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SPI-256, a Highly Potent HIV Protease Inhibitor with Broad Activity against MDR Strains
Sergei Gulnik*1, E Afonina1, M Eissenstat1, N Parkin2, A Japour1, and J Erickson1
1Sequoia Pharma, Gaithersburg, MD, US and 2Monogram Biosci, South San Francisco, CA, US
Background: A majority of
drug-experienced patients in North America
harbor HIV that is resistant to 1 or more FDA-approved antiretroviral agents.
Recent studies suggest that the effectiveness of salvage therapies with
marketed HIV protease inhibitors (PI) may be diminished for patients with more
than 6 or 7 protease mutations at baseline. There is an urgent need for potent
and broad-spectrum HIV PI that can be used to prevent the development of MDR
HIV in primary treatment settings and to treat pre-existing MDR HIV strains.
Methods: We have implemented
a structure-based approach for the design of novel PI with high potency against
wild type and MDR viruses. One of these inhibitors, SPI-256, was evaluated
using Monogram Biosciences PhenoSense HIV assay in a
panel of wild type strains of clades A, B, C, and D (n = 7) and PI-resistant (n = 44) HIV-1 strains derived from
clinical isolates. The antiviral potency was compared to that of 7 FDA-approved
PI—saquinavir (SQV), ritonavir
(RTV), indinavir (IDV), nelfinavir
(NFV), lopinavir (LPV), amprenavir
(APV), and atazanavir (ATV).
Results: Resistant viruses
contained as many as 6 primary mutations in PR in a background of 5 to 21 total
mutations (median = 13). SPI-256 exhibited an average IC50 value of 0.3
nM (0.2 to 0.4) against wild type viruses and was 4-
to 50-fold more potent than FDA-approved PI (1.2 to 16.3 nM).
Importantly, SPI-256 was nearly 100-fold more potent against MDR viruses (average
IC50 of 3.9 nM, range 0.1 to34 nM), compared to FDA-approved PI (average IC50
of 344 nM; range >96 nM
to >1140 nM). For a subset of isolates with >50-fold
phenotypic resistance to reference PI or 6 primary PI mutations (n = 12), the average IC50
value for SPI-256 was 12.9 nM (range 1.8 to 34 nM) compared to >937 nM for the
FDA-approved PI (range >252 to >2925 nM).
Conclusions: SPI-256 displays 4- to 50-fold greater in vitro potency than currently approved
PI against wild type HIV-1 as judged by IC50 values in PhenoSense assay and maintains potency against highly
resistant MDR HIV isolates. This inhibitor represents a potential new antiviral
agent for first line as well as salvage therapy.
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