Replies to post #33805 on Biotech Values

[rwwine]

Re: Overview of HCV Therapies in Development

Dew, very nice summary and very much appreciated. Thank you,

Rich

[jellybean]

Thanks for the post, Dew. A few comments.

---Last fall at the AASLD meeting, it was reported that ITMN-A and ITMN-B were 1,000x more potent against HCV mutants that VX-950 or BILN-2061. What that means exactly, I can't say until numbers are published for the rate of HV resistance with ITMN-A/B. Here's the link. You will hve to scroll through all the preclinical abstracts to find Intermune, but if you are truly interested in HCV the scroll is worth it. http://www.hcvadvocate.org/news/reports/AASLD_2005/11%2013%20HCV%20Tx%20Pre%20and%20Early%

---the report did not mention Kamakura's work which has identified sphinoglipid biosynthesis as a new target for HCV and a secondary fungal metabolite which disrupts the viral assembly process. Maybe the development is too early on or the project has been discontinued, but the company had an abstract at the AASLD meeting linked above. A nature abstract follows at the bottom.

--Finally, many people have questioned which animal showed the severe immune response in the Anadys tox studies. The link below is the PR from anadys' AASLD report last fall, and the actual abstract can be found in the AASLD meeting link above (although, I have to say that the abstract is poorly written in some places). Cynomolgus monkeys are the only preclinical animal mentioned in either of these. I do not know how similar monkey innate immune systems are to humans. However, I can say that rat and human innate immune systems diverge dramatically when it comes to toll-like receptors; and so, a severe resonse in a rat would leave room for hope. 20Dev.htmhttp://ir.anadyspharma.com/phoenix.zhtml?c=148908&p=irol-newsArticle_Print&ID=782461&hig...

Nature Chemical Biology 1, 333-337 (2005)
doi: 10.1038/nchembio742

Host sphingolipid biosynthesis as a target for hepatitis C virus therapy
Hiroshi Sakamoto1, Koichi Okamoto1, Masahiro Aoki1, Hideyuki Kato1, Asao Katsume1, Atsunori Ohta1, Takuo Tsukuda1, Nobuo Shimma1, Yuko Aoki1, Mikio Arisawa1, Michinori Kohara2 and Masayuki Sudoh1

Top of pageAn estimated 170 million individuals worldwide are infected with hepatitis C virus (HCV), a serious cause of chronic liver disease. Current interferon-based therapy for treating HCV infection has an unsatisfactory cure rate1, 2, and the development of more efficient drugs is needed. During the early stages of HCV infections, various host genes are differentially regulated3, and it is possible that inhibition of host proteins affords a therapeutic strategy for treatment of HCV infection. Using an HCV subgenomic replicon cell culture system, here we have identified, from a secondary fungal metabolite, a lipophilic long-chain base compound, NA255 (1), a previously unknown small-molecule HCV replication inhibitor. NA255 prevents the de novo synthesis of sphingolipids, major lipid raft components, thereby inhibiting serine palmitoyltransferase, and it disrupts the association among HCV nonstructural (NS) viral proteins on the lipid rafts. Furthermore, we found that NS5B protein has a sphingolipid-binding motif in its molecular structure and that the domain was able to directly interact with sphingomyelin. Thus, NA255 is a new anti-HCV replication inhibitor that targets host lipid rafts, suggesting that inhibition of sphingolipid metabolism may provide a new therapeutic strategy for treatment of HCV infection.

[nerdseeksblonde]

recent polymerase + protease result:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&l...

[DewDiligence]

Valeant’s Viramune Inferior to Ribavirin in HCV Efficacy

[“Inferior” in the sense that this trial failed to establish non-inferiority: the Viramune arm produced an SVR of only 40% while the ribavirin arm produced an SVR of 55%. (Viramune is a prodrug of ribavirin.) Despite these poor results and similarly poor results in a prior trial, VRX is not giving up and will attempt to attain suitable Viramune efficacy at a higher dose in a new trial.]

http://biz.yahoo.com/bw/060912/20060912005562.html?.v=1

>>
Valeant Pharmaceuticals Reports VISER2 Results for Viramidine(R)

Tuesday September 12, 6:30 am ET

Company Initiates Phase 2b Weight-Based Dose-Ranging Study

COSTA MESA, Calif.--(BUSINESS WIRE)--Sept. 12, 2006--Valeant Pharmaceuticals International (NYSE: VRX ) today reported summary results of VISER2, the second of two Phase 3 pivotal trials, for Viramidine®. The company is developing Viramidine (taribavirin hydrochloride), a nucleoside (guanosine) analog prodrug of ribavirin, in oral form, for administration in combination with a pegylated interferon for the treatment of chronic hepatitis C in treatment-naive patients. The VISER2 trial included two co-primary endpoints: one for safety (superiority to ribavirin in the incidence of anemia) and one for efficacy (non-inferiority to ribavirin in sustained viral response, SVR).

The VISER2 study did not meet the non-inferiority efficacy endpoint on an intent-to-treat (ITT) basis, with overall SVR rates of 40 percent versus 55 percent for the Viramidine and ribavirin arms, respectively. However, consistent with the results seen in VISER1, SVR rates in VISER2 trended higher among patients receiving increased exposure on a mg/kg basis in the Viramidine arm without a substantial increase in the anemia rate.

Consistent with results from the VISER1 trial released earlier in the year, VISER2 confirmed the safety advantages of Viramidine. Anemia rates (Hgb less than 10g/dL) during the treatment period were significantly lower in patients treated with Viramidine than those treated with ribavirin (6 percent versus 22 percent; p less than 0.001).

As a result of the combined VISER1 and VISER2 data, the company also announced that it is initiating a Phase 2b program to evaluate the efficacy of Viramidine at higher doses. The Phase 2b program is a multi-center, randomized, parallel, open-label study in 240 treatment naive, genotype-one patients and will evaluate Viramidine at 20 mg/kg, 25 mg/kg, and 30 mg/kg per day in combination with pegylated interferon alpha-2b. There also will be a control group comprised of ribavirin and pegylated interferon alpha-2b. Treatment duration will be 48 weeks with a post-treatment follow-up period of 24 weeks. Based on a 12-week interim analysis of this study, the company will decide whether to begin a third Phase 3 study at the appropriate higher dose indicated by the Phase 2b study. The company will seek to co-develop the product should it decide to pursue another phase 3 registration trial next year.

Timothy C. Tyson, president and chief executive officer, said, "As expected, VISER2 results were consistent with those seen in VISER1. Although VISER1 and 2 did not meet non-inferiority efficacy endpoints, Viramidine demonstrates meaningful clinical efficacy. Our retrospective analyses of 750 patient plasma samples indicate that Viramidine could be as effective as ribavirin at higher doses. These analyses, coupled with feedback from the medical community that there will continue to be a strong need for ribavirin or ribavirin analogues in the treatment of hepatitis C, indicate that further clinical testing is prudent. Our Phase 2b program should provide us with sufficient information at little relative cost and time to confirm the dose response, select an appropriate dose, test safety at higher doses, establish the path for registration of the drug and make a go/no-go decision."

The company also announced the issuance of a U.S. patent for Viramidine for use in the treatment of hepatitis C, which will not expire until 2020.

The following table summarizes the anemia and SVR rates for both VISER1 and VISER2:

VISER1 and VISER2: Safety and Efficacy

(Intent-to-Treat Analysis)



Anemia (Hgb less than Sustained Virologic

10g/dL) Response(a)

------------------- ------------------------ -------------------------

Study Viramidine Ribavirin Viramidine Ribavirin

------------------- ------------ ----------- ------------ ------------

VISER1 (N=970) 5% 24% 38% 52%

------------------- ------------ ----------- ------------ ------------

VISER2 (N=962) 6% 22% 40% 55%

------------------- ------------ ----------- ------------ ------------



(a) Percent of Patients with Undetectable HCV RNA; NGI SuperQuant

Assay, sensitivity to 39 IU/mL (100 copies/mL)

Additional planned analyses of VISER1 and VISER2 data based on weight (mg/kg) indicated that SVR was improved with increased mg/kg concentrations while preserving the safety benefit as summarized below:

VISER1 and VISER2: Viramidine Exposure Analysis

Percent of Patients with Undetectable HCV RNA

(Intent-to-Treat Analysis)



VISER1 VISER2

------------------- ------------------------- ------------------------

Anemia Anemia

(Hgb less (Hgb less

than 10 than 10

Viramidine Exposure N SVR g/dL) N SVR g/dL)

------------------- ------ ------- ---------- ------ ------ ----------

greater than or

equal to 13 mg/kg 179 32% 4% 171 26% 4%

------------------- ------ ------- ---------- ------ ------ ----------

greater than 13-15

mg/kg 147 31% 4% 164 42% 2%

------------------- ------ ------- ---------- ------ ------ ----------

greater than 15-18

mg/kg 182 38% 7% 190 47% 8%

------------------- ------ ------- ---------- ------ ------ ----------

greater than 18

mg/kg 138 52% 7% 119 48% 13%

------------------- ------ ------- ---------- ------ ------ ----------

The majority of adverse events other than anemia and gastrointestinal side effects were similar between treatment groups. The anemia rate was lower in the Viramidine arm, while the gastrointestinal rate was lower in the ribavirin arm. The most common other adverse events associated with combination therapy included fatigue, headache, insomnia, depression and myalgia.

VISER2 Trial Design

The VISER2 trial (VISER stands for VIramidine's Safety and Efficacy vs. Ribavirin) evaluated a fixed 600 mg BID dose of Viramidine to a weight-based 1,000/1,200 mg daily dose of ribavirin, both in combination with peginterferon alfa 2a. The study, conducted in the United States, Canada, Europe, Israel, Argentina and Australia, enrolled 962 treatment-naive subjects with chronic HCV. Treatment duration was based on genotype, with genotypes 2 and 3 receiving 24 weeks of treatment and genotype non 2, 3 receiving 48 weeks of treatment, each with a post-treatment follow-up period of 24 weeks. The study was stratified for genotype, weight and viral load.

Additional information regarding the Phase 3 trial will be furnished by the company today with the Securities and Exchange Commission on Form 8-K and is also available on the company's Web site at www.valeant.com.

Viramidine is an investigational compound that has not been found by the Food and Drug Administration (FDA) or any other regulatory agency to be safe or effective in the diagnosis, mitigation, treatment or cure of any disease or illness. It may not be sold or promoted in the United States unless and until FDA has approved a New Drug Application. Similar restrictions apply in other countries.

About Valeant

Valeant Pharmaceuticals International (NYSE:VRX - News) is a global specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of neurology, infectious disease and dermatology. More information about Valeant can be found at www.valeant.com. Viramidine is a registered trademark of Valeant Pharmaceuticals International or its related companies. All other trademarks are the trademarks or the registered trademarks of their respective owners.
<<

[DewDiligence]

Updated HCV Scorecard

Programs killed during 2007:

HCV-796 ( WYE / VPHM )
NM283 ( NVS / IDIX )
Actilon ( COLY )
ANA975 ( ANDS )
XTL-2125 ( XTLB )
AVI-4055 ( AVII )

Programs on ‘life support’ or unlikely (IMO) to succeed:

R1626 ( Roche )
Celgosivir ( Migenix )
Bavituximab ( PPHM )