Preclinical Development History - Achillion sublicensed elvucitabine from Vion Pharmaceuticals (which licensed the relevant patents and intellectual property from Yale University) and initiated development activities in 2000. In preclinical studies, elvucitabine was shown to be approximately four-fold more potent in vitro than Epivir (3TC) against wild-type HIV, meaning HIV without mutations associated with drug resistance. In addition, elvucitabine demonstrated greater potency in vitro against HIV with resistance to most of the commonly used NRTIs, such as Epivir (3TC), Retrovir (AZT), Zerit (d4T) and Viread (tenofovir). These studies were conducted at several laboratories with more than 70 clinical strains of HIV obtained from patients with drug resistance and eight laboratory strains of HIV with known reverse transcriptase resistance mutation profiles.
Clinical Development History - Between 2001 and 2003, Achillion conducted several clinical trials to determine the safety, tolerability and pharmacokinetic profile of elvucitabine for use against both hepatitis B virus, or HBV, and HIV. Specifically, the Company conducted three Phase 1 clinical trials in healthy subjects, two Phase 2 clinical trials in patients infected with HBV, and one Phase 2 clinical trial in patients infected with HIV. In the Phase 2 clinical trials for HBV, doses of 5, 10, 20 and 50 mg once daily were evaluated and it was noted that all doses greater than 5 mg were effective in reducing HBV viral load by 99%, or 3.5log10 copies/ml.
In the initial Phase 2 clinical trial for HIV, doses of 50 and 100 mg once daily were evaluated and it was noted that both dose groups demonstrated reduction in viral load by 80%, or 0.7log10 copies/ml. It was further noted that doses of 50 mg or greater per day were associated with an unacceptable reduction in the number of patient's white and red blood cells. In 2003, the clinical trial was discontinued, and the elvucitabine program was placed on clinical hold while determination of the appropriate dosing regimen for elvucitabine was made.
In 2004, while operating under a partial clinical hold placed by the FDA, Achillion evaluated the therapeutic window and pharmacokinetic profile of elvucitabine in HIV-infected patients with a 21-day, open label Phase 2 clinical trial of 24 HIV treatment-nave patients (ACH443-012). The patients received elvucitabine at either 5 mg or 10 mg once daily, or 20 mg every 48 hours, in each case in combination with the protease inhibitor Kaletra (lopinavir + ritonavir). Frequent measurements were made of elvucitabine plasma levels throughout the trial. Results from the trial demonstrated that all three doses were similar in antiviral activity, reducing the viral load by approximately 98%, or 1.9log10 copies/ml.
Mean Change in HIV RNA (log) 21 day study of ELV in combination with Kaletra
All three doses also showed similar safety profiles without the occurrence of any serious adverse events, particularly white or red blood cell reduction. Importantly, the trial also demonstrated that the amount of elvucitabine present in patients plasma 24 hours following their previous dose was well in excess of those amounts necessary to deliver potent antiviral activity.
Mean Elvucitabine Plasma Concentrations
From this trial, it was concluded that the plasma half-life of elvucitabine is approximately 100 hours and a dose of 10 mg once daily was chosen for evaluation in the current Phase 2 safety and efficacy trials in HIV-infected patients. Following the completion of this clinical trial, the FDA removed the partial clinical hold.
In May 2006, Achillion completed a randomized, double-blind Phase 2 trial (ACH443-017) that evaluated the viral kinetics, safety and pharmacokinetics of elvucitabine in 24 treatment-naive HIV patients. Patients received either 10 mg of elvucitabine or a placebo once daily for seven days. An acceptable treatment response for this trial was defined as the elvucitabine cohort demonstrating greater reduction in HIV viral load on day seven, as compared to the viral load observed in patients taking a placebo.
The results from this trial demonstrated that patients who received a 10 mg dose of elvucitabine once daily experienced a mean viral load reduction of 0.85 logs, or 83%, on day seven. Patients who received a placebo experienced a mean -0.06 log change, or less than 1%, at day seven. In addition, patients who received elvucitabine experienced a mean increase in CD4 cells of approximately 20%, compared to a mean increase of less than 1% in patients receiving a placebo.
This trial confirmed that the plasma half-life of elvucitabine is approximately 100 hours and that its intracellular half-life is also greater than 100 hours. During this trial, elvucitabine had not achieved steady state, that is, the point at which minimum plasma levels no longer increase after repeat dosing. Based upon the previous clinical studies of elvucitabine, it is believed that elvucitabine's steady state occurs following 21 days of dosing. No serious or clinically significant adverse events were observed during this trial. It should be noted that these results are based on a small number of patients in an early-stage clinical trial and are not necessarily predictive of results in later-stage clinical trials with larger and more diverse patient populations.
In May 2006, Achillion initiated a randomized, double-blind Phase 2 trial (ACH443-015) of elvucitabine in combination with two additional antiretrovirals, Sustiva (efavirenz) and Viread (tenofovir), as compared to Epivir (3TC) in combination with the same two additional antiretrovirals, in 78 treatment-naive HIV patients. The safety, antiviral efficacy and pharmacokinetics at 12 weeks of therapy was evaluated with these two treatment regimens. If patients responded favorably, they were eligible to receive an additional 84 weeks of therapy with elvucitabine.
In October 2007, Achillion announced results from the first 12 week treatment segment of this trail. Data demonstrated that elvucitabine was safe, well-tolerated and similar in efficacy to 3TC, reducing viral RNA levels by -2.8log10 (+/- 0.8), vs. viral load reduction of -3.0 log10 (+/- 0.8) in the 3TC arm.
In June 2008, Achillion announced results from the 48 week treatment segment of this trial. The data continued to demonstrate the potent antiviral effect of elvucitabine similar to 3TC with a mean change in HIV-RNA from base-line in the elvucitabine treatment group of -3.0 log10 (+/-0.55) vs. -3.2 log10 (+/- 0.6) in the 3TC treatment group in the as-treated patient analysis. In the elvucitabine-treated group, 96% of patients reached undetectable viral load, defined as achieving fewer than 50 copies/ml after 48 weeks of therapy, compared to 97% in the 3TC group. Elvucitabine was well-tolerated and demonstrated a safety profile comparable to 3TC for both incidence and severity of adverse events. See graphical depiction of these results below.
Also in 2006, Achillion initiated another randomized, double-blind Phase 2 trial (ACH443-014A) to evaluate the viral kinetics, safety and pharmacokinetics of elvucitabine in 18 HIV-infected patients in a difficult-to-treat subgroup, specifically those who have failed a HAART regimen that includes Epivir (3TC). Treatment failure is defined as the presence of the M184V mutation, which signifies Epivir (3TC) drug resistance. Patients received either 10 mg of elvucitabine once daily in place of Epivir (3TC) or continued receiving 300 mg of Epivir (3TC) once daily for 14 days. The patients other two HAART regimen drugs remain unchanged. If patients responded favorably, they were eligible to receive an additional 48 weeks of therapy with elvucitabine.
In January 2008, Achillion announced results from this trial, which included a first phase consisting of exploratory viral kinetic and pharmacokinetic analysis, followed by an open label extension phase. After 14 days of therapy, the Company noted similar viral load reductions in the elvucitabine and 3TC treatment groups. Importantly, however, the trial results demonstrated significant improvement in response in the second open-label extension phase where 8 of 14 patients who received elvucitabine, or 57%, had achieved 0.5 log10 reduction or more in viral load, likely related to the fact that elvucitabine reaches steady-state levels in patients after approximately 21 days of treatment.
