Medical Device industry makes a run at Pharma in the HCV space...

Posted 8/9/12 on The OTC Investor.com. Aethlon Medical is serious about it's Hemopurifier, a blood filtration device being looked at for several indications. If it is indeed capable of lowering HCV viral load to a point where pegylated interferon and ribavirin could be more effective and bump up response rates over 50% with less toxicity... and can do so at a cost lower than that of Direct Acting Antiviral combination therapy... Aethlon may be on to something. Yet another reason not to dismiss interferon just yet. 

Bristol’s Halted Hepatitis C Trial Reinforces Aethlon Medical’s Non-Toxic Therapy
By Paul Archie · Thursday, August 9th, 2012

In the biotechnology world, the sun rises and set around the two key words “safety” and “efficacy.”  A serious safety concern last week resulted in Bristol-Myers Squibb (NYSE: BMY) voluntarily halting its ongoing Phase 2 study of BMS-986094, a drug in development as a new indication for hepatitis C as part of the drug maker’s quest for an all-oral regimen for hep C.  A patient who had received a 200 milligram dose of the nucleotide polymerase inhibitor, or “nuke,” suffered heart failure; causing Bristol to stop the trial and begin evaluating participants to determine any correlation between the new drug and the heart damage.

In February, Bristol paid $2.5 billion to acquire Inhibitex, a 163-percent premium to the valuation of Inhibitex at that time, primarily to snag its hepatitis C drug candidate (then called INX-189).  The halted trial could seriously hamper Bristol in its race with Gilead (NASDAQ: GILD) and Abbott Labs (NYSE: ABT) to bring a new hepatitis C drug to market.  It is widely expected that an all-oral drug therapy for the liver disease that affects about 170 million people across the world will generate billions annually in sales.  It is the reason that Bristol paid the premium for Inhibitex and Gilead dished-out $11.1 billion last November to acquire Pharmassets and its hep C drug in development.

Investors that recognize the upside potential of new therapies for hepatitis C should be taking a close look at Aethlon Medical (OTCBB: AEMD), the maker of a first-in-class blood filtration device called the Hemopurifier®.  Recently released clinical research by Aethlon showed that the two most recent hepatitis C-infected patients to receive its Hemopurifier® therapy in combination with the standard of care peginterferon+ribavirin (PR) drug therapy achieved undetectable viral load at day-7.  In lay terms, that means that none of the hepatitis C virus was found in the patients’ bloodstream after seven days of treatment.

As an adjunct, the Aethlon Hemopurifier® selectively targets the rapid clearance of the hepatitis C virus from the entire circulatory system to improve benefit, dose, duration and tolerability of drug therapies.  Drugs, like that of Bristol, Gilead or Abbott, carry substantial safety risks because they are “additive” in nature, meaning that they are putting a foreign substance into the body.  Aethlon’s Hemopurifier® is “subtractive.”  It removes the virus through a proprietary filtering process, which does not carry the same, potentially deadly toxicity risks that can cost major pharma billions to finally realize.

The OTC Investor (http://s.tt/1kpgX)

HALT-C trial analysis shows reduced HCV viremia has clinical benefit...

Posted ahead of print of the American Journal of Gastroenterology on www.nature.com. A new analysis of the mammoth HALT-C trial revealed some very cool news for patients patients who achieved a significant viral load reduction while on Peg-Inf + RBV but relapsed after end of treatment (dubbed "responder relapsers). Those patients who showed improved HAI (Ishak Hepatic Activity Index) demonstrated reduced hepatic inflammation and thus less fibrosis progression and clinical complications followed out a median of 6 years than those not in that group. Bottom line, patients who were 'responder relapers' didn't go through therapy all for naught and experienced a benefit in lower fibrosis progression and it's associated complications. Hopefully this benefit will extend as well to those same patients that responded to new triple therapy but relapsed after end of treatment.


The American Journal of Gastroenterology , (12 June 2012) | doi:10.1038/ajg.2012.137


Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Chihiro Morishima, Mitchell L Shiffman, Jules L Dienstag, Karen L Lindsay, Gyongyi Szabo, Gregory T Everson, Anna S Lok, Adrian M Di Bisceglie, Marc G Ghany, Deepa Naishadham, Timothy R Morgan, Elizabeth C Wright and for the HALT-C Trial Group15

Abstract
OBJECTIVES:

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.

METHODS:

Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.

RESULTS:

Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.

CONCLUSIONS:

Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

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)

Aethlon Medical Reports Undetectable Hepatitis C Virus (HCV) in Genotype 1, Genotype 3, and Genotype 5 Patients Treated with Hemopurifier® Therapy

Posted on 5/8/12 on MarketWatch.com. Good news for San Diego's microtech, Aethlon Medical in the form of a trial results looking at it's Hemopurifier filtration device in combination with pegylated interferon and ribavirin in patients infected with HCV genotype 1, 3 and 5. The hemopurifier is a first-in-class device that selectively targets HCV by filtering the circulatory system for virus thus enhancing the work of traditional oral and injectable anti-HCV drugs. If proven effective, Hemopurifier could be a great asset to HCV providers by possibly being able to lower the dose and duration of HCV therapy - and, given the cost of the 1st generation of oral anti-HCV Direct Acting Antivirals - could provide a cost benefit as well. The Hemopurifier seems to be very effective in genotype 1 patients which is encouraging - if just pegylated interferon and ribavirin are used there is not only a possible cost benefit, but also a possible greatly reduced propensity for the patient to develop drug-resistant variants. Further studies are needed of course, but this initial bit of news is encouraging. 


Aethlon Medical Reports Undetectable Hepatitis C Virus (HCV) in Genotype 1, Genotype 3, and Genotype 5 Patients Treated with Hemopurifier® Therapy

SAN DIEGO, May 8, 2012 /PRNewswire via COMTEX/ -- Aethlon Medical, Inc. AEMD +22.68%  , the pioneer in developing selective therapeutic filtration devices to address infectious disease, cancer and other life-threatening conditions, reported today that the presence of Hepatitis C virus (HCV) is currently undetectable in all infected patients that have been treated with the Aethlon Hemopurifier® in combination with peginterferon+ribavirin (PR) drug therapy and monitored for at least ninety days.

In a study conducted at the Medanta Medicity Institute (Medicity), HCV-infected individuals were enrolled to receive up to three, six-hour Hemopurifier® treatments during the first three days of PR drug therapy. The Medicity is a $360 million multi-specialty medical institute established to be a premier center for medical tourism in India. The Aethlon Hemopurifier® is a first-in-class medical device that selectively targets the rapid clearance of HCV from the entire circulatory system to improve benefit, dose, duration and tolerability of drug therapies.

In the Medicity study, Aethlon reported that Hemopurifier® therapy has been well tolerated and without device-related adverse events in nine treated patients. Of these nine patients, six patients were infected with HCV genotype-1; two patients were infected with HCV genotype-3; and one patient was infected with HCV genotype-5. Of the nine reported patients, seven have been monitored for more than ninety days. All seven currently maintain undetectable viral load, including three patients who have been monitored for 48-weeks. Two patients initiated Hemopurifier® therapy on April 18th and April 30th, and therefore have not yet been monitored for extended viral load suppression.

The Immediate Impact of Hemopurifier® Therapy

In addition to demonstrating safety and early efficacy against multiple HCV genotypes, a clinical objective of the Medicity study was to evaluate whether the Hemopurifier® could accelerate HCV eradication to levels associated with treated patients who achieve the highest rate of viral cure, including individuals that previously failed or relapsed PR drug regimens. In the study, Aethlon observed that viral load depletion during the Hemopurifier® + PR drug therapy phase was greatest in hard-to-treat genotype-1 patients with high viral load. In one treated patient, baseline HCV RNA dropped from 5,800,000 IU/ml to 1,840 IU/ml when measured after the third day of Hemopurifier® + PR therapy, representing a 3.49 log or 99.96% reduction of viral load. In another patient, baseline HCV RNA dropped from 8,760,000 IU/ml to 4,665 IU/ml when measured on day-3, representing a 3.27 log or 99.96% reduction. By contrast, a moderate viral load Hemopurifier® patient with baseline HCV RNA of 1,340,000 IU/ml dropped to 54,900 IU/ml when measured on day-3, representing a 1.38 log or 95.9% reduction.

As a point of reference, the landmark IDEAL Study of 3,070 HCV genotype-1 patients documented that less than 5% of treated patients will achieve a 2-log or greater reduction of viral load when measured 7-days after the start of PR drug therapy. While the IDEAL study did not report day-3 viral load, a 2-log+ reduction at day-7 is a rare occurrence defined as an immediate virologic response (IVR). The IDEAL study confirms the viral cure or sustained virologic response rate of IVR patients to be greater than 90%. Based on Medicity treatment outcomes, Hemopurifier® therapy had a significant impact in accelerating HCV eradication in high viral load patients.

Capacity of the Hemopurifier® to Capture HCV During Treatment

As the result of discussions with reviewers at the Center for Devices and Radiological Health (the FDA branch responsible for approving medical devices in the US), Aethlon recently expanded the Medicity protocol to establish a data point that would quantify the amount of HCV captured within the Hemopurifier® during a single treatment. In one analyzed cartridge, researchers recovered and measured that approximately 300 billion (300,000,000,000) copies of HCV had been captured within the Hemopurifier® during a single six-hour treatment at the Medicity. Beyond the impact of inhibiting progeny virus replication, the viral capture data point defines the contribution Hemopurifier® therapy can provide to current and future antiviral drug treatment regimens. Aethlon considers this data point to be unprecedented as the previous ability to measure the benefit of HCV therapies has primarily been limited to measuring changes in the amount of virus that can be detected in circulation.

Next Steps

As a result of Hemopurifier® + PR therapy outcomes, Aethlon has requested permission from the Medicity internal review board (IRB) to begin offering Hemopurifier® therapy to HCV-infected individuals that reside outside of India. The Company has also requested IRB permission to expand the treatment protocol to allow for up to seven Hemopurifier® treatments to be administered during the first week of PR drug therapy. Based on previous three-treatment protocol outcomes, Aethlon anticipates an expanded Hemopurifier® dosing schedule could establish new milestones for early undetectable viral load achievement. The Company also disclosed it will resubmit an investigational device exemption (IDE) which incorporates the Medicity data as part of its effort to gain FDA approval to initiate clinical programs in the U.S.

It is estimated that approximately 4 million Americans and 170 million people worldwide are infected with HCV, which leads to chronic liver disease or cirrhosis, and is the leading cause of liver transplant in the U.S. To date, almost 100 Hemopurifier® treatments have been administered in human studies. Previously, studies of the Hemopurifier® have been conducted at the Apollo, Fortis, and Sigma New Life hospitals in India. These studies demonstrated that Hemopurifier® therapy could safely reduce viral load in both HIV and HCV-infected dialysis patients without the administration of antiviral drug therapies. The Medicity study represents the first Hemopurifier® study in non-dialysis patients. In vitro studies have further validated the ability of the Hemopurifier® to capture a broad-spectrum of viral pathogens classified as bioterror or pandemic threats.

About Aethlon Medical

The Aethlon Medical mission is to create innovative medical devices that address unmet medical needs in cancer, infectious disease, and other life-threatening conditions. Our Aethlon ADAPT(TM) System is a revenue-stage technology platform that provides the basis for a new class of therapeutics that target the selective removal of disease enabling particles from the entire circulatory system. The Aethlon ADAPT(TM) product pipeline includes the Aethlon Hemopurifier® to address infectious disease and cancer; HER2osome(TM) to target HER2+ breast cancer, and a medical device being developed under a contract with DARPA that would reduce the incidence of sepsis in combat-injured soldiers and civilians. For more information, please visit www.aethlonmedical.com .

Certain statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, that the FDA will not approve the initiation of the Company's clinical programs or provide market clearance of the company's products, future human studies of the Aethlon ADAPT(TM) system or the Aethlon Hemopurifier® as an adjunct therapy to improve patient responsiveness to established cancer therapies, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings. These statements, including patient data, are based on information currently available to the Company's management and future patient results may differ from present results. The Company undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Contacts:

James A. JoyceChairman and CEO858.459.7800 x301jj@aethlonmedical.com

Jim FrakesChief Financial Officer858.459.7800 x300jfrakes@aethlonmedical.com

Marc Robins877.276.2467mr@aethlonmedical.com

SOURCE Aethlon Medical, Inc.

Copyright (C) 2012 PR Newswire. All rights reserved

More difficult-to-treat patients relapse in Gilead GS-7977 hepatitis C trial...

Posted on 3/6/12 on Reuters.com: Two more G1 null responder patients relapsed on 12 weeks of Gilead nuc GS-7977 + PEG and RBV. Investors are spooked, but really shouldn't be.  GS-7977 + PEG & RBV is a powerful drug combo, but given the head-spinning replicative capacity of this virus and it's lack of a proof-reading mechanism, 12 weeks is probably not long enough to quash the virus in a null responder patient and will probably require more than just one DAA targeting more than just one cycle of the virus's replicative process. The most intriguing part of this is the speculation of just what the 'Rescue Protocol' involves in terms of added drugs to GS-7977 and duration of therapy.

More patients relapse in Gilead hepatitis C trial

Tue Mar 6, 2012 5:17pm EST

(Reuters) - Two more patients in a 10-patient segment of a mid-stage trial testing Gilead Sciences Inc's experimental hepatitis C drug GS-7977 had the virus return within four weeks of treatment, researchers said on Tuesday.

The company, which recently paid nearly $11 billion to acquire the drug and its developer, Pharmasset, said last month that six out of 10 patients with a prior "null response" to standard hepatitis C therapy saw the virus return within four weeks of treatment with a combination of GS-7977 and the antiviral drug ribavirin.

The latest results from the mid-stage trial bring to eight the number of patients who have relapsed.
One patient has not reached the four-week point and the other showed a response to the drug, Dr. Edward Gane from New Zealand's Auckland City Hospital and the study's lead investigator said here at the Conference on Retroviruses and Opportunistic Infections.

The trial segment he updated involved patients infected with genotype 1 hepatitis C -- the most common, but also the most difficult to treat, subset of the disease.

"The majority of null responders have relapsed post treatment," Dr. Gane said, adding that such patients will likely need either a longer duration of therapy or combination treatment with other direct-acting antiviral agents.

He said the relapsed patients will be offered a "rescue protocol" in the form of another trial of GS-7977 in combination with a different experimental drug.

Shares of Gilead have dropped 18 percent since the company's announcement of the trial results, which suggested that an all-oral treatment for hepatitis C may be further away than many had hoped.

Dr. Gane said ongoing pivotal-stage trials of GS-7977 "should establish that interferon-free treatment is not a dream. It's a reality that should be here within the next five years."

Current hepatitis C drug regimens require injections of interferon, which causes severe flu-like symptoms and cannot be tolerated by some patients.

GS-7977 is designed to block an enzyme essential to the replication of the hepatitis C virus. It is one of a new class of treatments designed to be given without injections of interferon, which helps boost the body's immune system but can also cause debilitating flu-like side effects.

Gilead has said it expects to announce at the end of this month results from a mid-stage trial of GS-7977 in previously untreated hepatitis C patients.

Hepatitis C is a liver-destroying disease that affects some 170 million people worldwide. Untreated, it can lead to cirrhosis, liver cancer and the need for a liver transplant.

Medgenics developing new therapeutic therapy for anemia...

Article by Ray Dirks from Seeking Alpha.com. Although not directly related to Hepatitis C drug development, patients on the current treatments for Hepatitis C carry the risk of developing anemia. Sometimes this requires the administration of a medicines that increases red blood cell production, but is expensive and carries it's own risks, such as red cell aplasia or cardiac events. The Seeking Alpha investiment website covers a new treatment for anemia in development from a company called Medgenics. They have developed a mini-bio pump delivery system that results in sustained levels of erythropoietin naturally with very little side effects and at a fraction of the cost. They are entering phase 1 trials for Hepatitis C treatment-related animeia later this year.

Medgenics' Disruptive Biotechnology Is One To Watch
By Ray Dirks
Medgenics (AMEX:MDGN) has, what I believe to be, the most disruptive biotechnologies of the last 20 years. This company is poised to own the 90 billion plus protein therapy market. We are talking about an enormous indication. Nomura (the big investment bank) calls this one of the top 10 biotech companies to watch over the next 5 years.
Currently the only form of treatment for Anemia is Epogen. Epogen is a synthetic version of the Erythropoietin that increases your red blood cell production. It is a $12B a year product monopolized by Amgen (AMGN) and affects nearly 1-2 billion worldwide.
When you are diagnosed with anemia, you go to your doctor. Your doctor is going to tell you that you have an abnormally low hemoglobin count and he will prescribe an epogen shot to get your hemoglobin into check and into a 10-12 count range which is considered healthy.

These shots cost about $25K a patient per year and are very painfully administered. What is going to occur is a spike of your Epo level from very low up to a 100x, which can lead to high blood pressure, a percentage increase of fatal cardiac events (as per the FDA) and all sorts of side effects. Over the next 48 hours, your Epo will crash back to a low level after which you will be treated with another shot of epogen, and this happens over and over again for the rest of your existence.

It's a terrible way to live, costs the system billions and is one of the worst FDA procedures on the market. In fact, Amgen has already received a black box warning because of the side effects and increased risks and is under major scrutiny for reimbursements issues as well.

The holy grail of Anemia treatment is to treat the patient without the infections and without that "spike" in Epo which is deadly in nature and provides a terrible quality of life.

Medgenics has developed a therapeutic system that can provide a dosage of the sustained levels (no spikes) of Erythropoietin naturally with literally no side effects and only two primary clinic visits for a fraction of the money. Let me explain exactly what they do and how they do it:

Medgenics takes a small piece of your skin about the size of a one inch toothpick from your abdomen.

This piece of tissue is then processed in a lab by inserting a small piece of DNA that teaches it to continuously produce the missing protein; which in this case is Erythropoietin.

Once this engineered piece of tissue is making the protein you are missing and at the levels needed, it is injected back under your skin and the result is a mini biobump that produced natural Epogen without the spikes, without the shots, without the side effects or dropouts. And for a fraction of the cost of Amgen's Epogen shots.

The Phase I/II study was done with 20 patients, all people diagnosed with anemia obviously. In all 20 patients you have biopumps producing Erythropoietin safely for as long as 36 months without any follow up, within that 10-12 count and without the injections and their dangerous spikes.

The most compelling thing about this story is that this isn't just a treatment for only Anemia; it is a platform that can be used on ALL protein therapies. In fact the company is entering Phase 1 for Hep C (Interferon) in Q2 of this year. Hepatitis C/Interferon is a 3.5 billion dollar Market this year. Gilead (GILD) paid 11 billion for a HEP C company… Inhibitex (INHX) was taken over for 2.5 billion (another Hep C company).

Medgenics already has an active program for Hemophilia developed with Baxter (BAX), and they will also be starting programs for:

* Growth Failure/growth hormone
* Multiple Sclerosis/Interferon Beta
* Diabetes/Insulin
* many others

In summary you have a company that has:

* $50 million invested
* the most disruptive technology in biotech today
* a management team that is arguably from top to bottom the best I have ever seen. Former head of Stanford Medicine, and an entrepreneur who sold his last company for $600 million
* Baxter collaboration and the potential for many more collaborations on multiple indications
* already finished Phase I/II and entering Phase IIB, this is NOT pre Clinical; this is tested and proven in human
* a ridiculously low valuation relative to its competitors.
* the potential of two probably partnerships in the near term
* a science which is not a one trick pony, it is a platform that covers every protein therapy which is more than a 91 billion dollar market
* largest shareholders are Joel Kanter and Isaac Blech. Joel has just sold Clarisonic for $600 million. Isaac has founded over 35 billion in companies

Enough of the science. Let me walk you through the value proposition of the investment. There are two public companies and one collaboration that I will use as comparisons.

Protalix (PLX) has a platform technology and is at about the same stage of clinical as Medgenics, but is only for an indication of 25,000 patients and trades at a 520 million dollar market cap.

Prolor (PBTH), which has a treatment which only increases the half lives of protein therapies, trades at a 300mm market cap.

And of course Zymogenetics which only has an interferon lasting slightly longer than the usual 5-6 hours for Hep C, was bought by Bristol-Myers Squibb (BMY) for $545 million.

Medgenics' market value is currently approximately $32 million and is clearly poised to be the leader in a multi billion dollar space, and I believe will far exceed the market value of the the companies mentioned in this article.

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

Medscape article: Adverse CNS Effects of HCV Treatment Discourage Adherence

Medscape interviews clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City and Raymond Chung, MD,vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston regarding a large prospective study looking at CNS effects of Peg + riba and the resulting effect on adherence because of depression and/or 'brain fog'.

Adverse CNS Effects of HCV Treatment Discourage Adherence

Neil Canavan

November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.

"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.

"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."

This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.

There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.

After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."

How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.

CNS and the Hepatologist

Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."

He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.

Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.

Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.

Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to news@medscape.net.

Anadys Pharmaceuticals intiates Phase IIb study of HCV Polymerase Inhibitor ANA598

Anadys getting it's non-nuc to Phase IIb, that's a pretty big hurdle for this company. If this gets to Phase III, they will have done what many drug developers previously have not. The Phase II graveyard for the DAA's is huge. Interesting that no week 4 (RVR) timepoint is mentioned for this protocol - Chris

SAN DIEGO, January 4, 2011 --Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced today that it has initiated the planned Phase IIb study of ANA598 in combination with pegylated interferon and ribavirin. The protocol for the study has been cleared by the United States Food and Drug Administration (FDA) and Health Canada. Patient screening has begun and patient dosing is expected to commence within the next several weeks. In the study ANA598 will be tested in both treatment-naïve patients and treatment-experienced patients who failed a prior course of therapy with interferon and ribavirin. ANA598 is the Company’s direct-acting antiviral, or DAA, being developed for the treatment of hepatitis C.

“We are excited to initiate this Phase IIb study of ANA598,” said James L. Freddo, M.D., Anadys’ Senior Vice President, Drug Development and Chief Medical Officer. “By establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment, we hope to position ANA598 as a highly attractive HCV agent ready for Phase III development.”
Phase IIb Protocol Design

In the study, approximately 200 chronically infected genotype 1 hepatitis C patients are expected to receive ANA598 200 mg twice a day (bid) in combination with Pegasys® (peginterferon alfa2a) and Copegus® (ribavirin, USP) (a current standard of care, or SOC) with a loading dose of 800 mg bid on day 1, while approximately 66 patients are to receive placebo and SOC. Enrollment is expected to include approximately equal numbers of treatment-naïve patients and patients who have failed a prior course of SOC, including difficult to treat prior null-responders. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients conclude all treatment, known as SVR24. Anadys is conducting the study at sites within and outside the United States.
Naïve Arm

Approximately 100 treatment-naïve HCV patients are expected to receive ANA598 in combination with SOC and 33 treatment-naïve HCV patients are to receive placebo plus SOC. Treatment duration for naïve patients will be response-guided; patients who achieve undetectable levels of virus at Week 8 and maintain undetectable levels of virus will be scheduled to conclude all treatment at Week 28. For naïve patients with detectable virus at Week 8 dosing with ANA598, or placebo, and SOC is planned to continue through Week 48. The Company expects to receive Week 8 antiviral response data by the end of the second quarter of 2011, Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.

Treatment-Experienced Arm, Including Prior Null Responders

Approximately 80 patients who were partial responders during, or relapsers after, a prior course of therapy with SOC alone are expected to receive ANA598 in combination with SOC, and 33 corresponding patients are to receive placebo plus SOC. Additionally, approximately 28 prior null responder patients are to receive ANA598 in combination with SOC. All treatment-experienced patients who receive ANA598 are scheduled to receive triple combination therapy for 48 weeks. For the treatment-experienced patients, the Company expects to receive Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.

Excerpts from a "Hepatology" commentary on the future of Taribavirn - by Paul Kwo, MD and Rakesh Vinayek MD.... (Thank you NATAP.org)

The Next Step for Taribavirin - Commentary        Hepatology Sept 24 2010   Paul Y Kwo and Rakesh Vinayek   Excerpts:   In this issue of Hepatology, Poordad and colleagues report the SVR rates of weight-based TBV compared to weight-based RBV in naïve genotype I HCV-infected patients. In this US Phase 2b randomized open-label controlled parallel group study, 278 naïve genotype I subjects were randomized to TBV 20, 25, or 30 mg/kg/day or RBV 800-1400 mg, pegIFN alfa-2b for 48 weeks. An early virologic response (EVR) defined as undetectable HCV RNA (< 39 I.U. at Week 12) or a 2 log reduction in baseline HCV RNA, the primary endpoint of the study, was comparable across all treatment arms. The SVR rate was also preserved across all treatment arms, ranging between 27 and 28%. The overall response rates in this trial were low though the high percentage of African Americans (20%) and those with advanced fibrosis may explain the lower SVR rates. It would be interesting to know the IL-28 composition of the treatment population as there may have been a high prevalence of unfavorable Il-28 CT or TT genotype patients present which could also explain in part the low SVR rates.   While SVR rates were not different between treatment arms, a lower relapse rate was seen with an incremental increase in the dose of TBV, similar to that observed with RBV. In addition, the per protocol SVR rates were substantially higher again demonstrating the importance of adherence to therapy to provide optimal SVR rates in the genotype I population. Lower anemia rates (defined as hemoglobin < 10 grams/dL) were seen in the TBV arms throughout the entire 48 weeks, with cumulative anemia rates being significantly lower across the two lower TBV arms (20 mg and 25 mg/kg) compared to weight-based RBV. However, as the dose of TBV was increased to 30 mg/kg, the anemia rate was numerically lower than with RBV but was not significant, other than at week 4, suggesting that higher doses TBV may lead to similar rates of anemia and other side effects observed with RBV. The pharmacokinetic analysis showed that this effect correlated with RBV plasma exposure. Furthermore, within the first 12 weeks of treatment when maintaining the dose of RBV has been shown to be most critical, significantly lower rates of anemia were observed with TBV compared with RBV (7-15% vs 24%, respectively) within the first 12 weeks of treatment although this translated clinically into comparable, not superior SVR rates in the TBV arms. Even though, fewer patients treated with TBV required dose reduction (13-28%) compared to 32% patients treated with RBV, it should also be noted that dropout rates for anemia were not different amongst the TBV arms compared to the RBV arms in this study, though this may be due to relatively small sample size. There does appear to be an increased rate of diarrhea in the TBV arms compared to RBV. This may be significant as some DAA agents are also associated with increased GI side effects and, as we enter an era where DAA agents and other drugs are combined, side effects could limit the efficacy of multi-drug combinations. Finally, while not statistically significant, insomnia was numerically higher in the TBV arms and should be a side effect of some concern in future trials. Thus, as significantly fewer dose reductions were noted only in the TBV 20 mg/kg arm as compared to the higher doses of TBV and RBV with similar SVR rates, the dose of 20 mg/kg may also require study in the future with DAA agents  So what does the future hold for taribavirin? Phase 2 and ongoing Phase 3 trials strongly suggest that DAA agents will be added to pegIFN and RBV to obtain higher SVR rates, albeit at the expense of higher rates of anemia and other side effects. Currently, the role of ESAs in the treatment of HCV with DAA agents is not yet precisely defined, though we await the results of ongoing trials. The inclusion of TBV into the HCV armamentarium may serve as an opportunity to combine with pegIFN and DAA agents to reduce the rates of anemia and avoid RBV dose reduction or introduction of ESAs. As RBV reduction or removal of RBV is associated with increased rates of breakthrough and development of resistance to DAA agents, TBV may have a role in populations particularly sensitive to ribavirin-related anemia , including those with advanced liver disease, older patients, patients who have undergone liver transplantation, HIV/HCV coinfected individuals, patients with hemoglobulinopathies and chronic renal failure 20. However, with the commencement of several trials comprising of multiple combinations of DAA agents with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle. Studies with combinations of DAA agents with PEGIFN/RBV have been initiated and these studies will multiply. Whether or not RBV (and TBV) can be eliminated altogether remains to be determined.  Particularly in those patients with unfavorable treatment characteristics, RBV may remain a part of our therapeutic armamentarium for years to come; and, if so, TBV could be an option which has the potential to limit toxicity and potentially reduce costs. The ideal study may be to combine TBV with a DAA agent and pegIFN and compare it to RBV, to see if SVR rates can be preserved or improved by minimizing dose reductions and reducing the emergence of resistance. Given the long wait between the approval of pegIFN and RBV and yet unapproved DAA agents, one should not discount the potential contribution of TBV. Many promising agents have already been stopped in development due to lack of efficacy or toxicity 21-22. Thus, if TBV can be shown to preserve or improve efficacy rates in combination with DAAs and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat.