Janssen HCV Drug Research & Development

Provided by NATAP

Reported by Jules Levin

In the Spring Janssen & Gilead submitted New Drug Applications to the FDA requesting approval. The FDA hearing appears to be scheduled for Oct 24-25.

A Study of the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of JNJ-47910382 at Different Doses and Dose Regimens in Asian Genotype-1, Chronic, HCV-Infected Patients

Study in HCV-Infected Patients to Determine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of JNJ-47910382

A Study in Healthy Participants Investigating the Safety, Tolerability and Plasma Pharmacokinetics (PK) of Single Oral Doses of JNJ-47910382

IDX719 in Combination With Simeprevir and Ribavirin for 12 Weeks in Subjects With Chronic Hepatitis C Infection
http://www.clinicaltrials.gov/ct2/show/NCT01852604?term=Janssen+AND+Hepatitis+C&recr=Open&no_unk=Y&rank=9

Antiviral Drugs Advisory Committee .........October 24-25
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm153468.htm

Simeprevir (TMC435) with peginterferon/ribavirin for chronic hCV genotype 1 infection in treatment-naïve patients: results from QUEST-1, a Phase III trial
http://www.natap.org/2013/EASL/EASL_10.htm

Simeprevir (TMC435) with peginterferon-α2a or -α2b and ribavirin in treatment-naïve HCV genotype 1 patients: QUEST-2, a randomised Phase III trial
http://www.natap.org/2013/EASL/EASL_18.htm

Simeprevir with Peginterferon/ribavirin for Treatment of Chronic HCV Genotype 1 Infection in Patients Who Relapsed After Previous Interferon-based Therapy: Results from PROMISE, a Phase III Trial
http://www.natap.org/2013/DDW/DDW_06.htm

COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders
http://www.natap.org/2013/CROI/croi_34.htm

Medivir Press Release: New Drug Application has been filed with FDA for Simeprevir (TMC435) for combination treatment of adult patients with genotype 1 chronic hepatitis C
http://www.natap.org/2013/HCV/040213_01.htm

Idenix Pharmaceuticals Announces Initiation of Phase II All-Oral Combination Study of Samatasvir (IDX719) and Simeprevir (TMC435) for the Treatment of Hepatitis C Virus (HCV) Infection
http://www.natap.org/2013/HCV/060213_04.htm

Combination Therapy of TMC647055 With Simeprevir (TMC435) in Genotype 1 HCV Patients
http://www.natap.org/2013/EASL/EASL_41.htm

TMC055 Monotherapy data:
Human safety, pharmacokinetics and antiviral activity of TMC647055, a novel HCV non-nucleoside polymerase inhibitor....... http://www.natap.org/2011/AASLD/AASLD_04.htm

Here is the link to the study on clinical trials.gov where you can see low dose 30mg RTV is used:
A Study to Evaluate the Safety, Tolerability, and Effectiveness of a 12-Week Combination Therapy of TMC647055 and TMC435 With a Pharmacokinetic Enhancer With and Without Ribavirin in Chronic Genotype-1 Hepatitis C Infected Patients.......http://clinicaltrials.gov/ct2/show/NCT01724086?term=tmc647055&rank=3

EASL: Combination Therapy of TMC647055 With Simeprevir (TMC435) in Genotype 1 HCV Patients - (04/30/13)

2nd generation NS5As

In Vitro Resistance Analysis of Merck's HCV NS5a Inhibitor MK-8742 Demonstrates Increased Potency AgainstClinical Resistance Variants and Improved Resistance Profile
http://www.natap.org/2012/EASL/EASL_46.htm

GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier
http://www.natap.org/2013/EASL/EASL_34.htm

Healthy Volunteer First-in-Human Evaluation of GS-5816, a Novel Second Generation Broad-Genotypic NS5A Inhibitor With Potential for Once-Daily Dosing - (04/29/13)

ACH-3102, A Second Generation NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients with Genotype 1A HCV Infection Despite the Presence of Baseline NS5A-Resistant Variants - (05/09/13)

FINDINGS FROM CLINICAL VIROLOGY STUDIES ON ACH-3102 ARE CONSISTENT WITH PRECLINICAL OBSERVATIONS ON ITS IMPROVED POTENCY AGAINST GENOTYPE-1A HCV AND RESISTANT VARIANTS - (05/09/13)

No Clinically Significant Pharmacokinetic Interaction Between Sovaprevir and ACH-3102 in Healthy Volunteers - (05/09/13)

Synergistic Interactions of HCV NS5A Replication Complex Inhibitors Sensitize Resistant Variants and Enhance the Efficacy of Daclatasvir (DCV, BMS-790052) In Vitro and In Vivo - (04/27/13)

PRECLINICAL CHARACTERISTICS OF ACH-3102: A NOVEL HCV NS5A INHIBITOR WITH IMPROVED POTENCY AGAINST GENOTYPE-1A VIRUS AND VARIANTS RESISTANT TO 1ST GENERATION NS5A INHIBITORS
http://www.natap.org/2012/EASL/EASL_79.htm

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Experts address ethical issues raised by FDA's approval of Truvada for HIV prevention

Published on August 1, 2013 at 2:36 AM

The Food and Drug Administration's approval last year of the drug Truvada for prevention of HIV infection was a milestone in the fight against HIV/AIDS, but experts are cautioning that it is only the beginning of new ethical concerns for health care professionals, policy makers, researchers and those taking Truvada to prevent HIV infection.

"For the first time, we will have a large number of individuals who are not infected with HIV taking medication for HIV, which introduces ethical concerns of well-being and justice," says Jeremy Sugarman, Deputy Director for Medicine at the Johns Hopkins Berman Institute of Bioethics. He and Kenneth Mayer, the director of HIV prevention research at Beth Israel Deaconess Medical Center, advocate for ethical issues to be considered along with medical data in the Journal of Acquired Immune Deficiency Syndromes.

Sugarman and Mayer argue it is ethically critical to ensure that use of an antiretroviral drug like Truvada for "pre-exposure prophylaxis"(PrEP) does not have the ironic consequence of making individuals and communities less safe and healthy. Inconsistent, rather than daily, use of PrEP could result in HIV transmission and the evolution of drug-resistant strain of HIV, the authors warn. Likewise, misunderstanding of PrEP's prevention capacity could lead to the spread of other sexually transmitted infections.

"Communication and careful monitoring by health care professionals is essential for PrEP to be successful," says Sugarman. "Reinforcing the importance of daily dosing, incorporating safer sex counseling and frequent HIV testing will help meet the moral imperative that HIV be prevented and not exacerbated by PrEP," he says. He and Mayer recommend training programs for health care professionals that include explicit consideration of PrEP's ethical issues and their management.

Additionally, Sugarman and Mayer highlight what they say are 'critical, unanswered questions' of access and allocation. When limited antiretroviral drugs are available, should prevention be prioritized over treatment for those already infected with HIV, or vice-versa? Is a clinic environment the best setting to provide necessary counseling as part of PrEP? These questions, as well as how much PrEP should cost and who should pay for it, need to be answered as PrEP continues to be used and evaluated, the authors say.

"The fundamental moral claim for using PrEP, or any other HIV prevention strategy, is decreasing the burden of new HIV infections," Sugarman says. "For PrEP's full promise and medicine's moral obligations to be fulfilled, these complex ethical issues must be monitored along with the performance of PrEP."

Source: Johns Hopkins Medicine

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FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen

Page Last Updated: 08/01/2013

FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen

View and print full Drug Safety Communication¹ (PDF - 130KB)

Safety Announcement

[8-1-2013]  The U.S. Food and Drug Administration (FDA) is informing the public that acetaminophen has been associated with a risk of rare but serious skin reactions.  These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal.  Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products.

Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen.  These reactions can occur with first-time use of acetaminophen or at any time while it is being taken.  Other drugs used to treat fever and pain/body aches (e.g., non-steroidal anti-inflammatory drugs, or NSAIDS, such as ibuprofen and naproxen) also carry the risk of causing serious skin reactions, which is already described in the warnings section of their drug labels.

Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away.  Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers.

Health care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.

This new information resulted from the Agency’s review of the FDA Adverse Event Reporting System (FAERS) database and the medical literature^1-20 to evaluate cases of serious skin reactions associated with acetaminophen (see Data Summary).  It is difficult to determine how frequently serious skin reactions occur with acetaminophen, due to the widespread use of the drug, differences in usage among individuals (e.g., occasional vs. long-term use), and the long period of time that the drug has been on the market; however it is likely that these events (i.e., SJS, TEN, and AGEP) occur rarely.

FDA will require that a warning be added to the labels of prescription drug products containing acetaminophen to address the risk of serious skin reactions.  FDA will also request that manufacturers add a warning about serious skin reactions to the product labels of OTC acetaminophen drug products marketed under a new drug application and will encourage manufacturers of drug products marketed under the OTC monograph do the same.

FDA has prepared a list of questions and answers² to provide more information about this safety issue.

Facts about acetaminophen

• It is widely used in both prescription and over-the-counter (OTC) products to reduce pain and fever.
• It is available in single-ingredient drug products and in fixed-dose combination drug products (i.e., a combination of two or more ingredients in a single drug product).

Additional Information for Patients and Consumers

• Acetaminophen is available alone in single-ingredient products and also combined with other medicines in products used to treat colds, coughs, allergies, pain, and sleeplessness.
• Acetaminophen is an ingredient in many over-the-counter (OTC) and prescription medicines.  On OTC medicines, the word “acetaminophen” appears on the front of the package and on the Drug Facts label under the Active Ingredient(s) section.  On prescription medicines, the label may spell-out acetaminophen or it may have a shortened version of it such as “APAP,” “acet,” “acetamin,” or “acetaminoph.”  If you aren’t sure if your medicine contains acetaminophen, ask a pharmacist or your health care professional for additional information. 
• Acetaminophen may rarely cause serious skin reactions.  Symptoms may include skin reddening, rash, blisters, and the upper surface of the skin may become separated from the lower layers.
• Serious skin reactions can occur even if you have taken acetaminophen in the past without any problems.
• If you develop any skin rash or reaction while using a medicine containing acetaminophen, stop the medicine and seek medical attention immediately.  A health care professional will evaluate you to determine if you are experiencing a serious skin reaction.  
• If you have had a serious skin reaction with acetaminophen, do not take it or any products containing acetaminophen again.  Doing so could cause you to have another serious skin reaction.
• Talk to your health care professional if you have any questions or concerns about acetaminophen or other pain relievers/fever reducers.
• Other medicines used to treat fever and pain/body aches (e.g., non-steroidal anti-inflammatory drugs, or NSAIDs, such as ibuprofen and naproxen) also carry the risk of causing serious skin reactions.  However, having experienced a serious skin reaction with acetaminophen does not necessarily mean that you will also experience the reaction with other pain reliever/fever reducer medicines.
• Report side effects from acetaminophen to the FDA MedWatch program, using the information in the Contact FDA box at the bottom of this page.

Additional Information for Health Care Professionals

• Rarely, acetaminophen can cause serious, potentially fatal skin reactions, such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN).
• The evidence supporting causality primarily comes from a small number of cases published in medical literature in which patients were rechallenged with acetaminophen and had a recurrence of the serious skin reaction.^1-3  Other supportive data include reports from the FDA Adverse Event Reporting System (FAERS) database and case control studies (see Data Summary).^21-26
• Inform patients about the signs of serious skin reactions and that use of acetaminophen should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
• Inform patients that acetaminophen may be an ingredient in over-the-counter (OTC) and prescription fixed-dose combination drug products, including those used to treat colds, coughs, allergy, pain, and sleeplessness.
• Other drugs used to treat fever and pain/body aches (e.g., NSAIDs) also carry the risk of causing serious skin reactions.  However, there does not appear to be cross-sensitivity between acetaminophen and other pain reliever/fever reducer drugs.
• Report adverse events involving acetaminophen to the FDA MedWatch program, using the information in the Contact FDA box at the bottom of this page.

Data Summary

FDA reviewed the FDA Adverse Event Reporting System (FAERS) database and the medical literature for evidence of an association between acetaminophen and Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).  The evidence supporting causality between acetaminophen and serious skin reactions primarily comes from a small number of published cases in which patients were rechallenged with acetaminophen and had a recurrence of a serious skin reaction.^1-3

• In one case, a 7-year-old girl with fever and sore throat was treated with three doses of acetaminophen (10 mg/kg), and 12 hours later, she developed an erythematous rash over her gluteal region and legs.  Her condition worsened, and she was admitted to a hospital.  Her skin biopsy was compatible with TEN.  Six months later, an allergist questioned the diagnosis of TEN due to acetaminophen and performed an oral rechallenge with acetaminophen 250 mg.  No other drugs were used.  Thirty minutes later, the patient developed diffuse urticaria and erythema and was readmitted to the hospital.¹
• In another case, an 11-year-old boy was hospitalized for SJS.  He had taken acetaminophen for a cold and presented to medical attention with malaise, fever, and erythematous macules that progressed to erosive, hemorrhagic lesions.  Laboratory testing included a biopsy that was compatible with SJS.  A later oral test with acetaminophen (clinicians were unaware the original reaction was associated with acetaminophen) resulted in erythema multiforme, diagnosed clinically with a compatible biopsy.²
• In a third case, an 83-year-old man took acetaminophen and multiple other drugs for a hip replacement.  He was admitted to the hospital with an erythematous rash with hundreds of small, nonfollicular pustules; biopsy showed subcorneal pustules, spongiosis, papillary edema, and a perivascular infiltrate consistent with AGEP.  All drugs were stopped with resolution of the eruption and widespread desquamation.  Skin patch tests with acetaminophen only resulted in subcorneal pustules.  He experienced a recurrence of AGEP with subsequent administration of intravenous propacetamol, a prodrug of acetaminophen.³

In addition to the three positive rechallenge cases, the medical literature contained several cases of SJS, TEN, and AGEP (3, 17, and 6 cases, respectively) in which the only drug administered prior to the reaction was acetaminophen, or acetaminophen hypersensitivity was demonstrated by skin testing or other means.^1-20  There were no deaths reported in the literature, but the majority of cases required hospitalization.  All cases resolved with discontinuation of the drug.

A search of FAERS from 1969 to 2012 identified 91 cases of SJS/TEN and 16 cases of AGEP, which resulted in 67 hospitalizations and 12 deaths.  The majority of the cases involved single-ingredient acetaminophen products.  A small number of cases involved injectable acetaminophen products or oral acetaminophen/opioid fixed-dose combination products.  Indications for acetaminophen use varied between pyrexia and analgesia, and the majority of the reported doses were consistent with labeled dosing recommendations.

Of the 91 cases of SJS/TEN, 6 were categorized as probable cases associated with acetaminophen, with the rest categorized as possible cases.  Of the 16 cases of AGEP, 1 was categorized as a probable case associated with acetaminophen, with the rest categorized as possible cases.  These seven probable cases had a confirmed diagnosis of SJS/TEN or AGEP by a dermatologist and/or histological findings temporally associated with acetaminophen; confounding medications were not administered within two weeks preceding the events.  The time to event, which was measured from the initiation of acetaminophen to the onset of cutaneous signs and symptoms, ranged from less than 24 hours to 8 days.  Among these probable cases, six people were hospitalized and one died.

FDA’s review of five SJS/TEN case-control studies and one of AGEP indicated that risks of SJS/TEN may be increased with the use of acetaminophen and were generally independent of the effects of other drugs.^21-26  However, all but two of these case control studies failed to address the possible presence of protopathic bias, which in this setting refers to a false increase in the risk of SJS/TEN attributable to acetaminophen, due to its use to treat fever, a prodromal symptom of SJS/TEN.  In one of the two studies that controlled for the confounding effect of protopathic bias by limiting the acetaminophen exposure period to a time preceding the prodromal period, acetaminophen remained significantly associated with SJS/TEN.²⁶

References

1. Halevi A, Ben-Amitai D, Garty BZ. Toxic epidermal necrolysis associated with acetaminophen ingestion. Ann Pharmacother 2000;34:32-4.
2. Trujillo C, Gago C, Ramos S. Stevens-Johnson syndrome after acetaminophen ingestion, confirmed by challenge test in an eleven-year-old patient. Allergol Immunopathol (Madr) 2010;38:99-100.
3. Leger F, Machet L, Jan V, Machet C, Lorette G, Vaillant L. Acute generalized exanthematous pustulosis associated with paracetamol. Acta Derm Venereol 1998;78:222-3.
4. Bygum A, Gregersen JW, Buus SK. Acetaminophen-induced toxic epidermal necrolysis in a child. Pediatr Dermatol 2004;21:236-8.
5. Bouziri A, Khaldi A, Hamdi A, Borgi A, Ghorbel S, Kharfi M, et al. Toxic epidermal necrolysis complicated by small bowel intussusception: a case report. J Pediatr Surg 2011;46:e9-11.
6. Reese D, Henning JS, Rockers K, Ladd D, Gilson R. Cyclosporine for SJS/TEN: a case series and review of the literature. Cutis 2011;87:24-9.
7. Dragojevic-Simic V, Vukovic J, Kovacevic A. Paracetamol-induced toxic epidermal necrolysis in adult: clinical pharmacology unit case report. Basic & Clinical Pharmacology & Toxicology. Volume 105(Supplement 1):98.
8. Verneuil L, Ratajczak P, Allabert C, Leboeuf C, Comoz F, Janin A, et al. Endothelial cell apoptosis in severe drug-induced bullous eruptions. Br J Dermatol 2009;161:1371-5.
9. Yamane Y, Aihara M, Tatewaki S, Matsukura S, Kanbara T, Yamakawa Y, et al. Analysis of treatments and deceased cases of severe adverse drug reactions--analysis of 46 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arerugi 2009;58:537-47.
10. Pyo KS, Heung YD, Jung KS, Hyeong CS, Soo CN. A case of toxic epidermal necrolysis (TEN) induced by nonsteroidal anti-inflammatory drug (NSAID) in Emergency Medical Center. Toxicology Letters 2008;180(Supplement 5):S140.
11. Yun SJ, Choi MS, Piao MS, Lee JB, Kim SJ, Won YH, et al. Serum lactate dehydrogenase is a novel marker for the evaluation of disease severity in the early stage of toxic epidermal necrolysis. Dermatology 2008;217:254-9.
12. Gerdts B, Vloemans AF, Kreis RW. Toxic epidermal necrolysis: 15 years' experience in a Dutch burns centre. J Eur Acad Dermatol Venereol 2007;21:781-8.
13. Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003;139:26-32.
14. Takeuchi Y, Katagiri K, Hatano Y, Fujiwara S. A case of toxic epidermal necrolysis due to acetaminophen. Sainichi Hifu 2004;56:1-10.
15. Khare KC, Khare S, Mathew G. Stevens Johnson syndrome with keratitis following paracetamol injection. Indian J Dermatol Venereol Leprol 1997;63:209.
16. Szepietowski J, Wasik F, Szybejko-Machaj G, Maj J. Toxic epidermal necrolysis successfully treated with cyclosporin: report of three cases. J Eur Acad Dermatol Venereol 1997;9:169-72.
17. Sezer E, Sezer T, Koseoglu D, Filiz NO. Acute generalized exanthematous pustulosis in a child. Pediatr Dermatol 2007;24:93-5.
18. Wohl Y, Goldberg I, Sharazi I, Brenner S. A case of paracetamol-induced acute generalized exanthematous pustulosis in a pregnant woman localized in the neck region. Skinmed 2004;3:47-9.
19. Mashiah J, Brenner S. A systemic reaction to patch testing for the evaluation of acute generalized exanthematous pustulosis. Arch Dermatol 2003;139:1181-3.
20. De Coninck AL, Van Strubarq AS, Pipeleers-Marichal MA, Huyghens LP, Suys ET, Roseeuw DI. Acute generalized exanthematous pustulosis induced by paracetamol. A case with severe hemodynamic disturbances. Dermatology 1996;193:338-41.
21. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-7.
22. Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157:989-96.
23. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008;128:35-44.
24. Gau SS, Chao PF, Lin YJ, Chang CJ, Gau CS. The association between carbamazepine and valproate and adverse cutaneous drug reactions in patients with bipolar disorder: a nested matched case-control study. J Clin Psychopharmacol 2008;28:509-17.
25. Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 2010;88:60-8.
26. Levi N, Bastuji-Garin S, Mockenhaupt M, Roujeau JC, Flahault A, Kelly JP, et al. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics 2009;123:e297-304.

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Related Information

• Questions and Answers: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen³
• FDA Warns of Rare Acetaminophen Risk⁴
• View and Print: FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen (PDF - 130KB)⁵

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TheraSphere® Recommended by the National Institute for Health and Care Excellence (NICE) for the Treatment of Primary and Secondary Liver Cancer

LONDON, July 30, 2013 /PRNewswire/ --

BTG plc (LSE: BTG), the specialist healthcare company, today announces that the National Institute for Health and Care Excellence (NICE) has issued guidance recommending the use of Selective Internal Radiation Therapy (SIRT)⁽¹⁾, which includes TheraSphere^®, for patients with liver cancer across the NHS. The guidance supports the use of this innovative treatment for patients with primary hepatocellular carcinoma as well as for those with intrahepatic cholangiocarcinoma⁽²⁾ and follows the previous recommendation for its use in patients with colorectal cancer liver metastases⁽³⁾.

The NHS in England is currently preparing guidelines on how SIRT should be used as a treatment option for patients with liver cancer, including those with colorectal cancer liver metastases and cholangiocarcinoma, after recently issuing an interim policy on how this therapy should be funded⁽⁴⁾. It is anticipated that this latest NICE guidance will result in a similar evaluation for patients with primary liver cancer. "NICE's guidance further highlights the growing acceptance and understanding of radioembolization in the treatment of liver cancer," said Peter Pattison, General Manager TheraSphere^®. "With over 4,000 new liver cancer cases diagnosed annually in the UK⁽⁵⁾, this new guidance will potentially provide patients with access to a broader range of treatment options."

Pattison added: "With many countries looking to the UK for direction on their own reimbursement decisions and processes, this guidance should lead to greater awareness amongst physicians and patients and may also prompt similar guidance in other geographies. In addition to increasing liver cancer treatment options for physicians and patients in the UK, this guidance will assist BTG as we continue to explore other reimbursement opportunities in various regions across the world."

About TheraSphere®

TheraSphere is a form of radioembolization therapy that consists of millions of small glass beads (20 to 30 micrometers in diameter) containing radioactive yttrium-90 (Y-90). The product is injected by physicians into the artery of the patient's liver through a catheter, which allows for a high dose of radiation to be delivered directly to the tumour via blood flow thereby limiting the damage to surrounding healthy tissue and side effects to the patients.

TheraSphere is used in the European Union and in Canada for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters. Since its introduction in Europe, more than 1,000 patients have been treated with TheraSphere.

Common side effects include mild to moderate fatigue, pain and nausea for about a week. Physicians describe these symptoms as similar to those of the flu. Some patients experience some loss of appetite and temporary changes in several blood tests. For details on rare or more severe side effects, please refer to the TheraSphere package insert/instructions for use at http://www.nordion.com/therasphere.

1. National Institute of Care Excellence. IPG460 Selective internal radiation therapy for primary hepatocellular carcinoma: guidance. London. 24 July 2013.
2. National Institute of Care Excellence. IPG459. Selective internal radiation therapy for primary cholangiocarcinoma. London.  24 July 2013.
3. National Institute of Care Excellence. IPG401. Selective internal radiation therapy for non-resectable colorectal metastases of the liver: guidance. London. July 2012 (updates May 2013).
4. NHS England. Interim Clinical Commissioning Policy Statement: Selective Internal Radiotherapy (SIRT). June 2013.
5. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/liver/

About BTG

BTG is an international specialist healthcare company that is developing and commercialising products targeting critical care, cancer and varicose veins. The company has diversified revenues from sales of its own marketed products and from royalties on partnered products, and is seeking to acquire new programmes and products to develop and market to specialist physicians. For further information about BTG please visit our website at http://www.btgplc.com.

For further information please contact:

BTG
Andy Burrows, Director of Investor Relations
+44(0)20-7575-1741; Mobile: +44(0)7990-530605

FTI Consulting
Ben Atwell/Simon Conway
+44(0)20-7831-3113

SOURCE BTG plc

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Getting hepatitis on the policy agenda in Asia

For Vietnam, where 15-17% of the population have hepatitis B or C, the global health burden has been heavy. Photograph: Hemis/Alamy

For health ministries trying to tackle hepatitis, the advice is: know your epidemic, get government on board to find a solution, educate the population and have the right policy in place

Guardian Professional, Sunday 28 July 2013 03.00 EDT

Viral hepatitis causes 1 million deaths a year in the Asia Pacific region, the equivalent of one death every 30 seconds and more than three times as many as HIV. Of the 350 million people in the world living with hepatitis B, 74% of them live in Asia, but getting the disease on the health policy agenda of some of the worst affected countries has not been easy.

"We have a vaccine for hepatitis B and new treatments for chronic hepatitis C that could save millions of lives, but none of these matter if governments fail to tackle viral hepatitis," says professor Stephen Locarnini, director of the WHO Regional Reference Laboratory for Hepatitis B at the Victorian Infectious Diseases Reference Laboratory in Melbourne and joint secretary of the Coalition to Eradicate Viral Hepatitis in Asia Pacific (Cevhap).

"What we need is for governments across the region to approach viral hepatitis in the same way that most have HIV/Aids, TB and malaria. This starts with the development of a national action plan and our expert members are ready and willing to help governments in the development of these, following the framework for global action blueprint provided by WHO."

Dr Robert Gish, Cvevhap's co-founder has been doing just that with the government in Vietnam, where an estimated 15-17% of the country's 100 million people have hepatitis B or C. "It's clear that the country needs a policy for liver health," he said.

Gish, together with colleagues in Vietnam and from UN and other international agencies has been working to get hepatitis and liver health on the Vietnamese government's health agenda.

A white paper published in 2011 in the Journal of Gastroenterology and Hepatology spelt out the rationale for a dedicated policy for liver health in Vietnam: 12% estimated prevalence of chronic hepatitis B, at least 2% prevalence of chronic hepatitis C and heavy alcohol use by men, adding up to liver cancer as the most common cause of cancer death in the country. Despite the sizeable liver cancer wards in all of Vietnam's major hospitals, a general lack of understanding of liver disease both among the public and health professionals and no systematic screening for those at risk has left the epidemic unchecked.

The white paper advocated liver disease education for the public and healthcare workers and an expansion of countrywide screening, hepatitis B vaccination and treatment of chronic hepatitis. These measures coupled with long-term surveillance for liver cancer, enhanced infection control to prevent transmission in health care settings and ongoing prevalence data analysis can help bring the epidemic of liver disease under control.

The message fell on fertile ground: in December 2012 the ministry of health set up a technical action group and by the end of this year is likely to have a draft policy in place.

Vietnam currently vaccinates approximately 60% of babies within 24 hours of birth and, says Gish, has the rural healthcare system in place to reach the WHO's revised target of 90% coverage (up from 80%).

Vaccination for adults is far less widespread but Gish and his colleagues are currently running pilot projects to test and vaccinate 20,000 adults, recruited from medical, dental pharmacology and nursing schools. "They are easy to reach and can carry the message forward to their patients, but they can only do so effectively if they themselves have been tested and vaccinated," says Gish.

But progress is stunted in parts of Asia, such as the Philippines, where hepatitis is accompanied by discrimination. Prevalence estimates range from 8% to 20% across different segments of the 96 million population and the stigma attached to hepatitis B is severe. Pre-employment tests for the disease screen out those who test positive. Overseas workers from the Philippines face similar discrimination notably in Middle Eastern countries. People with hepatitis are blatantly discriminated against," says Gish. "Workplace discrimination is a huge problem that deters people from getting voluntarily tested."

Gish has also been working with the Hepatology Society of the Philippines, which is leading the effort in the country, and also with hepatitis activist group Yellow Warriors Society Philippines to get hepatitis on the health policy agenda but, he says the contrast with Vietnam at government level has been "like night and day. The department of health has sat on a draft hepatitis policy for three years, so we're trying to revitalise a lot of activity. In Vietnam we were starting from scratch, but now the Vietnamese ministry of health is moving forward quite aggressively on its own."

Having become interested in hepatitis in Asia when treating Asian patients in his practice in San Francisco, Gish decided he could make a bigger impact on the disease by supporting colleagues to get it more widely recognised in Asia. His interest has spread to central Asia, another hepatitis hotspot, with a regional project underway in Armenia.

"Every country I've worked with has different customs and problems, but what they have in common is a need to know their hepatitis epidemic, get government on board to find a solution, educate the population and have the right policy in place."

Source

CHMP OKs Eltrombopag for HCV Patients With Thrombocytopenia

International Approvals > Medscape Medical News

Troy Brown

Jul 30, 2013

The indications for eltrombopag (Revolade, GlaxoSmithKline Trading Services) should be extended to include adults with chronic hepatitis C virus (HCV) infection who have thrombocytopenia severe enough to prevent the initiation of interferon-based therapy or limit the maintenance of optimal therapy, according to a July 25 recommendation by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

"Treatment with pegylated interferon and ribavirin is the current standard of care for patients with HCV, however both the European Association for the Study of the Liver guidelines and the American Association for the Study of Liver Diseases report the presence of thrombocytopenia among the relative contraindications to antiviral therapy," according to a GlaxoSmithKline statement.

"A sustained virologic response is the goal for treatment of hepatitis C infection and our clinical study, the largest ever in cirrhotic patients with low platelet counts and chronic hepatitis C infection, demonstrated that eltrombopag in combination with interferon-based therapy, allowed more cirrhotic patients with low platelet counts to reach this goal," Rafael Amado, MD, head of oncology research and development at GlaxoSmithKline said in the statement.

The committee's opinion was based on data from 2 randomized, double-blind, placebo controlled, multicenter phase 3 studies with a total of 1521 patients with platelet counts below 75000 µl, the ENABLE 1 and 2 (Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE) trials. Patients in ENABLE 1 received peginterferon alfa-2a (Pegasys, Genentech) plus ribavirin for antiviral treatment and patients in ENABLE 2 received peginterferon alfa-2b (Pegintron, Merck) plus ribavirin.

Eltrombopag was previously approved in the European Union to treat thrombocytopenia in adult splenectomized patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who haven't responded to other treatments including corticosteroids and immunoglobulins. It can be considered as a second-line treatment for adult nonsplenectomized patients in whom surgery is contraindicated.

Eltromopag is marketed in the US under the trade name Promacta (GlaxoSmithKline) and is approved for both indications there.

Limitations to the use of eltrombopag include:

• Eltrombopag should not be used to normalize platelet counts;
• Eltrombopag should only be used in patients with chronic HCV whose thrombocytopenia is severe enough to prevent initiation of interferon therapy or maintenance of optimal interferon therapy; and
• The safety and efficacy of eltrombopag have not been established in combination with direct-acting antiviral agents that are approved to treat chronic hepatitis C genotype 1 infection.

Eltrombopag can cause hepatotoxicity, and hepatic enzymes should be measured before beginning therapy. When used in combination with interferon-based antiviral therapy, eltrombopag can increase the risk for hepatic decompensation, so patients should be monitored closely.

Venous and arterial thrombotic and thromboembolic events have occurred in patients receiving eltrombopag, with portal vein thrombosis reported most frequently. Patients with poor baseline liver function are at increased risk and should be monitored closely.

At least 10% of patients in both trials experienced headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, muscle weakness, chills, and peripheral edema.

The European public assessment report (EPAR) will be revised to include the updated summary of product characteristics (SmPC) after the European Commission grants marketing authorization for this indication.

The European Commission generally follows the recommendations of the CHMP and usually delivers its final decision within 3 months of the CHMP recommendation.

European Medicines Agency statement, July 25, 2013. Overview

Source

HBV vaccine birth dose practices in Laos need more improvement

Provided by Healio

CDC. MMWR. 2013;62:587-590.

July 31, 2013

The median hepatitis B vaccine birth dose coverage at facility-based births was 74% in Laos, where hepatitis B virus is highly endemic, according to data published in Morbidity and Mortality Weekly Report.

From December 2011 to February 2012, the Laos Ministry of Health and WHO staff members evaluated coverage at 37 health facilities. At 18 of the facilities (49%), the HBV vaccine was not in stock. Among the 17 facilities that assisted with home births, seven included the vaccination in the services. Twenty-three facilities conducted postnatal visits, and only 15 of these provided the vaccine in the visit.

“Administration of the hepatitis B vaccine birth dose followed by timely completion of the hepatitis B vaccine series is 70% to 95% effective in preventing mother-to-child HBV transmission,” the researchers wrote. “During 2006 to 2011, the reported coverage in Laos increased from 3% to 34%. Despite this increase, the country continues to have the lowest coverage in the region, largely because only 37% of women in Laos give birth with the assistance of a skilled birth attendant.”

The study was conducted in five of the 24 provinces of Laos and included provincial or central hospitals, as well as two district hospitals and four health centers. Staff members at each facility participated in an in-person interview, answering questions about the HBV vaccine birth dose procedures.

Among the 31 facilities that provided birthing services onsite, all reported proving the vaccine to newborns. There were 5,072 onsite births recorded during the 3-month study period, of which 70% received the vaccine. Four additional facilities that did not provide onsite birthing services also reported providing newborns with the vaccine.

“Laos has shown a strong commitment toward the Western Pacific Region goal of reducing chronic HBV infection prevalence in children aged 5 years and younger to less than 1%,” the researchers wrote. “Such a reduction in HBV prevalence will require prevention of both perinatal and early childhood infections.”

Disclosure: The researchers report no relevant financial disclosures.

Source

Labeling for HBV medication updated following new safety, efficacy data

Provided by Healio

July 31, 2013

The FDA has approved changes to the labeling for Viread, a treatment for chronic hepatitis B, following the results of a 96-week study.

Updated labeling for tenofovir disoproxil fumarate (Viread, Gilead Sciences) reflects that the indication was the product of trials of treatment-experienced, lamivudine-resistant adult patients with chronic HBV and chronic liver disease who were naive to nucleoside-based therapy. Adverse events observed among these patients during treatment were similar to those observed in other HBV-related clinical trials.

In a randomized, double blind, active-controlled study, 141 patients with chronic HBV, HBV DNA of 1,000 IU/mL (mean 6.4 log₁₀ copies/mL) or more and resistance to lamivudine received Viread for 96 weeks. Forty-six percent of the cohort were HBeAg-positive, and 56% had abnormal serum ALT levels at baseline (mean 71 U/L).

Upon completion of treatment, 89% had HBV DNA below 400 copies/mL, and 62% of those with abnormal ALT had normalized. HBeAg loss occurred in 15% of the HBeAg-positive patients, and 11% experienced anti-HBe seroconversion through the final treatment week.

The labeling also indicates a potentially significant drug-drug interaction between Viread and didanosine. A didanosine dose reduction is recommended upon coadministration with Viread: to 250 mg once daily among patients weighing more than 60 kg and 200 mg among those weighing less than 60 kg. The drugs should be taken under fasting conditions or with a light meal containing fewer than 400 kcal and 20% fat.

Source

Turmoil for AIDS Conference Organizers

FLICKR, NIAID

Conflict between former conference organizers has shuttered a website that has come to serve as a resource for the HIV/AIDS community.

By Kate Yandell | July 30, 2013

The website for the annual Conference on Retroviruses and Opportunistic Infections (CROI), a major US HIV/AIDS meeting, is currently offline following a conflict between the two groups that formerly organized the event, ScienceInsider reported.

CROI, which has taken place annually for the past 20 years, has been the site of many important announcements in the history of HIV/AIDS research. The conference website was host to years’ worth of conference abstracts and other resources for AIDS researchers and the public.

The nonprofit CROI Foundation and the for-profit CROI LLC have previously been responsible for organizing the conference each year. But the two groups appear to have had a falling out. “I’m not allowed by our confidentially agreement to divulge anything,” Constance Benson, CROI Foundation board president and a professor at the University of California, San Diego, told ScienceInsider. “We reached an impasse this past couple of years over several issues and decided we needed to go in a different direction.”

Melissa Sordyl, head of CROI LLC, told ScienceInsider, “CROI LLC is no longer the conference secretariat and that is why the site is no longer active.”

Benson told The Scientist in an email that anyone seeking information on the 2014 conference, which will take place in Boston in March, should go to a new website: www.CROI2014.org. “We have no further update on the old website at this time,” Benson said. She added that Sordyl owned and maintained the old website and that it does not belong to the CROI Foundation.

The CROI Foundation is partnering with the International Antiviral Society-USA to put on the 2014 conference, according to the new website.

Simon Collins, head of HIV i-Base, a website for HIV treatment activism and information, wrote on his site that the loss of the CROI website was a frustrating one: “CROI is established as the most important HIV scientific meeting,” he wrote, adding that  “the website is a vital resource not only as a record of previous meetings but as a free open-access research tool.”

Benson told The Scientist that the conference organizers are “working on a solution for the old content from past meetings.”

Source

Engineered mice act as hepatitis C model

Hepatitis C particles (yellow) infect liver cells, causing disease and cancer.

THOMAS DEERINCK, NCMIR/SPL

Nature | News

Rodents may eventually replace chimpanzees in vaccine research.

Beth Mole

31 July 2013

Researchers have created the first strain of mouse that is completely vulnerable to hepatitis C. The advance, reported today in Nature¹, promises to aid efforts to develop a vaccine against the virus, which causes liver disease and cancer.

Chimpanzees have been the primary animal model for studying hepatitis C infection over the last several decades. But in the past few years scientists have begun phasing out chimp experiments, a process accelerated by the US government’s decision to retire most of its research chimps. That has created a need for alternative models to test potential drugs and vaccines.

Enter the mouse, which is naturally immune to hepatitis C. To transform the rodent into a model organism for studying infections with the virus, researchers genetically altered the animals to hamper their natural immune response. The team also engineered the animals to produce proteins found on the outside of human liver cells.

“It has been very difficult to get to this point,” says Alexander Ploss, a virologist at Princeton University in New Jersey and lead author of the study.

In 2011, Ploss — then at Rockefeller University in New York — and his colleagues showed that hepatitis C could infect mice engineered to produce the two human proteins². But the virus did not replicate well in those animals, making them a poor model for human infections. So the team created another strain by breeding the human-protein-containing mice with animals that carried a broken version of a gene involved in antiviral responses. The result, they report, is mice in which hepatitis C can take root and flourish, creating new viral particles to spread the disease.

“For the first time you can study the whole spectrum of hepatitis C replication” in a mouse model, says Lishan Su, an immunologist at the University of North Carolina at Chapel Hill, who was not involved with the study.

Strong immune system

Researchers have previously tested candidate hepatitis C drugs using a mouse containing human liver cells, developed in 2010 by Karl-Dimiter Bissig, a virologist at Baylor College of Medicine in Houston, Texas, and his colleagues³. But that mouse model had no immune system. Su says that Ploss and colleagues' strain may be more useful for testing vaccines, because most of the mouse's immune system is intact.

Michael Houghton, a hepatitis C researcher at the University of Alberta in Edmonton, Canada, says that scientists should still be careful when interpreting results from tests with the latest mouse model. The mouse's immune system is still partially damaged, so the response to vaccines may be altered — which could cause falsely negative results when testing vaccines that are actually effective.

“This model still cannot replace chimpanzees,” says Ploss, who is working with his colleagues to improve the mouse strain. “It gives us a first glimpse of what may be possible with mice in coming years.”

Nature doi:10.1038/nature.2013.13477

Source

‘HCC-4 risk score’ IDs hepatitis C patients likely to develop HCC

^{Courtesy US. Dept of Veterans Affairs}

A new risk score may help identify the patients with chronic hepatitis C who are most at risk for developing hepatocellular carcinoma.

By: MARY ANN MOON, Family Practice News Digital Network

07/31/13

Vitals

Major finding: The annual incidence of HCC was 0.06% in the group designated as low risk, 0.5% in the group designated as medium risk, and 2.6% in the group designated as high risk, indicating that the HCC-4 risk score was highly predictive of actual outcomes.

Data source: A retrospective study of data collected in a 17-year longitudinal cohort study involving 829 adults with chronic hepatitis C, of whom 58 developed HCC.

Disclosures: There was no external funding source for this study, and no financial conflicts of interest were reported.

A risk score derived from four simple test results readily obtained during routine care may help identify the patients with chronic hepatitis C who are most at risk for developing hepatocellular carcinoma, according to a retrospective study published online July 12 in the European Journal of Internal Medicine.

The score could enable physicians to target only the highest-risk patients for annual surveillance for malignant hepatic nodules, which is crucial because current screening methods are too invasive, too expensive, and too low-yield to be applied broadly across all risk groups.

The new risk score also may help identify patients with chronic hepatitis C who are at lowest risk for developing HCC, who can then be reassured that they can safely forgo invasive and expensive surveillance, reported Dr. Juan Carlos Gavilan and his associates at University Hospital Virgin de la Victoria, Malaga (Spain).

The investigators reviewed data from a 17-year longitudinal cohort study involving 829 patients with chronic hepatitis C. These subjects were assessed every 6 months for the development of HCC using serum alpha-fetoprotein (AFP) levels and ultrasound imaging to detect new focal hepatic lesions.

A total of 58 subjects (7%) developed HCC during follow-up.

An initial univariate analysis identified numerous clinical and epidemiologic factors associated with elevated risk for HCC. The researchers constructed a formula for predicting risk using the four independent factors that were most predictive of HCC in this cohort: patient age, platelet count, gamma-globulin level, and AFP level at baseline.

By dividing the study population into tertiles, Dr. Gavilan and his colleagues established cutoff ranges for low, medium, and high risk. They then classified each study participant as belonging to one of these three categories, to see how well this risk score correlated with the actual rates of HCC.

The annual incidence of HCC was 0.06% in the group designated as low risk, 0.5% in the group designated as medium risk, and 2.6% in the group designated as high risk, indicating that this "HCC-4 risk score" was indeed highly predictive, Dr. Gavilan and his associates said (Eur. J. Intern. Med. 2013 July 12 [doi: 10.1016/j.ejim.2013.06.010]).

In fact, the score was more accurate at predicting HCC than was the commonly used fibrosis index, they noted.

According to recently published recommendations, surveillance is only justified in populations with an HCC incidence of 1.5% or more per year. Thus, patients found to be high risk using this HCC-4 risk score would be appropriate for such surveillance, while those at medium or low risk would not be.

"These results must be confirmed in other studies," the investigators said.

There was no external funding source for this study, and no financial conflicts of interest were reported.

Source

Hepatitis C genotype 1 virus with low viral load and rapid virologic response to peginterferon/ribavirin obviates a protease inhibitor

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Viral Hepatitis

Brian L. Pearlman^1,2,3,4,*, Carole Ehleben²

DOI: 10.1002/hep.26624

© 2013 by the American Association for the Study of Liver Diseases

Publication History Accepted manuscript online: 19 JUL 2013 10:11AM EST, Manuscript Accepted: 3 JUL 2013, Manuscript Revised: 12 JUN 2013 , Manuscript Received: 6 MAY 2013

Abstract

Keywords: Sustained virologic response; rapid virologic response; African American; IL-28B; boceprevir

The new standard of care for treatment-naïve patients with hepatitis C virus (HCV) genotype 1 includes triple therapy with peginterferon, ribavirin, and a protease inhibitor. However, patients who achieve a rapid virologic response after 4 weeks of peginterferon and ribavirin therapy are likely to achieve a sustained virologic response (SVR), and we hypothesized that protease inhibitor therapy may be unnecessary in these patients. Treatment-naïve, noncirrhosis patients infected with genotype-1 HCV and a low viral load at baseline were considered for inclusion (n = 233). After 4 weeks of lead-in therapy with peginterferon α-2b and ribavirin, 101 patients (48%) had a rapid virologic response (defined as undetectable levels of hepatitis C virus RNA at 4 weeks) and were eligible to participate. Patients were randomized 1:1 to 20 weeks of additional therapy with peginterferon α-2b and ribavirin (double therapy) or to 24 weeks of peginterferon α-2b, ribavirin, and boceprevir (triple therapy). There was no significant difference in rates of SVR-12 in patients treated with double versus triple therapy. This similarity persisted regardless of viral subtype (genotype 1a or 1b), interleukin (IL)−28b genotype (CC or non-CC), or ethnicity (African American versus non-Hispanic white). Conclusion: Protease inhibitor therapy could be obviated in genotype 1-infected treatment-naïve patients with low viral load at baseline who achieve undetectable viremia after 4 weeks of peginterferon/ribavirin. (Hepatology 2013;)

Source

Interferon-free treatment for genotype-1b hepatitis C patients: an interview with Professor Wulf Boecher, Boehringer Ingelheim

Published on July 30, 2013 at 6:32 AM

Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)

Please can you give a brief introduction to genotype-1b hepatitis C and how it differs from subtype 1a?

Genotype 1 is, worldwide, the most prevalent genotype of the hepatitis C virus. It accounts for around seventy percent of all hepatitis C infections.

With the introduction of protease inhibitors, it became known that the subtypes 1a and 1b make a difference in terms of treatment response.

Subtypes 1a and 1b are genetically closely related. They share seventy to eighty percent of their genome. However, 1a turned out to be more difficult to treat than 1b, which is easier to treat.

That was also the case with the already approved protease inhibitors, and still is the case with the second generation of protease inhibitors (PIs) like faldaprevir or other second generation PIs that are in late stage development. And it applies for interferon based as well as interferon-free treatments.

Faldaprevir's target in viral polyprotein processing.

*Please note faldaprevir (BI 201335) is an investigational compound and not yet approved. Its safety and efficacy has not yet been fully established.

Source: Boehringer Ingelheim

Do genotypes 1a and 1b affect equal numbers of people, or is one more common than the other?

It is regionally very different. In the US, genotype 1a is more prevalent where it accounts for roughly seventy percent of genotype 1 infections.

In Europe, there is slightly more genotype 1b. So there’s roughly a sixty-forty split, with sixty percent being genotype 1b, forty percent 1a.

If you go further East the prevalence of 1b becomes nearly the only genotype 1. So in Japan, in China, and in large parts of Asia, genotype 1b is basically the vastly prevailing or the only genotype 1 subtype.

Hepatitis C virus travelling in the bloodstream.

Source: Boehringer Ingelheim

Why is eliminating injectable interferon from HCV treatment regimens highly desirable?

I have been working on hepatitis C treatment for many years and it is not only subcutaneous injections that make patients uncomfortable. Interferon really makes patients sick for the whole course of treatment and with current treatments this can be as long as twenty four or forty eight weeks, so nearly one year.

Patients feel like they have the flu, with fever, myalgia, chills, and many other symptoms. Also their neuro-cognitive function is reduced. They have low blood cell count that can lead to infections and to severe bleedings. They suffer from psychiatric side effects like severe depression. There are suicides associated with treatment with interferon.

So interferon is really a trouble-maker for patients; it makes patients sick for the duration of their treatment and it is less effective than the oral treatments that are to come. Treatment lasts longer and there is a high chance patients won’t be cured at the end. In contrast, current triple therapies the next generation triple therapies, as well as the future interferon-free treatments, offer shorter treatment duration and higher cure rates.

Faldaprevir* Protease Inhibitior Mode of Action.

*Please note faldaprevir (BI 201335) is an investigational compound and not yet approved. Its safety and efficacy has not yet been fully established.

Source: Boehringer Ingelheim

How did your interferon-free combination treatment originate and what stage of development is it currently at?

It’s actually based on the knowledge of HIV and tuberculosis treatment; where by combining different oral drugs with a different mode of action it is possible to control or eliminate the virus or mycobacteria.

In HCV, we had two different mode-of-action drugs in late stage development that we combined. We had actually thought we may possibly have a forty-five percent cure rate, which would still have been a very attractive cure rate for patients without any treatment options.

Up to fifty percent of hepatitis c patients right now do not tolerate interferon or have contra-indications against interferon.

But then in our phase two studies we found out that by focusing on the easier-to-treat genotype 1b patients, eighty five to ninety five percent of patients can be cured. This makes this combination very attractive as an alternative to replace interferon-based treatments.

And with this interferon-free treatment, we are currently in phase III development.

Please can you tell us about the recent Phase IIb study into the efficacy and safety of this combination treatment?

This is our second phase IIb trial. Initially (in the SOUND-C2 trial) we tested our interferon-free treatment regimen of faldaprevir, deleobuvir and ribavirin in a large study. We had 362 patients, including patients with liver cirrhosis and all stages of liver disease.

We found that genotype 1a patients are indeed difficult to treat, achieving lower cure rates. That would have been attractive maybe three, four years ago, but not nowadays.

But in this study genotype 1b patients had a cure rate of eighty-five percent.

Then we modified the regimen. We shortened treatment from twenty eight to sixteen weeks in SOUND-C3, which is the study we just published at the Asian Pacific Liver Conference (APASL) in June.

We also dropped a so-called induction dose. So in the old regimen, we had a high dose of our polymerase inhibitor and this was not so well tolerated, as we found out.

So we dropped this, we shortened treatment and we found in genotype 1b patients ninety five percent achieved viral cure. But it turned out that in the more difficult to treat population of genotype 1a patients, only two of seventeen patients were cured. And that confirmed our decision to focus on genotype 1b patients with this regimen.

Progression of liver damage caused by infection with hepatitis C.

Source: Boehringer Ingelheim

What were the results of this study and what do they indicate?

The very high cure rates of ninety five percent confirm our decision to focus on genotype 1b patients with this regimen.

We dropped genotype 1a patients from this regimen. However we are currently investigating a third compound in combination with our interferon free combination with which we strive to address genotype 1a patients.

The tolerability was very good. This was as expected from interferon-free treatment. We saw only minor effects on the red blood cells, which was due to the ribavirin component of the regimen, but we didn’t see any effects on white blood cells or platelets.

We did see mostly mild adverse events like mild rashes or nausea, which were the most common side effects.

Did any patients experience serious adverse events during the trial?

Only two patients had to discontinue treatment for adverse events and only one patient reported a serious adverse event (SAE). So overall, I think we can say that this is very good tolerability.

What serious adverse event did the patient experience?

The SAE patient was a patient who had severe dehydration. He was hospitalized to get some infusions and discontinued HCV treatment early after 6 weeks of treatment. However the condition was managed and resolved and the patient recovered completely from the event but also from his hepatitis C.

What are your plans for the future?

For genotype 1b patients we are in the middle of our phase III evaluations. We are expecting results early next year.

We have three on-going phase III trials:-

• One in treatment-naive genotype 1b patients.
• One in a treatment-naive population that includes interferon ineligible patients, which are patients who have contra indications to interferon based treatments. So these patients have currently no treatment option at all.
• We have a third trial that goes to the highest unmet medical need population, which are patients with decompensated liver cirrhosis.

The first two trials also include patients with compensated liver cirrhosis, but the third trial really addresses the late stage liver cirrhosis, or decompensated liver cirrhosis. These are patients that will die if they do not receive a liver transplant. All studies are on-going as we speak.

Our trials are comprehensively designed and address the real-world patients that physicians see every day in clinical practice. Through robust science, our goal is to provide a safe and highly effective interferon-free treatment for genotype-1b patients.

How do you think the future of genotype-1b hepatitis C treatments will progress?

From a patient and a prescriber or physician’s perspective, the future is very bright.

There are several companies and there will be several regimens available to physicians to pick the best treatment option for a given patient.

There are many factors that need to be considered when prescribing HCV treatments, so there will be no one-size-fits-all approach. In the future individualized treatment will become a reality. Physicians will be able to pick the best treatment option for a given patient depending on:-

• the virus genotype and patient genetics
• on individual patient conditions
• age
• gender
• co-morbidities
• co-medications

Everything will play into this and there will be several interferon-free treatment options that can be really tailored individually to a given patient.

It is exactly our strategy to provide tailored therapy which is optimal for specific patient populations. I think this is where we believe we will excel in.

The treatment landscape will become more complex. In the past, we had only to pick between prescribing pegylated interferon for twenty four, or forty eight weeks, and ribavirin in eight hundred, one thousand or twelve hundred milligrams. This was very easy, no drug-drug interactions.

The future looks like it will be more individualized, with physicians choosing which regimen to provide based on the individual patient’s profile. But this is in fact a luxury situation and a great opportunity.

Where can readers find more information?

Readers can find more information on Boehringer Ingelheim at: http://www.boehringer-ingelheim.com/

Readers can also find more information on HCV at: http://www.newshome.com/

About Professor Wulf Boecher

Wulf trained and worked more than 15 years at Mainz University Hospital in Germany as a Gastroenterologist/ Hepatologist and Infectious Diseases Specialist, where he lectures as an Associate Professor for Internal Medicine.

His main scientific focus has been immune pathogenesis and new treatments of HBV, HCV and HIV infection.

Wulf joined Boehringer Ingelheim for the clinical development of new HCV treatments in 2007 and currently holds the position of Associate Therapeutic Area Head Virology.

Source

Sign-on letter to Gilead about sofosbuvir/ Pétition adressée a Gilead sur le sofosbuvir

Request for sign-ons/ Appel à signatures

Sign-on letter to Gilead about sofosbuvir/ Pétition adressée a Gilead sur le sofosbuvir

publication: 28 juillet 2013

The TRT-5 and the CHV are requesting individual and organizational sign-ons to a letter urging Gilead to provide early access to sofosbuvir for people with the most urgent need / Le TRT-5 et le CHV sollicitent des signatures individuelles ou d’organisations pour une pétition demandant à Gilead de donner un accès précoce au sofosbuvir aux personnes qui en ont le besoin le plus urgent.

SIGN-ON LETTER TO GILEAD - 26th JULY 2013

Version française ci-dessous

GILEAD REFUSES ACCESS TO TREATMENT TO SERIOUSLY ILL HEPATITIS C PATIENTS

People living with HCV who are in an urgent need of new treatments should get an early access to compounds that are in nearing approval, and therefore not yet on the market. In France, there is an early access system, called ATU (Temporary Authorization of Use), to allow for early access to potentially life-saving drugs.

The French national regulation agency ANSM (Agence Nationale de Sécurité du Médicament) has granted many name-based temporary authorizations of use (ATU) for sofosbuvir, a compound from Gilead that is nearing approval, for transplanted people, people awaiting a liver transplant and cirrhotic patients with no other treatment options since the drug appears to be safe and effective for these populations.

But Gilead has refused to provide sofosbuvir to some of the people with the most urgent need : patients with late-stage cirrhosis (Child-Pugh B or C).

For their refusal, Gilead argued that it would be unfair to provide access only to patients in France. We do not accept this reason.

Gilead filed a European marketing application for sofosbuvir in April 2013. Although there are patients throughout Europe who need early access to sofosbuvir, many other countries do not have the legal or regulatory framework to provide early access. If Gilead provides sofosbuvir in France, where the system already exists, it will pave the way for desperately ill patients and their advocates in other countries to gain access. A European initiative could allow early access programs without delaying the provision of sofosbuvir in the countries with adequate regulatory and medical agencies.

It is cruel to withhold potentially life-saving treatment from the patients who meet the clinical criteria for being most likely to benefit from it, or die without it.

In addition, Gilead has much to gain by providing sofosbuvir through early access programs. Scientific data can be collected in patients with the most urgent need, who are also likely to be the first to receive the drug when it will be approved. Data from early access programs can be used to determine the safest and most effective way to treat HCV in people who need it most. For example, the CUPIC study (French ANRS) provided critical information on which cirrhotic patients were most likely to benefit—or be harmed by —boceprevir or telaprevir-based regimens.

If Gilead refuses to study sofosbuvir in « real life » cohorts, the opportunity to minimize harm and maximize benefits is lost.

Therefore, we ask Gilead to provide sofosbuvir NOW, for the people with urgent need, including patients with late-stage cirrhosis (Child-Pugh B or C), among whom people living with HIV or other illnesses.

To sign the letter, please go to change.org

PÉTITION ADRESSÉE À GILEAD - 26 JUILLET 2013

GILEAD REFUSE DE DONNER UN TRAITEMENT A DES PERSONNES GRAVEMENT MALADES DE L’HÉPATITE C

Les personnes vivant avec une hépatite C et dont l’état de santé présente une urgence doivent pouvoir bénéficier des médicaments en cours de développement et proches de leur mise sur le marché. Pour cela, il existe en France un dispositif appelé Autorisations Temporaires d’Utilisation (ATU), qui permet l’accès précoce à des médicaments susceptible de sauver des vies.

L’Agence Nationale de Sécurité du Médicament (ANSM) a accordé des ATU de sofosbuvir, une molécule développée par Gilead proche de sa mise sur le marché, à des personnes transplantées, des personnes en attente de transplantation et des personnes cirrhotiques en impasse thérapeutique. Le sofosbuvir apparaît comme sûr et efficace chez ces populations de patients.

Mais Gilead refuse de donner la molécule à certains des patients qui en ont un besoin urgent : les patients avec une cirrhose avancée (score Child-Pugh B ou C). Cet antiviral du virus de l’hépatite C leur est refusé par Gilead au motif de l’équité entre les pays européens. Nous n’acceptons pas cette justification.

Gilead a déposé une demande européenne de mise sur le marché pour le sofosbuvir en avril 2013. Bien que des patients aient besoin d’un accès précoce au sofobuvir partout en Europe, de nombreux autres pays ne possèdent pas le cadre légal ou réglementaire nécessaire. Si Gilead met le sofosbuvir à disposition en France, où le système existe déjà, cela ouvrira une voie pour obtenir l’accès précoce aux malades très avancés et aux associations de défense des patients d’autres pays d’Europe. Une initiative européenne pourrait permettre la mise en place de programmes d’accès précoce à l’échelle européenne, sans retarder la mise à disposition du sofosbuvir dans les pays ayant déjà les structures médicales et administratives adéquates.

Il est cruel de bloquer des traitements susceptibles de sauver des vies lorsque les personnes auxquelles ils sont refusés présentent des critères cliniques qui montrent qu’elles ont une très forte probabilité d’en retirer un bénéfice, ou de mourir sans.

De plus, Gilead a beaucoup à gagner en fournissant le sofosbuvir par le biais de programmes d’accès précoce. Des données scientifiques peuvent ainsi être collectées chez des patients qui en ont un besoin urgent, dont il est probable qu’ils seront aussi les premiers à recevoir le produit quand il sera approuvé.

Les données issues de programmes d’accès précoce (ou compassionnel) peuvent être utilisées pour déterminer les façons les plus sûres et les plus efficaces de traiter le VHC chez les personnes qui ont le plus besoin d’un traitement. Par exemple, la cohorte ANRS CUPIC a fourni des informations essentielles pour comprendre quels patients cirrhotiques étaient les plus susceptibles d’aller mieux- ou moins bien – avec des traitements basés sur le boceprevir ou le telaprevir.

Si Gilead refuse d’étudier le sofosbuvir « dans la vraie vie », l’occasion est perdue de minimiser les dommages et de maximiser les bénéfices.

C’est pourquoi nous demandons à Gilead de donner le sofosbuvir MAINTENANT aux personnes qui en ont le besoin le plus urgent, y compris celles avec une cirrhose avancée (Child-Pugh B ou C), parmi lesquelles certaines vivent avec le VIH ou une autre maladie.

Pour signer la pétition, merci d’aller sur change.org

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TRT-5 : Actions Traitements, Act Up-Paris, Act Up-Sud Ouest, AIDES, ARCAT, Dessine-Moi Un Mouton, Nova Dona, Sida Info Service, SolEnSi

CHV : Actif Santé, Actions Traitements, ARCAT, Association Française des Hémophiles (AFH), ASUD, CIGaLes, Nova Dona, Sida Info Service / Hépatites Info Service, SOS Hépatites, Transhépate

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Activists demand cheaper Hepatitis C drugs

The Jakarta Post, Jakarta | National | Tue, July 30 2013, 2:24 PM

A group of 14 non-governmental organizations running a campaign titled “People living with HIV/AIDS (ODHA) have a right to health” signed an online petition urging a drug manufacturer to offer Hepatitis C drugs at lower prices.

The petition launched via public campaign platform change.org is aimed at urging Roche Indonesia to immediately cut the prices of Hepatitis C drugs, the patent of which belongs to it parent Swiss multinational pharmaceuticals company.

In Indonesia, the official figure of people with Hepatitis C is estimated at 7 million, although the actual figure is likely higher due to low the awareness of the need to have a Hepatitis C test. The high cost of the test aggravates the problem.

For people living with HIV/AIDS, Hepatitis C infection has become a particular source of concern because co-infection of HIV and hepatitis C virus (HCV) exacerbates their condition and can lead to death.

The campaign’s public campaigner, Ayu Oktariani, said many ODHA managed to survive and were still healthy because the government provided HIV-infected people with anti-retroviral drugs for free.

“But ODHA co-infected with Hepatitis C makes their life expectancy lower because in Indonesia, Hepatitis C medication is costly,” said Ayu in a statement made available to The Jakarta Post, on Tuesday.

Currently, Hepatitis C medication costs around Rp 25 million (US$2,425) per month, with medication until recovery costing more than Rp 250 million per patient.

“The role of our government in regulating the trade of pharmaceuticals is still very weak. As a result, multinational companies can set the prices of drugs as they like,” said Indonesia AIDS Coalition executive director Aditya Wardhana. (ebf)

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Prices of treatment are killing patients with hepatitis C - a protest action in Russia

29/07/2013

On 24 July 2013 a protest action was carried out in Moscow in front of the Ministry of health of Russia. Activists of the "Patients’ control" came to officials with the requirement to force manufacturers of hepatitis C drugs to decrease prices. The protest took place under the slogans: "There are 5 million people with hepatitis C in Russia", "Treatment costs 500,000 rubles", "Prices Roche and Merck are killing us", "Force Roche and Merck to lower prices".

The same day activists of the "Patients’ control" held pickets at the offices of pharmaceutical companies Roche and Merck and sent letters to them demanding price reductions for hepatitis C treatment.

The prices of the main component of HCV treatment - pegylated interferon – are constantly high for the last 15 years. There are only two major manufacturers of pegylated interferons in the world - Roche and Merck.

“As for today 5 million people are affected by hepatitis C in Russia. Not everyone can afford Hepatitis C treatment. People are getting into debt, sometimes they are forced to sell their homes to buy treatment. We have repeatedly asked the manufacturers to lower prices, but haven’t received any reply. Our last hope - that the new composition of the Ministry of Health will hear us and will take drastic measures to ensure affordable treatment - namely, force companies to decrease prices”, - says Andrey Skvortsov, leader of “Patients’ control” movement.

"Hepatitis C is curable", - says Alexei Mikhailov, activist. "If we cure all people the epidemic would stop. If prices are reduced the state could provide treatment to more people, save the budget and, thus, more people could afford to buy life-saving drugs".

Russia is not the only country where activists call on the manufacturers of pegylated interferon to cut prices. In anticipation the International Hepatitis Day similar events take place or will take place in Ukraine, Georgia, Armenia, India, Thailand, Moldova, Latvia, the United States and other countries.

For information:

The average price of hepatitis C treatment (48 weeks of pegylated interferon in combination with ribavirin) in the commercial market in Russia is more than half a million of rubles (~$15.000) while the drugs do not always allow the patient to fully recover from a virus and have a number of serious side effects.

Because of the very high cost of HCV treatment the state provides with treatment an extremely small number of patients: according to the independent patients monitoring, the federal program in 2012 covered less than 4,000 patients.

Source

Assessment of health-related quality of life predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C

J Gastroenterol Hepatol. 2013 Jul 22. doi: 10.1111/jgh.12337. [Epub ahead of print]

Matsushita H, Ikeda F, Iwasaki Y, Seki H, Nanba S, Takeuchi Y, Moritou Y, Yasunaka T, Onishi H, Miyake Y, Takaki A, Nouso K, Yamamoto K.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama.

Abstract

BACKGROUND: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin, in addition to IL28B polymorphisms.

METHODS: The present study enrolled 228 CHC patients, and assessed their HRQOLs prospectively with the 36-item short-form health survey.

RESULTS: The patients with chronic hepatitis C have lower physical HRQOL status than the general population (P = 0.037, the Z test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and ribavirin than the non-SVR group (P = 0.031, the Mann-Whitney U test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score ≤400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable SNP type of IL28B, and HCV serotype 2. The patients with low HRQOL score will had significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045).

CONCLUSIONS: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and ribavirin independently from IL28B polymorphism.

This article is protected by copyright. All rights reserved.

KEYWORDS: Interferon, QOL, and HCV

PMID: 23869873 [PubMed - as supplied by publisher]

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