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AASLD 2014: ACH-3102 plus Sofosbuvir Cures All Hepatitis C Patients in Phase 2 Study

Achillion's second-generation HCV NS5A inhibitor ACH-3102 combined with sofosbuvir (Sovaldi) was well-tolerated and led to sustained virological response in all treatment-naive genotype 1 hepatitis C patients in a Phase 2 proxy study, according to late-breaking findings presented at the American Association for the Study of Liver Diseases (AASLD) Liver Meetinglast month in Boston. Another early study showed promising results for Achillion's nucleotide polymerase inhibitor ACH-3422.

The advent of interferon-free direct-acting antiviral regimens has brought about a new era of hepatitis C treatment. Recently approved regimens such Gilead Science's Harvoni (sofosbuvir/ledipasvir) and AbbVie's Viekira "3D" combination (paritaprevir/ombitasvir + dasabuvir) are highly effective and well-tolerated, but researchers continue to investigate new therapies that are active across multiple HCV genotypes, more effective for hard-to-treat patients, and allow a shorter duration of treatment. Such advances would be especially welcome if they come with a lower cost than current options.

Edward Gane from Auckland Hospital in New Zealand and colleagues presented interim results from a Phase 2 trial of ACH-3102, Achillion Pharmaceuticals' pan-genotypic (active against HCV genotypes 1 through 6) second-generation NS5A inhibitor. This study used Gilead's sofosbuvir (marketed separately as Sovaldi) as a proxy for Achillion's investigational drug ACH-3422, both being pan-genotypic uridine nucleotide HCV NS5B polymerase inhibitors. The ledipasvir in the Harvoni coformulation is a NS4A inhibitor, like ACH-3102, but it is active only against genotype 1.

This open-label crossover study included 30 previously untreated genotype 1 chronic hepatitis C patients without liver cirrhosis. Nearly two-thirds were men and the mean age was 47 years. Most (73%) had harder-to-treat HCV subtype 1a, a majority had high baseline HCV viral load (>6,00,000 IU/mL), and about half had unfavorable IL28B gene variants associated with poor interferon response.

In Cohort 1, 12 participants were randomly assigned to receive 50 mg ACH-3102 plus 400 mg sofosbuvir, both once-daily for 8 weeks, while 6 underwent monitoring without treatment for 12 weeks. After obtaining promising sustained virological response rates at 4 weeks post-treatment (SVR4), the study proceeded with Cohort 2, which included the 6 untreated patients from Cohort 1 and 12 new participants. The 6 untreated patients and half the new participants received ACH-3102 plus sofosbuvir for 6 weeks, while the rest were monitored without treatment for 10 weeks.

The AASLD poster reported interim findings for Cohort 1 and preliminary findings for patients in Cohort 2 who had completed treatment.

Results

• In Cohort 1, all 12 patients treated for 8 weeks achieved undetectable HCV RNA by week 5 and 100% went on to achieve sustained virological response at 12 weeks post-treatment (SVR12).
• In Cohort 2, all 5 of the 12 patients who completed therapy had undetectable HCV RNA at the end of treatment.
• ACH-3102 plus sofosbuvir was generally safe and well-tolerated.
• There were no serious adverse events or treatment discontinuations due to adverse events in Cohort 1.
• The most common adverse events were upper respiratory tract infections, sprains, insomnia, and headache.
• Laboratory abnormalities were generally mild, transient, and asymptomatic.
• The mean alanine aminotransferase level decreased from 99 to 34 IU/mL after starting therapy and stabilized at around 20 IU/mL in the active treatment arm, while decreasing only slightly in the untreated observational arm.
• There were no significant electrocardiogram or echocardiogram changes.

"Combination treatment with ACH-3012 and sofosbuvir for 8 weeks achieved rapid and sustained viral load decline with 100% SVR12," the researchers concluded. "Available data for 6 weeks of treatment with ACH-3012 and sofosbuvir has also demonstrated a rapid viral load decline."

In late December Achillion issued a press release providing further data from Cohort 2. The company reported that 100% of the 12 patients treated with ACH-3012 plus sofosbuvir for 6 weeks achieved SVR4, which is a good predictor of a cure. Again, treatment was well-tolerated with no serious adverse events and no discontinuations for this reason.

"The ACH-3102 Phase 2 results continue to support the best-in-class profile of our second-generation NS5A inhibitor," said Achillion president and CEO Milind Deshpande. "We believe the ability to achieve 100 percent SVR4 after only six weeks of therapy highlights the role ACH-3102 could play in unleashing the full potential of a NS5A-nuc combination regimen."

Achillion scientists also reported findings at AASLD from a laboratory study of ACH-3422 combined with various other drugs in HCV genotype 1b replicon models.

They found that ACH-3422 alone showed potency up to 7-fold greater than sofosbuvir against genotype 1 through 4 replicons. Short-term combination studies of ACH-3422 with ribavirin, ACH-3102, or 2 investigational HCV protease inhibitors (sovaprevir and ACH-2684) showed additive to synergistic antiviral potency. ACH-3422 demonstrated a high barrier to resistance both alone and in combination with the other agents.

The December press release also announced that a Phase 1 proof-of-concept study of healthy HCV-uninfected volunteers and treatment-naive genotype 1 patients showed that ACH-3422 was safe and well-tolerated at doses ranging from 50 to 700 mg once-daily. Again, there were no treatment-related serious adverse event, no discontinuations due to adverse events, and no clinically significant laboratory or ECG abnormalities.

ACH-3422 monotherapy produced a maximum HCV RNA decline of 4.8 log within 14 days using the highest dose, and 3 out of 6 treated patients achieved undetectable HCV RNA.

"[These] data, combined with the Phase 2 proxy study results, lead us to believe that the doublet regimen of ACH-3102 and ACH-3422 can be a highly competitive regimen to cure HCV," said Achillion vice president and chief medical officer David Apelian. "Furthermore, the ability to explore a triplet regimen with sovaprevir, our protease inhibitor, may allow for shorter treatment durations especially in harder-to-treat patient populations."

12/23/14

References

EJ Gane, H Kocinsky, C Schwabe, et al. Interim Sustained Virologic Response (SVR), Safety and Tolerability Results of 8-Week Treatment with ACH-3102 and Sofosbuvir in Chronic Hepatitis C (HCV), Genotype-1 (GT-1), Treatment-Naive Patients: A Phase 2 "Proxy" Study. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract LB-23.

D Patel, Y Zhao, JL Fabrycki, et al. Antiviral Activity and Resistance Emergence: Combinations of the NS5B Nucleotide Inhibitor ACH-3422 with Other Antiviral Agents in Vitro. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 1985.

Other Sources

Achillion Pharmaceuticals. Achillion Reports 100% SVR12 in a Phase 2 Combination Study With ACH-3102 at the Liver Meeting 2014 (AASLD). Press release. November 8, 2014.

Achillion Pharmaceuticals. Achillion Shows Potential for "Best-in-Disease" HCV Regimen -- 100% SVR4 Following a Dual 6-Week ACH-3102-Based Regimen and Separately a 4.8 Log₁₀ Reduction With ACH-3422. Press release. December 22, 2014.