First data on third-generation integrase inhibitor from ViiV
10 August 2024. Related: Conference reports, Antiretrovirals, World AIDS 25 Munich 2024.
Simon Collins, HIV i-Base
Results from a phase 1 placebo-controlled study of single and multiple doses of the investigational integrase inhibitor VH4524184 (VH-184) in 84 HIV negative individuals were presented in an oral presentation by ViiV.
Single doses ranged from 10 to 460 mg and multiple doses from 160 to 480 mg for 14 days and PK/food interactions were included.
Participant characteristics included racial and ethnic diversity (34 were Black and 28 Hispanic) and 5 women (most phase 1 studies predominantly enrol white men).
Tolerability was good with only mild side effects reported by 29/84 participants, none serious. Pharmacokinetic results showed mean half-life of 24 hours, minimal likelihood of CYP3A4-related drug interactions and the drug levels were moderately boosted with food.
In vitro data on the resistance profile of VH-184 were presented against single and multiple drug resistance isolates from people who experienced virological failure while taking dolutegravir in the SAILING (treatment-experienced, n=19) and DAWNING (second-line ART, n=17) studies.
In the SAILING study in treatment-experienced participants, 10 single isolates showed broadly similar minimal fold changes in sensitivity against VH-184, cabotegravir and dolutegravir. VH-184 was generally more sensitive to most of the 9 multiple isolates, but not all.
Results from DAWNING involved much higher fold changes in sensitivity against dolutegravir and cabotegravir (from 10- to 80-fold) while most isolates retained sensitivity to VH-184.
Further details were presented in a poster which confirms that VH-184 has a distinct resistance profile compared to second generation integrase inhibitors but implications for likely treatment response are not yet clear.
For example, the highly drug resistant isolate E138K/G140S/Q148H/N155H that is associated with >100-fold resistance to dolutegravir and cabotegravir appears to still have 25-fold resistance to VH-184. The rough results are based on a difficult to read graphic in both the abstract and the poster.
VH-184 is now being studied in a phase 2 study as first-line ART in people living with HIV and as a long-acting slow-release subcutaneous injection using rHuPH20 in people who are HIV negative.
commentS
It is actually crucial that pipeline research is looking at compounds that could overcome drug resistance to current integrase inhibitors. Even though the number of people currently affected is still relatively low, the global dependence on second-generation integrase inhibitors for treatment, which is also increasing for prevention, means these numbers will increase.
Although VH-184 activity is not reduced against single mutants, this would be dependent on identifying early viral failure on current integrase-based combinations which is likely to be much easier in high- compared to low- and middle-income settings.
Session co-chair Chloe Orkin also asked whether ViiV plans to present resistance results from the VIKING study which enrolled participants with greater drug resistance at baseline.
References
- Rogg L et al. Phase 1 study of VH4524184 (VH-184), a new third-generation integrase strand transfer inhibitor (INSTI) with a unique resistance profile. AIDS 2024, 22–26 July 2024, Munich. Oral abstract OAB2603.
https://programme.aids2024.org/Abstract/Abstract/?abstractid=6938 (abstract) - Seki T et al. In vitro characterization of VH4524184 (VH-184, S-365598), a new third-generation integrase strand transfer inhibitor (INSTI) with a unique resistance profile. Poster abstract WEPEB114.
https://programme.aids2024.org/Abstract/Abstract/?abstractid=8629 (abstract)
https://aids2024.iasociety.org/cmVirtualPortal/_iasociety/aids2024/eposters#/PosterDetail/818 (poster) - clinicaltrials.gov. VH4524184 proof-of-concept in treatment-naive adults living with HIV-1.
https://clinicaltrials.gov/study/NCT06214052 - clinicaltrials.gov. First time in human study of long acting VH4524184 formulations.
https://clinicaltrials.gov/study/NCT06310551