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 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.
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
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.
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:
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
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
Labels: ACH-3102 plus sofosbuvir, achillion, FDA breakthrough designation, Regulus, RG-101, Sofosbuvir/PEG/RBV