FDA issues draft guidance on abuse-deterrent opioids

FDA NEWS RELEASE

For Immediate Release: Jan. 9, 2013
Media Inquiries: Morgan Liscinsky, 301-796-0397; morgan.liscinsky@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

The U.S. Food and Drug Administration today issued a draft guidance document to assist industry in developing new formulations of opioid drugs with abuse-deterrent properties.

The document “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling,” explains the FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties, how those studies will be evaluated by the agency, and what labeling claims may be approved based on the results of those studies.

“The FDA is extremely concerned about the inappropriate use of prescription opioids, which is a major public health challenge for our nation,” said FDA Commissioner Margaret A. Hamburg, M.D. “This draft guidance is an important part of a larger effort by FDA aimed at preventing prescription drug abuse and misuse.”

Opioids can be abused in a number of ways. Abuse-deterrent formulations target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance in that formulation. The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. In working with industry, the FDA will take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products.

“While prescription opioids are an important component of pain management, abuse and misuse of these products have resulted in too many injuries and deaths across the United States,” said Douglas Throckmorton, M.D., deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research. “An important step towards the goal of creating safer opioids is the development of products that are specifically formulated to deter abuse.”

The FDA continues to encourage the development of abuse-deterrent formulations of opioids and believes that these products have promise to help reduce prescription drug abuse. At the same time, the FDA remains committed to ensuring that patients with pain have appropriate access to opioid analgesics.

This draft guidance fulfills mandates under the Food and Drug Administration Safety and Innovation Act (FDASIA) and the Office of National Drug Control Policy’s (ONDCP) Prescription Drug Abuse Prevention Plan.

“Our nation is in the midst of a prescription drug abuse epidemic,” said Gil Kerlikowske, director of National Drug Control Policy. “While there are no silver bullet solutions to this public health and safety challenge, abuse-deterrent formulations of powerful prescription opioids can make a difference in addressing this epidemic. This guidance is a vitalcomponent of the Administration’s comprehensive effort to reduce prescription drug abuse in America, and we commend the FDA for its commitment to this challenge.”

FDA is seeking public comment on the draft guidance for 60 days and encourages additional scientific and clinical research that will advance the development and assessment of abuse-deterrent technologies. Instructions on how to submit comments will be announced in an upcoming Federal Register notice. The FDA will also hold a public meeting to discuss and receive feedback on the draft guidance. In finalizing the guidance document, the agency will consider the information received from the public.

For more information:

FDA: Draft Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling¹

ONDCP: Prescription Drug Abuse²

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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HBV Treatment Reverses Cirrhosis

Published in Journal Watch Infectious Diseases January 9, 2013

Nearly three quarters of hepatitis B virus–infected patients with cirrhosis at baseline were no longer cirrhotic after 5 years of tenofovir therapy.

Hepatitis B virus (HBV) is a common cause of cirrhosis, end-stage liver disease, and hepatocellular carcinoma, particularly in areas of the world where infection rates are high. Although short-term studies have shown that tenofovir and other antiviral drugs lead to improvement in liver histology, the effect of extended treatment on severe hepatic fibrosis or cirrhosis is less certain. Now, investigators have evaluated the effect of long-term tenofovir use on liver histology in a large number of HBV-infected patients.

Of 641 patients participating in double-blind, phase III trials comparing tenofovir with adefovir therapy for 48 weeks, 585 entered a manufacturer-sponsored, open-label study in which they were to receive 7 additional years of tenofovir therapy; 348 of these patients had liver biopsies performed at baseline and again after 240 weeks of treatment. Liver histology was improved in 87% of these patients at year 5; individuals with the most pretherapy liver injury showed the greatest improvement. Strikingly, of 96 patients with cirrhosis prior to treatment, 74% were no longer cirrhotic at year 5 of therapy. Patients with lower body-mass indexes were more likely to have fibrosis regression. Only 12 patients developed hepatocellular carcinoma, and only 2 developed decompensated liver disease. Virologic breakthrough was uncommon, and no resistance to tenofovir was detected.

Comment: This large trial demonstrates that long-term suppression of HBV replication results in improved liver histology, even in patients who have previously developed cirrhosis. The low rates of hepatocellular carcinoma and end-stage liver disease in patients receiving tenofovir suggest that effective antiviral therapy will lead to improved survival — as has recently been demonstrated in patients treated successfully for hepatitis C virus infection (JAMA 2012; 308:2584).

— Rajesh T. Gandhi, MD

Citation(s):

Marcellin P et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study. Lancet 2012 Dec 10; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(12)61425-1)

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Targeting Hepatitis C Treatment: The Importance of Interleukin (IL)-28

Jan. 8, 2013 — A metanalysis published in BioMed Central's open access journal BMC Medicine has confirmed that polymorphisms (SNP) in the gene coding for interleukin-28 (IL28B) influence natural hepatitis C viral (HCV) clearance and response to pegylated interferon-α plus ribavirin (PEG-IFN/RBV). Information about IL28B genotype could be used to provide personalized medicine and target treatment options effectively.

Over 200 million people worldwide are chronically infected with hepatitis C virus (HCV) and about a quarter of these will go on to develop cirrhosis of the liver. Treatment with (PEG-IFN/RBV) only works in 40-80% of patients, depending in part on HCV strain, and treatment often has severe side effects. It is consequently important to separate people who will not respond to treatment, from those who may, so that treatment is targeted effectively.

Researchers from the Health Institute Carlos III, Spain, incorporated 67 studies that investigated IL28B polymorphisms with the suppression of viral activity to undetectable levels (sustained virologic response -- SVR), and ten that looked at IL28B polymorphisms and spontaneous clearance, into a metanalysis. Approximately 23,500 people were included overall.

The results of this analysis showed that IL28B polymorphisms influence how well IFN treatment works and natural clearance of HCV infection. Having a favourable genotype at any one of seven IL28B polymorphisms equated to more than double the probability of achieving SVR. The study also found that two SNP were associated with spontaneous clearance. Detailed analysis showed that the effect of ethnicity and viral type also influenced the strength of individual association. Consequently the association between favourable variants and SVR for HCV types 2 and 3 was three times lower than types 1 and 4.

María Ángeles Jiménez-Sousa, Amanda Fernández-Rodríguez and Salvador Resino who led this study explained, "Treatment with (PEG-IFN/RBV) is costly and can have side effects which prevent patient compliance. Consequently knowing a patient's IL-28B status will help target interferon treatment to those who will benefit most, and play a substantial role in the selection of candidates for standard treatment versus triple therapy with direct-acting antivirals (DAA). Also, because IL28B genotyping needs be performed only once in a patient's life, it is relatively cheap."

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Idenix says FDA seeks more time to review hepatitis C drug

Wed Jan 9, 2013 12:12pm EST

(Reuters) - Idenix Pharmaceuticals Inc said the U.S. health regulator had informed the company that it would need more time to conduct a safety review of Idenix's hepatitis C drug.

The company said on its website that the FDA had conveyed the need for additional time earlier this month. (r.reuters.com/jah25t)

Idenix said it submitted data to the U.S. Food and Drug Administration in December.

The FDA had placed the drug, IDX184, on a partial clinical hold last August, citing adverse cardiac events seen in rival Bristol-Myers Squibb Co's hepatitis C drug.

Idenix cannot enroll patients in further studies until it gets FDA clearance for the trial design. The company now expects a response in the first quarter of 2013.

Shares of the Cambridge, Massachusetts-based company were down 7 percent at $4.67 on Wednesday morning on the Nasdaq.

(Reporting by Pallavi Ail in Bangalore; Editing by Roshni Menon)

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Clinical Trials: GS-7977 Liver Transplant Studies

Clinical Trials

An Open-Label Study to Explore the Clinical Efficacy of GS 7977 With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant

The primary objective is to determine if the administration of a combination of GS 7977 and ribavirin to HCV-infected subjects with hepatocellular carcinoma (HCC) meeting the MILAN criteria prior to undergoing liver transplantation for up to 24 weeks can prevent post-transplant re-infection as determined by a sustained post-transplant virological response (HCV RNA < LLoQ) at 12 weeks post-transplant.

Study to Investigate GS-7977 and Ribavirin for 24 Weeks in Subjects With Recurrent Chronic HCV Post Liver Transplant

This is an open-label, single-arm study of GS-7977 and ribavirin (RBV) in subjects who have had a liver transplant which has become re-infected with hepatitis C. The treatment period is 24 weeks with up to 48 weeks of follow up. The total time in this study will last up to 72 weeks not including the screening visit

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Mount Sinai researchers foresee new therapies and diagnostics for deadly fibrotic diseases

Public release date: 9-Jan-2013

Contact: Press Office
newsmedia@mssm.edu
212-241-9200
The Mount Sinai Hospital / Mount Sinai School of Medicine

A team of scientists has developed a playbook for ending the devastating impact of fibrotic diseases of the liver, lung, kidney, and other organs, which are responsible for as many as 45 percent of all deaths in the industrialized world. Despite the prevalence of these illnesses, which are caused by buildup of scar tissue, there are no approved antifibrotic drugs on the market in the U.S. A top fibrosis expert from the Icahn School of Medicine at Mount Sinai and three other institutions have described drug targets and compounds they hope will prove broadly effective in an article, "Therapy for Fibrotic Diseases: Nearing the Starting Line," appearing in the January 9 issue of Science Translational Medicine.

Scientists and drug companies are taking important steps to address the unmet need for fibrosis treatments. Among other advances, researchers have discovered and started to validate biomarkers that will facilitate testing of new drugs in clinical trials, according to the article.

"The insights we have described lay the groundwork for a new understanding of treatment approaches and diagnostics," said Scott Friedman, MD, the Dean for Therapeutic Discovery at Mount Sinai and lead author of the article. Diseases such as pulmonary fibrosis, renal fibrosis and hepatic cirrhosis represent "a huge unmet medical need," said Dr. Friedman, who is also the Director of the Division of Liver Diseases and its Centers for Fibrosis Research and Alcohol Liver Disease. "New treatments that are already in clinical trials exemplify a range of strategies harnessed by several pharmaceutical and biotechnology companies."

In the past, the fibrosis field has suffered from a lack of communication among disease experts focused on individual organs, and scientists did not fully consider similarities in cellular dysfunction found in all fibrotic diseases. However, growing synergies across medical specialties have sharpened the perspective on how fibrotic diseases are triggered by injury to epithelial tissues—the layers of densely packed cells that line all the organs of the body.

Recent research has produced a more coherent, comprehensive view of how these tissue injuries provoke dysregulation of cell differentiation, signaling, and protein secretion, Dr. Friedman said. "Investigators across the field are putting aside organ-centric views and coming up with what we think are the overarching characteristics of fibrosis. Understanding how the disease develops can help us diagnose and treat it, regardless of where in the body the fibrotic tissue presents," said Dr. Friedman, who co-authored the review article with colleagues from the University of California, San Francisco, the University of Washington, Seattle and Biogen Idec, based in Cambridge, Mass.

Dr. Friedman estimated that hundreds of clinical trials are currently underway, testing dozens of antifibrotic drugs. Some of the most promising studies focus on blocking a pathway driven by a molecule known as TGFß, which was identified more than 20 years ago as a central mediator of fibrosis. While there have been concerns that inhibiting this pathway could also impair the healthy process of tumor suppression, authors of the article describe several promising experimental drugs, including a variety of humanized antibodies developed by Genzyme, Eli Lilly, and Biogen Idec.

Following a different strategy, Gilead Sciences is using antibodies to block an enzyme that promotes cross-links among proteins in scar tissue. Such cross-linking is thought to stiffen the scar and hamper normal tissue repair and scar resolution. A third approach, explored by Genentech, Novartis, MedImmune and Sanofi, targets cytokines, or messenger chemicals, IL-4 and IL-13, which regulate fibrosis in several animal models.

"This is really the tip of the iceberg," said Dr. Friedman. "In all likelihood, a large number of clinical trials will follow, built, in part, on the lessons learned through these studies."

"We hope our publication will serve as a template, not just for investigators, but for drug companies that are starting to inch into this space," said Dr. Friedman, who was the first scientist to isolate and characterize the hepatic stellate cell, the key cell type responsible for scar production in liver. "Our intention was to capture the leading edge of the science and also to provide pointers for how to move the field forward."

Researchers in this area face a number of hurdles. One challenge, for example, involves developing an appropriate design for clinical trials in illnesses such as hepatic cirrhosis, which involves scarring of the liver over as much as 30 years. "If a trial lasts only one or two years in a disease that affects patients for decades, developing measurements that accurately reflect the disease is difficult," Dr. Friedman noted. "This really represents the current Achilles' heel in trial design, which could be overcome with better methods to detect improvements following therapy."

###

Dr. Friedman receives financial compensation as a consultant for the following companies mentioned above: Biogen Idec, Genzyme, Genentech (Roche Group), Gilead Sciences, Novartis and Sanofi. Additionally, Dr. Friedman is a named inventor and receives royalty payments on inventions licensed by the Icahn School of Medicine at Mount Sinai to F. Hoffman-La Roche (Roche Group) and Novartis.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

For more information, visit: http://www.mountsinai.org/.

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Inovio Pharmaceuticals to Initiate Clinical Trial for its Hepatitis C Therapeutic Vaccine (INO-8000) Later this Year

Phase I/IIa Trial Follows Preclinical Study Demonstrating for First Time that a Multi-Antigen HCV Vaccine Can Generate Potent T-Cell Response in Liver

Jan 9, 2013

BLUE BELL, Pa., Jan. 9, 2013 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE MKT: INO) and its development partner VGX International, Inc. (KSE: 011000) will move Inovio's hepatitis C (HCV) DNA vaccine into a phase I/IIa clinical trial by the end of 2013. This advancement is based on outstanding results of a preclinical study which demonstrated for the first time that a multi-antigen SynCon® HCV vaccine can generate robust T-cell responses not only in the blood but, more importantly, in the liver, an organ known to supress T-cell activity. VGX International is funding all preclinical and clinical development.

In preparation for entering clinical trials with its HCV vaccine (INO-8000), Inovio has completed manufacturing of its multi-antigen HCV vaccine and is performing IND (Investigational New Drug application)-enabling toxicity testing in animals. INO-8000 is a SynCon HCV therapeutic vaccine targeting NS3/4A, NS4B, and NS5A proteins of HCV. INO-8000 was designed with Inovio's SynCon process to broadly cover HCV genotypes 1a and 1b, the types that have been most difficult to treat with drug therapies.

It is estimated that more than 5 million people in the United States are infected with hepatitis C, and perhaps as many as 200 million around the world. This makes HCV one of the greatest public health threats of this century.

HCV vaccine research to date has mostly focused on one area of the virus (the NS3/4A proteins) to induce T-cell responses; however, there has been little research aimed at elucidating whether vaccines targeting proteins other than NS3/4A can induce potent T-cell responses within the liver. In this study, Inovio and its collaborators developed SynCon antigen constructs that targeted three other areas of the HCV virus (NS4B, NS5A and NS5B) and then demonstrated that each vaccine construct expressed its respective protein and that all three constructs induced potent HCV-specific T-cells in mice.

Prior research has also identified that a successful HCV vaccine must be able to induce not only strong HCV-specific T-cell responses that target several components of the virus but that these cells must migrate to the liver and remain activated. In this study, Inovio researchers observed in the liver not only NS4B-, NS5A- and NS5B-specific CD4+ and CD8+ (or killer T-cell) responses, but also a large pool of vaccine-specific T-cells. This pool of vaccine-specific T-cells was shown to be fully functional in an environment in which T-cell activity is usually suppressed. In fact, using a transient HCV infection model in mice, therapeutic immunization with INO-8000 was able to clear HCV antigens from the liver, demonstrating the therapeutic potential of this vaccine.

The pioneering preclinical research appears in the peer-reviewed journal Plos One in an article entitled: "Induction of Intrahepatic HCV NS4B, NS5A and NS5B Specific Cellular Immune Responses following Peripheral Immunization."

In addition to moving forward with INO-8000, Inovio has a long-standing partnership with ChronTech Pharma, which is developing its NS3/4A-based HCV DNA vaccine using Inovio's proprietary delivery technology. Interim results of ChronTech's open-label, randomized phase II trial are expected later in the first quarter of this year.

Dr. J. Joseph Kim, Inovio's President and CEO, said, "Inovio is a leader in developing therapeutic vaccines for HCV and HBV. The major hurdle to developing therapeutic vaccines for these ailments has been the inability to generate a functional T-cell response in the liver. The fact that our preclinical model demonstrated functional T-cells in the liver in this published study suggests that INO-8000 has the capacity to clear that hurdle. There have been important recent drug therapy advances for HCV; however, a safe and effective therapeutic vaccine could play a vital role in enhancing the potency of HCV treatments, especially for genotype 1, while achieving the desired goal of eliminating the use of interferon/ribavirin and their undesirable side effects."

About Hepatitis C and Inovio's SynCon® Vaccines

Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to liver failure or liver cancer. Approximately 80% of people who become infected with hepatitis C virus develop chronic infection.

The major obstacle to HCV vaccine development has been the extensive genetic variation between different strains and genotypes, and even the significant antigenic variation among virus within individual patients. In addition, the absence of a clearly defined protective immune response after natural infection has historically complicated the prospects of developing a vaccine against HCV infection.

However, unlike traditional vaccines constrained by the paradigm of matching a preventive or therapeutic vaccine to a single pathogen strain or strains, Inovio's SynCon vaccines are based on genetic code for a specific antigen from multiple strains of the target pathogen. Thus, while the SynCon antigens may not be perfectly (100%) matched to the pathogenic strains, they are designed to protect against multiple existing strains as well as changing strains of a virus. Extensive preclinical data has validated their ability to protect against many strains of a disease; initial human data for our influenza vaccine has also provided evidence of this capability.

About Inovio Pharmaceuticals, Inc.

Inovio is revolutionizing vaccines to prevent and treat today's cancers and challenging infectious diseases. Its SynCon vaccines are designed to provide universal cross-strain protection against known as well as newly emergent unmatched strains of pathogens such as influenza. These synthetic vaccines, in combination with Inovio's proprietary electroporation delivery, have been shown in humans to generate best-in-class immune responses with a favorable safety profile. Inovio's clinical programs include phase II studies for cervical dysplasia, leukemia and hepatitis C virus and phase I studies for influenza and HIV. Partners and collaborators include the University of Pennsylvania, Merck, ChronTech, National Cancer Institute, U.S. Military HIV Research Program, NIH, HIV Vaccines Trial Network, University of Southampton, US Dept. of Homeland Security, University of Manitoba and PATH Malaria Vaccine Initiative. More information is available at www.inovio.com.

This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that pre-clinical studies and clinical trials may not commence or be completed in the time periods anticipated, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, our ability to secure new partnerships and collaborations, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2011, our Form 10-Q for the quarter ended September 30, 2012, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.

CONTACTS:
Investors: Bernie Hertel, Inovio Pharmaceuticals, 858-410-3101 , bhertel@inovio.com
Media: Jeff Richardson, Inovio Pharmaceuticals, 267-440-4211 highlighting, jrichardson@inovio.com

SOURCE Inovio Pharmaceuticals, Inc.

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