Achillion’s lead product candidate, elvucitabine, is an L-cytosine nucleoside analog reverse transcriptase inhibitor (NRTI) that has demonstrated potent antiviral activity against HIV, including strains resistant to other NRTIs. L-cytosine NRTIs represent the most frequently prescribed class of NRTIs based upon sales, accounting for approximately 34% of the worldwide NRTI market in 2004. L-cytosine NRTIs are frequently prescribed given their established potency, favorable short-and long-term safety profile and fewer and less severe adverse side effects.
NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) prevent HIV replication by interacting with reverse transcriptase. NRTIs, such as Epivir (3TC), Emtriva (FTC), Viread (tenofovir), Retrovir (AZT) and Zerit (d4T), have become the predominant class of drugs in HIV therapy. Without successful reverse transcription, the virus is unable to reproduce itself. When reverse transcription occurs in the presence of an NRTI, the NRTI is incorporated into the newly synthesized DNA strand and stops the reverse transcription process, thus preventing a complete copy of the viral RNA from being transcribed into DNA.
Achillion believes elvucitabine addresses the limitations of currently available NRTIs in the following ways:
Long Half-Life. Elvucitabine’s plasma half-life has been demonstrated in clinical trials to be approximately 100 hours, or up to 20 times greater than that of Epivir (3TC) and up to ten times greater than that of Emtriva (FTC). In addition, elvucitabine’s intracellular half-life has been demonstrated in a clinical trial to be over 100 hours, or more than five times greater than that of Epivir (3TC) and Emtriva (FTC). This long half-life may mitigate the negative effects of less-than-perfect patient compliance, providing a more durable NRTI for use in HAART regimens.
Comparative Plasma Half-Lives of Marketed Nucleosides
In a clinical trial, elvucitabine's intracellular half-life has been demonstrated to be over 100 hours, or more than five times greater than that of Epivir (3TC) and Emtriva (ETC).
Superior Potency Against Common Resistance Mutations. The laboratory antiviral profile of elvucitabine demonstrates superior potency against many of the most common resistance mutations associated with NRTIs typically used in combination with Epivir (3TC) and Emtriva (FTC), including those associated with Viread (tenofovir), Retrovir (AZT) and Zerit (d4T). In addition, although elvucitabine’s resistance profile is similar to Epivir (3TC) and Emtriva (FTC), elvucitabine retains greater antiviral activity in laboratory tests against HIV with resistance to Epivir (3TC) and Emtriva (FTC). This enhanced antiviral activity could provide an increased barrier to the emergence of drug resistance in patients and improve antiviral suppression in patients with emerging resistance to commonly used NRTIs.
Patient Compliance. A well tolerated L-cytosine NRTI with convenient, flexible oral dosing could significantly enhance patient compliance and would make elvucitabine an attractive component of HAART regimens. With a projected daily dose of elvucitabine of 10 mg in a tablet formulation, compared to 200 mg for Emtriva (FTC) and 300 mg for Epivir (3TC), elvucitabine could also be an attractive candidate as part of a fixed dose combination product for use in HAART regimens.
To date, Achillion has completed clinical studies evaluating the use of elvucitabine in patients chronically infected with HIV. In these studies, elvucitabine demonstrated potent anti-HIV activity in patients whose virus carries the M184V mutation, a mutation associated with lamivudine (3TC) resistance.
Clinical and pre-clinical data collected to date indicate that elvucitabine can be dosed as one pill once a day and may be used in combination therapy. In addition, the L-nucleoside configuration of the compound may provide protection against mitochondrial toxicity, a serious side effect often seen with D-nucleosides.
The majority of HIV infected patients are initially treated with a regimen containing a cytosine nucleoside analog, thus elvucitabine could address a large and growing market.
