Biotech Values

[DewDiligence]

ANDS –The proposed phase-2 trial for ANA598 is likely to fail, IMO. Here are the details as presented in ANDS’ PR today:

Anadys is preparing for the first Phase II trial in hepatitis C patients of ANA598 in combination with interferon-alpha and ribavirin… and intends to submit a protocol to the U.S. Federal Drug Administration (FDA) containing the proposed trial design in July 2009.

…The current protocol design calls for 12 weeks of dosing ANA598 in naive genotype 1 patients in combination with SOC, compared to a control arm that will receive a placebo and SOC. After 12 weeks, patients are expected to continue to receive SOC alone. The primary endpoints of the study are designed to be safety, tolerability and the percentage of patients with undetectable virus at four weeks (defined as Rapid Virologic Response, or RVR) and 12 weeks (defined as Early Virologic Response, or EVR). For patients who achieve an RVR and EVR response, the duration of treatment with SOC after week 12 will be at the clinical investigator's discretion. [This is an unusual feature for a trial of this nature and it suggests to me that ANDS received considerable pushback from the clinicians whom the company solicited for PI’s.] Anadys expects that some patients who achieve RVR would stop receiving all treatment at 24 weeks. All patients who complete 24 or 48 weeks of treatment will be assessed for virus negativity 12 and 24 weeks after treatment is ended. [These are the standard SVR12 and SVR measurements.]

The proposed dose levels in this study are 200 mg and 400 mg, each dosed twice daily (bid). In order to maximize early viral suppression, each patient receiving ANA598 would receive two 800 mg doses on day one, known as a loading dose. The decision to initiate dosing of patients in the 400 mg dose group will be determined after assessing 28-day data from the 200 mg dose group. [I.e. they want to see how bad the rash will be in the low-dose arm before starting any patients in the high-dose arm.] Anadys intends to enroll 90 patients in this study, in the proportions of 30 patients receiving ANA598 and 15 receiving placebo at each dose level.

OK, so what is the problem? In the 14-day monotherapy trial in healthy volunteers (#msg-37263272), 19% (3/16) of the subjects in the 800mg qD and 600mg BID cohorts suffered a severe rash that led to dropout from the trial. In other words, severe rash was seen with ANA598 monotherapy at cumulative daily loads of 800-1200mg. Given this background, how likely is it that the 400mg BID (800mg cumulative daily load) cohort in the planned phase-2 study will allow rash-free treatment when ANA598 is being added to interferon and ribavirin? Not very likely, IMO.

My prediction for the ANA598 phase-2 trial as currently planned is that the 200md BID dose will be too low for meaningful efficacy and the 400mg BID dose will produce severe rash. If the FDA concurs with this thinking, the phase-2 trial as currently planned may never even get off the ground.