HCV Research and News: 12/13/13

December 13, 2013

Telaprevir Twice Daily is Noninferior to Telaprevir Every 8 hrs for Patients with Chronic Hepatitis C

Gastroenterology. 2013 Dec 4. pii: S0016-5085(13)01728-9. doi: 10.1053/j.gastro.2013.11.047. [Epub ahead of print]

Buti M, Agarwal K, Horsmans Y, Sievert W, Janczewska E, Zeuzem S, Nyberg L, Brown RS Jr, Hezode C, Rizzetto M, Parana R, De Meyer S, De Masi R, Luo D, Bertelsen K, Witek J.

Hospital Valle Hebron and Ciberehd del Institut Carlos III, Barcelona, Spain. Electronic address: mbuti@vhebron.net.

Abstract

BACKGROUND & AIMS: We performed an open-label, multi-center, Phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis.

METHODS: Patients were randomly assigned to groups given telaprevir 1125 mg twice-daily or 750 mg every 8 hrs, plus peg-interferon alfa-2a and ribavirin for 12 weeks; patients were then given peg-interferon alfa-2a and ribavirin alone for 12 weeks if their week 4 level of HCV RNA was <25 IU/mL, or for 36 weeks if their level was higher. The primary objective was noninferiority of telaprevir twice-daily vs every 8 hrs in producing a sustained virologic response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups).

RESULTS: At baseline, of 740 patients, 85% had levels of HCV RNA ≥800,000 IU/mL, 28% had fibrosis (F3-4), 14% had cirrhosis (F4), 57% were infected with HCV genotype 1a, and 71% had the non-CC IL28B genotype. Of patients who received telaprevir twice-daily, 74.3% achieved SVR12, compared with 72.8% of patients who received telaprevir every 8 hrs (difference in response, 1.5%; 95% confidence interval, -4.9% to 12.0%), so telaprevir twice-daily is noninferior to telaprevir every 8 hrs. All subgroups of patients who received telaprevir twice-daily vs those who received it every 8 hrs had similar rates of SVR12. Most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), anemia (42%), nausea (37%), rash (35%), and headache (26%); serious AEs were reported in 9% of patients. Rates of AEs and serious AEs were similar or slightly higher among patients receiving telaprevir every 8 hrs.

CONCLUSIONS: Based on a phase 3 trial, telaprevir twice-daily is noninferior to every 8 hrs in producing SVR12, with similar levels of safety and tolerability. These results support use of telaprevir twice-daily in patients with chronic HCV genotype 1 infection, including those with cirrhosis. ClinicalTrials.gov number: NCT01241760.

KEYWORDS: AEs, AUC, BMI, C(max), C(max,ss), C(min), C(trough,ss), CI, DAA, DRESS, ESA, G1, HCV, ITT, IU, LLOQ, OPTIMIZE, P, Peg-IFN, PK, PP, PR, R, RBV, RVR, SD, SE, SSC, SVR, TVR, adverse events, area under curve, bid, body mass index, clinical trial, confidence interval, drug reaction with eosinophilia and systemic symptoms, e-diary, eRVR, electronic diary, erythropoiesis-stimulating agents, every 12 hours, every 8 hours, extended rapid virologic response, genotype 1, hepatitis C virus, intent-to-treat, international unit, lower limit of quantification, maximum concentration, maximum steady-state concentration, peginterferon, peginterferon alfa/ribavirin, per-protocol, pharmacokinetics, predose concentration, predose steady-state concentration, protease inhibitor, q12h, q8h, rapid virologic response, ribavirin, special search category, standard deviation, standard error, sustained virologic response, telaprevir, twice daily

PMID: 24316262 [PubMed - as supplied by publisher]
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New hepatitis C treatment may be too expensive – Egypt

NATURE MIDDLE EAST | HOUSE OF WISDOM

12 Dec 2013 | 10:31 GMT | Posted by Mohammed Yahia | Category: Health, Research

Egypt has the highest hepatitis C burden in the world, with some 14.7% of Egyptians testing positive for HCV antibody. Therefore, it was no surprise that news of the latest oral HCV treatments approved by the FDA in the United States generated quite a buzz in local Egyptian media. The new drugs are very effective and have nearly no side effects, unlike the current regimens that cause depression, anaemia and severe nausea and do not have high success rates.

However, Raymond Schinazi, an Italian-Egyptian pharmacologist who oversaw the development of the new antiviral sofosbuvir which has generated excitement, warned that Egyptians should not be rejoicing just yet, in an interview with the Al-Ahram daily.

The new drug might be too expensive for developing countries, he warns. A 12-week treatment regimen could cost US$86,000 – which is far well more than 0.5 million EGP – much more than most people can afford. With the large number of people needing treatment, it would be impossible for the government to use the new drug instead of its current regimen, in which a full, 48-week course of HCV medication using the antiviral drug ribavirin and interferon costs around US$3,500.

“The drug can save the lives of millions around the world. But at its current price, it can bankrupt developing countries,” Schinazi tells Al-Ahram.

He goes on to stress that most of the studies conducted on sofosbuvir were on genotype 1, which is the genotype most present in North America and Europe. However, it has not been widely tested against genotype 4 which is the predominant one in Egypt and the Middle East.

“The cost of treatment will eventually go down, similar to what happened with antiretroviral treatments for HIV/AIDS. However, I think it may still be a huge burden for Egypt due to the large number of people infected with the virus,” adds Schinazi in his interview.

He goes on to suggest that a more reliable strategy for Egypt would be to invest in medical and pharmacological research and develop it’s own affordable drugs, similar to what countries in Southeast Asia have done. “You spend millions annually to treat a few thousand people and the infection rate is still high. This money should be better managed to improve research and raise awareness to limit new infections.”

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Cellular Biomedicine Group Announces Completion of Patient Treatment for Phase I Clinical Trial for Liver Cancer

PRESS RELEASE

Dec. 13, 2013, 3:33 p.m. EST

PALO ALTO, Calif., Dec. 13, 2013 /PRNewswire via COMTEX/ -- Cellular Biomedicine Group, Inc. (otcqb:CBMG), a biomedicine firm engaged in the development of new treatments for degenerative and cancerous diseases, is pleased to announce that it has treated the final patient of its Phase I clinical trial which evaluates the safety and preliminary efficacy of TC-DC (Tumor Stem Cell Specific Dendritic Cell) therapy for hepatocellular carcinoma (HCC), the most common type of liver cancer.

The Phase I clinical trial for TC-DC therapy for HCC is an open-label clinical trial conducted with Shanghai's PLA 85 Hospital, one of China's largest Liver Disease Centers. The trial evaluated the safety and preliminary efficacy in lowering the incidence of tumor recurrence and metastasis by means of autologous immune cell therapy in primary HCC patients following standard tumor resection and TACE chemotherapy.

"We are very pleased to reach this important milestone in our clinical trial and we look forward to reporting the full data readout early in the new year," said Dr. Wei (William) Cao, PhD, BM, CEO at Cellular Biomedicine Group.

Hepatocellular Carcinoma in China Fifty-five percent (55%) of the world's HCC patients are in China, and there are more than 340,000 new patients diagnosed per year in China, according to the journal titled Chinese Clinical Oncology, Mar 2009, Vol. 14, No. 3. Currently, the most common therapies used to treat most HCC patients are surgery and local chemotherapy, with a 2-year recurrence rate of 51%.

About Cellular Biomedicine Group: Cellular Biomedicine Group, Inc. develops proprietary cell therapies for the treatment of certain degenerative diseases and cancers. Our developmental stem cell, progenitor cell, and immune cell projects are the result of research and development by scientists and doctors from China and the United States. Our flagship GMP facility, consisting of eight independent cell production lines, is designed, certified and managed according to U.S. standards. To learn more about CBMG, please visit: www.cellbiomedgroup.com

Forward-Looking Statements: Statements in this press release relating to plans, strategies, trends, specific activities or investments, and other statements that are not descriptions of historical facts may be forward-looking statements. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors, which include, but are not limited to, risk factors inherent in doing business. Forward-looking statements may be identified by terms such as "may," "will," "expects," "plans," "intends," "estimates," "potential," or "continue," or similar terms or the negative of these terms. Although CBMG believes the expectations reflected in the forward-looking statements are reasonable, they cannot guarantee that future results, levels of activity, performance or achievements will be obtained. CBMG does not have any obligation to update these forward-looking statements other than as required by law.

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Hepatitis C: Expensive cure in sight

Original article in German

Friday 13 December 2013

Rockville - The manufacturer Gilead has come under criticism because of the pricing of the hepatitis C drug Sovaldi. Each tablet with the active ingredient Sofosbuvir will cost U.S. $ 1,000. The critics hold for grossly overpriced.

The polymerase inhibitor Sofosbuvir is considered the current best medication for the treatment of hepatitis C. In combination with ribavirin and pegylated interferon Sofosbuvir achieved in clinical trials of up to 90 percent of patients with genotype 1, a "sustained virologic response" (SVR), which is equated with a cure.

Without Sofosbuvir chances are less than half as large and the therapy lasts twice as long. Genotype 1 is the most common variant in the industrialized countries. For genotypes 2 and 3 can even be dispensed to the accompanying interferon therapy.

However, these advantages over the existing treatment has its price. The wholesale price for Sovaldi should be 28,000 U.S. dollars per bottle. Each bottle contains 28 tablets, taken once daily. The price for Germany is not yet known. That means likely to be approved shortly after the EMA has issued a positive recommendation in November.

The high price of Sofosbuvir is not the result of a complex synthesis. The production cost is low. The pharmacologist Andrew Hill of the University of Liverpool she appreciated against Science at 68-136 U.S. dollars - and not for a tablet but for the total ration a 12-week therapy. The high sale price has a different reason, according to observers.

about

Press release from the FDA

Press release from the manufacturer

aerzteblatt.de

Sofosbuvir: New hepatitis C drug confident in clinical trials

Gilead has Sofosbuvir not self-developed, but bought from a small company and paid for it in January 2012 not less than 11.2 billion U.S. dollars. Hepatitis C is considered by manufacturers as a lucrative business in which many companies have to buy their own lack of innovation. Why should the many other resources that are currently in clinical trials are very expensive.

Most hepatitis C patients, there is, however, not in the industrialized countries, where today almost exclusively infect intravenous drug users (sexual transmission is also possible, but rare). The manufacturer speculate mainly on the treatment of an unknown number of people who iatrogenic before discovery of the virus and the test development infected with non-A, non-B hepatitis.

Most cases occur in poorer countries. Experts estimate the percentage to 90 percent.For these patients Sovaldi is priceless. The non-profit organization Treatment Action Group (which emerged from the ACT-Up movement of HIV-infected) therefore demands that the manufacturer provides the drug available at low cost.

Gilead has over Science signaled some willingness, but at the same time pointed out the "complex challenges" of a two-price policy. In fact, the cheaper delivery to patients could quickly lead to a black market in poorer countries.

Since decades later the hepatitis C leads to liver cirrhosis and cancer, many patients in developing countries are likely to be willing to ignore the personal risk, and low acquired drug to multiples of the price to sell more. © rme / aerzteblatt.de

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Pain management in patients with liver cirrhosis

Gastroenterol Hepatol. 2013 Dec 2. pii: S0210-5705(13)00167-2. doi: 10.1016/j.gastrohep.2013.05.007. [Epub ahead of print]

[Article in Spanish]

Ojeda A, Moreno LA.

Servicio de Anestesiología y Reanimación, Hospital Clínic de Barcelona, Barcelona, España; Unidad del Dolor, Servicio de Anestesiología y Reanimación, Hospital Clínic de Barcelona, Barcelona, España. Electronic address: ojeda@clinic.ub.es.

Abstract

Pain management in patients with liver cirrhosis is a real challenge and is often inadequate due to a lack of therapeutic efficacy or the high incidence of adverse effects. The focus of treatment differs depending on whether the pain is acute or chronic and involves understanding the causative pathophysiological mechanism. Analgesics should be started with the minimum effective dose and should be titrated slowly with avoidance of polypharmacy. Adverse effects must be monitored, especially sedation and constipation, which predispose the patient to the development of hepatic encephalopathy. The first-line drug is paracetamol, which is safe at doses of 2-3g/day. Non-steroidal anti-inflammatory agents are contraindicated because they can cause acute renal failure and/or gastrointestinal bleeding. Tramadol is a safe option for moderate-severe pain. The opioids with the best safety profile are fentanyl and hydromorphone, with methadone as an alternative. Topical treatment can reduce oral drug consumption. In neuropathic pain the first-line therapeutic option is gabapentin. The use of antidepressants such as amitriptyline can be considered in some patients. Interventional techniques are a valuable tool in moderate to severe pain, since they allow a reduction in drug therapy and consequently its adverse effects. Psychological treatment, physical therapy and rehabilitation should be considered as part of multimodality therapy in the management of chronic pain.

KEYWORDS: Adverse drug events, Cirrosis hepática, Hepatic cirrhosis, Manejo del dolor, Pain management, Reacciones adversas farmacológicas

PMID: 24309482 [PubMed - as supplied by publisher]

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Clinical effects and complications of TIPS for portal hypertension due to cirrhosis: A single center

World J Gastroenterol. 2013 Nov 28;19(44):8085-92. doi: 10.3748/wjg.v19.i44.8085.

Qin JP, Jiang MD, Tang W, Wu XL, Yao X, Zeng WZ, Xu H, He QW, Gu M.

Jian-Ping Qin, Ming-De Jiang, Wen Tang, Xiao-Ling Wu, Xin Yao, Wei-Zheng Zeng, Hui Xu, Department of Digestion, Chengdu Military General Hospital, Chengdu 610083, Sichuan Province, China.

Abstract

AIM: To determine the clinical effects and complications of transjugular intrahepatic portosystemic shunt (TIPS) for portal hypertension due to cirrhosis.

METHODS: Two hundred and eighty patients with portal hypertension due to cirrhosis who underwent TIPS were retrospectively evaluated. Portal trunk pressure was measured before and after surgery. The changes in hemodynamics and the condition of the stent were assessed by ultrasound and the esophageal and fundic veins observed endoscopically.

RESULTS: The success rate of TIPS was 99.3%. The portal trunk pressure was 26.8 ± 3.6 cmH2O after surgery and 46.5 ± 3.4 cmH2O before surgery (P < 0.01). The velocity of blood flow in the portal vein increased. The internal diameters of the portal and splenic veins were reduced. The short-term hemostasis rate was 100%. Esophageal varices disappeared completely in 68% of patients and were obviously reduced in 32%. Varices of the stomach fundus disappeared completely in 80% and were obviously reduced in 20% of patients. Ascites disappeared in 62%, were markedly reduced in 24%, but were still apparent in 14% of patients. The total effective rate of ascites reduction was 86%. Hydrothorax completely disappeared in 100% of patients. The incidence of post-operative stent stenosis was 24% at 12 mo and 34% at 24 mo. The incidence of post-operative hepatic encephalopathy was 12% at 3 mo, 17% at 6 mo and 19% at 12 mo. The incidence of post-operative recurrent hemorrhage was 9% at 12 mo, 19% at 24 mo and 35% at 36 mo. The cumulative survival rate was 86% at 12 mo, 81% at 24 mo, 75% at 36 mo, 57% at 48 mo and 45% at 60 mo.

CONCLUSION: TIPS can effectively lower portal hypertension due to cirrhosis. It is significantly effective for hemorrhage of the digestive tract due to rupture of esophageal and fundic veins and for ascites and hydrothorax caused by portal hypertension.

KEYWORDS: Cirrhosis, Complication, Portal hypertension, Therapeutic effect, Transjugular intrahepatic portosystemic shunt

PMID: 24307804 [PubMed - in process] PMCID: PMC3848158

Free PMC Article

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Treatment of decompensated cirrhosis secondary to hepatitis C with antiviral therapy

J Coll Physicians Surg Pak. 2013 Dec;23(12):833-6. doi: 12.2013/JCPSP.833836.

Khokhar N, Qureshi MO, Niazi TK.

Department of Gastroenterology / Medicine, Shifa International Hospital, Islamabad.

Abstract

Objective: To treat decompensated hepatitis C patient with interferon, ribavirin and amantidine to ascertain the sustained viral response. Study Design: Descriptive study. Place and Duration of Study: Shifa International Hospital, Islamabad, from January 2007 to January 2012. Methodology: HCV PCR patients with decompensated hepatitis C, who had developed a complication like ascites, encephalopathy or variceal bleeding were included in the study. Those with uncontrolled ascites or other complications were excluded. Treatment with standard interferon 3 miU subcutaneously three times a week along with ribavirin 800 mg to 1200 mg and amantidine 100 mg b.i.d. was administered for 12 months. Patients were followed every month with CBC and ALT and HCV PCR was performed after 3 months to document early viral response. They had HCV PCR at the end of the treatment to document end of treatment response. All were further followed for another 6 months at monthly intervals and HCV PCR was performed at the end of this period to document sustained viral response. Results: In all, 165 patients were treated. Treatment had to be discontinued in 42 (26%) patients. Out of these, 16 patients died. Thus, 123 completed treatment. Sustained viral response was documented in 58 out of the 123 (47%) patients. Hepatic encephalopathy, gastrointestinal bleeding, sepsis and development of ascites were the major complications during treatment. Conclusion: Forty seven percent of patients with decompensated hepatitis C cirrhosis were able to achieve sustained viral response after one year treatment with anti-viral therapy. However, complications developed during treatment and, therefore, frequent and close monitoring is necessary in these patients.

PMID: 24304983 [PubMed - in process]

Source

Post-treatment Levels of α-fetoprotein Predict Incidence of Hepatocellular Carcinoma After Interferon Therapy

Clin Gastroenterol Hepatol. 2013 Dec 6. pii: S1542-3565(13)01840-5. doi: 10.1016/j.cgh.2013.11.033. [Epub ahead of print]

Oze T, Hiramatsu N, Yakushijin T, Miyazaki M, Yamada A, Oshita M, Hagiwara H, Mita E, Ito T, Fukui H, Inui Y, Hijioka T, Inada M, Katayama K, Tamura S,Yoshihara H, Inoue A, Imai Y, Hayashi E, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kasahara A, Hamasaki T, Hayashi N, Takehara T; the Osaka Liver Forum.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Abstract

BACKGROUND & AIMS: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pre-treatment factors are known to affect HCC incidence, less is known about post-treatment factors- many change during the course of interferon therapy.

METHODS: We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsies were collected before treatment; all patients received Peg-IFN plus ribavirin for 48-72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings.

RESULTS: HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in non-responders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 and older age; among those without SVRs, risk factors included higher AFP24, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (>10 ng/ml, 10-5 ng/ml, and then <5 ng/ml) was a better predictor of HCC incidence than pre-treatment level of AFP among patients with and without SVRs.

CONCLUSIONS: In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. UMIN: C000000196, C000000197.

KEYWORDS: AFP, AFP24, ALT, ALT24, CH-C, CT, EOT, HCC, HCV, IFN, MRI, NR, Peg-IFN, PreAFP, PreALT, SVR, alanine aminotransferase, alanine aminotransferase levels at 24 weeks after the end of treatment, alanine aminotransferase levels at the start of treatment, alpha-fetoprotein, alpha-fetoprotein levels at 24 weeks after the end of treatment, alpha-fetoprotein levels at the start of treatment, chronic hepatitis C, computed tomography, end of treatment, hepatitis C virus, hepatocellular carcinoma, i-ALT, integrated alanine aminotransferase value after the end of treatment, interferon, liver cancer, magnetic resonance imaging, non-response, outcome, pegylated interferon, response to therapy, risk factor, sustained virologic response

PMID: 24321207 [PubMed - as supplied by publisher]

Source

Single measurement of hemoglobin predicts outcome of HCC patients

Med Oncol. 2014 Jan;31(1):806. doi: 10.1007/s12032-013-0806-2. Epub 2013 Dec 11.

Finkelmeier F, Bettinger D, Köberle V, Schultheiß M, Zeuzem S, Kronenberger B, Piiper A, Waidmann O.

Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Abstract

Anemia is a common complication in several types of cancer including hepatocellular carcinoma (HCC). The prognostic potential of hemoglobin (Hb) levels has not yet been investigated in HCC patients. One hundred and ninety-nine patients were prospectively recruited and Hb levels were determined. Hb levels were compared to the stages of liver cirrhosis and HCC stages. The association of the Hb levels and overall survival (OS) was assessed by univariate and multivariate Cox regression models. The relation of Hb levels and OS was further validated in an independent cohort of 87 HCC patients. Hb levels negatively correlated with the stage of liver cirrhosis (model of end stage liver disease score and Child-Pugh stage) and differed between stages of HCC. Low Hb levels (≤13 g/dl) were associated with higher mortality in the test [hazard ratio (HR) 2.422, 95 % confidence interval (CI) 1.357-4.322, P = 0.003] as well in the validation cohort (HR 2.486, 95 % CI 1.097-5.632, P = 0.029) in univariate Cox regression model. Low Hb levels were associated with mortality independently from the tumor stage, age, gender and the C-reactive protein levels in a multivariate Cox regression model. Anemia should be considered as a risk factor for mortality in HCC patients.

PMID: 24326985 [PubMed - in process]

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Don't Short Gilead Sciences Just Yet

Provided by Seeking Alpha

Dec 13 2013, 11:08 | 9 comments

Pharma Reports

Articles (28), Instablog (2), Comments, (39), Profile

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

"We will identify which drugs can be pitted against each other and will make some really tough formulary decisions." Steven Miller

Late Friday, the FDA approved Gilead Sciences' (GILD) Sovaldi for hepatitis C. After a very brief rise on the much anticipated news, Gilead's stock went into decline mode.

News that John Martin and Gregg Alton, Gilead's CEO and Executive VP, respectively, have been selling shares in the company, coupled with an announcement by Steven Miller, Chief Medical Officer of Express Scripts (ESRX), the largest U.S. prescription benefits manager (PBM), that his company is planning to preempt a price war between Sovaldi and, the yet to be approved,AbbVie's (ABBV) new hepatitis medication, sent Gilead's stock lower.

Sovaldi's price of $1,000 per daily pill, or $84,000 per treatment cycle has been the subject of contention among activits and PBMs alike. The activists outrage is really not justified, since the patient will co-pay only $5. However, The Express Scripts' Chief Medical Officer's statement deserves a deeper examination.

Gilead paid $11 billion to acquire Sovaldi, together with Pharmasset, its developer, two years ago. The company spent another $2 billion to bring the drug to market, without any assurance of success. Gilead is not a charity but a for-profit-business and deserves to make a return on its investment and to reward its shareholders for co-sharing the risk.

Chronic hepatitis C, which affects an estimated 3.2 million Americans, causes liver cancer which leads to the need for very costly liver transplantation and eventually death.

Sovaldi, at $84,000 per treatment cycle, is priced much less than many of the other new cancer drugs that came to market recently. We believe that the statements coming out of Steven Miller, a medical professional and a high level executive at one of the country's largest prescription management companies, are misguided.

When Dr. Miller says, "If the difference in convenience cannot be demonstrated to have a difference in outcomes, we often recommend coverage of the equally effective, less-convenient product," he is actually stepping his bounds as medical insurance person and inserting himself between "the patient" and his or her "physician".

Physician-Patient relationships are bound by the Hippocratic oath not by exuberantly salaried bureaucrats working at extremely profitable insurance companies that have gotten fat on patients' premiums in the first place.

But let us suppose that Dr. Miller is justified in trying to rob the insurance paying patients out of the convenience of receiving the life-saving drug that their physician thinks that they need, would he be able to do it?

Sovaldi's Potential Competitors

Several companies are developing hepatitis C treatment regimens that do not require injectable interferon, which causes miserable flu like symptoms that lead many patients to discontinue or delay treatment.

AbbVie, Bristol-Myers Squibb (BMY) and Merck (MRK) are all seen as potential rivals with oral regimens that have shown impressive cure rates and also cut the current treatment duration to 12 weeks or less from the current 48-week treatment regimens.

AbbVie, which is developing a three-drug treatment regimen of ABT-333, ABT-450 and ABT-267 direct acting antivirals that each attack a different viral target necessary for the virus replication, has just releasedthat its therapy regimen has cured 96% of difficult-to-treat patients after 12 weeks in a late-stage clinical trial.

However, the regimen currently involves four pills a day plus typically 2 ribavirin pills a day. Despite receiving FDA fast tract designation, the cocktail is not likely to be approved before 2015.

BMS, which is developing a two-drug regimen of daclatasvir and asunaprevir in late phase 3, is even further behind AbbVie in its drug development efforts. The company's first presentation of its phase 3 interim findings was presented last month in Japan, which is likely to be the first market the cocktail is approved in.

Merck currently markets Victrelis for hepatitis C. However, the drug's sales has been declining recently because many doctors have advised their patients to wait for the more superior Sovaldi to be approved.

Merck, after realizing Victrelis disadvantage, is playing catch up with a combination of MK-5172, an NS3/4A protease inhibitor, and the NS5A treatment MK-8742. Cure rates have been good, ranging from 96% to 100% in genotype 1a and 1b patients. However, the number of patients tested was small with a total of 58 evaluable patients included in the readout.

First Mover Advantage

Gilead is first to market with Sovaldi which is expected to achieve steep sales revenue from its moment of launch due to the fact that many doctors advised their patients to wait for this new revolutionary therapy rather than start on one of the old, sometimes ineffective, treatment regimens.

According to the average of six analysts' estimates compiled by Bloomberg, Sovaldi could generate $9.5 billion in annual sales before the end of 2017. To put that in perspective, during 2012 Gilead generated a total of $9.7 billion.

Even if any of the potential competitors enters the market before 2017, I think they would be foolish to play into the hands of PBMs' fat cat bureaucrats and enter into a price war that could jeopardize the future of pharmaceutical research, development and innovation for years to come.

As for John Martin and Gregg Alton recent insider sales, though unfortunate, they were part of a 10b5-1 scheduled insider sale plan, rather than a deliberate selling on the good news and the peaking of the shares.

Source

Tumor necrosis factor-α inhibitors and chronic hepatitis C: A comprehensive literature review

World J Gastroenterol. 2013 Nov 28;19(44):7867-7873.

Pompili M, Biolato M, Miele L, Grieco A.

Maurizio Pompili, Marco Biolato, Luca Miele, Antonio Grieco, Department of Internal Medicine, Università Cattolica del Sacro Cuore, 8-00168 Roma, Italy.

Abstract

Tumor necrosis factor-α (TNF-α) inhibitors are known to increase reactivation of concurrent chronic hepatitis B, but their impact on the hepatitis C virus (HCV) is controversial. Some conditions of immunosuppression, such as liver transplantation, typically cause an increase in the rate of HCV evolution. Inhibition of TNF-α, a cytokine involved in the apoptotic signaling pathway of hepatocytes infected by HCV, could potentially increase viral replication. Currently available clinical data appear to contradict this hypothesis. A review of medical literature revealed that a total of 216 patients with HCV were exposed to one or more treatments with TNF-α inhibitors, with a median observation time of 1.2 years and 260 cumulative patient-years of exposure. Only three cases of drug withdrawal due to suspected HCV liver disease recrudescence were reported. Treatment with TNF-α inhibitors in patients with HCV infection appears to be safe in the short term, but there are insufficient data to assess their long-term safety. Universal screening for HCV before beginning treatment with TNF-α inhibitors is currently controversial. The presence of HCV is not a contraindication to therapy with TNF-α inhibitors, with the exception of cirrhotic patients. In cases of cirrhosis, the benefit/risk ratio should be evaluated at the individual level. Prior to treatment with TNF-α inhibitors, patients with HCV should be referred to a hepatologist to determine the necessity of hepatic disease assessment, using liver biopsy or non-invasive methods, and the potential indication for antiviral therapy. In patients with HCV infection who are treated with TNF-α inhibitors, liver function monitoring every three months is advised.

KEYWORDS:

Adalimumab, Etanercept, Hepatitis C virus, Inflammatory bowel disease, Infliximab, Psoriasis, Rheumatoid arthritis

PMID: 24307780 [PubMed - as supplied by publisher] PMCID: PMC3848134

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Surprising Discovery: Skin Communicates With Liver

Scientists covered the mice with blue latex to prevent evaporation from the skin and thus stop the heat loss. With this loss the mice stopped accumulating fat in the liver. This shows that the skin is communicating with the liver. (Credit: Birgitte Svennevig/SDU. Film: Henrik Gautier/SDU)

Dec. 6, 2013 — Researchers from the University of Southern Denmark have discovered that the skin is capable of communicating with the liver. The discovery has surprised the scientists, and they say that it may help our understanding of how skin diseases can affect the rest of the body.

Professor Susanne Mandrup and her research group in collaboration with Nils Færgeman's research group at the Department of Biochemistry and Molecular Biology at the University of Southern Denmark was actually studying something completely different when they made the groundbreaking discovery: That the skin, which is the body's largest organ, can "talk" to the liver.

"We have showed that the skin affects the metabolism in the liver, and that is quite a surprise," say Susanne Mandrup and Ditte Neess, a former student in the Mandrup research group and now laboratory manager in Professor Nils Færgeman's group.

The phenomenon was observed in the researcher's laboratory mice. The Mandrup and Færgeman groups work with so-called knock-out mice, in which a specific fat binding protein called acyl CoA binding protein has been removed (knocked out). Some knock-out mice produced by the researchers had a strange greasy fur, and they had difficulties being weaned from their mother. In the weaning period they gained less weight and showed a failure to thrive. Analyses also showed that the mice accumulated fat in the liver at weaning.

"At first we thought that the fat accumulation in the liver was linked with the fact that the gene was missing in the liver of the knock-out mice. But this was ruled out by a series of studies, and we had to find another explanation," says Ditte Neess.

She and her colleagues took another look at the rumpled and weak knock-out mice. Their fur was greasy, and they had a leaky skin from which they lost more water than normal mice.

"When they lose water, they also lose heat. We therefore asked ourselves whether this water and heat loss could be the reason why the mice accumulated fat in the liver and became weak when weaned from their mother," says Ditte Neess.

To clarify this, the researchers made some mice that lacked the fat binding protein only in the skin. Similar to the full knockouts these mice had difficulties after weaning and accumulated fat in the liver. So this showed that the lack of the fat-binding protein in the skin was sufficient to induce accumulation of fat in the liver.

To get to the bottom of how a defect in the skin "talks" to the liver, the researchers decided to cover the mice with Vaseline. This would prevent water evaporating from the skin and thus stopping the heat loss. As a result the fat accumulation in the liver disappeared. But as Vaseline contains fat, that could theoretically be absorbed by the skin or ingested by the mice, the researchers were a little unsure if there were side effects from the Vaseline. A student proposed to cover the mice with liquid latex, which she found in a local sex shop.

Having covered the mice in blue latex the researchers saw that fat accumulation in the liver again disappeared.

"We believe that the leaking of water from the skin makes the mice feel cold, and that this leads to breaking down of fat in their adipose (fat) tissue. The broken down fat is then moved to the liver. The mice move energy from the tissues to the liver," Susanne Mandrup and Ditte Neess explain.

Story Source:

The above story is based on materials provided by University of Southern Denmark.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Ditte Neess, Signe Bek, Maria Bloksgaard, Ann-Britt Marcher, Nils J. Færgeman, Susanne Mandrup. Delayed Hepatic Adaptation to Weaning in ACBP−/− Mice Is Caused by Disruption of the Epidermal Barrier. Cell Reports, 2013; DOI: 10.1016/j.celrep.2013.11.010

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Impact of ribavirin priming on viral kinetics and treatment response in chronic hepatitis C genotype 1 infection

Journal of Viral Hepatitis

Volume 21, Issue 1, pages 42–52, January 2014

Original Article

U. Mihm^1,†, M.-W. Welker^1,†, G. Teuber², H. Wedemeyer³, T. Berg⁴, C. Sarrazin¹, S. Böhm⁴, U. Alshuth⁵, E. Herrmann⁶, S. Zeuzem^1,*

Article first published online: 21 JUN 2013

DOI: 10.1111/jvh.12124

Abstract

Keywords: IL28B genotype; ribavirin monotherapy; ribavirin priming; viral kinetics

Summary

Ribavirin amplifies the interferon-alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)-IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG-IFN2a/ribavirin combination therapy on viral kinetics, on-treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty-eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG-IFN2a (PEG-IFN2a arm) for 6 weeks prior to 12 weeks of PEG-IFN2a/ribavirin combination therapy within a double-blind, placebo-controlled trial. Then, standard PEG-IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG-IFN2a at a dose of 180 μg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of −0.58 log₁₀ IU/mL (P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG-IFN2a-induced first- or second-phase viral decline (P values >0.100) nor on-treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG-IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG-IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG-IFN2a/ribavirin combination therapy did neither increase the first- or second-phase viral decline nor on-treatment response or SVR.

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Risk of transmission associated with sharing drug injecting paraphernalia: analysis of recent hepatitis C virus (HCV) infection using cross-sectional survey data

Journal of Viral Hepatitis

Volume 21, Issue 1, pages 25–32, January 2014

Original Article

N. Palmateer^1,*, S. Hutchinson^1,2, G. McAllister³, A. Munro⁴, S. Cameron³,D. Goldberg¹, A. Taylor⁴

Article first published online: 28 MAY 2013

DOI: 10.1111/jvh.12117

Abstract

Keywords: cross-sectional; hepatitis C; incidence; injecting paraphernalia; needles/syringes

Summary

Sharing injecting paraphernalia (containers, filters and water) poses a risk of transmitting the hepatitis C virus (HCV). The prevalence of, and risk of HCV from, such behaviour has not been extensively reported in Europe. People who inject drugs (PWID) were recruited in cross-sectional surveys from services providing sterile injecting equipment across Scotland between 2008 and 2010. Participants completed a questionnaire and provided a blood spot for anonymous testing. Logistic regression was used to examine the association between recent HCV infection (anti-HCV negative and HCV-RNA positive) and self-reported measures of injecting equipment sharing in the 6 months preceding interview. Twelve per cent of the sample reported sharing needles/syringes, and 40% reported sharing paraphernalia in the previous 6 months. The adjusted odds ratios (AOR) for sharing needles/syringes (+/− paraphernalia), and sharing only paraphernalia in the last 6 months were 6.7 (95% CI 2.6–17.1) and 3.0 (95% CI 1.2–7.5), respectively. Among those who reported not sharing needles/syringes, sharing containers and filters were both significantly associated with recent HCV infection (AOR 3.1, 95% CI 1.3–7.8 and 3.1, 95% CI 1.3–7.5, respectively); sharing water was not. We present the first study to apply a cross-sectional approach to the analysis of the association between sharing paraphernalia and incident HCV infection and demonstrate consistent results with previous longitudinal studies. The prevalence of paraphernalia sharing in our study population is high, representing significant potential for HCV transmission.

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