Resistance benefits for Achillion's NS5A inhibitor as combos progress for HCV
This article was originally published in Scrip
The US firm Achillion Pharmaceuticals has positive proof-of-concept data that justify further development of its second-generation, pan-genotypic NS5A inhibitor ACH-3102 to treat hepatitis C virus (HCV) as part of a combination therapy with ribavirin or the company's protease inhibitor sovaprevir (ACH-1625).
New Haven, Connecticut-based Achillion's stock went up $0.81, or 8.5%, to $10.30 per share on 27 September after it announced that administration of a single-dose of ACH-3102 to 14 genotype 1a HCV-infected patients in a Phase Ib clinical trial resulted in a mean maximum 3.74 log10 reduction in HCV RNA. There also were significant reductions in HCV RNA in patients with drug-resistant genetic mutations of the virus.
Achillion president of research and development, and chief scientific officer, Milind Deshpande said NS5A inhibitors generally will be an important part of combination HCV therapies, but the drug class has been susceptible to drug resistance that has not been observed to date in preclinical and Phase I studies for ACH-3102.
"The important thing for us was to identify a compound with good activity to begin with, but to also demonstrate activity against the emergence of resistance. ACH-3102's resistance profile is significantly better than other NS5A inhibitors," Dr Deshpande said.
In the Phase Ib study, two of the patients infected with genotype 1a chronic HCV received placebo and 12 were treated with a single 50mg, 150mg or 300mg dose of ACH-3102.
Among the study's participants with HCV genetic mutations that previously have shown a high level of resistance to first-generation NS5A inhibitors, one patient in the 300mg dosing group had a baseline L31M mutation and experienced a maximum HCV RNA decline of 3.4 log10.
Another patient from the 300mg group had a baseline Y93C mutation and their maximum HCV RNA decline was 4.6 log10.
For all four patients treated with the 300mg dose, log10 reductions ranged from 3.4 to 4.6 and the mean maximum log10 reduction was 3.93.
ACH-3102 was safe and well-tolerated at all doses given to healthy volunteers treated in Phase Ia studies with single and multiple ascending doses of ACH-3102, including a 14-day study with 32 healthy individuals. Adverse events were mild or moderate and transient.
Achillion recently began dosing patients in a Phase II pilot study evaluating ACH-3102 in combination with ribavirin for 16 treatment-naive individuals with chronic genotype 1b HCV.
Patients will be treated with 225mg of ACH-3102 on the first day followed by once-daily 75mg doses of ACH-3102 in combination with twice-daily ribavirin for the other 13 days of the clinical trial. The primary objective is to determine the safety and sustained virologic response 12 weeks after treatment (SVR12).
Secondary endpoints include safety, pharmacokinetics, pharmacodynamics and virologic endpoints that include rapid virologic response (RVR) and extended RVR (eRVR). Initial RVR results will be reported during the fourth quarter of 2012.
sovaprevir
A Phase II clinical trial for ACH-3102 in combination with sovaprevir is expected to begin before the end of 2012 after completion of a drug-drug interaction study. "We are looking at, between now and mid-2013, completing early Phase II studies with both of the combinations," Dr Deshpande said.
If ACH-3102 is successful in combination with ribavirin and in combination with sovaprevir, both combinations will move into larger Phase III studies.
In August, Achillion reported that sovaprevir achieved sustained viral response (SVR4) rates of 85-100% percent in an ongoing 12-week, multi-dose Phase II clinical trial evaluating the once-daily protease inhibitor in combination with pegylated interferon plus ribavirin (P/R) followed by another 12 weeks of P/R (scripintelligence.com, 10 August 2012).
The company has not determined when or if it will study ACH-3102 in combination with its second-generation, pan-genotypic protease inhibitor ACH-2684, which also has completed Phase I clinical trials.
ACH-2684 achieved a mean maximum 3.73 log10 reduction in HCV RNA after three days of once-daily 400mg dosing in a Phase Ib study. In May, Achillion said it expected to report longer-term safety data from a Phase Ia study in the third quarter of 2012.
Dr Deshpande said ACH-2684 is a very potent protease inhibitor and based on certain characteristics of the compound it is worth evaluating in difficult to treat HCV populations, such as patients with cirrhosis or HIV.
He also said that Achillion has at least three good options based on its ongoing clinical trials. Those options depend on the results of the two Phase II ACH-3102 studies in combination with ribavirin and with sovaprevir as well as the results of early studies with the company's three lead HCV drug candidates in combination with other firms' compounds.
"We are evaluating compounds from other companies that would complement what we have currently," Dr Deshpande said.
Achillion has the capital it needs for the two Phase II ACH-3102 combination studies, since it had $60 million in cash and investments at the end of the second quarter of 2012 and the company raised $41.8 million through a registered direct offering of common stock to funds managed by QVT Financial in early September.
Dr Deshpande said interim data will be available from the ACH-3102 plus ribavirin study at the end of 2012 or early next year, which will offer a look at the effectiveness of the combination therapy after one week of treatment.