In vitro and animal data support safety profile BMS 986001: d4T-like NRTI currently in clinical trials

Two posters were presented on a new d4T-like nucleoside in development with BMS.

This molecule is structurally similar to d4T but, according to in vitro data, it is 75-fold more virologically potent and more than 200-fold less active as an inhibitor of mitochondrial polymerase-gamma, responsible for toxicity associated with d4T.

While d4T (stavudine) has long been dropped as an option in Western countries and even in WHO guidelines, it continues to be widely used in resource-limited settings where it continues to produce irreversible peripheral neuropathy and facial lipoatrophy.

Both side effects, together with more rare but potentially fatal complications that include lactic acidosis, are mediated by the impact of the drug on mitochondrial function. So the prospect of a new d4T-like compound rolling into clinical trials must be dependent on pre-clinical data that has cleared this toxicity hurdle.

The first of two posters reported in vitro results from exposing renal, muscle and fat cells to therapeutic dose concentrations of BMS 986001 and four other NRTIs: tenofovir, AZT, d4T and abacavir.

Primary cultures of human renal proximal tubule epithelium, muscle, preadipocytes and differentiated adipocytes (subcutaneous) were exposed to each of the NRTIs at their reported Cmax concentration and at 200 uM for 5, 10, 14 and 19 days.

Six in vitro cytotoxicity parameters were measured: percent dead cells, cell protein and ATP content, lactate concentration in the media, and mtDNA (ATP8) content by qualitative PCR.

BMS 986001 was not cytotoxic in any of the four cell cultures tested. Tenofovir showed toxicity in muscle cells and preadipocytes with regard to mtDNA content which decreased in a concentration- and time-dependent manner to approximately 40% control values. In contrast, AZT and d4T were cytotoxic in all four cell culture types and for all measured parameters. Abacavir was only significantly cytotoxic at the 200 uM concentration.

A second poster reported finding no BMS-986001-related changes in renal function (serum and/or urine urea, creatinine, total protein and excretion, albumin, phosphorus, calcium, and glucose) or biomarkers of renal toxicity (serum cystatin C and renal b2-microglobulin, clusterin, and NGAL), or in bone formation (serum osteocalcin) or bone resorption (serum free deoxypyridinoline and C-terminal cross-linking telopeptide of type I collagen [C-Tx]; and urine N-Tx) following oral six month dosing, at any dose tested compared to control group in rat and cynomolgus monkeys. [2]

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These in vitro data contribute to supporting the safety of the ongoing clinical trials programme for this new compound.

The major pre-clinical toxicity with BMS-986001 (up to 6-month duration) at high exposures has been dyserythropoiesis in the bone marrow with lower myeloid to erythroid ratios and decreased red blood cells, and thrombocytopenia.

There remains a need for NRTIs with improved tolerability both in the developed and developing world. If this compound is being primarily developed for the former, it should have a parallel programme for the later, including early discussions with generic manufacturers to help ensure its access (if successful and approved) where d4T continues to be used.