This year’s American Association for the Study of Liver Disease (AASLD) conference included information on many new drugs under development to treat hepatitis C, so much in fact that it is difficult to include all the new drugs that were presented at AASLD – the result being that I will not report on the pre-clinical data presented at AASLD. Even excluding the pre-clinical trials, there is so much information to include that the report will be divided into two parts that will appear in the December 2008 and the January 2009 HCV Advocate newsletter.

It’s amazing how far HCV drug development for treating hepatitis C has advanced over the years. Just 5 years ago at the November 2003 AASLD conference I reported on the first HCV protease inhibitor that entered into human trials – BILN 2061. I also reported on the pre-clinical data on VX-950 (telaprevir), early data on a long acting type of interferon (Albuferon) and a prodrug of ribavirin called viramidine.

Since 2003, the clinical development of BILN 2061 has been halted due to safety concerns, and so far viramidine has not been shown to be as effective as ribavirin. However, the good news is that telaprevir is still going strong, is now in Phase III clinical trials and has been shown to be safe, well-tolerated, and more effective than current treatments. Albuferon is also in Phase III studies, but, unfortunately, the once a month dosing arms of the clinical trials had to be discontinued due to pulmonary (lung) problems. It looks like the once every 2 weeks dosing is still a viable option although the effectiveness of albuferon does not seem to be any better than pegylated interferon. But all in all the data presented at this year’s conference on HCV drugs in development are very encouraging.

Telaprevir
The final and interim results from various studies of Vertex’s telaprevir, an HCV protease inhibitor, were released at this year’s conference.

PROVE 3: interim data on 453 patients who did not achieve a sustained virological response (SVR) with a previous course of pegylated interferon plus ribavirin – non-responders, relapsers and viral breakthroughs – was presented. This included the interim results from the arms that received 12 weeks of telaprevir in combination with pegylated interferon plus ribavirin followed by 12 weeks of pegylated interferon plus ribavirin (without telaprevir). HCV RNA negative was defined as less than 10 IU/mL).

Note: the results given are SVR12 (12 weeks after treatment ends) and SVR24 (24 weeks after treatment ends) and the totals are combined:

Overall SVR results	52% (60 out of 115 patients-total)
Non-responders	41% (27 out of 66 patients)
Relapsers	73% (29 of 40 patients)
Breakthroughs	44% (4 of 9 patients)

Results for the control arm group (48 weeks of pegylated interferon plus ribavirin) are still pending.

The side effect profile is consistent with pegylated interferon except there were higher incidences of pruritus (itching) and rashes, including severe rashes. Sixteen percent of patients in the telaprevir-based arms discontinued treatment due to adverse events (side effects) compared to 4% in the group that received pegylated interferon plus ribavirin (without telaprevir).

Study 107
Study 107 is another clinical trial that is evaluating the use of telaprevir in HCV prior non-responders, partial responders, relapsers and viral breakthroughs. The patients in this study were people who were enrolled in the control arm (pegylated interferon/ribavirin without telaprevir) of a previous telaprevir study.

The interim results at week 24 are listed below by type of prior response. HCV RNA negative is defined as <10 IU/mL:

Null-reponders	43% (18 of 42 pts)
Partial responders	82% (18 of 22 pts)
Relapsers	83% (5 of 6 pts)
Breakthroughs	0% (0 of 1 pt)

The safety profile is consistent with other studies of telaprevir, pegylated interferon and ribavirin.

Prove 2
The final PROVE 2 study results of 323 HCV genotype 1 treatment-naïve patients (never been treated) were also released at this year’s AASLD conference. HCV RNA negative was defined as < 10 IU/mL. The results showed that the 24-week arm (12 weeks of telaprevir plus pegylated interferon plus ribavirin followed by 12 weeks of pegylated interferon plus ribavirin without telaprevir) had the highest SVR rate, 69%, (56 out of 81 patients) compared to 46% (38 out of 82 patients) in the arm that received 48 weeks of pegylated interferon plus ribavirin (control arm). The side effect profile was consistent with the side effects reported above. Fourteen percent of patients discontinued treatment due to adverse events compared to 7% in the control group who received pegylated interferon plus ribavirin (without telaprevir).

Study C208
Study C208 is a newer study that is evaluating different doses of telaprevir – 750 mg every 8 hours (q8h or three times a day) compared to a 1125 mg dose every 12 hours (q12h or twice a day) in HCV genotype 1 treatment-naïve patients. In addition, the two different brands of pegylated interferon – alfa-2a (Pegasys) and alfa-2b (PegIntron) – were used. The previous studies of telaprevir only included Pegasys.

The very preliminary results of patients who were undetectable (less than 10 IU/mL) at week 12 are listed below by dose and pegylated product:

q8h alfa-2a	93% (37 out of 40 pts)
q8h alfa-2b	93% (39 out of 42 pts)
q12h alfa-2a	83% (33 out of 40 pts)
q12h alfa-2b	85% (33 out of 39 pts

To date 13 patients have discontinued therapy due to adverse events – 6 patients in the q8h and 7 patients in the q12h arms. A total of 9 patients had viral breakthrough – 4 patients in the q8h and 5 patients in the q12h.

If the results between the different dosing schedules can be carried through to the end of the trial and the results of this trial can be replicated in a larger study, a twice-a-day dose of telaprevir may be a future option.

The results from these studies are very encouraging, showing higher treatment response rates in a variety of populations with HCV genotype 1 including treatment-naïve patients and patients who have not achieved an SVR with a prior course of pegylated interferon and ribavirin therapy. Telaprevir began Phase III studies in March 2008 and it is believed that Vertex will apply to the Food and Drug Administration for approval to market telaprevir for the treatment of chronic hepatitis C in 2010-2011.

New Study – 3 Antivirals, No Interferon:
Roche, InterMune, Inc, and Pharmasset jointly announced on November 10 a new study called INFORM-1 to evaluate the safety and antiviral activity of three antivirals – R7227 (ITMN-191) an HCV protease inhibitor, R7128 an HCV polymerase inhibitor and ribavirin.

This will be the first clinical trial combining three antiviral medications without the use of interferon as a possible treatment of hepatitis C.

The study will evaluate the three antiviral medications in HCV genotype 1 treatment-naïve patients. The clinical study will be conducted in Australia and New Zealand. Hopefully, this first of its kind study for treating hepatitis C will usher in a new era that will include many combinations of antivirals to treat hepatitis C, and which may ultimately lead to therapies that do not contain interferon or ribavirin.

Boceprevir
Interim results from Schering’s HCV protease inhibitor, boceprevir, were also presented at AASLD. The SPRINT-1 study was a very complex study that included 5 treatment arms. The study population consisted of HCV genotype 1 treatment-naïve patients. The results below are listed by treatment arm.

Sustained Virological Response (SVR12 & SVR24)

Treatment Arm	All patients
a) No lead-in, 28 weeks	55% SVR 24 (59 out of 107 pts)
b) Lead-in, 28 weeks	56% SVR 24 (58 out of 103 pts)
c) No lead-in, 48 weeks	66% SVR 12 (68 out of 103 pts)
d) Lead-in, 48 weeks	74% SVR 12 (76 out of 103 pts)
e) P/R control, 48 weeks	38% SVR 12 (39 out of 104 pts)

a) Boceprevir, PegIntron, ribavirin (no lead-in phase) – total treatment duration = 28 weeks.

b) PegIntron, ribavirin for 4 week lead-in followed by boceprevir, PegIntron, ribavirin for 24 weeks – total treatment duration = 28 weeks

c) Boceprevir, Pegintron, ribavirin (no lead-in phase) – total treatment duration = 48 weeks.

d) PegIntron, ribavirin for 4 weeks followed by boceprevir, PegIntron, ribavirin for 44 weeks – total treatment duration = 48 weeks.

e) Control group that received only PegIntron, ribavirin – total treatment duration = 48 weeks.

*Dosing: PegIntron 1.5 ug/kg once a week, ribavirin 800-1400 mg/day & boceprevir 800 mg/3 times a day.

Results for the boceprevir arm and control arm that included low-dose ribavirin are still pending.

The side effects reported were similar in the d) group (lead-in, 48 weeks) compared to the e) control group except for higher prevalences of fatigue (71% vs. 55%), Anemia (56% vs. 34%), neutropenia (low white blood cells, 30% vs. 12%), taste changes (27% vs. 9%) and muscle pain (26% vs. 16%).

The increase in the SVR rates in group d (boceprevir lead-in phase,48 weeks treatment duration) is very impressive. Schering began their Phase III studies in May 2008 and they are expected to apply to the FDA for marketing approval sometime in 2010 or 2011.

Nitazoxanide
At last year’s AASLD nitazoxanide (brand name Alinia) burst upon the HCV treatment scene with impressive results as an add-on to Pegasys and ribavirin therapy. Nitazoxanide is approved to treat diarrhea that is caused by Cryptosporidium parvum and Giardia lamblia, and has been found to have only mild side effects. A last year’s conference, a 12 week lead-in phase of nitazoxanide followed by 36 weeks of nitazoxanide, Pegasys and ribavirin in genotype 4 treatment-naïve patients produced a 79% SVR (in the triple combo arm) for treatment-naïve patients and 25% SVR in the treatment-experienced patients. Since this time, Romark has launched a study on HCV genotype 1 patients.

At this year’s conference, information about a small study of 44 patients to evaluate effectiveness of a 4 week lead-in phase of nitazoxanide dosed at 500 mg twice a day (taken with food) followed by the combination of nitazoxanide and pegylated interferon (no ribavirin used) for 36 weeks was released. The SVR results are listed below:

100% SVR	3 of 3 HCV genotype 1 patients
100% SVR	1 of 1 HCV genotype 2 patient
78% SVR	31 of 40 HCV genotype 4 patients

The authors commented that a 12-week nitazoxanide lead-in phase can be reduced to 4 weeks without compromising SVR rates. It was also concluded that more studies are needed to compare the effectiveness of nitazoxanide in combination with pegylated interferon with and without ribavirin in treatment-naïve and treatment-experienced patients. Imagine that – a possibility of eliminating ribavirin from combination treatment. Of course, much larger studies are needed to confirm these findings.

Drugs in Early Clinical Development

R7128 is an HCV polymerase inhibitor that is being developed by Pharmasset and Roche. Preliminary results from studies on HCV genotype 1 treatment-naïve and treatment-experienced patients have resulted in impressive HCV RNA (viral load) reductions. Based on various studies, Pharmasset will further develop the 1000 mg dose TID (twice a day) in HCV genotype 1 treatment-naïve patients and the 1500 mg dose TID in HCV genotype 1 treatment-experienced patients – both doses in combination with Pegasys plus ribavirin.

What about HCV genotypes 2 or 3? At this year’s conference a study of R7128 in people with HCV genotype 2 or 3 who either were prior treatment non-responders or relapsers was released at AASLD. Patients were given R7128 (1500 mg twice a day) in combination with Pegasys plus ribavirin for 28 days or placebo/Pegasys/ribavirin. At the end of the treatment period there was a mean decrease in HCV RNA of 5.0 log10 in the R7128 arm compared to a 3.7 log10 in the placebo arm. No serious adverse events were reported and the side effects reported in the R7128 group were similar to the group that did not receive R7128. More studies are being planned.

ITMN-191 is an HCV protease inhibitor being developed by InterMune and Roche. The results from a monotherapy study of HCV genotype 1 treatment-naïve and treatment-experienced patients were released. In the study there were 50 patients who received doses up to 600mg (every 12 hours or every 8 hours) or placebo for 14 days. The mean reduction in the 200 mg every 8 hours group by day 14 was 3.8 log10 in treatment-naïve. In the treatment-experienced patients the median viral load reduction was 2.5 log10. The reduction in HCV RNA was dose dependent. The doses were considered safe and were well-tolerated with only one serious adverse event reported – vertigo – that was not considered related to the study drug.

AASLD 2008—Drugs in Development: Part 2
Alan Franciscus, Editor-in-Chief

In last month’s HCV Advocate newsletter I wrote about many new drugs in development to treat hepatitis C that were presented at the American Association for the Study of Liver Diseases (AASLD) conference. The report included four studies on telaprevir as well as the results on boceprevir, nitazoxanide, R7128, and ITMN-191. This month I will report on studies of drugs that are in an earlier phase of clinical development: TMC435, BI 201335, PF-00868554, GI-5005 (a DNA based HCV vaccine) and farglitazar (anti-fibrotic).

TMC435

TMC435 (formerly TMC435350) is a new HCV protease inhibitor that is being developed by Tibotec Pharmaceuticals Ltd. One poster presented data on cloned HCV genotype 1 through 6 proteases that found TMC435 was a potent inhibitor of the serine protease in all genotypes tested.

In another poster two groups of patients were studied – healthy patients and patients infected with hepatitis C.

In the group of healthy volunteers the once-a-day 200 mg dose was to evaluate the safety, antiviral activity and pharmacokinetics (absorption, distribution, metabolism and excretion) of TMC435. The 200 mg capsule formulation reached a steady state in 7 days.

In yet another study, 48 HCV-infected patients received either the 25 mg or 75 mg dose (once a day) given as a monotherapy or in combination with pegylated interferon plus ribavirin. After 7 days of treatment there was a mean viral load reduction of 2.63 log10 IU/mL in the 25 mg arm and 3.43 log10 IU/mL in the 75 mg/day arm both given as monotherapy. The triple combination arm (TMC435, pegylated interferon, ribavirin) given for 28 days produced a mean viral load reduction of 3.47 log10 IU/mL in the 25 mg arm and 4.55 log10 IU/ml in the 75 mg/day arm.

The most common adverse events reported were nausea, diarrhea, and headache – no serious adverse events were reported.

BI 201335

Boehringer Ingelheim’s BI 201335 is an HCV protease inhibitor that is in early clinical development. Information about the safety, antiviral activity and pharmacokinetics of BI 210335 in HCV genotype 1 treatment-naïve patients and treatment-experienced patients were presented.

The treatment-naïve study was divided into two parts, the first part of which was a monotherapy study evaluating 4 doses of BI 201335 (20, 48, 120, 240 mg or placebo) for 14 days. If a patient had ≥ 1 log10 decrease in HCV RNA they were rolled over to the second part of the study that included BI 201335 plus Pegasys and ribavirin from day 15 through day 28. All of the patients in the study (except one patient in the 20 mg arm) achieved greater than 2.8 log10 drop in HCV RNA. The maximal HCV RNA reduction was 2.9 log10 (20 mg) to 4.0 log10 (240 mg) which was achieved within 2-4 days. The drug was generally safe and well-tolerated with no dose dependent increase in adverse events. The only case for concern was a dose dependent change in bilirubin.

The second study included 19 treatment experienced patients who did not achieve more than a 2 log10 reduction in HCV RNA with a previous course of pegylated interferon plus ribavirin. The patients were given doses of 48, 120, or 240 mg (once daily) in combination with Pegasys plus ribavirin for 28 days. The maximal HCV RNA reduction was 5.0 log10 (48 mg) to 5.3 log10 (240 mg) during the 28 days of treatment. BI 201335 was found to be safe and well-tolerated with no severe adverse events except the usual side effects seen in people who receive pegylated interferon plus ribavirin.

The antiviral activity of the once a day dose of BI 201335 was remarkable and further clinical trial development is expected.

PF-00868554

Pfizer’s entry into HCV drug development is an HCV polymerase inhibitor PF-00868554. Two studies were released at AASLD – one was on the safety, tolerability and pharmacokinetics of PF-00868554 dosed in healthy volunteers, and the other poster measured the antiviral activity in HCV genotype 1 infected patients.

In the first study of healthy volunteers, 33 male patients were randomized to receive 50,100, and 300 mg BID (twice a day), and one group received 300 mg TID (three times a day) for 14 days. The researchers found that the drug was safe and well-tolerated at all doses and drug plasma concentrations were achieved that would be expected to inhibit HCV RNA replication.

The second study included 32 HCV treatment-naïve genotype 1 male patients who received the same doses listed above for 7 days. The drugs were found to be safe and well-tolerated and the HCV antiviral activity was dose dependent with mean reductions in HCV RNA from -0.97 to -2.13 log10. Based on these results Pfizer has initiated a study of PF-0086854 in combination with pegylated interferon alpha-2a and ribavirin.

GI-5005

GlobeImmune’s therapeutic vaccine study of GI-5005, used with and without pegylated interferon plus ribavirin in 140 HCV genotype 1 treatment-naïve and non-responders was presented in a poster. In the monotherapy phase of the study no patients discontinued therapy due to adverse events. In the pegylated interferon/ribavirin therapy (without GI-5005), 5 patients discontinued therapy due to side effects. In the triple therapy arm 3 patients discontinued therapy due to side effects, but the investigators did not attribute the side effects to GI-5005.

The authors reported that in the triple therapy arm that was given to HCV patients with a high viral load (>600,000 IU/mL) the patients showed a 2.6-fold improvement in RVR rates compared to those who received just pegylated interferon/ribavirin. Based on these results the authors suggested that GI-5005 may increase the rate of HCV clearance.

Farglitazar

Given the amount of people who do not respond to current HCV therapies it is of the utmost importance that other options to help with HCV disease progression are developed. An area that is vitally important is the development of anti-fibrotic medications to treat moderate to severe HCV disease progression. There are currently clinical trials underway on a variety of anti-inflammatory and anti-fibrotic drugs such as PF-03491390, MitoQ, CTS-1027, and farglitazar. Unfortunately, the results from a trial of farglitazar (G1262570) in 177 people with chronic hepatitis C who had moderate fibrosis did not show any benefit when given various doses of Farglitazar. Hopefully, the other drugs in current clinical development and new anti-fibrotic drugs will be developed to help stop or reverse disease progression.

There are currently clinical trials underway on a variety of anti-inflammatory and antifibrotic drugs such as PF-03491390, MitoQ, CTS-1027, and farglitazar.

http://www.hcvadvocate.org/news/newsLetter/2009/advocate0109.html