had a half-life of 30 hours and the researchers projected a half-life in humans of about 40 hours -- potentially adequate for once-weekly dosing.

"BMS-986197 is a long-acting (projected weekly dose) biologic molecule containing 3 individual inhibitors of HIV-1 entry that can be dosed subcutaneously," the researchers concluded. "BMS-986197 is effective at lowering viral loads in a mouse model of infection."

3/14/16

Reference

M Krystal, DWensel, Y Sun, et al. HIV-1 Combinectin BMS-986197: A Long-Acting Inhibitor With Multiple Modes of Action. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 97.