Post-Scripps Conference Download "New Treatments in Chronic Liver Disease"

I attended the Scripps Clinic 'New Treatments in Chronic Liver Disease' conference this past weekend in La Jolla, CA.  There were three sessions focusing just on HCV - 'Management of Chronic Hepatitis C in the DAA Era'; 'Controversy - Should We Treat IL28B CC Patients Without DAAs?' and the 'New Directions for HCV Therapy (2012 - 2014)'.  Adrian Di Bisceglie MD, Paul Pockros MD and Anna Lok, MD - all three superstars of Hepatology - did the honors. Below are some of the highlights (for me, anyway) in terms of the future of HCV treatment. Reductionism at its most subjective.

·        The future of Interferon & Ribavirin:

o   Interferon will likely be with us for at least the next 5 years, but may be regulated to patients that are tough to treat (i.e. cirrhotics, G1a)

o   Ribavirin will be a mainstay of therapy for the majority of patients.

o   A nuc may be able to replace RBV in a small subset of patients in combination therapy (PI +nuc + nonnuc, for example) The subset of patients were characterized as G2 & G3, non-cirrhotic, low BMI, non-smoking and/or post-transplant / dialysis patients and perhaps G1b with CC allele). 

o   The  economic ramifications of this strategy where examined. if a generic like RBV worked just as well as a nuc, then why use two or more DAAs where the cost of treatment will likely be much higher?

·        Ribavirin dose reduction with current therapy:

o   Docs doing CDCs every two weeks. When patient drops below 10 g/Dl, theydrop RBV down to 600.  If that doesn’t provide enough EPO is added.

o   Approval of EPO an issue – may take three weeks, what do we do then?

o   One doctor on the panel said “we don’t know how how we can go with RBV. Can we stop RBV for a couple of days until the patient normalizes? We don’t know.”

o   Another doctor on the panel replied that the current data on stopping RBV is “inadequate” (very vociferous on this).  Referenced the HCV Target registry Mike Fried was involved in to take a closer look at this issue.  Cautioned against this until the data is more clear.

·         New treatment notables: 

o   GS-7977 + RBV (no INF)  much less likely to cause anemia than current DAA therapy. Referenced a slide from the ELECTRON study that showed only an average of a 2 g drop in hemoglobin, no reduction in absolute neutrophil count. Also much less propensity for DDIs than current DAA therapy.

o   All agreed that the data they are most anxiously awaiting is the G1 treatment naïve data from the ELECTRON trial with GS-7997 + RBV (to be presented at EASL)

o   Doctor on the panel referenced ELECTRON demographics – G1a, no cirrhosis. “We need to see VERY high SVR rates in this INF-free trial in this population. I’m looking for 100% SVR”.

o   Resistance will always be a concern given the error-prone, highly replicative capacity of the virus. Less of a concern with the polymerase inhibitors because of the higher barrier to resistance.

o   Future much more certain for polymerase inhibitors and protease inhibitors than cyclophilin inhibitors at this point.

o   Less danger of drug-drug interactions with upcoming therapies – good news for post-transplant, dialysis and HIV/HCV co-infected patients.

·         Timeline predictions on evolution of HCV therapy:

o   Q4 2013/ Q1 2014 – Quad therapy vs new triple therapy options (PI + nuc/nonnuc + PEG/RBV)

o   Q4 2013/Q1 2014 IFN-free regimens for G2/3 and perhaps G1b (w/ CC allele)        and for those intolerant to IFN. (PI +nuc/nonnuc/NS5A w/+ RBV)…. Maybe w/out RBV for small segment of patients.

Seeking Alpha.com: Will Medgenics Become The Next Hepatitis C Take Over Candidate?

Posted on 3/12/12 on Seeking Alpha.com. The following comments by the Viral Matters editor: Seeking Alpha contributor Ray Dirks speculates that Medgenics - with it's proprietary EPODURE (for anemia) and INFRADURE (for interferon) biopump devices - would be an attractive candidate for take over. EPODURE might be a go, but the market for INFRADUR could be severely limited to disease states outside of HCV if 'interferon free' therapy becomes a reality.  As it is only in preclinical trials, INFRADUR has plenty of time to see where the 2nd and 3rd generation of anti-HCV Direct Acting Antivirals take us

Will Medgenics Become The Next Hepatitis-C Take Over Candidate?

By Ray Dirks - Seeking Alpha

Interest in the hepatitis-C space has been hot since the euphoria of Big Pharma's acquisition of Inhibitex (INHX) and others began to spread further in early January. Smaller biotechs are being snapped up by larger pharmaceutical companies driven by the need to pump up their product pipelines.

Last November, Gilead Sciences (GILD) bought Princeton, NJ-based Pharmasset for $11 billion for the next generation of hepatitis-C treatments. Vertex Pharmaceuticals, working with Merck, is offering a pill for hepatitis-C, but it has to be taken three times a day though stands the chance to make $2 billion in a couple of years, when approved.

Then there was the Bristol-Myers Squibb (BMY) acquisition of Inhibitex for $2.5 billion and Roche's (RHHBY.PK) purchase of Anadys Pharmaceuticals for $230 million. Let's not forget that Novartis (NVS) and Enanta Pharmaceuticals are in collaboration to develop and sell a brand-new hepatitis-C inhibitor for nearly $500 million.

When one looks at Medgenics (MDGN), at a market cap of only $46 million, we have have to wonder how a company with an innovative approach to treating hepatitis-C would not be of interest to a bigger pharmaceutical partner or buyer. The firm has a very unique way to treat the disease which may not have been recognized by investors yet, but we're betting that will soon change.

Last month when shares were trading at around the $3.50 level, we made a case for the disruptive technology being developed by Medgenics, focusing on the value it has for the $90 billion protein therapy market that is projected to grow to over $130 million over the next several years. Shares nearly doubled after that report and have since seen a healthy pull back.

We've looked specifically at Medgenic's EPODURE product, a proprietary biopump that produces erythropoietin within the patient's own body, now in Phase I/II clinical trials to treat anemia in chronic kidney disease. The anemia market is dominated by Amgen's Epogen that carries with it a high price tag and serious side effects.

Now we'd like to draw attention to another of Medgenic's products in development, using its biopump technology - INFRADURE, that produces interferon-alpha and is currently in the preclinical stage for the treatment of hepatitis-C. In the U.S., hepatitis-C ranks second only to alcoholism as a cause of liver disease and is the leading reason for liver transplants. The Center for Disease Control and Prevention estimates that 3.2 million people in the U.S. have chronic hepatitis-C (far out-passing HIV) and costs due to treating the disease now exceed $600 million each year, with a projection of growing to $11 billion in 2019.

Interferon, or the more popular form, peginterferon-alpha, is usually used in combination with ribavirin, another antiviral medication. Treatment is expensive, around $20,000 per year for a 48-week injected dose, which puts it out of reach in developing countries where it is badly needed. Further, only 50% of patients benefit. There is clearly a medical call for a cheaper and more effective drug.

Medgenic's INFRADURE provides an answer. Like EPODURE and other products under development, INFRADURE uses Medgenic's biopump platform technology where the patient's own tissue, taken during a biopsy, is processed then inserted into the biopump to continuously produce and deliver interferon-alpha, a natural protein produced by the body. Also like EPODURE, this approach would eliminate weekly and expensive injections, particularly since Hepatitis-C progresses very slowly.

Two drugs are on the market to treat hepatitis-C: Pegasys, made by Genentech and PEG-Intron, made by Schering-Plough. Both are meant for weekly injections. Both are very similar and meant to be used in combination with ribavirin. Side effects for this combination are startling, the most reported ones being mental illness, thoughts of hurting or killing yourself or others, unusual thoughts or behaviors, the compulsion to use street drugs if they had been used in the past, alcohol abuse, and aggressiveness. Heart disease and autoimmune disorders are also common. Pegasys and PEG-Intron used with ribavirin causes birth defects or death in an unborn baby.

For example,the FDA's review of Schering Plough's application for PEG-Intron included a number of patients that either committed or attempted suicide, murdered others, relapsed to drug or alcohol addiction, and underwent severe depression. As we mentioned, heart attacks and heart valve disease also appeared, as well as lupus, extremely low red blood cell count, kidney failure, partial blindness, and hearing loss.

INFRADURE will go into human clinical trials in the first half of this year. Based on laboratory and animal data that reported up to six months of consistent delivery of interferon-alpha, Phase I clinical trial results should show efficacy based on results seen with EPODURE.

We draw your attention to the value of Medgenic's platform technology. Besides anemia and hepatitis-C, Medgenic's product is being designed for use in hemophilia, multiple sclerosis, arthritis, obesity and diabetes.

We advise our readers to watch this company going forward as we continue to expect even more bullish developments and positive news flow going forward.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

Scynexis aims to raise $15M to support phase 2 development of cycophilin inhibitor SCY-635...

(Scynexis aims to raise $15 M to support phase 2 trials for it's lead candidate, cycophilin inhibitor SCY-635 which they hope to eventually replace recombinant interferon)

Scynexis aims to raise $15M; hepatitis C drug candidate in phase 2 trials

Posted By Frank Vinluan On December 19, 2011 @ 11:09 am In MedCity News

Drug discovery and development firm Scynexis which is moving forward on a new hepatitis C treatment, has raised $5 million in a fundraising effort targeted to reach up to $15 million.

A total of nine investors have invested in the round that is a combination of equity, debt, warrants and options, according to securities filings. Durham, North Carolina-based Scynexis’ investors include Alta Partners, Burrill & Company, KBL Healthcare Ventures, Societe Generale, Ventech, CDC Innovation and SR One, the venture capital arm of GlaxoSmithKline. Scynexis’ last fundraiser was in 2008 when the company hauled in $13.5 million in equity financing.

Scynexis collaborates with pharmaceutical companies on their drug discovery and development efforts and it already has a long list of drug partners that include Merck, Sanofi and Roche. In the last five years, Scynexis has helped its partners advance 11 preclinical and clinical drug candidates.

The company also has drug candidates of its own. Scynexis’ proprietary internal pipeline is based on cyclophilin inhibitors, a class of drugs that Scynexis believes hold potential to treatment of a broad range of diseases. Hepatitis C is Scynexis’ first target. SCY-635, the first drug candidate to emerge from the drug pipeline, is being studied as a treatment for hepatitis C virus infection. The compound, currently in phase 2 clinical trials, works by reactivating the body’s natural defense mechanism that makes it capable of inhibiting replication of the virus.

According to the World Health Organization, an estimated 3 percent of the world’s population is infected with hepatitis C and there are more than 170 million carriers at risk of developing liver cirrhosis or liver cancer. Scynexis sees SCY-635 as meeting an unmet medical need by serving as a potential replacement for recombinant interferon, the current standard hepatitis C treatment that has several serious side effects.

Medco database analysis says patients on antidepressants more likely to be adherent to HCV treatment...

Interesting study from the Medco folks, published in the American Journal of Managed Care and presented recently at the 2011 International Conference on Viral Hepatitis. Medco used de-personalized data from their drug claims database to look at 3,607 patients newly Rx'd Peg-interferon and ribavirin for treatment of HCV. They evaluated adherence using a ratio called the 'medication possession ratio' or MPR, which measures the percent of time that HCV patients had medication available for their use. Patients with a MPR that was equal or greater than 80% were considered adherent. The study found that among patients with HCV who were both on HCV therapy and using an antidepressant, 68.5 percent were adherent. Grant it, database studies - like any study - comes with it's own inherent biases and it's hard to gather what other extraneous variables might have had impact on adherence, such as support groups, family support system, physician or mid-level check-ins, etc. Still, pretty impactful and compelling data that makes sense - if you feel better, one can assume that you'd feel more compelled to take one's medication.

BALTIMORE, April 11, 2011 /PRNewswire/ -- Adherence to interferon, an important medication used to treat Hepatitis C, is critical to successfully clearing the virus that causes the disease. A new observational analysis by Medco Health Solutions, Inc. (NYSE: MHS) finds that when Hepatitis C patients are also being treated for depression -- a frequent side effect of interferon use -- they are more likely to remain on their interferon therapy. The analysis is being presented today at the International Conference on Viral Hepatitis 2011.

According to the study, approximately 40 percent of Hepatitis C patients on interferon and ribavirin -- an antiviral medication used in combination with interferon -- were not adherent to their medication regimen. This puts patients at risk for progression of their disease due to their inability to eliminate the virus. The research found that the patients also using an antidepressant had the highest rates of adherence to their Hepatitis C treatment. Among patients with Hepatitis C who were using an antidepressant, 68.5 percent were adherent to their interferon therapy. For patients being treated for both Hepatitis C and HIV, 77.3 percent taking antidepressants were properly complying with their interferon therapy. Overall, 46 percent of patients with Hepatitis C were on an antidepressant.

"A common side-effect of interferon is depression, but little research has been done looking at the impact of treating depression on a patient's adherence with their Hepatitis C medications," said Mary Cassler RPh, Director of Clinical Innovation in Medco's Advanced Clinical Science and Research Group, who conducted the analysis. "These findings point to the need to proactively screen patients on interferon for depression and make sure that those who show signs of depression receive the proper interventions."

The usual course of interferon therapy for patients with Hepatitis C lasts either 24 or 48 weeks depending on the genotype of the virus, which influences the duration of treatment. Patients who discontinue use of the medication before treatment is completed, or those who do not take their medication as prescribed, frequently need to be retreated. Patients who fail to completely eliminate the virus have a higher risk of developing liver cancer. According to a study published in the American Journal of Managed Care, therapy can cost more than $40,000 per patient.

"Depression, whether interferon-induced or a separate co-morbid condition, can sabotage efforts to effectively treat Hepatitis C," said Dr. David Muzina, National Practice Leader, Medco Neuroscience Therapeutic Resource Center®. "All health care professionals, including pharmacists, need to know how to detect depression and work together to support safe, effective and affordable treatments."

Details

The analysis reviewed de-identified prescription drug claims from Medco's database and identified 3,607 patients who were newly prescribed interferon and ribavirin to treat Hepatitis C. Among the Hepatitis C patients who were identified, only 1,657 were being treated for depression. For the 109 patients who were also co-infected with HIV, 66 were on an antidepressant.

Adherence was evaluated by using the medication possession ratio (MPR) which measures the percent of time that patients have medication available for their use. Patients whose MPR was 80 percent or greater were considered adherent.

Added Richard Faris, PhD, RPh, National Practice Leader of the Accredo Rare and Specialty Pharmacy Therapeutic Resource Center: "These findings are important because they help in identifying patients experiencing depression while being treated in the home, and enable intervention to drive better outcomes for the patient and reduced costs for the payer."

About Medco

Medco Health Solutions, Inc. (NYSE: MHS) is pioneering the world's most advanced pharmacy® and its clinical research and innovations are part of Medco making medicine smarter™ for approximately 65 million members.

With more than 20,000 employees worldwide dedicated to improving patient health and reducing costs for a wide range of public and private sector clients, and 2010 revenues of nearly $66 billion, Medco ranks 35th on the Fortune 500 list and is named among the world's most innovative, most admired and most trustworthy companies.

For more information, go to http://www.medcohealth.com.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties that may cause results to differ materially from those set forth in the statements. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. We undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the risks and uncertainties that affect our business, particularly those mentioned in the Risk Factors section of the Company's Annual Report on Form 10-K and Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission.

SOURCE Medco Health Solutions, Inc.

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Locteron beats it's pegylated cousin in 72 week SELECT 2 results at EASL...

I know the Pharmasset folks are bullish about a interferon-free drug combo to treat HCV - actually, we ALL are, but until we have SVR data from that particular combination and others like it in development, interferon is here to stay. Biolex (who features ex-Vertex CCO Kurt Graves as it's Executive Chairman of the Board) is the entity here in the States that is developing Locteron. The deal with Locteron is that it's a Peg-less PegIntron with a sexy new controlled release technology that allows it to be dosed every other week. Added benefits are a nice reduction in flu-like side-effects and interferon-related depression. Results of it's Phase IIb study, SELECT-2, comparing it to Pegintron look pretty good. Locteron maintains and/or beats it's pegylated cousin in the SVR department (SVR 41% (640 μg); 34% (480 μg); 36% (320 μg); 33% (Pegintron))while chopping the number of shots in half and reducing AE's. The big problem at this point isn't the threat of an interferon-free HCV drug combo, but lack of data with a DAA. I'm not schooled in Biolex, but I'm sure that's the company's hope going forward. Or it may just file with a DAA-less indication if the Phase III data and competitive environment look promising enough. Either way, the thought of a more user-friendly interferon is pretty enticing. Hopefully, investors will feel the same way.

OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data highlight important tolerability advantages of Locteron versus current HCV treatments.

Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments."

The following information was taken directly from Biolex' press release (see www.biolex.com).

Biolex announces that final 72-week results from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. Data presented today show that Locteron achieved the SELECT-2 study objectives by demonstrating viral kinetics and response rates that were comparable with or exceeded the PEG-Intron® control while also achieving a statistically significant reduction in flu-like adverse events, reduced rates of depression, lower use of concomitant medications and a reduced rate of discontinuation due to adverse events. Locteron, the only controlled-release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.

Locteron dosing convenience and efficacy
Locteron is administered once every other week and requires half as many injections as the currently marketed interferons, each of which are injected once per week. In SELECT-2, the sustained virologic response rate (SVR) for each of the three Locteron doses studied was comparable with or exceeded the response rate for the PEG-Intron control as outlined in the table below.

Click on the link for the press release including tables.

Electronic patient diaries vs on-site side-effect reports: A case study featuring Locteron

Very nice article here on the power of ePRO (Electronic patient diaries) vs on-site patient reports to the physician on adverse events. It appears that evolving technology is helping to undermine the incidence of under-reporting of adverse events. This particular example adds credibility to Biolex's Locteron (Interferon Lambda) Phase IIb trial.

Biolex reveals ePRO surprise; selection process
By George Miller
Created Nov 22 2010 - 1:32am

Biolex CEO Jan Turek notes something unforeseen in the ePRO element of the company's recent trial of a hepatitis C treatment: The degree of difference in reports of side-effect severity in the weekly case report forms completed by clinicians versus the daily ePRO accounts of trial volunteers. Some 85 percent of reports by doctors describe mild side-effects, whereas the volunteers reporting electronically most often rated the severity as moderate or severe.

It was "a surprise to us and our key opinion leaders," Turek says in a phone interview. "It brought home the need for patient reports to be taken more seriously."

Findings from the trial do, however, reflect commonality between the reporting media types in the trial's side-effect result--a statistically significant 40 to 50 percent drop in the frequency and severity of flu-like symptoms for the 480-microgram dose of Biolex's Locteron compared with the PEG-Intron control.

Researchers were tracking the flu-like symptoms as a means of comparing the treatments in the Phase IIb trial. "What you measure drives how you gather data," explains Biolex CFO Dale Sander in the interview. Investigators as well as the key opinion leaders thought ePRO fit the bill. The side-effect data collected through the ePRO system are considered supplemental to the reports taken during weekly clinic visits.

Biolex used an ePRO system from Unithink [1] in the global trial. Among the key factors in its choice was the system's ability to instantaneously receive reports and capture them in the EDC system, rather than a set-up that involves reporting and later docking and uploading, says Amy Rigney, clinical ops director. "That was a differentiator."

Another was ease of patient use. "We wanted to be sure the ePRO system was programmed for several languages." Also, ePRO/EDC set-up allowed trial volunteers to report side effects via cellphone or laptop. "It didn't force the issue one way or the other," she says.

Biolex evaluated available ePRO systems in 2008 and had several months of discussions involving investigators, the data management group, and the clinical group. The company's IT team participated throughout the process to ensure overall systems compatibility, says Rigney, including the final selection of Unithink.

"Volunteers' recall and ability to assess a side effect is better when they are entering the data simultaneous with the event," she says. "You're getting it unfiltered."