New data was presented for an NRTI in development at BMS.
The degree of cross-resistance between commonly used first-line NRTIs leave a role for new drugs in this class, especially if they prove to also reduced toxicity concerns. This is perhaps even more important in countries where failing treatment is currently maintained until clinical failure, as accumulated mutations increase cross-resistance to potential drugs for subsequent treatment.
An NRTI in development with BMS, compound name BMS-986001 (BMS-001) that has a similar structure to stavudine (d4T) but without causing mitochondrial-related toxicities is currently in Phase II studies.
BMS-001 was hypersusceptible to K65R (0.43 fold change) and L74V (0.65 fold change): key mutations associated with tenofovir and abacavir resistance but this reverted to levels similar to wild-type virus in the presence of M184V. In clinical practical, M184V is often the first mutation to occur in combinations that include 3TC or FTC, so the joint mutation is commonly seen. It was also hypersusceptible to the MDR Q151M mutation but this steadily reduced in the presence of other mutations including M184V (from 0.17 fold to 1.24-fold), with one isolate including 151 and 184 mutations dropping to > 40-fold loss in sensitivity.
Susceptibility was significantly reduced by 6-8 fold to virus from common thymidine analogue mutations (TAMs) (M41L, L210W, T215Y or D67N, K70R, T215Y).
The new compound is not able to overcome resistance to the MDR T69SSS with TAMs (> 40-fold).
This profile highlights the potential for a new NRTI that may have a role for patients failing a first-line combination containing tenofovir or abacavir, but results from clinical trials will need to correlate these response in vivo.
Li P et al. The in vitro cross-resistance profile of the NRTI BMS-986001 against known NRTI resistance mutations. 20th Intl Drug Resistance Workshop, 5-9 June 2012, Sitges. Abstract 2. Antiviral Therapy 2012: 17 Suppl 1:A10.
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