HCV Drugs —Alan Franciscus, Editor-in-Chief

In this month’s column, there is more good news about drugs in development.  Achillion is developing a potential treatment for genotype 1 that could shorten treatment time to 6 weeks.  However, there is also some disappointing news from the Food and Drug Administration (FDA)—they are rescinding the “breakthrough therapy designation” for hepatitis C drugs.  Other news which is also disappointing is that the ‘one-shot’ cure for hepatitis C does not look as if it is going to pan out.  Finally, data released from a small trial with sofosbuvir, pegylated interferon and ribavirin to treat genotype 2 and 3 shows that it may help cure some people with genotype 3 and advanced liver disease.

 

Achillion
Achillion has had HCV drugs in development for almost as long as the HCV Advocate has been reporting on HCV inhibitors.  Their latest drug and clinical trial—ACH-3102—combined with sofosbuvir (brand name Sovaldi)—was given to 12 HCV genotype 1 treatment-naïve patients for 6 weeks.  One hundred percent (12 of 12 patients) achieved SVR 12 (virologic cure).  Achillion is exploring additional trials with their other HCV inhibitors and perhaps shorter treatment durations (4 and 6 weeks).  Don’t pin all your hopes on this though—there were only 12 patients in the trial.  The combination should be studied in more people and the theory of treating for 4 or 6 weeks needs to be tested.  However, it is worth keeping an eye on.

FDA
The FDA is rescinding its “breakthrough therapy designation status” from Bristol-Myers Squibb for Daclatasvir and Merck for its combination of elbasvir (MK-8742) and grazoprevir (MK-5712). “Breakthrough therapy designation status” is given to drug(s) that demonstrate a substantial improvement over existing therapies.  Now that we have drugs that can cure over 90% of people with genotype 1 the newer drugs are unlikely to improve the cure rates.  The standard time it takes the FDA to review an application for approval is about 10 months.  Based on this it is unlikely that any new HCV drugs will be approved until 2016—at least for genotypes 1, 2 and 4.  This is unfortunate because it limits treatment choices for patients, and it affects the price of drugs already on the market.  What about genotype 3?  There is clearly a need for better therapies with shorter treatment durations.

Regulus
We have been following an on-going study of RG-101 as a possible treatment for genotype 1 that would require only one shot—yes you read that right – a possible one-shot treatment.  In a small study (2 mg/kg) dose, it was reported that 6 of 14 patients were undetectable 57 days after receiving the shot.  However, unfortunately, after 12 weeks that number dropped to only 4 patients.  Regulus started another study at a higher dose of RG-101 (4 mg/kg), but even at the higher dose the interim results (9 of 14 patients undetectable 57 days post-shot) cure rates were not as high as the current standard of care.

There is also the possibility that the single shot can be given in combination with 4 weeks of antiviral pills.  No side effect profile was given—an important issue since the current therapy has a low side effect profile.

Sofosbuvir/PEG/RBV
Current standard of care (SOC) treatment for genotypes 2 and 3 is the combination of sofosbuvir plus ribavirin.  The cure rates in the Phase 3 clinical trials of treatment-experienced patients with cirrhosis included:

• Genotype 2 = 88% (12 weeks)
• Genotype 3 = 60%  (24 weeks)

While the genotype 2 cure rates are impressive the genotype 3 rates were less than optimal and a 24-week course of treatment is a considerable period of time and expense.  Additional therapies are needed, but in this case perhaps interferon may be an option.

The current phase 2 study included 47 treatment-experienced patients—23 genotype 2 patients (14 with cirrhosis); 24 genotype 3 patients (12 with cirrhosis).  Treatment duration was 12 weeks.  The treatment was sofosbuvir, pegylated interferon (PEG) and ribavirin.

 

Genotype 2:  Cure rates = 93% (without cirrhosis); 96% (with cirrhosis).

The cure rates for genotype 2 were similar to the cure rates seen with sofosbuvir plus ribavirin—needless to say there is no need (or desire) to include PEG.

Genotype 3:  Cure rates = 83% with and without cirrhosis.

Clearly, much higher cure rates than 24 weeks of sofosbuvir plus ribavirin (without PEG).

There were 4 patients who had 5 serious side effects mostly related to interferon and ribavirin.

Adding pegylated interferon, however, may be an alternate therapy for genotype 3.  This regime is listed in the Guidance documents of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) for those who can tolerate 12 weeks of PEG therapy.

There are many therapies in development to treat genotype 3 (BMS, Gilead, Merck).  I hope that the FDA will recognize the need for newer therapies for genotype 3 that produce higher cure rates—especially for treatment-experienced patients with cirrhosis—that have fewer side effects and grant them “breakthrough therapy” designation.  That part of the articles about Merck and BMS losing their “breakthrough designation” status was not that clear.


http://hcvadvocate.org/news/newsLetter/2015/advocate0315.html#1

Could This Be The Biggest Advance in Hepatitis C since Gilead Sciences' Sovaldi?

Tiny biotech stock Achillion Pharmaceuticals (NASDAQ: ACHN ) reported what could be pretty big news for hepatitis C patients this week. The clinical stage biotechnology company released data showing that combining its ACH-3102 with Gilead Sciences' (NASDAQ: GILD ) Sovaldi achieved 100% cure rates in as little as six weeks of treatment. The success of that combination is prompting Achillion to launch a study of the two drugs over an even shorter 4-week dosing period. If that study pans out, it could be the biggest advance in hepatitis C treatment since Sovaldi won approval in 2013.

Read more....

UPDATED: Buoyed by 6-week hep C data, Achillion sets out to test even faster cure

While Regulus was getting dinged this morning following some careful scrutiny of its latest hep C data, Achillion came out on top with new trial results which demonstrated that a combination of its NS5A inhibitor and Gilead's Sovaldi triggered a 6-week cure among all of the patients in a small study. And now researchers are using the data to set the stage to see if the results can be replicated even faster in a 4-week trial.

Investigators found that 50 mg of ACH-3102 and 400 mg of sofosbuvir did the trick for 12 out of 12 treatment-naive genotype 1 patients. CEO Milind Deshpande touted the results as the shortest duration, highest response results yet seen. He added: "Given the exceptional profile of ACH-3102, we will now be evaluating four- and six-week treatment durations that leverage all of our HCV assets including ACH-3102, ACH-3422, and sovaprevir."

Achillion is still looking to enter a fast-crowding marketplace. Competing drugs from Gilead and AbbVie have forced out earlier standard remedies with oral combos that are much easier to tolerate and much more likely to provide a lasting cure. The goal now is to find ways to do it quicker and with less expense, providing an opening for some of the companies still in the hunt.


Read more...

Achillion Achieves 100% SVR12 in Phase 2 Trial Evaluating 6-Week Combination Treatment With ACH-3102

- Achillion achieves 100% SVR12 in six-week regimen with combination of ACH-3102 and sofosbuvir for treatment-naïve genotype 1 HCV -

- Achillion to initiate 4-week treatment regimens based on the strength of ACH-3102 antiviral data -

NEW HAVEN, Conn., Feb. 9, 2015 (GLOBE NEWSWIRE) --Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced updated interim results from the ongoing interferon-free, ribavirin-free, Phase 2 study to evaluate the efficacy, safety, and tolerability of six weeks of 50 mg of ACH-3102 and 400 mg of sofosbuvir, a marketed nucleotide polymerase inhibitor, in treatment-naïve genotype 1 HCV-infected patients. The primary objective of the study is determination of sustained viral response 12 weeks (SVR12) after completion of therapy. One hundred percent of patients (12/12) in the six-week treatment duration arm achieved SVR12, which included patients with high baseline viral load.

"The ability to further shorten treatment duration to only six weeks and maintain excellent SVR12 rates remains the goal for clinicians and patients, and I am pleased that these Phase 2 results support that goal. The profile of ACH-3102, represents an important and exciting treatment option to shorten treatment duration for patients infected with HCV," commented Professor Edward Gane, M.D., Deputy Director and Hepatologist, New Zealand Liver Transplant Unit, Auckland City Hospital in New Zealand, and Lead Investigator in the Phase 2 study of ACH-3102 and sofosbuvir and the ACH-3422 nucleotide inhibitor program.

Dr. Milind Deshpande, President and Chief Executive Officer of Achillion, commented, "Our goal is to deliver short duration, widely accessible treatments to all HCV patients. We believe that these results with ACH-3102 represent the shortest duration and highest response achieved to date with any two-drug, direct-acting antiviral regimen for HCV. Given the exceptional profile of ACH-3102, we will now be evaluating four- and six-week treatment durations that leverage all of our HCV assets including ACH-3102, ACH-3422, and sovaprevir."

Overview of Phase 2 Proxy Study Design and Top-line Results
This ongoing study is a Phase 2 open-label, randomized, partial-crossover study to evaluate the efficacy, safety, and tolerability of eight- and six weeks of 50 mg of ACH-3102 and 400 mg of sofosbuvir, a marketed nucleotide polymerase inhibitor, once daily, in treatment-naïve genotype 1 HCV-infected patients. Initially, eighteen patients were enrolled, including six observational patients, into an eight-week treatment cohort.

Following the achievement of 100 percent SVR12 (12/12) in the eight-week cohort, the six-week treatment cohort was initiated. In all, eighteen patients were enrolled, including twelve active and six observational patients. Mean baseline HCV RNA viral load was 10 million (7 log₁₀) IU/ml, range 2 million (6.23 log₁₀) - 97 million (7.99 log₁₀) IU/ml, including seven patients with baseline HCV RNA viral load exceeding 6 million (6.78 log₁₀) IU/ml. Of the 12 active patients enrolled, seven patients were genotype 1a and five were genotype 1b.

Twelve weeks after the completion of therapy, 100 percent (12/12) achieved SVR12, independent of baseline viral load, gender, and IL28B status, in the six-week treatment arm. Additionally, one hundred percent of patients (12/12) in the eight-week treatment duration arm have achieved SVR24. The combination of ACH-3102 and sofosbuvir was well-tolerated with no serious adverse events, no discontinuations due to adverse events, and no clinically significant laboratory or ECG abnormalities.
"The achievement of 100% SVR12 after six weeks of treatment with a dual NS5A-nucleotide regimen, even in patients with high baseline viral load who would otherwise require extended duration treatments, supports our belief that ACH-3102 can unleash the potential of this combination to drive down treatment duration," commented Dr. David Apelian, Executive Vice President of Clinical Development and Chief Medical Officer at Achillion. "We are currently preparing to initiate our SPARTA Phase 2 program which evaluates short treatment durations with our proprietary once-daily regimens of ACH-3102 and ACH-3422, with or without sovaprevir, for treatment naïve genotype 1 HCV patients. In parallel, we plan on exploring sofosbuvir-sparing regimens that will leverage shorter durations of sofosbuvir in combination with ACH-3102 and sovaprevir as part of our global development program."

Read complete press release here...