Forbes.com: Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Posted 6/29/12 on Forbes.com . Commentary on the implications of BMS restricting enrollment in COMMAND-3 to subjects with genotype 1b, which makes up only 25% of the genotype 1 patients here in the US. Also see http://www.viralmatters.blogspot.com/2012/06/presidio-pharmaceuticals-completes.html on a tx-naive patient having baseline resistance to PPI-668, Presidio's NS5A inhibitor.

Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Is a promising new class of drugs for treating hepatitis C going to be limited because patients with the most common genotype of the virus are likely to develop resistance to the medications? This is the possibility raised by a Wall Street analyst after learning that Bristol-Myers Squibb has altered the protocol for a clinical trial for its daclatasvir antiviral, which is believed to be the most potent in the forthcoming NS5a class of hepatitis c treatments.

According to ClinicalTrials.gov, the drugmaker changed the protocol to its COMMAND-3 trial, which compares its drug in combination with interferon and ribavirin to Incivek, a protease inhibitor sold by Vertex Pharmaceuticals, along with interferon and ribavarin. What was the change? Bristol-Myers restricted future enrollment to patients who have only genotype 1b HCV, rather than all genotype 1 patients (see this and this).

“This effectively eliminates from the trial the most common HCV genotype in the US – 75 percent of HCV is genotype 1 in the US, 80 percent of genotype 1 is genotype 1a,” Sanford Bernstein analyst Tim Anderson wrote in a recent investor note. “This change, some three months after the study started enrollment, suggests that some form of virologic failure has emerged in the patients with these genotypes… The NS5a class, as a whole, might be limited by the propensity to rapidly develop virological resistance, and by significant differences in potency from one viral genotype to another.”

He adds that the change in the protocol has “major strategic and tactical implications” for the hot and fast-growing hepatitis C market. How so? Several drugmakers are developing NS5a treatments and the possibility that these drugs generate resistance to the virus may prompt changes in how different types of medications are combined and, consequently, alter various corporate strategies for drug development, alliances and dealmaking.

Take Gilead Sciences. The drugmaker is developing an NS5a, which has the code name of GS5885, as well as another that is a nucleotide inhibitor, or nuke, which Gilead calls GS7977 and believes could be the cornerstone of the first all-oral regimen for hepatitis C. Gilead, you may recall, acquired GS7977 last fall as part of its $11 billion acquisition of Pharmasset, a bet that has transformed the investor view of the drugmaker (back story).

Two months ago, results of a study that combined daclatasvir with GS7977 suppressed hepatitis C in most patients four weeks after completing treatment, raising hopes about the prospects for a therapy that does not involve an injectable medication. But further collaboration between the two drugmakers appeared uncertain, because Gilead indicated a preference for developing its own NS5a drug with GS7977 (look here).

However, as Anderson notes, the Gilead NS5a drug is less potent than daclatasvir, which “increases the risk for Gilead of sticking with GS5885. On the Bristol side, their ‘go-it-alone’ strategy may be developing a hole, increasing the urgency of incorporating daclatasvir into an all-oral combination with a potent resistance-fighting nuke such as GS7977. This collaboration appears to have become more important to both parties,” he writes.

Both drugmakers declined comment on this topic, although late last month, Bristol-Myers ceo Lamberto Andreotti renewed a call for Gilead to jointly develop their hepatitis C medications. And Bristol-Myers has not responded to questions about the change in the trial protocol.

Looking ahead, Anderson sees greater potential for combination therapy that relies on three drugs, instead of two, including GS7977 from Gilead, since the response to NS5a drugs suggests there can be limitations to at least one of the agents that drug developers would want to use in a one-two punch. And he believes Gilead’s prospects for creating one “super-regimen” for all subtypes with GS7977 and GS5885 alone, or even with ribavirin, have fallen.

As for other drugmakers, the questions concerning the NS5a drugs may result in slightly extended utility for Incivek as well as Victrelis, another protease inhibitor that is sold by Merck. This also suggests additional jockeying surrounding the NS5a drugs being developed by Achillion Pharmaceuticals and Idenix Pharmaceuticals, since larger drugmakers may decide to adjust their strategies and portfolios in response to the changing dynamics of this class of treatments.

Presidio Pharmaceuticals completes Phase 1b proof-of-concept trial with HCV NS5A inhibitor PPI-668...

Posted 6/26/12 on Market Watch.com.  San Francisco's Presidio Pharmaceuticals successfully completed it's Phase 1 Proof-of-Concept trial for it's (perhaps pan-genotypic) HCV NS5A inhibitor, PPI-668. The data was convincing enough for the company to slot PPI-668 for Phase II trials, although in what combination remains a mystery. One patient in the highest dose group (240mg) was found to be fully resistant to PPI-668 at baseline - a little worrisome given that these were treatment-naive genotype 1 subjects. This may or may not provide insight into why BMS narrowed enrollment to it's COMMAND-3 trial with daclatasvir to genotype 1b subjects. 


SAN FRANCISCO, Jun 26, 2012 (BUSINESS WIRE) -- Presidio Pharmaceuticals, Inc. announced today successful completion of Phase 1b clinical testing of its lead HCV NS5A inhibitor in patients with HCV genotype-1 infection, with positive efficacy and safety observations supporting advancement of PPI-668 to Phase 2 combination studies.

The randomized, blinded Phase 1b trial of PPI-668 involved sequential cohorts of treatment-naive HCV genotype-1 patients who received oral doses of PPI-668 of 40, 80, 160 or 240 mg, once daily for three consecutive days. Within each 10-patient cohort, patients were randomized 8:2 to PPI-668 or placebo.

In all of the Phase 1b dose cohorts, PPI-668 was well tolerated with no serious or severe adverse events, no premature treatment discontinuations and no apparent pattern of treatment-related clinical side effects or laboratory abnormalities.

The Phase 1 clinical results indicate that PPI-668 had a favorable pharmacokinetic (PK) profile that included rapid achievement of high (micromolar) plasma levels, prolonged maintenance of potentially effective levels between doses, and achievement of steady-state pharmacokinetics after the first dose.

The Phase 1b efficacy observations indicated consistently rapid, marked reductions in patients' serum viral load (HCV RNA levels), that were dose-related. Patients' HCV RNA reductions typically exceeded 3 log10 IU/ml (99.9%) by Day 2. During the 3-day treatment period, mean maximal HCV RNA reductions for the 4 dosing groups were:

-- 3.2 log10 IU/mL in the 40 mg dose group

-- 3.5 log10 IU/mL in the 80 mg dose group

-- 3.5 log10 IU/mL in the 160 mg dose group

-- 3.7 log10 IU/mL in the 240 mg dose group

There was only one minimal-responder in the trial. A patient in the 240 mg dose group was found to be fully resistant at baseline with 100% of this patient's pre-treatment HCV RNA containing 3 genetically linked NS5A resistance mutations. This patient was excluded from the efficacy analysis of the 240 mg cohort, since he was pre-resistant and could not contribute to dose-response inferences.

Five other patients with detectable resistance mutations at baseline, including those harboring the relatively common L31M variant, responded well to PPI-668 treatment, with multi-log HCV RNA reductions.

A protocol amendment has been completed to explore the pan-genotypic clinical efficacy of PPI-668 in HCV genotype-2a/3a patients. Recruitment is currently underway for this added cohort.

"The rapid 3.5 to 3.7 log10 HCV RNA reductions observed with PPI-668 at the three higher dose levels and the encouraging safety profile support advancement of PPI-668 to Phase 2 combination studies with other promising HCV antiviral agents," said Nathaniel A. Brown, M.D., Presidio's Chief Medical Officer. "The PK profile of PPI-668 appears to be a major factor in its efficacy profile, with rapid achievement of potentially effective plasma levels and with inter-dose plasma concentrations exceeding those needed to inhibit both wild-type HCV and many naturally-occurring HCV variants."

Detailed results of the completed trial are expected to be presented at a scientific meeting in the fall of 2012.

About Hepatitis C

Chronic hepatitis C is a progressive inflammatory liver disease caused by chronic infection with the hepatitis C virus (HCV). Approximately 170 to 200 million persons have chronic HCV infection worldwide, resulting in more than 350,000 deaths annually.

The current standard treatment for patients with hepatitis C genotype-1 infection in the United States and several other countries is combined administration of pegylated-interferon-alfa, ribavirin, and an HCV protease inhibitor. This treatment is characterized by incomplete efficacy and severe side effects in some patients.

There is a continuing need for all oral, more consistently effective and better tolerated antiviral combinations for HCV infection, regardless of HCV genotype, patient genetic factors, or disease stage.

About Presidio

Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company focused on the discovery and development of novel oral antiviral therapeutics. For more information, please visit our website at: www.presidiopharma.com

SOURCE: Presidio Pharmaceuticals, Inc.

BMC Gastroenterology: More evidence that Hepatitis C resistance is linked to insulin resistance

Now online at Biomedcentral.com, a provisional article  (available in PDF version) to be published in BMC Gastroenterology, entitled "Hepatitis C virus E2 protein involved in insulin resistance through an impairment of Akt/PKB and GSK3beta signaling in hepatocytes".  This study is only part of a growing body of evidence supporting that the Hepatitis C virus is indeed associated with Type II diabetes through a variety of possible physiological mechanisms, most of which I willingly admit I don't understand.  If someone is willing to sit down and teach me this stuff as if I were a kindergartner, I would gladly accept. 



Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt/PKB and GSK3beta signaling in hepatocytes
Ming-Ju Hsieh, Kuang-Ping Lan, Hao-Yu Liu, Xiao-Zong Zhang, Yaw-Feng Lin, Tzy-Yen Chen and Hui-Ling Chiou

BMC Gastroenterology 2012, 12:74 doi:10.1186/1471-230X-12-74

Published: 21 June 2012

Abstract (provisional)

Background

Hepatitis C virus (HCV) infection may cause liver diseases of various severities ranging from primary acute infection to life-threatening diseases, such as cirrhosis or hepatocellular carcinoma with poor prognosis. According to clinical findings, HCV infection may also lead to some extra-hepatic symptoms, including type 2 diabetes mellitus (DM). Since insulin resistance is the major etiology for type 2 DM and numerous evidences showed that HCV infection associated with insulin resistance, the involvement of E2 in the pathogenesis of type 2 DM and underlying mechanisms were investigated in this study.

Results

Results showed that E2 influenced on protein levels of insulin receptor substrate-1 (IRS-1) and impaired insulin-induced Ser308 phosphorylation of Akt/PKB and Ser9 phosphorylation of GSK3beta in Huh7 cells, leading to an inhibition of glucose uptake and glycogen synthesis, respectively, and eventually insulin resistance.

Conclusions

Therefore, HCV E2 protein indeed involved in the pathogenesis of type 2 DM by inducing insulin resistance.

Competing interests: The authors declare that they have no competing interests

Authors' Contributions:

Ming-Ju Hsieh has made substantive intellectual contributions to a published study and drafted the manuscript.

Kuang-Ping Lan, Hao-Yu Liu, Xiao-Zong Zhang and Yaw-Feng Lin have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data.

Shun-Fa Yang and Hui-Ling Chiou conceived of the study, and participated in its design and coordination and helped to draft the manuscript.

All authors read and approved the final manuscript.

Medgenics scores Orphan Drug designation for Infradure Hepatitis D indication...

Press release posted 6/21/12 on Reuters.com. A victory for Medgenics Infradure and their proprietary proprietary tissue-based Biopump platform technology which uses a biopsy of the patients own skin to deliver therapeutic proteins currently delivered via injection. The FDA has designated Infradure an orphan drug for the treatment of Hepatitis D here in the States, while clinical trials are ongoing in Israel for other indications, most notably, for Hepatitis C. This orphan drug designation doesn't ensure the FDA will grant Infradure an expedited review, but clearly that is a probability which could speed Infradure to market for a Hep D indication while trials for the remaining targeted indications carry on. 


CEO Sees FDA's Designation as Significant Validation of Medgenics' Novel Technology for Treatment of hepatitis D

Thu Jun 21, 2012 11:05am EDT

In near record time, Andrew L. Pearlman, Ph.D., President and Chief Executive Officer of Medgenics (AMEX:MDGN) has helped position his relatively new publicly traded company at a much higher level-- one that most other biotech firms usually take far longer to reach.

Earlier this week on Tuesday, his firm raised $9.5 million via a Private Placement and twenty-four hours later, he announced that Medgenics' INFRADURE(TM) for the treatment of hepatitis D had received Orphan Drug Designation from U.S. regulators at the FDA.

The significant news effectively made every protein therapy and hepatitis drug developer (not to mention investors) looks up and take notice.

"We see this as a really significant validation of our technology by the world's toughest regulatory agency," explains Pearlman. "This coming literally just a month after the FDA approved our first clinical trials- which went straight to Phase IIB- in the United States."

Asked to explain the significance of having achieved this designation for Medgenics' proprietary tissue-based Biopump(TM) platform, Pearlman doesn't miss a beat.

"First of all, Orphan Status is a very really significant milestone for any company in pharma or biotechnology," Pearlman says. "Because Orphan Drug Status means that the FDA recognizes that the treatment that you're developing is promising and looks like it can address the need for a specific patient population base."

Medgenics has been diligently developing the same proprietary tissue-based Biopump(TM) platform technology for the sustained production and delivery of therapeutic proteins using the patient's own skin biopsy for the treatment of a range of chronic diseases including anemia, hepatitis C and hemophilia among others. Pearlman believes this approach has multiple benefits compared with current treatments, which include regular and costly injections of therapeutic proteins and if he's right, his firm may have just taken one giant step toward convincing the rest of the world he was right.

"The reason why this is so important for our Company is that this is the first Orphan designation that we've attained for the use of our Biopump(TM) system and the beauty of this situation for us is that with Orphan designation, often what happens is that firms are granted an accelerated approval path by the FDA and although that's not guaranteed, we feel we have a good chance and are certainly hoping for that. Also, after a designation like this, the actual size of the clinical trials one needs to conduct is usually considerably smaller than you have to do for any of the major indications," says Pearlman.

"In Israel, we are hoping to be approved to commence the studies of our Biopump(TM) technology in Hepatitis C. Now Hepatitis C is an enormous indication. One hundred and eighty million people in the world have it and the INFRADURE Biopump(TM) has a very appealing and advantageous value proposition for the treatment of hepatitis C. It has an even more, I would say, compelling case for treating hepatitis B and there are some 350 million patients in the world with hepatitis B. All of these indications would use the same INFRADURE Biopump(TM) approach. The Biopump(TM) stimulates your body's immune system to fight the viral infection- whether its hepatitis B, C or D. The advantage of the combined approach that we're doing in going after hepatitis D as an orphan drug in the United States while commencing the clinical testing in hepatitis C in Israel is that we believe that we will demonstrate safety and efficacy in both of these indications, but that in the case of hepatitis D, there is a very improved likelihood for a relatively rapid route to a product approval compared to hepatitis B or hepatitis C-in which there would likely be much larger clinical trials and a longer path toward approval."

Following a late morning confirmation about the FDA news, shares of the company soared 25.36% to $8.65 +1.75 during regular market hours and headed higher in early trading on Thursday. If trading has been any indication thus far, the low-float stock may continue to appreciate in value as the market continues to digest the significance of the news. Particularly since some of Big Pharma's recent buyouts have targeted Drug makers developing hepatitis treatments.

Even some which have shown, arguably, less promise and innovation than Medgenics' own novel platform-- which aims to reduce some of the terrible side effects many patients endure with other treatments-have been acquired at huge premiums

Pearlman is focused on making sure that his firm will continue to build its pipeline and add value beyond its current $83.73 million market cap by executing and continuing to share positive developments like this one with investors.

"This is now the second approval that we've gotten for our technology, for our company and we think it will give a lot more confidence to would-be partners and institutional investors who may have been looking for a clear sign from a regulatory agency that we have a straight shot for an approvable product within a reasonable time."

Are HCV NS5A inhibitors as potent as we thought?

Posted on 6/20/12 on Pharmalot.com. Commentary on a change in protocol in BMS's COMMAND-3 trial for it's NS5A inhibitor daclatasvir by Pharmalot's Ed Silverman. BMS has restricted future enrollment for the trial to include only genotype 1b - a big statement in that 80% of genotype 1 (the most dominant genotype of HCV in the US) are of the 1a subtype. Does this mean there has been some virologic breakthrough in genotype 1a subjects in the COMMAND-3 trial? Hard to say, but the change in inclusion criteria has cast some doubt on the NS5A class. We'll have to wait for further data to see how this plays out. 

Bristol Hep C Trial Change Has Big Implications

By Ed Silverman // June 20th, 2012 // 8:02 am

Is a promising new class of drugs for treating hepatitis C going to be limited because patients with the most common genotype of the virus are likely to develop resistance to the medications? This is the possibility raised by a Wall Street analyst after learning that Bristol-Myers Squibb last week altered the protocol for a clinical trial for its daclatasvir antiviral, which is believed to be the most potent in the forthcoming NS5a class of hepatitis c treatments.

According to ClinicalTrials.gov, the drugmaker changed the protocol to its COMMAND-3 trial, which compares its drug in combination with interferon and ribavirin to Incivek, a protease inhibitor sold by Vertex Pharmaceuticals, along with interferon and ribavarin. What was the change? Bristol-Myers restricted future enrollment to patients who have only genotype 1b HCV, rather than all genotype 1 patients (see this and this).

“This effectively eliminates from the trial the most common HCV genotype in the US – 75 percent of HCV is genotype 1 in the US, 80 percent of genotype 1 is genotype 1a,” Sanford Bernstein analyst Tim Anderson writes in an investor note. “This change, some three months after the study started enrollment, suggests that some form of virologic failure has emerged in the patients with these genotypes… The NS5a class, as a whole, might be limited by the propensity to rapidly develop virological resistance, and by significant differences in potency from one viral genotype to another.”

He adds that the change in the protocol has “major strategic and tactical implications” for the hot and fast-growing hepatitis C market. How so? Several drugmakers are developing NS5a treatments and the possibility that these drugs generate resistance to the virus may prompt changes in how different types of medications are combined and, consequently, alter various corporate strategies for drug development, alliances and dealmaking.

Take Gilead Sciences. The drugmaker is developing an NS5a, which has the code name of GS5885, as well as another that is a nucleotide inhibitor, or nuke, which Gilead calls GS7977 and believes could be the cornerstone of the first all-oral regimen for hepatitis C. Gilead, you may recall, acquired GS7977 last fall as part of its $11 billion acquisition of Pharmasset, a bet that has transformed the investor view of the drugmaker (back story).

Two months ago, results of a study that combined daclatasvir with GS7977 suppressed hepatitis C in most patients four weeks after completing treatment, raising hopes about the prospects for a therapy that does not involve an injectable medication. But further collaboration between the two drugmakers appeared uncertain, because Gilead indicated a preference for developing its own NS5a drug with GS7977 (see this).

However, as Anderson notes, the Gilead NS5a drug is less potent than daclatasvir, which “increases the risk for Gilead of sticking with GS5885. On the Bristol side, their ‘go-it-alone’ strategy may be developing a hole, increasing the urgency of incorporating daclatasvir into an all-oral combination with a potent resistance-fighting nuke such as GS7977. This collaboration appears to have become more important to both parties,” he writes.

Both drugmakers recently declined comment on this topic, although late last month, Bristol-Myers ceo Lamberto Andreotti renewed a call for Gilead to jointly develop their hepatitis C medications. We asked Bristol-Myers about the change in the trial protocol and will update you with any reply that we receive.

Looking ahead, Anderson sees greater potential for combination therapy that relies on three drugs, instead of two, including GS7977 from Gilead, since the response to NS5a drugs suggests there can be limitations to at least one of the agents that developers would want to use in a one-two punch. And he believes Gilead’s prospects for creating one “super-regimen” for all subtypes with GS7977 and GS5885 alone, or even with ribavirin, have fallen.

As for other drugmakers, the questions concerning the NS5a drugs may result in slightly extended utility for Incivek as well as Victrelis, another protease inhibitor that is sold by Merck. This also suggests additional jockeying surrounding the NS5a drugs being developed by Achillion Pharmaceuticals and Idenix Pharmaceuticals, since larger drugmakers may decide to adjust their strategies and portfolios in response to the changing dynamics of this class of treatments.

“All this incremental insight about the limitations of different classes means the portfolios of the committed participants in the field will likely need to be larger than previously anticipated,” Anderson opines. “If, indeed, the field migrates to a three-mechanism standard, then smaller companies with one or more relatively isolated drugs, will be even more compelled to accept offers from buyers, and those buyers are likely to also require even more compounds than they have today, increasing the pressure on them to secure the few remaining independent assets.”

Idenix hep C polymerase inhibtor shows promise in mid-stage study...

Posted 6/19/2012 on the Chicago Tribune website. Not a whole lot of info in this bare-bones press release, but it looks like Idenix's HCV polymerase inhibitor IDX184 is faring pretty well, at least with an n=31 in this mid-stage clinical trial in combo with P/R. More info to follow as soon as I can dig some up. 

Idenix hep C drug shows promise in mid-stage study
 
Reuters
4:34 p.m. CDT, June 19, 2012

(Reuters) - Idenix Pharmaceuticals Inc said interim data from a mid-stage trial on its experimental hepatitis C drug showed promise, sending its shares up 12 percent.

The drug, IDX184, was given to 31 patients in combination with the standard hep C treatments pegylated interferon and ribavirin.

Nine patients received the combination therapy for 12 extended weeks and were checked four weeks later for signs of the virus in the blood to determine if there was a sustained virologic response, or SVR.

All four patients in the 100 mg arm and four out of five patients in the 50 mg arm achieved a sustained virologic response four weeks after the completion of treatment.

Patients who did not have undetectable levels of virus at 4 weeks and 12 weeks automatically entered the 36-week combination therapy extended treatment phase which is ongoing, the company said.

Idenix shares rose 12 percent to $10.45 in extended trade, after closing at $9.37 on Tuesday on the Nasdaq.

(Reporting by Shailesh Kuber in Bangalore; Editing by Saumyadeb Chakrabarty)

First Annual Viral Hepatitis Congress program announcement...

Please visit www.viral-hep.org/ for more info. 

The Viral Hepatitis Congress, 7-9 September 2012

The first annual Viral Hepatitis Congress is scheduled to take place 7-9 September 2012 in Frankfurt, Germany at Goethe University. Viral Hepatitis Congress has been developed following broad demand from various scientific and industry groups that there was need for an international meeting in Hepatitis in general, with a strong scientific focus on research and therapy but also with a strong international and commercial flavour in this fast moving sector.

The Viral Hepatitis Congress Scientific Committee, co- chaired by Professor Ira Jacobson and Professor Stefan Zeuzem under the auspices of Weill Cornell Medical College and Goethe University respectively have collaborated to develop a highly relevant and exciting programme. Furthermore, an event that should become an annual milestone for the exchange of information and ideas amongst the scientific community as well as forming a valuable forum for pharmaceutical and other companies with products and data in Hepatitis. There will be various output opportunities including webcasts but accepted abstracts will also be published as a journal supplement in the Journal of Viral Hepatitis.

1. Although we now have a largely completed roster of sponsors there are some further sponsor opportunities and if you would be interested please send me an email sophie.lea@kp360group.com.

2. Secondly if you have any suggested or desired delegates including yourself please let us know and we will be happy to assist in their registration

You can find the full draft programme and faculty at www.viral-hep.org