October 29, 2013

Treatment of Chronic Hepatitis C: The Revolution!

Provided by NATAP

Reported by Jules Levin
EACs - European AIDS Conference - Oct 16-19 Brussels, Belgium

Heiner Wedemeyer
Hannover Medical School

from Jules: here is Dr Wedemeyer's slide presentation where he does a long review including vaccines, immune-based new therapies including Alisporivir, DAAs, direct acting activirals, new oral drugs, and reviews many of the reported studies from phase 2 & 3.

The FDA hearings on Oct 24/25 reviewed Simeprevir+PR for 24 weeks and Sofosbuvir +PR for 12 weeks, and as expected the panels voted unanimously to approve both 19-0 & 15-0. This is just the prelude to next year when the first 2 IFN-free regimens will be considered for approval by the FDA in the early part of 2014 & of course approval is expected, they are Gilead's Sofosbuvir+Ledipasvir & Abbvie's ABT450+ABT267+ABT333 both with and/or without RBV, phase 3 studies are ongoing, fully enrolled, phase 2 studied reported 95-100% SVR rates with 12 weeks therapy. FDA approval is expected around end of November & beginning of Decmber 2013. In phase 2 studies, Sofosbuvir+Simprevir has yielded 96% SVR rates in hard-to-treat null responders & patients with advanced disease, and Sofosbuvir+Daclatasvir has yielded 100% SVR rates in naives & patients who previously failed telaprevir or boceprevir. Earlier in research is Merck's 2nd generation drugs, MK8472, their NS5A & MK5172, their protease, phase 2 data will be reported at AASLD next week, phase 3 is planned. Boerhinger Ingelheim is studying a 3-drug oral combination for which they reported early results a few weeks ago with 90-100% SVR rates, which includes their protease Faldaprevir, their non-nuc & the Presidio NS5A. BMS is planning phase 3 now for their 3-drug IFN/Rbv free regimen which yielded a 94% SVR rate in phase 2. Vertex is studying their nucleotide in combination with other DAAs from other companies. Janssen istudying their own 3-drug oral combination, last week they announced acquisition of the GSK NS5A inhibitor to combine with their protease Simeprevir and their non-nuc. Roche is reporting results at this AASLD for their ANNAPR+URNA Study which looked at their 3-4 drug oral regimen which included their protease Danoprevir, Mericitabine, their nuc, and their non-nuc.

"All oral therapy will lead to a change in treatment paradigm"
"The number of treatable patients will dramatically increase! Interferon-Free"
"There is an association between SVR & all-cause mortality & liver-related mortality"

'New HCV oral IFN-free drug regimens will provide with 12-24 weeks convenient therapy an SVR is associated with reduced risk of progression to advanced liver disease, liver cancer and mortality
Will prevent HCV transmission and be cost-effective.....therapies will be once or twice daily, much less side effects than current IFN-based therapy Drug interactions will be an issue but we can deal with that'

Continue here to view complete slide presentation …..

Faldaprevir regimen is effective as first treatment for HCV genotype 1


By: SUSAN LONDON, Family Practice News Digital Network

SAN DIEGO – A regimen containing the oral investigational protease inhibitor faldaprevir is efficacious and safe as initial treatment for chronic hepatitis C virus genotype 1, a randomized phase III trial showed.

A team led by Dr. Christophe Moreno, a gastroenterologist at the Erasme Hospital, Université Libre de Bruxelles, Brussels, conducted the trial, known as STARTverso 1, among 652 patients in Europe and Japan.

More than three-fourths of patients given a faldaprevir-containing interferon-based regimen had achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), Dr. Moreno reported. This compared with only about half of patients given a placebo-containing regimen.

A low dose of faldaprevir worked just as well as a high one. In addition, most faldaprevir-treated patients met criteria for early treatment success and were therefore able to stop treatment after half the full duration.

The rate of serious adverse events was similarly low across treatment groups, and rates of most laboratory abnormalities were comparable.

"Faldaprevir is highly efficacious in European and Japanese patients infected with HCV [hepatitis C virus] genotype 1. Almost 90% of patients treated with faldaprevir were eligible for a shortened treatment duration of 24 weeks," Dr. Moreno commented. "Faldaprevir was well tolerated with few discontinuations due to adverse events at both dosages."

"Since this was primarily a European and Japanese study, there were no patients from this country [the United States], with African American ethnicity, which is one of the negative predictors of response," noted session comoderator Dr. Zobair N. Younossi, executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va.

"Do you think that that would change [the results], if you ran the trial in this country and had 20%-30% of patients with African American ethnicity?" he asked.

Two-thirds of the patients in the trial had HCV genotype 1b, Dr. Moreno replied. "As genotype 1a is more frequent in the U.S. and African Americans, we can suppose that maybe the results would be quite different.

"There is another trial, STARTverso 2, which is evaluating the efficacy of faldaprevir in patients from the U.S., Canada, and also other countries," he added.

The investigators enrolled in STARTverso 1 patients with treatment-naive HCV genotype 1and randomized them in 1:2:2 ratio to 24 weeks of pegylated interferon alfa-2a and ribavirin plus placebo for 24 weeks (arm 1), plus faldaprevir 120 mg once daily for 12 or 24 weeks depending on response (arm 2), or plus faldaprevir 240 mg once daily for 12 weeks (arm 3).

Patients meeting criteria for early treatment success (HCV RNA less than 25 IU/mL at week 4 and undetectable at week 8) in arms 2 and 3 stopped treatment at week 24. Patients who did not meet these criteria and all patients in arm 1 received interferon and ribavirin out to 48 weeks.

The main trial results showed that the rate of SVR12 was higher in both the high-dose faldaprevir group (80%) and the low-dose faldaprevir group (79%) than in the placebo group (52%, P less than .0001 for both comparisons).

Fully 87% of patients treated with low-dose faldaprevir and 89% treated with high-dose faldaprevir achieved early treatment success and therefore qualified for the shortened treatment duration of 24 weeks. Among these patients, 86% and 89%, respectively, achieved SVR12.

Just 1% of all patients treated with faldaprevir had a primary nonresponse. About 4%-10% of patients had a viral breakthrough, and 6%-15% had a relapse.

"Common baseline polymorphisms were not found to affect the efficacy of faldaprevir," Dr. Moreno commented. In particular, the drug worked equally well in the 23% of patients with genotype 1a who had the Q80K polymorphism, which has been found to reduce the efficacy of other protease inhibitors.

"The high dose of faldaprevir showed no benefit over the 120-mg dose in any subgroup analyzed," he added.

The rate of serious adverse events was 7% with both doses of faldaprevir and 6% with placebo. Moderate or worse gastrointestinal adverse effects were more common with faldaprevir (7%-12%) than with placebo (3%).

Rates of grade 3 or higher laboratory abnormalities were largely the same. The faldaprevir groups had a higher rate of hyperbilirubinemia (12%-53% vs. 1%); however, "bilirubin elevations were benign and transient," Dr. Moreno noted.

Compared with placebo, faldaprevir was not associated with an increase in the incidence of anemia, one of the leading adverse effects of first-generation protease inhibitors.

Dr. Moreno disclosed that he is a board member for Janssen, Gilead, MSD, and Bristol-Myers Squibb; is a consultant for Janssen and MSD; receives grants from Janssen, MSD, Roche, and Novartis; is on the speakers’ bureau for MSD, Janssen, and BMS; and receives travel support from Janssen, Gilead, MSD, and Novartis. The trial was sponsored by Boehringer Ingelheim Pharmaceuticals. Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.


Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients

J Hepatol. 2013 Nov;59(5):964-71. doi: 10.1016/j.jhep.2013.06.030. Epub 2013 Jul 10.

Scherzer TM, Stättermayer AF, Stauber R, Maieron A, Strasser M, Laferl H, Schwarzer R, Datz C, Rutter K, Beinhardt S, Steindl-Munda P, Hofer H, Ferenci P.

Department of Internal Medicine III, Medical University, Vienna, Austria.


BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1.

METHODS: Hemoglobin levels at baseline (Hb0) and the decline after 4weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9±11.1, male:185, female:123, BMI 25.3±3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180μg peginterferon-alpha 2a and ribavirin [1000-1200mg/d; females: mean (95% CI) 15.8mg/kg (15.4-16.2); males 14.3 (14.1-14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System.

RESULTS: 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8); p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1); p<0.001].

CONCLUSIONS: Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Age, GWAS, Gender, HCV, Hepatitis C virus, ITPA, RVR, Ribavirin-induced anemia, SNP, SVR, genome-wide association study, rapid virologic response, single nucleotide polymorphism, sustained virologic response

PMID: 23850877 [PubMed - in process]



A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C

J Hepatol. 2013 Nov;59(5):926-33. doi: 10.1016/j.jhep.2013.06.019. Epub 2013 Jun 26.

Carrión JA, Gonzalez-Colominas E, García-Retortillo M, Cañete N, Cirera I, Coll S, Giménez MD, Márquez C, Martin-Escudero V, Castellví P, Navinés R, Castaño JR, Galeras JA, Salas E, Bory F, Martín-Santos R, Solà R.

Liver Section, Gastroenterology Department, Hospital del Mar, Universitat Autònoma de Barcelona, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain. Electronic address: 95565@parcdesalutmar.cat.


BACKGROUND & AIMS: Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC.

METHODS: 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003-2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model.

RESULTS: Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes.

CONCLUSIONS: MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: 95% CI, 95% confidence interval, ALT, ANC, BOC, CHC, Cost-effectiveness, DAA, EOT, EPO, G-CSF, HADS, HBV, HCC, HCV, HIV, Hb, Hepatitis, ICER, MSP, NR, OR, PCR, PHQ, PLT, Programme, QALY, RBV, Response, SE, SVR, TVR, Treatment, ULN, absolute neutrophil count, alanine aminotransferase, boceprevir, chronic hepatitis C, direct-acting antivirals, end of treatment, erythropoietin, granulocyte colony-stimulating factor, haemoglobin, hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, hospital anxiety and depression scale, human immunodeficiency virus, incremental cost-effectiveness ratio, multidisciplinary support programme, non-responders, odds ratio, patient health questionnaires, pegIFN, pegylated interferon, polymerase chain reaction, potentially life threatening, quality-adjusted life year, ribavirin, standard error, sustained virological response, telaprevir, upper limit of normal

PMID: 23811030 [PubMed - in process]


Doctors urge hepatitis C tests for boomers

October 29, 2013, 11:29 AM

By Matthew Heimer

Hepatitis C is a virus surrounded by a considerable stigma, with much of the general public associating infection with drug addiction and unsanitary living. But if a trend in the medical establishment continues to gain momentum, doctors will soon be telling millions of their otherwise healthy middle-aged patients to get tested for the disease, as Joseph Walker of The Wall Street Journal reports this week. (Walker discusses the phenomenon with Wendy Bounds of WSJLive in the clip below.)

About 3.2 million Americans carry the hepatitis C virus, or HCV, according to the Centers for Disease Control and Prevention, but the majority of them don’t know it; most don’t realize they’re carriers until the virus causes complications like liver cancer or cirrhosis, often decades after infection took place. The CDC estimates that HCV killed roughly 16,600 people in 2010. And this summer, the U.S. Preventive Services Task Force, a board that sets guidelines for medical practice, recommended that everybody born between 1945 and 1965 get screened for the disease at least once—an advisory that Walker estimates could affect as many as 60 million people.

Why single out the boomers? It’s partly a Me Generation issue: Intravenous drug users are among the highest-risk groups for infection, and boomers came of age during a time when experimentation with those drugs was relatively common. But the safety of the blood supply is a bigger factor: Blood donations weren’t routinely monitored and screened for many viruses before the early 1990s, and anyone who received a transfusion for any reason before then could potentially have been infected.

That task-force decision will mean some relief for boomers’ wallets. Testing can cost up to $200, not including follow-ups, but the fact that HCV screening has made the recommended list means that most private insurers are now required to cover the screening at no charge to the patient. (Medicare administrators say they’ll decide by next summer whether to cover screening.)

Still, as Walker reports, some doctors have misgivings about adding another blood test to older Americans’ medical to-do lists. HCV could be somewhat akin to prostate cancer as a midlife medical challenge: Since the majority of those infected won’t develop serious symptoms, many patients will have to decide whether to spend money, time and energy monitoring a condition that may never significantly affect them. (Then again, unlike prostate cancer, HCV can be transmitted from an infected person to someone else.)

On this front, at least, there’s some good news: Monitoring the liver for potential damage is now more likely to involve non-invasive procedures like blood tests, rather than more dangerous and complicated biopsies.


Estrogen protects women with NASH from severe liver fibrosis

Provided by MedicalXpress

October 29, 2013

New research suggests that estrogen protects women with nonalcoholic steatohepatitis (NASH) from severe liver fibrosis. According to the study published online in Hepatology, a journal of the American Association for the Study of Liver Diseases, men are at higher risk of more severe fibrosis compared to women prior to menopause, but liver fibrosis severity is similar in men and post-menopausal women.

Non-alcoholic fatty liver disease (NAFLD) includes a range of liver disorders from simple fatty liver to inflammation, fibrosis, and cirrhosis. With the rapid rise in obesity, diabetes and metabolic syndrome, the prevalence of NAFLD—the result of insulin resistance—has also steadily increased. In fact, studies suggest that the NAFLD prevalence is 10% to 30%, making it the most common liver disease in the U.S.

"While most NAFLD patients have a mild disease known as fatty liver or hepatic steatosis, some patients present with NASH, which is more severe and increases overall mortality," explains Dr. Ayako Suzuki with the Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences in Little Rock, the lead author of the present study. "Our study aim was to investigate whether gender and menopause significantly impact fibrosis severity among adult patients with NAFLD."

The research team analyzed data from 541 adults with NASH who were seen at Duke University Liver Clinics and the Duke Metabolic and Weight Loss Surgery Program. The mean age of subjects was 48 years, with 35% of the group being men, 28% pre-menopausal women and 37% post-menopausal women.

Findings indicate that 22% of the cohort had advanced fibrosis. After adjusting for known predictors of fibrosis, the risk for greater fibrosis severity in post-menopausal women and men vs. pre-menopausal women was 1.4-fold and 1.6-fold, respectively. Furthermore, when dividing the cohort at age 50, which is the average age at menopause in the US, the risk for greater fibrosis severity in men vs. women before age 50 was 1.8-fold, while after the age 50 the risk was reduced to 1.2-fold.

"Our findings suggest a protective effect from estrogen against development of severe fibrosis," concludes Dr. Suzuki. "Further study of the impact of estrogen on fibrosis progression in NASH patients is needed." Explore further: Cardiovascular issues up mortality rates in patients with advanced fibrosis

More information: "Gender and Menopause Impact Severity of Fibrosis Among Patients with Nonalcoholic Steatohepatitis." Ju Dong Yang, Manal F Abdelmalek, Herbert Pang, Cynthia D Guy, Alastair D Smith, Anna Mae Diehl and Ayako Suzuki. Hepatology; (DOI: 10.1002/hep.26761) Published online: October 1, 2013.

Journal reference: Hepatology

Provided by Wiley


Newly Approved Ultrasound Device Eliminates Risks and Pain of Liver Biopsy


DETROIT, Oct. 29, 2013 /PRNewswire/ -- Henry Ford Hospital is the first in Michigan to use a pioneering ultrasound device that can help patients with liver disease avoid invasive biopsies to manage their disorders.

FibroScan® replaces repeated and sometimes painful liver biopsies for patients with chronic hepatitis C and B, fatty liver diseases and other hepatic disorders with a quick and painless procedure similar to the familiar ultrasound tests used to track pregnancy and diagnose internal diseases.

The device is based on a technology called transient elastography, which measures liver "stiffness" to assess disease and guide ongoing treatment.

"FibroScan® is designed to measure liver fibrosis using a painless, non-invasive method of assessing many of the same conditions measured with biopsy," says Stuart Gordon, M.D., Director of Hepatology at Henry Ford Hospital. "It's an outpatient procedure taking less than 15 minutes."

At the annual meeting of the American Association for the Study of Liver Disease being held in Washington, DC, a multi-center study will be presented Monday, Nov. 4, which "confirms that (Fibroscan®) very accurately assesses presence of cirrhosis in patients with chronic type B and C viral hepatitis."

Henry Ford Hospital was one of the seven U.S. institutions that conducted the study.

The patient feels only a slight vibration on the skin, the results are immediate and, because it does no harm, the procedure can be safely repeated as often as necessary.

About 150,000 people in the U.S. are diagnosed with chronic liver disease annually, about a fifth of them with cirrhosis, a scarring of the liver.

By one conservative estimate, more than 30,000 liver biopsies are performed in the U.S. each year, a number that led to medical discussions and calls for ways to make the procedure more "acceptable" to patients.

Cirrhosis and other diseases of the liver result from or cause hepatic fibrosis, in which fibrous scars develop as part of the liver's mechanism to heal its own damage.

Sometimes it's beneficial because the scar tissue surrounds and blocks off the cause of the damage. But often this scarring develops to the point that it interferes with liver function, as in cirrhosis.

For decades, a liver biopsy has been considered the "gold standard" for assessing liver disease. In most cases, the biopsy involves using a needle inserted through the skin and underlying tissue and into the liver to collect a sample of tissue. It's widely regarded as safe, but because it is invasive, it carries risks ranging from bleeding to rare instances of death. In addition, a proportion of liver biopsy patients complain of severe pain during the procedure.

Using FibroScan ®, the skin in the area of the liver is first coated with a water-based gel. The doctor then passes an ultrasound sensor over the area to take 10 consecutive readings. The sensor produces vibrations that create a low-frequency seismic wave sent between the ribs and into the liver. The speed of the wave as it passes through the liver is used to determine the hardness or stiffness of the organ – the faster the wave, the harder the tissue.

The data collected during the readings are collected and analyzed in the console connected to the sensor, and provides immediate results on the presence and severity of liver fibrosis.

FibroScan® is produced by Paris-based Echosens, entered the European market in 2003 and was already being used in more than 70 countries worldwide when it received approval by the U.S. Food and Drug Administration in April.

Note: To access Fibroscan® a patient needs a physician referral. The cost is $200. Email: FIBROSCAN@hfhs.org.

SOURCE Henry Ford Hospital


HIV -- Geneticists map human resistance to AIDS

Provided by Science Codex

Posted By News On October 29, 2013 - 4:30am

The key to future HIV treatment could be hidden right in our own genes. Everyone who becomes infected deploys defense strategies, and some even manage to hold the virus at bay without any therapy at all. This immune system struggle leaves its mark within the pathogen itself – genetic mutations that indicate how the virus reacted to its host's attacks. Scientists from EPFL and the Vaud university hospital center (UNIL-CHUV) retraced the entire chain of events in these battles, from the genome of the virus to the genome of the victim. They have created the first map of human HIV resistance. The goal of their research, which has been published in the journal eLife on the 29th of October, is to find new therapeutic targets and to enable individualized treatment strategies.

The human immune system is constantly developing strategies to fight HIV. Unfortunately, "the genome of the virus also changes rapidly, at a rate of millions of mutations a day," explains Jacques Fellay, co-author and EPFL researcher. In the majority of cases, the pathogen finds an effective strategy via this natural selection.

Sometimes the virus is faced with a tougher opponent. It resists, but its ability to replicate is compromised. "The virus survives but replicates more slowly, and thus its capacity for destruction is in some sense neutralized," says the scientist.

By studying strains of HIV that have been living in human hosts, the researchers can identify specific genetic mutations. These are like scars that each bear witness to a very specific attack launched by the immune system. What are the human genes involved in these defense strategies? And which, among all our genetic variations, predispose us to increased HIV resistance or, on the contrary, increased vulnerability? The scientists developed a method that allowed them to find answers to these questions.

A supercomputer, 1,071 patients and millions of combinations

To draw up the first map of human HIV resistance, the researchers had to analyze an enormous amount of data. They studied various strains of HIV from 1,071 seropositive individuals. They crossed more than 3,000 potential mutations in the viral genome with more than 6 million variations in the patients' genomes. Using supercomputers, they studied all these possible combinations and identified correspondence between patients.

"We had to study the virus before the patient had undergone treatment, which is far from easy," says Fellay. This meant they had to search in data banks established in the 1980s, before effective therapies were made available.

This novel, indirect method made it possible to obtain the most complete global overview to date of human genes and their implications in terms of HIV resistance. It allows us to not only better understand how we defend ourselves from attack but also how the virus adapts itself to our defense mechanisms. "We now have a true database that tells us which human genetic variation will induce which kind of mutation in the virus", explains Amalio Telenti, co-author and UNIL-CHUV researcher.

Therapies inspired by our own natural defense

This research has two major implications. New therapies could be developed based on studying humans' natural defenses, particularly those that result in a reduced replication of the virus. In addition, the scientists hope that by profiling the genome of HIV-infected individuals, it will be possible to develop individually targeted treatments that take into account the patients' genetic strengths and weaknesses.

Source: Ecole Polytechnique Fédérale de Lausanne


FDA and Opioids: What's Going On Here?

Published: Oct 28, 2013 | Updated: Oct 29, 2013

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today; Kristina Fiore , Staff Writer, MedPage Today


Against the recommendation of its own advisors, the U.S. Food and Drug Administration approved a new high-dose narcotic painkiller, a drug that the FDA concedes has a high risk for abuse and one which was using a method that critics say may give the drug the appearance of greater efficacy.

Zohydro ER will be the first hydrocodone-only opioid, and it will come in doses packing five to 10 times more heroin-like narcotic than traditional hydrocodone products such as Vicodin that combine hydrocodone with over-the-counter pain relievers such as acetaminophen or ibuprofen.

Abuse Potential

Though the narcotic in Zohydro ER is designed to be released slowly over 12 hours, pleasure seekers will be able to crush it, chew it or mix it with alcohol to unleash its full punch at once. That abuse potential would have been blunted if the FDA required that the drug be formulated with abuse-prevention technology -- a process the FDA has publicly backed, but did not require in this case.

A November 2012 memo from the FDA's own staff warns that the drug will be abused more than traditional hydrocodone products. The memo compares what likely will occur with Zohydro to what happened with extended release oxycodone-containing opioids.

The most famous oxycodone product, OxyContin, for years was one of the most abused narcotics in America. In 2010, its maker, Purdue Pharma, reformulated its recipe to make it abuse resistant, a protection that Zohydro won't have.

In an email, FDA spokesperson Morgan Liscinsky said that while the agency supports a transition to abuse-deterrent opioids, "we do not believe it is appropriate or feasible at this time to require all products in the class to be abuse-deterrent.

"Rather, FDA will continue to take a product-by-product approach to regulatory decisions concerning the abuse-deterrent properties (or lack thereof) of opioid products."

Zohydro drugmaker Zogenix, based in San Diego, said in a statement to the Journal Sentinel/MedPage Today that it plans to develop an abuse-deterrent formulation of the drug and is "committed to advancing the program as rapidly as possible."

Liscinsky added that the FDA concluded that the benefits of Zohydro outweighed its risks and that data show it is safe and effective for round-the-clock use. Its label will have prominent warnings about abuse, she said. The label will urge prescribers to monitor patients for addiction or misuse.

"Prescribers now have a hydrocodone option for patients who require an extended-release opioid, which is important for several reasons," she said. "First, individual patients can respond differently to different opioids. Second, the benefits of opioids can wane as the patient becomes opioid-tolerant."

"While the current formulation of Zohydro ER does not have abuse-deterrent or tamper-proof features, we have started the development of an abuse-deterrent formulation and are committed to advancing the program as rapidly as possible," said a statement from Zogenix, the company that makes Zohydro.

But during the FDA advisory committee hearing last December, a company official said an abuse-deterrent formulation of the drug was only in early development and was "several years away from the market."

Friday's approval of Zohydro is the latest action by the agency, which recently has been the target of claims that it is too friendly toward the opioid industry. And it comes follows closely complaints that the FDA had not done enough over the years to curtail the booming overuse of opioids.

The U.S. already consumes 99% of the hydrocodone used in the world.

In 2010, Vicodin was the most prescribed medication in the U.S. with 131 million filled prescriptions. That same year, more than 16,000 people died of overdoses from narcotic painkillers, up from about 4,000 in 1999.

Vicodin comes in doses of 5, 7.5 and 10 mg of hydrocodone along with 300 mg of acetaminophen. Zohydro will come in six doses: 10, 15, 20, 30, 40 and 50 mg without any acetaminophen, which can cause liver damage in high amounts.

"If the FDA was really interested in protecting the public, they would have said, 'No thanks.... we have too many people dying of opioids in this country to justify approving Zohydro,'" said David Juurlink, MD, PhD, director of pharmacology and toxicology at the University of Toronto. "Minus the pesky acetaminophen, plus the crushability, it's a disaster in the making."

An FDA "Flip-Flop?"

On Thursday, after years of resisting the measure, the FDA finally moved to tighten restrictions on hydrocodone products. When the change occurs next year, hydrocodone products will have the same Schedule II restrictions as oxycodone products such as OxyContin.

However the day after the move, the agency reversed course, and approved Zohydro, despite the fact that its own advisory panel voted 11-2 in December not to approve the drug.

The Zohydro decision is "worrisome," U.S. Rep. Harold "Hal" Rogers (R-Ky.), said in a statement provided to the Journal Sentinel/MedPage Today. Kentucky has experienced substantial opioid abuse over the years.

"I am counting on the FDA to perform rigorous post-marketing studies and analysis to ensure this drug doesn't create another new wave of addiction," he said.

Rogers is chairman of the House Appropriations Committee and has co-hosted the National Rx Drug Abuse Summit.

"I am surprised," said Jeanmarie Perrone, MD, an associate professor of emergency medicine at the University of Pennsylvania and member of the FDA advisory panel who not to approve Zohydro.

Perrone said she was concerned about the safety of the drug and its lack of abuse resistance. At the advisory panel meeting, she also questioned its effectiveness.

The approval also suggests that the FDA is trying to help drug makers show that that opioids are safe and effective for treating long-term non cancer pain, said Lewis Nelson, MD, a New York emergency medicine specialist who has served as an FDA advisory panel member on opioid issues.

"I don't see any reason why the FDA should be helping pharma," said Nelson, also a medical toxicologist at NYU School of Medicine.

Enriched Data

The main research on Zohydro took place over a 12-week period. Experts say there is little rigorous research showing the drugs are beneficial when used for many months or years.

A Journal Sentinel/MedPage Today investigative report earlier this month documented how, for years, FDA officials and executives of companies that make pain drugs held annual private meetings at expensive hotels through an organization funded by the drug companies. The story was based on emails obtained through public records requests and provided to the Journal Sentinel/MedPage Today.

A topic at those meetings was a research approached called enriched enrollment, a technique that allows drug companies to weed out people who don't respond well to a drug or who can tolerate it before the actual clinical trial begins.

Zohydro clinical trials used the enriched enrollment methodology.

Experts say that approach makes it much more likely a drug will prove effective and possibly win FDA approval. It's also cheaper for drug companies to conduct such trials.

However, the approach has been described by critics as cheating because drugs tested that way are not likely to reflect what will happen when the drug gets on the market and is prescribed for large numbers of people.

Indeed, when the panel of FDA advisors voted against approving Zohydro last December, several of them expressed concerns about what would happen once the drug moved from the rarefied realm of clinical trials to the real world of everyday medicine, according to a transcript of the hearing.

"The question of what's effective is much greater than (the pain score of the test subjects) at the end of 12 weeks in a very limited, controlled experiment that somehow was a little bit better than a placebo group," panel member Judith Kramer, MD, a professor of medicine at Duke University, said at the meeting.

"...With treatment of chronic pain, are we really, in the long run, helping people, or are we creating an epidemic? This drug will almost certainly cause dependence in the people that are intended to take it," Kramer said.

Liscinsky, the FDA spokesperson said enriched enrollment follows the concept of personalized medicine in that it attempts to find those who a drug will be most effective in.

"Enrichment will not save a drug that is not safe of effective, but it will help find one that is," she said.

However, advisory panel members had a different view, according to a transcript of the meeting.

"I happen to live in the real world, and I would think that the (Zohydro) study population is very different than the real world population," said Alan Kaye, MD, PhD, a professor of anesthesia at Louisiana State University School of Medicine. "And as such, I certainly feel there would be quite a bit of morbidity and mortality that would result."