Anormed/PGS/rfj,
Pfizer’s maraviroc gives me hope. Anormed valuation is low and it is not valued upon HIV drugs but only on Mozobil at present.
Pfizer's results:
At Bangkok, Pfizer presented five posters on its CCR5 blocker, UK-427,857, including results from a 10-day proof-of-concept study. Patients with CD4 counts above 250 cells/mm3 and currently off treatment or treatment-naive were randomized to a series of escalating doses or to placebo. Dosing began at 25 mg once-a-day (QD) and went up to 300 mg twice-a-day (BID) and included one arm with 150 mg taken with food. Monitoring was continued for 30 days after treatment was stopped on day 10.
All doses above 100 mg QD produced viral load reductions greater than -1.0 log copies/mL. At the 150 mg BID dose, food reduced the peak concentration and total exposure to the drug by about half, although there was no difference in viral load reductions at that dose whether taken with food or not. This may be because blood concentrations of CCR5 blockers will not be as important as how many R5 receptors are occupied by drug molecules and for how long. It seems that these drugs may tend to stick to their target and not let go, a quality which could extend the effective potency of a dose by several days. In this study, high levels of receptor saturation were achieved at every dose except 25 mg QD.
Adverse events were mild to moderate and included headache and dizziness. A separate report found no impact on QT interval, the cardiac rhythmic parameter that was disturbed by Schering's first R5 blocker.
But I know GlaxoSmithKline’s aplaviroc went down, because it was rarely associated with severe hepatotoxicity, Schering-Plough’s vicriviroc phase II trial was halted, because the drug wasn’t measuring up to Combivir (zidovudine/lamivudine, AZT/3TC) + efavirenz (EFV, Sustiva, Stocrin) in treatment naive patients.
I know the company's first X4 drug candidate AMD3100, produced heart rhythm abnormalities in several patients during Phase I testing and only demonstrated limited efficacy at achievable concentrations.
But results from prelim trials for AMD070:
In Bangkok, results were presented from a Phase I dose escalation study of AMD070 in uninfected adult men conducted by the federal AIDS Clinical Trials Group (ACTG). Single 50 mg doses were initially given to three individuals then escalated to 100, 200 then 400 mg in subsequent groups of three. Next, multiple (7) doses were given at 100 mg every 12 hours to a cohort of six individuals, then escalated to 200 mg in a subsequent cohort. A group of six men also received single 400 mg doses with and without food to evaluate bioavailability in a fed state.
In the single dose studies, the maximum concentration of drug (Cmax), the total exposure to the drug over time (AUC), and the rate the drug was cleared from the body (half life) each tended to be proportional to the dose, although there was a great deal of variability between the subjects within the dose groups for each of these parameters. The half life was estimated as 6 to 10 hours. The single 400 mg dose produced blood concentrations at 12 hours that were above the EC90, a value derived from laboratory studies as the drug concentration required to achieve 90% of its maximum antiviral response. Multiple dosing doubled the concentrations seen with single dosing at 12 and 24 hours. However, multiple dosing at 100 mg could only sustain concentrations above the EC90 for 4 hours. Taking the drug with food tended to lift blood levels, but not significantly.
The only adverse events reported were several headaches.
I think Anormed should also plan to continue more PK studies in more diverse populations like people with liver disease.
However said and done, I will be doubtful about AMD 070 efficacy results and I think currently Anormed's valuation is based on only Mozobil at the moment and any HIV drugs success will be a bonus.
Regards,
Praveen
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