Background
Islatravir (ISL) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development in combination with ulonivirine (ULO), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), for once-weekly oral treatment of HIV-1. Resistance selection studies were performed in vitro to assess the barrier and pathways for the emergence of resistance to the combination.
Methods
In vitro resistance selection was performed with ISL and ULO alone or in combination (ISL+ULO) at multiples of each compound’s potency (IC50) against wild-type (WT) HIV-1. Selection was initiated with WT HIV-1 or a variant encoding reverse transcriptase (RT) M184I in 96-well plates. Wells were assessed for viral breakthrough (VBT) after 12 passages and the RT region of breakthrough viruses were genotyped. Viral clones encoding emergent mutations were produced and phenotyping was performed in MT4-GFP cells.
Results
With ISL alone, VBT was observed up to 8X IC50 with WT HIV-1 and up to 16X IC50 with M184I variant. With ULO alone, VBT was observed up to 16X IC50 with WT HIV-1 and up to 8X IC50 with M184I variant. With ISL+ULO, there was no VBT above the IC50 values for each compound with WT HIV-1 and VBT occurred in only 2 of 8 wells at 2X IC50 with M184I variant.
With ISL and ULO alone, M184I and V106A, respectively, were the most common emergent mutations observed with WT HIV-1. With ISL alone, no additional mutations emerged with M184I variant. With ULO alone, E138K and M230I/L emerged instead of V106A with M184I variant. With ISL+ULO, V108I/M184I and E138K/M184I were most prevalent with WT and M184I variant, respectively.
ISL had 6.2-fold reduced potency against M184I but retained WT potency (0.5- to 2-fold change) against ULO-associated variants. ULO potency was reduced by 8.9-, 4.2-, 13.7-, and 37.4-fold, against V106A, E138K, M230I, and M230L variants, respectively, but retained WT potency against M184I. ISL and ULO had mild reductions in potency against the V108I/M184I and E138K/M184I variants with ISL potency reduced 7.6- and 4.4-fold, respectively, and ULO potency reduced 2- and 5.2-fold, respectively.
Conclusions
The ISL+ULO combination was more effective than either agent alone at suppressing VBT and the compounds demonstrated complementary resistance profiles. The data indicate the combination is expected to retain activity against selected variants at clinical exposures and support further clinical development of ISL+ULO as a once-weekly oral treatment for HIV-1.