Medivir announces interferon-free phase IIa trial with HCV PI plus investigational non-nuc...

Press release  posted 9/20 on PR Newswire. Medivir announces a Phase IIa trial pairing it's HCV NS3/4A protease inhibitor simeprevir (TMC435) with Janssen's non-nuc TMC647055 and ritonovir (a potent CYP P450 inhibitor) with and without ribavirin in treatment naive, relapser genotype 1 patients as well as the difficult-to-treat genotype 1a null responder population. The latter population is incredibly important, as the efficacy with current anti-HCV regimens is notoriously low. The addition CYP P450 inhibitor ritonavir is used in regimens to block metabolism of the active molecule(s) leading me to believe that TMC435 may effect the drug levels of TMC647055, or both. Ritonavir, unfortunately, also limits concomitant meds also metabolized by CYP P450.  

A Phase IIa Interferon Free Combination Hepatitis C Trial of Simeprevir (TMC435) and TMC647055 Will Commence Shortly

STOCKHOLM, September 20, 2012 /PRNewswire/ --
Medivir AB (OMX: MVIR), announced today that simeprevir (TMC435) and TMC647055, a non-nucleoside inhibitor (NNI) will enter a phase IIa interferon free combination trial.

Simeprevir is a once daily potent HCV NS3/4A protease inhibitor in phase III clinical development for the treatment of chronic hepatitis C jointly developed by Medivir and Janssen Research & Development Ireland (Janssen). TMC647055 is a potent NNI (non-nucleoside inhibitor) of the HCV NS5B polymerase and is being developed by Janssen R&D.

"This study is in line with Medivir's and Janssen's strategy to evaluate different combination possibilities with simeprevir for interferon-free HCV treatments. This will broaden our understanding of simeprevir, which we believe has the necessary characteristics to potentially become a key component of future hepatitis C treatment regimens, including combination with interferon and ribavirin as well as interferon-free therapies," comments Charlotte Edenius, Medivir's EVP of Research and Development.

Study design
This will be an open label study in patients who are chronically infected with HCV genotype-1a or 1b to assess the efficacy, safety and tolerability of the combination. The primary endpoint in the study will be SVR12 (sustained virologic response 12 weeks after end of treatment). Simeprevir, TMC647055 and low-dose ritonavir will be co-administered once daily, with and without ribavirin.

Approximately 40 patients will be enrolled in this study, which is divided in two parts. The first part will include patients chronically infected with HCV genotype-1, who are either treatment-naive or have relapsed after prior pegylated interferon (PegIFN)/ribavirin treatment. The treatment will consist of simeprevir, TMC647055 and low-dose ritonavir, with and without ribavirin for 12 weeks.

The second part of the trial will investigate the same regimen in prior null responder patients chronically infected with HCV genotype 1a.

Additional information about this study will be posted on http://www.clinicaltrials.gov

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company's key pipeline asset is simeprevir (TMC435), a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Research & Development Ireland.
In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia. and today Medivir has a broad product portfolio with prescription pharmaceuticals in the Nordics.

Medivir's first product, the unique cold sore product Xerese®/Xerclear®, is launched in collaboration with GlaxoSmithKline to be sold OTC under the brand name ZoviDuo in Europe, Japan and Russia.

Medivir's IPO was in 1996 and currently the company has around 180 employees.
For more information about Medivir, please visit the Company's website: http://www.medivir.com
For more information about Medivir, please contact:

Medivir
Rein Piir, EVP Corporate Affairs & IR  
Direct: +46-8-440-6550 or:
Mobile: +46-708-537-292

M:Communications
Europe: Mary-Jane Elliott, Amber Bielecka, Hollie Vile  
medivir@mcomgroup.com
+44(0)20-7920-2330

SOURCE Medivir

PR Newswire (htt

Sofosbuvir (GS-7977) in HIV/HCV co-infected patients...

Posted 9/17/12 on Hep Mag.com. A small interferon-free Phase Ib 7-day trial of Sofosbuvir (GS-7977) plus ribavirin in 19 HIV/HCV co-infected patients yielded some impressive initial results in a population that is definitely in need of more anti-HCV options. Sofosbuvir showed no difference in viral kinetics vs non co-infected patients, no new safety signals, no HIV viral breakthrough and no added side-effects. Hopefully the larger Phase III trial in this population will be equally impressive in its results. 

Sofosbuvir (GS-7977) Shows Promise in HIV/Hep C-Coinfected People

Gilead Sciences' experimental NS5B polymerase inhibitor sofosbuvir (GS-7977) was just as likely to rapidly reduce hepatitis C virus (HCV) levels in people coinfected with HIV, compared with those living with HCV but not HIV, in a small seven-day study presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco. The clinical trial, which enrolled HCV/HIV-coinfected and HCV-monoinfected patients residing in Puerto Rico—75 percent of whom had difficult-to-treat genotype 1 HCV infection—also noted that side effects were no different or more severe among those with living with both viruses. After a week of sofosbuvir treatment, used without other hep C medications, HCV viral loads dropped by an average of 4 log (99.99 percent). Additionally, nearly 60 percent of patients achieved undetectable HCV viral loads during the study, with 15 percent maintaining undetectable levels seven days after treatment was discontinued. Sofosbuvir appeared to work equally well against the different HCV genotypes in the study and did not hinder the effectiveness of the antiretroviral regimens being used to suppress HIV. A Phase III clinical trial of sofosbuvir plus ribavirin enrolling people living with HCV and HIV began in July and is currently recruiting volunteers.

Journal of Medical Case Reports: Classic polyarteritis nodosa associated with hepatitis C virus infection: a case report

Interesting case report posted 9-14-12 on Journal of Medical Case Reports.com. Lately, there has been quite a bit of medical literature discussing the extrahepatic burden of disease associated with HCV. This is a case report of a patient diagnosed with HCV-related Polyarteritis Nodosa (often misdiagnosed as mixed cryoglobulinemia). Polyarteritis Nodosa is a Polyarteritis Nodosa is an inflammatory disease that damages arteries and the tissues the arteries feed also become damaged to to lack of oxygen and nourishment. Again, this points to the premise that although in most cases fibrosis progression is slow within the liver, that there are other extrahepatic risks associated with replicating HCV virus

Case report

Classic polyarteritis nodosa associated with hepatitis C virus infection: a case report
Damith Rodrigo, Ruwan Perera and Janaka de Silva

Journal of Medical Case Reports 2012, 6:305 doi:10.1186/1752-1947-6-305
Published: 14 September 2012

Abstract (provisional)

Introduction
Hepatitis C virus has been under-recognized as an etiologic factor for polyarteritis nodosa and the presence of hepatitis C antigenemia in patients with polyarteritis nodosa has been reported as insignificant. In the literature hepatitis C virus-associated polyarteritis nodosa is a rare and controversial entity.

Case presentation
A 34-year-old Sri Lankan Tamil man presented to our facility with a two-week history of slow-resolving pneumonia of the right mid and lower zones. On physical examination he had panniculitic type tender skin nodules with background livedo reticularis. A skin biopsy was suggestive of a small and medium vessel vasculitis compatible with polyarteritis nodosa. He was tested positive for hepatitis C antibodies. A serum cryoglobulin test was negative but perinuclear antineutrophilic cytoplasmic antibody test was positive. Serum complement levels were reduced. He was diagnosed as having classic polyarteritis nodosa associated with hepatitis C infection. He later developed left-sided radiculopathy involving both upper and lower limbs and an ischemic cardiac event. His hepatitis C infection was managed with polyethylene glycol-interferon 2alpha combined with oral ribavirin. Simultaneously, his classic polyarteritis nodosa was treated with prednisolone and cyclophosphamide. He made a good recovery.

Conclusions
Hepatitis C virus infection is capable of inducing a fulminant form of vasculitis in the form of polyarteritis nodosa. It may be easily confused early in its course with mixed cryoglobulinemia, which is commonly known to be associated with hepatitis C virus. Awareness of hepatitis C virus-related polyarteritis nodosa helps in diagnosing the condition early so combined immunosuppressive and antiviral treatment can be started as soon as possible.

Medivir moves to strengthen its HCV portfolio...

Press release dated 9-5-12 on the Medivir AB website. Medivir bolstered it's HCV portfolio by purchasing anti-HCV related preclinical research compounds from Novadex Pharmaceuticals. This purchase includes IP and prodrug technologies as well in hopes that it could be applied to both HCV protease inhibtors and nucleoside analogs to give a boost to the pharmacokinetic properties. Medivir already has TMC-435 in collaborative development with Janssen Pharaceuticals, now in Phase III clinical trials. 

Medivir acquires preclinical antiviral programs including hepatitis C and prodrug technologies

05-Sep-12 Stockholm, Sweden—Medivir AB (OMX: MVIR), announced today that it has acquired preclinical research stage assets from Novadex Pharmaceuticals AB. The acquisition includes intellectual property and prodrug technologies in order to further strengthen Medivir’s hepatitis C platform and know how.

The acquired portfolio of research stage antiviral programs includes novel nucleotide polymerase inhibitors that have been identified and developed. It also includes prodrug technologies which could be applied to both protease inhibitors and nucleoside analogues to enhance their overall pharmacokinetic properties.

“We are very pleased to be able to make these additions to the Medivir R&D portfolio, which will further strengthen our pipeline and capabilities in the antiviral disease area. There are several synergies with the Medivir anti-viral projects and prodrug approaches which we aim to explore” comments Charlotte Edenius, Medivir’s EVP of Research and Development

The transaction value, which consists of up-front payment as well as future potential milestone payments, is not disclosed.

For more information about Medivir, please contact:

Medivir Direct: +46 8 440 6550 or:
Rein Piir, EVP Corporate Mobile: +46 708 537 292
Affairs & IR
M:Communications medivir@mcomgroup.com
Europe: Mary-Jane Elliott, +44(0)20 7920 2330
Amber Bielecka, Hollie Vile

About Medivir

Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir (TMC435), a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.

In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia. and today Medivir has a broad product portfolio with prescription pharmaceuticals in the Nordics.

Medivir’s first product, the unique cold sore product Xerese®/Xerclear®, is launched in collaboration with GlaxoSmithKline to be sold OTC under the brand name ZoviDuo in Europe, Japan and Russia.

Medivir’s IPO was in 1996 and currently the company has around 180 employees.

For more information about Medivir, please visit the Company’s website: www.medivir.com

JID: 'Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study'

I reference this study entitled 'Chronic Hepatitis C Virus Infection Increases
Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term
Prospective Study' from the "Journal of Infectious Diseases" all the time in conversation and seem to get a good discussion going. I'm hoping for the same outcome on the Internet, thus this post. This is a HUGE cohort study from China (n = 23,820). Grant it, the 'n' representative of the HCV seropositive population is rather small (1095) compared to the seronegative population (19,636), and the population is of Eastern descent, but even given the sampling and ethnic disparity, there are compelling conclusions here which bear further study. Most notably, that having replicating Hepatitis C virus results in not only greater hepatic-related mortality, but extra-hepatic as well. Replicating virus = inflammation of all types. This gives compelling fuel to treatment advocates arguments that, barring contraindications and other special cases, Hepatitis C-positive patients should be considered for treatment now vs 'warehousing' for drugs that might/might not make it to market in the future. Hopefully further prospective and retrospective data based on the conclusions here will shed more light on this controversial subject. 

Investing Daily.com: Hepatitis C Drug Companies and All-Oral Treatment - A $20 Billion Market

Posted 8/28/12 on Investing Daily.com. Author and investor Jim Finks takes a look at the current HCV Drug Development space. Of note is the projected $20 billion worldwide HCV drug market which he feels will greatly be increased from the current $5 billion if drugs with better tolerability and efficacy make it to market, coupled with the benefit of interferon-free regimens for some patients.    

Hepatitis C Drug Companies and All-Oral Treatment: A $20 Billion Market

by JIM FINK on AUGUST 28, 2012
in STOCKS TO WATCH

Last week I wrote about 3 Stock Plungers and only liked the future prospects of one of the stocks: Idenix Pharmaceuticals (NasdaqGM: IDIX). My main reason for thinking a sustainable stock rebound is possible was because it’s a top-ten holding of value-investing legend Seth Klarman, who owns a 9.2% stake in the company (10 million shares) at an average purchase price of $8 per share (30% higher than the stock’s current price of $6.15). Klarman’s Baupost Group has bought shares in Idenix for five consecutive quarters.

This begged the question why Klarman is so enamored with Idenix. I couldn’t get an interview with Klarman to ask him and Baupost Group’s 2011 shareholder letter (dated Jan. 31, 2012) doesn’t mention Idenix — even though Klarman started buying the stock in Q2 2011. Consequently, I needed to research Idenix myself.

Hepatitis C Virus is a Global Killer
I discovered that the Idenix investment story is all about the market opportunity for treating Hepatitis C, a virus that infects the liver and is life-threatening – slowly destroying the liver over 20-30 years (resulting in cirrhosis or cancer). For those that are unsure, the liver is a vital organ that we cannot live without.

There is no vaccine for Hepatitis C, so the number of people who will get infected (e.g., sexual intercourse, tattoos, blood transfusions/dialysis, sharing dirty needles, mother/child) is predictable and not likely to go down. Furthermore, the body does not develop immunity from experiencing the disease, so people can get infected multiple times. In other words, the market demand for Hepatitis C drug cures is high and long-lasting. Below are some facts about Hepatitis C:

Worldwide, 180 million people are infected and 350,000 die each year.
In the U.S., 3.2 million people are infected, between 32,000 and 110,000 are newly infected each year, and 15,000 to 20,000 die each year.
75% of infections are curable, but up to 75% of all infected people don’t realize that they have the disease because they don’t look or feel sick – until it is too late.

Annual global sales of Hepatitis C drugs is currently $5 billion, but analysts project that new drug treatments with fewer side effects and oral application could generate a worldwide market opportunity of $20 billion.

The U.S. Centers for Disease Control and Prevention (CDC) recently recommended that all baby boomers born between 1946 and 1964 (76 million people aged 47 to 67) be tested for Hepatitis C infection.

Treating Hepatitis C with Interferon Injections is Unpleasant
Prior to 2011, the standard treatment for Hepatitis C was a combination of immune-boosting peginterferon injections – offered by Merck (NYSE: MRK) and Roche Holding AG (OTC Markets: RHHBY) — and ribavirin anti-viral pills (ribavirin patent has expired, so generic versions are available from several companies). Course of treatment was long at 48 weeks and costs $15,000 to $30,000, the cure rate was only 46% and there were severe side effects (e.g., flu-like symptoms, anemia, depression).

Treating Hepatitis C with Protease Inhibitors Is Better But Still Requires Interferon
Then, in May 2011, the Food & Drug Administration (FDA) approved two new Hepatitis C drugs called “protease inhibitors” that promise much higher cure rates (75%) and shorter treatment protocols (half as long at 24 weeks). Both of these drugs are taken orally in pill form but only work in conjunction with the standard peginterferon injections and ribavirin treatment. The two new drugs are:

Victrelis by Merck, which has a 66% cure rate, costs between $26,400 and $48,400 per course of treatment, and requires 12 pills per day.

Incivek by Vertex Pharmaceuticals (NasdaqGS: VRTX), which has a 79% cure rate, costs $49,200 per course of treatment, and requires 6 pills per day.

Based on the higher cure rate and simpler dosing from Incivek, it should come as no surprise that Incivek is outselling Victrelis 3-to-1.

Treating Hepatitis C with All-Oral Nucleotide Drugs is the Holy Grail

But Vertex’s dominance with Incivek could be short-lived because other drug companies are working on new Hepatitis C drugs called “nucleotides” that offer the holy grail of therapy: pill-only treatment that does not require the peginterferon/ribavirin injection albatross.

Perhaps in the forefront of all-oral Hepatitis C treatment is Gilead Sciences (NasdaqGS: GILD), which in November 2011 acquired biotech company Pharmhasset in a monstrous $10.8 billion all-cash deal. Pharmhasset’s Hepatitis C drug in Phase III trials is called PSI-7977 and could be on the market by 2014. According to Gilead, PSI-7977 is “way ahead of everybody else” and promises a cure in only 8-to-12 weeks of treatment. However, news in February that patients experience a relapse of Hepatitis C symptoms after stopping treatment with PSI-7977 caused Gilead’s stock price to suffer its largest one-day drop in 11 years. Since February, Gilead has recovered to all-time highs, which suggests investors have concluded that PSI-7977 will remain the core treatment for Hepatitis C – perhaps in combination with other drugs — despite the relapse issue.

Gilead’s drug may be best, but it won’t be the first all-oral treatment on the market because Roche Holdings is expected to offer an all-oral drug cocktail possibly consisting of setrobuvir (obtained in its acquisition of Anadys Pharmaceuticals in October 2011), danoprevir (purchased from InterMune (NasdaqGS: ITMN) in October 2010), and Merck’s Victrelis.

With Bristol-Myers Squibb’s (NYSE: BMY) abandonment of the Hepatitis C drug (BMS-986094) acquired from Inhibitex for $2.5 billion and the FDA clinical hold on Idenix’s Hepatitis C drug (IDX-19368) pending additional safety data, the path to riches in Hepatitis C treatment is proving to be a tortuous one. Other drug companies in the race for Hepatitis C drug treatments or vaccines include:

Achillion Pharmaceuticals (NasdaqGS: ACHN)
Abbott Laboratories (NYSE: ABT)
Dynavax Technologies (NasdaqCM: DVAX)
Peregrine Pharmaceuticals (NasdaqCM: PPHM)
Inovio Pharmaceuticals (NYSE: INO)
Medivir AB (OTC Markets: MVRBF) –  in partnership with Johnson & Johnson (NYSE: JNJ)

Achillion is a Prime Takeover Candidate
Of all of these companies, the best speculative buy right now may be Achillion. It is a pure-play on Hepatitis C with two promising drugs under development (one protease inhibitor and one NS5). There are no FDA clinical holds on Achillion’s drug pipeline like there are on Idenix and Achillion’s small market cap of $481 million makes the company an easily digestible acquisition for big boys like Gilead, Roche, Merck, or Abbott.

Furthermore, I have a soft spot for Achillion because it is located in New Haven, Connecticut (where I lived for four years) and is in partnership with my alma mater, Yale University. Good things happen to people and companies associated with a top-notch educational institution like Yale.

miR-122 inhibitor SPC3649 successfully inhibits HCV replication in chimps...

Posted 8/30/12 on Texas Biomed.org. Texas Biomedical Research Institute scientists in collaboration with Denmark's Santaris Pharma A/S have successfully inhibited HCV replication in chimpanzees using SPC3649, a DNA-based drug developed from Santaris's proprietary LNA ('Locked Nucleic Acid') technology. SPC3649 inhibits a host-based RNA molecule microRNA122 (miR-122) which HCV uses to replicate.  The drug is currently in phase II trials in humans and looks particularly compelling because of it's lack of any known side effects. 

Attacking the Silent Killer

Texas Biomed scientists have demonstrated that a new and novel class of drug targeting hepatitis C infections successfully inhibited replication of the virus in the liver of chimpanzees. The drug is now in phase two human clinical trials.

The drug was developed by the biopharmaceutical firm Santaris Pharma A/S in Denmark using its proprietary nucleic acid chemistry called “locked nucleic acid” or LNA. The drug, known as SPC3649, is a DNA-based drug that captures a small RNA molecule in the liver, called microRNA122 (miR-122) that is required for hepatitis C virus (HCV) replication.

“Our collaboration with Santaris Pharma proved that the drug worked exceptionally well in treating HCV infections in chimpanzees,” said Texas Biomed’s Robert E. Lanford, Ph.D., of the Department of Virology and Immunology. He was the lead author on the study appearing in the journal Science in January 2010.

One of the novel aspects of this drug is that it targets a host factor, miR-122, required by the virus, rather than directly targeting the virus itself. This helped prevent antiviral resistance, a major problem with therapies that directly target the virus.  Remarkably, this drug continued to work for several months after administration of the last dose.

The other novel aspect was the use of a DNA based therapy in what is called antisense technology. Antisense was supposed to be one of the “magic bullets” along with siRNA technology, but thus far no one has gotten them to work when systemically administered. Thus, this proof-of-concept study suggests that the LNA technology might also prove useful in using DNA based antisense drugs to treat many other diseases such as AIDS, cancer, and inflammatory diseases.

The study was conducted under a sponsored research grant to Texas Biomed. The primate studies were performed at Texas Biomed’s Southwest National Primate Research Center, which is supported by the National Institutes of Health.

HCV infections affect 170 million people worldwide and may progress over years to end-stage liver disease, including cirrhosis and liver cancer. In the United States, 4 percent of the adult population is chronically infected with HCV. The only U.S. FDA-approved therapy is pegylated-interferon and ribavirin, which is highly toxic, requires 48 weeks of treatment, and works in less than half of patients who are able to complete the full course of treatment. HCV infection is the leading reason for liver transplantation in the U.S, and HCV associated liver cancer is the most rapidly increasing cause of cancer death in the U.S.

Because it provides a high barrier to resistance, the new therapy could potentially replace interferon in future drug cocktails. “This antiviral could be used alone in long-term therapy to treat disease progression,” Lanford said. The new therapy may also be good to use after liver transplantation, because it may help suppress the replication of HCV in the new liver. The therapy has no known toxic or adverse reactions, and this is critical in the transplant setting.

In the study, four chimpanzees chronically infected with HCV were treated with the new antiviral drug. The two animals that received the higher dose had a reduction in virus levels in the blood and liver of approximately 350-fold. Additional surprising findings were the lack of antiviral resistant mutants and the fact that the therapy continued to work for several months after dosing stopped. An additional benefit of the drug was the reduction of total serum cholesterol by up to 45%, due to inhibition of the normal function of miR122 in cholesterol and fatty acid metabolism.

The new study was a critical proof of concept that the LNA technology could work for HCV. It proved that miR-122 is essential for HCV replication in an animal infected with HCV. Previously the role of miR-122 in HCV replication had only been shown in tissue culture. A second advance was the finding that LNA therapy could work against an important human disease in the chimpanzee model, suggesting that the new technology could be applied to other diseases.