October 31, 2013

Sofosbuvir: ATU French cohort is in place, but limited

This article has been translated from French to English

Posted by Renaud Persiaux on October 30, 2013, 1:18:03 p.m

The temporary use authorization (ATU) of sofosbuvir, a new drug against HCV developed by Gilead, opens in France on October 17. However, it is limited to situations of pre-and post-liver transplant, while the laboratory dramatically restricted access to the drug under the nominative ATU.

Hépatite chronique virale C.

Sought for months by collective TRT-5 (which AID is a member) and the group of viral hepatitis (CHV), this cohort ATU has finally opened, as expected, there is a few days. However, despite the association pressure and the desire of the French drug agency (which he said she lengthy negotiations with the laboratory broader criteria), it is clear that access is restricted to persons in the emergency treatment of extreme situation.

In fact, can only benefit from the new drug people "on the waiting list for a liver transplant and require treatment to prevent re-infection with HCV," or "underwent liver transplantation and have a recurrence of infection with HCV, aggressive, resulting in a worsening of liver disease with a life expectancy of less than 12 months in the absence of treatment. " It is the physician of the person making the request of ATU. The ATU is open to people co-infected HIV / HCV.

Protocol for therapeutic use ...

The "protocol for therapeutic use and information collection" is downloadable on the website of the National Security Agency of the drug (MSNA). It provides that, in the context of this ATU, the sofosbuvir (400 mg, 1 tablet daily, with or without food) is used in combination with ribavirin (1000-1200 mg) and pegylated interferon if its use is possible (it is against-indicated in patients with decompensated cirrhosis). Pre-transplant treatment is until liver transplantation without exceeding 11 months (48 weeks) of treatment. If relapse occurs before transplantation, a restatement may be considered. Post-transplantation, the treatment is for 6 months (24 weeks).

... And information gathering

If the first goal of the ATU is to save lives, the collection of information set up is very useful, both to evaluate the effectiveness in these difficult people to deal with the importance of adverse effects. And, as for the person himself than for other patients. The MSNA has also worked with the ANRS (National Agency for Research on AIDS and Viral Hepatitis) to set up an additional collection of information through the cohort CUPILT. The inclusion in this cohort will be offered to people receiving ATU.
The price of the drug in the context of this cohort ATU has not yet been reported by the laboratory.

What interactions?

According to the summary of product characteristics, we know that the particular sofosbuvir can be used without dose adjustments with:
● the following anti-suppressing drugs: cyclosporine (carefully) and tacrolimus
● methadone (opioid substitution treatment) ,
● the following anti-HIV drugs: efavirenz (Sustiva), emtricitabine and tenofovir (Truvada), rilpivirine (Edurant, Eviplera), darunavir / ritonavir (Prezista / Norvir), raltegravir (Isentress).
However, it should not be used with products containing St. John's wort, a plant sometimes used in the treatment of mild to moderate depression and mood disorders.

Nominative ATU

For people who do not fall within the criteria of the cohort ATU, but the treatment can not be delayed, the doctor can make a nominative ATU request from the MSNA.

Unfortunately, despite pressure from associations, on the hundred nominative ATU requests granted, the Gilead has actually supplied the product to a third of people, systematically refusing to cirrhotic individuals. And even though the emergency treatment and the possibility of a real clinical benefit status had yet been validated by the MSNA.

Enough to arouse the anger of the TRT-5 and CHV which launched at the beginning of the summer, a petition that gathered more than 850 signatures. But the firm, between the decisions of experts convened by the public agency, of its own experts, remained deaf to this request, endangering the health or life of many people.

The AMM expected in January

Meanwhile, drug evaluation is well underway. In the United States, the drug has received a positive opinion on October 25 experts from the Food and Drug Administration (unanimously), the U.S. marketing authorization is expected on December 8. In Europe, after an expedited review procedure, the decision of the experts from the European Medicines Agency (EMA) is expected for November 6, for a European marketing authorization should be formally granted by the European Union in January 2014.

Therefore, the product should be available soon for those falling within the scope of the marketing authorization and do not have appropriate therapeutic alternative. However, the new legislation, introduced in the bill funding the 2014 social security could delay access. In its initial version, the section 39 restricted access, despite the issue of the marketing, to situations of ATU established before the AMM until the final redemption price was not published in the "Official Gazette" , which takes an average of one year. The version finally adopted Friday by the National Assembly, under pressure from AIDS, the CISS (interassociative Collective Health), TRT-5 SOS Hepatitis and AFM-Telethon, discusses the criteria of MA, which is a half-victory. However, it states that the lack of appropriate alternative therapy should be assessed by the Authority for Health (HAS), without specifying a time limit for rendering the decision. Which, given the usual time decision venerable institution is somewhat disturbing. The examination of the text will be in the Senate from 12 November 2013.

Country: France

Source

Idenix Nucleotide/NS5A Update

Provided by NATAP

FOR IMMEDIATE RELEASE

IDENIX PHARMACEUTICALS REPORTS
THIRD QUARTER AND NINE MONTH 2013 FINANCIAL RESULTS
AND PROVIDES HCV PIPELINE UPDATE

- Enrollment initiated for a phase I/II clinical trial for IDX21437, a next-generation uridine nucleotide prodrug inhibitor for the treatment of hepatitis C virus infection (HCV)

- Initiation planned for HELIX-2 combination study in collaboration with Janssen Pharmaceuticals, Inc. including pan-genotypic HCV NS5A inhibitor, samatasvir

- Idenix to host conference call / webcast at 4:30 p.m. ET today

CAMBRIDGE, Mass., October 30, 2013 -- Idenix Pharmaceuticals, Inc. (NASDAQ: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today reported unaudited financial results for the third quarter ended September 30, 2013.

HCV Pipeline Review

Nucleotide Inhibitor Program

· IDX21437, a next-generation uridine nucleotide prodrug inhibitor, has received approval to enter clinical trials in Canada and Belgium. Idenix has initiated enrollment for the healthy volunteer portion of a phase I/II clinical trial. Extensive preclinical testing for IDX21437 demonstrated favorable antiviral activity across genotypes 1-6 and a safety profile which supported advancement into clinical trials.

· Idenix is conducting additional preclinical work as requested by the United States Food and Drug Administration for IDX20963, a uridine nucleotide prodrug candidate.

Samatasvir (IDX719), NS5A Inhibitor Program

All patients (n=63) have completed enrollment in Part A of the phase II 12-week HELIX-1 clinical trial evaluating an all-oral, direct-acting antiviral (DAA) HCV combination regimen of samatasvir, Idenix's once-daily pan-genotypic NS5A inhibitor, and simeprevir, a once-daily NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, and ribavirin in treatment-naïve, non-cirrhotic, genotype 1b or 4 HCV-infected patients. SVR4 data for patients in Part A of the study are anticipated to be available in the fourth quarter of 2013. Part B of the ongoing HELIX-1 clinical trial includes exploratory cohorts which have been added to evaluate the safety and antiviral activity of a 25 mg dose of samatasvir in genotype 1b-infected patients and of a 100 mg dose of samatasvir in genotype 6-infected patients.

· Idenix is planning to initiate a second 12-week phase II clinical trial in collaboration with Janssen Pharmaceuticals, Inc., HELIX-2, which will evaluate the 3-DAA combination of samatasvir, simeprevir and TMC647055, a once-daily NS5B non-nucleoside polymerase inhibitor boosted with low-dose ritonavir being developed by Janssen R&D Ireland, with and without ribavirin in genotype 1-infected patients who are either treatment-naïve or have previously relapsed after treatment with pegylated interferon and ribavirin.

"A key objective for our development teams has been to commence a clinical trial for our nucleotide prodrug program this year," said Ron Renaud, Idenix's President and Chief Executive

Officer. "Based on the differentiated profile we've seen in our preclinical research, we believe IDX21437 has strong potential to be a key component of a fixed-dose all-oral pan-genotypic regimen, specifically in combination therapy with our NS5A inhibitor."

Mr. Renaud continued, "We are also pleased with the progress of the phase II program for samatasvir. The ongoing HELIX-1 study is building the safety and antiviral efficacy profile for samatasvir as part of a 12-week all-oral treatment regimen and supporting future combination studies, including the 3-DAA HELIX-2 study, as well as the evaluation of a pan-genotypic combination with IDX21437 in 2014."

CONFERENCE CALL AND WEBCAST INFORMATION

Idenix management will host a conference call at 4:30 p.m. ET today. To access the call, please dial (877) 640-9809 (U.S./Canada) or (914) 495-8528 (International) and enter passcode 90503423. A live webcast will be available through the Investor section of the Idenix website at www.idenix.com under "Events & Presentations". The archived webcast will be available for two weeks following the call on the Idenix website.

---------------------------------------

Idenix HCV Pipeline/ uridine nucleotide prodrug inhibitor IDX21437

Excerpted from yesterday's company conference call, seeking alpha.com: we're happy to tell you today that a novel next-generation uridine nucleotide prodrug inhibitor IDX21437 has received approval to enter clinical trials in both Canada and Belgium. Based on its promising early profile IDX21437 was selected as one of our lead drug candidates resulting from our comprehensive nucleotide discovery effort that we have been discussing over the past few years.

this is really our first public announcement. We've been working as you can imagine with done multiple passing with Ð first with 963, but we had this going on in parallel and we've talked about that we continue to look for other potent and safe nucleus type pro-drug candidates and that continues to go on as aggressively as we have ever been.

I'm pleased to report important progress with our HCV programs. First, we're happy to tell you today that a novel next-generation uridine nucleotide prodrug inhibitor IDX21437 has received approval to enter clinical trials in both Canada and Belgium. Based on its promising early profile IDX21437 was selected as one of our lead drug candidates resulting from our comprehensive nucleotide discovery effort that we have been discussing over the past few years.

Extensive preclinical testing demonstrated a clean safety profile including no cardiac or genotoxicity signals. This along with favorable antiviral activity across genotypes 1 through 6 supported the advanced of this compound into the clinic. We have initiated enrollment for the healthy volunteer portion of a Phase I/II study, which will evaluate the safety and pharmacokinetics of single doses of IDX21437 and we anticipate dosing to begin next week.

In parallel sequential single doses of IDX21437 will be administered to HCV infected patients. The single dose safety PK and antiviral activity will come from the selected doses for the seven-day proof-of-concept portion of the study which will evaluate patients in fact through genotypes 1 through 6 and cirrhotic HCV genotype 1 infected patients.

For IDX2963 an additional uridine nucleotide prodrug candidate we are conducting further preclinical work in response to the FDA's request related to the positive in vitro Ames test result observed in our IND enabling studies, prior to the initiation of clinical trials. A key objective for our development teams has been to commence a clinical trial for our nucleotide prodrug program this year.

With the rapidly evolving HCV treatment landscape, we know the bar for safety is high. And based on a differentiated and competitive profile we've seen in our preclinical research we believe IDX21437 has strong potential to be a key component of a fixed dose all-oral pan-genotypic regimen specifically in combination with samatasvir our NS5A inhibitor. Turning to samatasvir, this program has also shown good progress over the last several months.

We have completed enrollment with 63 patients in Part A of the Phase II 12 week HELIX-1 clinical trial evaluating an all-oral direct acting antiviral or DAA HCV combination regimen, this regimen includes samatasvir and simeprevir a once daily NS3/4A protease inhibitor jointly developed by Janssen and METAVIR and ribavirin and treatment-naïve, non-cirrhotic, genotype 1b or 4 HCV-infected patients, [indiscernible] data for all patients in Part A of the study are anticipated to be available late in the fourth quarter of 2013. Part B of the HELIX-1 clinical trial includes exploratory cohorts which have been added to evaluate the safety in anti-viral activity of a 25 milligram dose of samatasvir and genotype 1b infected patients and a 100 milligram dose of samatasvir and genotype 6 infected patients, Idenix is also planning to initiate a second 12 week Phase II clinical trial in collaboration with Janssen, this trial called HELIX-2 will evaluate the three-DAA combination of samatasvir, simeprevir and TMC647055 a once-daily NS5B non-nucleoside polymerase inhibitor boosted with low dose ritonavir, being developed by Janssen with and without ribavirin.

This trial will include genotype 1 infected patients who are either treatment naïve or previously relapsed after treatment with pegylated interferon and ribavirin. The ongoing HELIX-1 study is building the safety and antiviral efficacy profile for samatasvir as part of a 12 week all-oral treatment regimen and supporting future combination studies including the three-DAA HELIX-2 study as well as the evaluation of a pan-genotypic combination with IDX21437 in 2014. 963 is at this point it's kind of the back up to 437? That's probably not unreasonable given that our intention is to begin dosing patients with 437 next week.

I think with regard to 963, as you recall, we reported earlier in the summer of this year that we had a positive Ames test, a positive TA1535 with 963. We're continuing to evaluate that toc [ph] signal before we put it into the clinic. So as that data becomes available we'll make it available, but at this point we don't have any additional update there.

Can you maybe give us a sense of the timeline for those additional studies? They're ongoing. We are continuing to work on it, but 437 emerged with a very strong profile and in terms of it being a clinical candidate that is now the lead candidate and that's where we're focusing a significant part of our attention. We will continue to look at the preclinical profile of 963 and try to solve what we saw earlier this summer, what we reported on earlier this summer and as I said, when that becomes available I don't have a specific timing on, but when it becomes available we'll have that focus now.

Doug Mayers: This is a very clean molecule. We done significant genotoxicity testing and then so fast we were line up very cleanly against each other in this testing. We had good safety margins as Ron mentioned it has a clean genotype profile and we did extensive cardio attacks with biomarkers, Actos in the monkeys baseline in one month, and basically we seen nothing in the cardiac profile suggest any potential for injury.

It is one of our new generation, you are dealing nucleotide prodrug. So it does have high triphosphate and when we factor that all in, we think we will able to get very good activity and it does significantly lower than that for [indiscernible] currently in the clinic when we testing that over next of few months.

Source

A Study of an Investigational Treatment Regimen of Daclatasvir(DCV)+Asunaprevir(ASV)+BMS-791325 in a Fixed Dose Combination(the Triple Regimen)With or Without Ribavirin(RBV)for 12 Weeks for the Treatment of Chronic Hepatitis C Virus(HCV)Genotype 1 Infection in Subjects With Compensated Cirrhosis

This study is not yet open for participant recruitment.

Verified October 2013 by Bristol-Myers Squibb

Sponsor: Bristol-Myers Squibb

Information provided by (Responsible Party): Bristol-Myers Squibb

ClinicalTrials.gov Identifier: NCT01973049
First received: October 25, 2013
Last updated: October 30, 2013
Last verified: October 2013
History of Changes

Purpose

To demonstrate the effectiveness of Triple fixed dose combination with or without Ribavirin in treatment naive cirrhotic subjects.

Condition Intervention Phase
Hepatitis C Virus
Drug: Daclatasvir
Drug: Asunaprevir
Drug: BMS-791325
Drug: Ribavirin
Drug: Placebo matching Ribavirin
Phase 3
Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3 Evaluation of a Daclatasvir/Asunaprevir/BMS-791325 Fixed Dose Combination in Subjects With Genotype 1 Chronic Hepatitis C and Compensated Cirrhosis

Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:

  • Proportion of treated subjects in each of the naive arms with sustained virologic response (SVR12) [ Time Frame: Post treatment 12 week ] [ Designated as safety issue: No ]

    SVR12 is defined as Hepatitis C virus ribonucleic acid (HCV RNA) < Limit of Quantification (LOQ) target detected or target not detected (LOQ TD/TND)

Secondary Outcome Measures:

  • Proportion of treated subjects in each of the experienced arms with SVR12 [ Time Frame: Post treatment 12 Week ] [ Designated as safety issue: No ]
  • Proportion of subjects in each arm who achieve HCV RNA < LOQ TD/TND [ Time Frame: Weeks: 1, 2, 4, 6, 8, and 12; Post treatment Weeks 4 (SVR4), 8 (SVR8) and 24 (SVR24) ] [ Designated as safety issue: No ]
  • Proportion of subjects in each arm who achieve HCV RNA < LOQ TND [ Time Frame: Weeks: 1, 2, 4, 6, 8, and 12; Post treatment Weeks 4 (SVR4), 8 (SVR8), 12 (SVR12) and 24 (SVR24) ] [ Designated as safety issue: No ]
  • Safety as measured by frequency of Serious Adverse Events(SAEs)and discontinuations due to Adverse Events(AEs) [ Time Frame: Up to end of treatment (week 12) + 7 days ] [ Designated as safety issue: Yes ]
  • Proportion of subjects with anemia defined as Haemoglobin(Hg) < 10 g/dL Events(AEs) [ Time Frame: Up to end of treatment (week 12) + 7 days ] [ Designated as safety issue: Yes ]
  • Differences in rates of selected Grade 3 - 4 laboratory test result abnormalities [ Time Frame: Up to end of treatment (week 12) + 7 days ] [ Designated as safety issue: Yes ]
  • Proportion of subjects achieving SVR12 associated with HCV geno subtype 1a vs 1b [ Time Frame: Post treatment 12 Week ] [ Designated as safety issue: No ]
  • Proportion of subjects in each arm achieving SVR12 associated with IL28B rs12979860 single nucleotide polymorphism(SNP) status (CC genotype or non-CC genotype) [ Time Frame: Post treatment 12 Week ] [ Designated as safety issue: No ]

Estimated Enrollment: 200
Study Start Date: December 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: A1: DCV/ASV/BMS-791325+Placebo matching RBV (naive)

Triple fixed dose combination (Daclatasvir 30 mg, Asunaprevir 200 mg, BMS-791325 75 mg) tablet orally twice a day for 12 weeks

Placebo matching Ribavirin 0mg tablet orally twice a day for 12 weeks

Drug: Daclatasvir
Other Name: BMS-790052
Drug: Asunaprevir
Other Name: BMS-650032
Drug: BMS-791325 Drug: Placebo matching Ribavirin
Experimental: A2: DCV/ASV/BMS-791325 + RBV (naive)

Triple fixed dose combination (Daclatasvir 30 mg, Asunaprevir 200 mg, BMS-791325 75 mg) tablet orally twice a day for 12 weeks

Ribavirin 200mg tablet orally twice a day for 12 weeks

Drug: Daclatasvir
Other Name: BMS-790052
Drug: Asunaprevir
Other Name: BMS-650032
Drug: BMS-791325 Drug: Ribavirin
Other Name: Ribasphere®
Experimental: A3: DCV/ASV/BMS-791325+Placebo matching RBV (experienced)

Triple fixed dose combination (Daclatasvir 30 mg, Asunaprevir 200 mg, BMS-791325 75 mg) tablet orally twice a day for 12 weeks

Placebo matching Ribavirin 0 mg tablet orally twice a day for 12 weeks

Drug: Daclatasvir
Other Name: BMS-790052
Drug: Asunaprevir
Other Name: BMS-650032
Drug: BMS-791325 Drug: Placebo matching Ribavirin
Experimental: A4: DCV/ASV/BMS-791325 + RBV (experienced)

Triple fixed dose combination (Daclatasvir 30 mg, Asunaprevir 200 mg, BMS-791325 75 mg) tablet orally twice a day for 12 weeks

Ribavirin 200mg tablet orally twice a day for 12 weeks

Drug: Daclatasvir
Other Name: BMS-790052
Drug: Asunaprevir
Other Name: BMS-650032
Drug: BMS-791325 Drug: Ribavirin
Other Name: Ribasphere®

Detailed Description:
Masking is Double blind for RBV: two or more parties are unaware of the intervention assignment.

Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

  • Subjects chronically infected with HCV genotype 1
  • Subjects with compensated cirrhosis
  • HCV RNA ≥ 10,000 IU/mL at screening
  • Treatment-naïve subjects with no previous exposure to an interferon formulation (ie, IFNα, pegIFNα), RBV, or HCV Direct Acting Antivirals (DAA) (protease, polymerase inhibitor, etc.)
  • Treatment-experienced subjects are eligible including exposure to anti-HCV agents of a mechanistic class other than those contained in the DCV/ASV/BMS-791325 triple regimen is permitted. Examples of permitted agents include, but are not limited to nucleoside/nucleotide inhibitors of nonstructural protein 5B (NS5B) polymerase, inhibitors of cyclophilin, or inhibitors of microRNA.

Exclusion Criteria:

  • Subjects without cirrhosis
  • Liver or any other organ transplant
  • Current or known history of cancer within 5 years prior to screening
  • Documented or suspected hepatocellular carcinoma(HCC)
  • Evidence of decompensated liver disease including, but not limited to, radiologic criteria, a history or presence of ascites, bleeding varices, or hepatic encephalopathy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01973049

Sponsors and Collaborators
Bristol-Myers Squibb

Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb

More Information

No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01973049     History of Changes
Other Study ID Numbers: AI443-113, 2013-002458-66
Study First Received: October 25, 2013
Last Updated: October 30, 2013
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: National Health and Medical Research Council
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
United States: Institutional Review Board
Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Fibrosis
Hepatitis C, Chronic
Liver Cirrhosis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Pathologic Processes
Ribavirin
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 30, 2013

Source

Medicare considers coverage of hepatitis C screening

By: MARY ELLEN SCHNEIDER, IMNG Medical News

09/10/13

Medicare officials will spend the next several months deciding whether to cover screening for hepatitis C, after other public health agencies recommended one-time screening for baby boomers.

The agency is scheduled to issue a formal proposal for possible screening coverage in March 2014 and make a final decision in June 2014.

In a memo issued Sept. 5, officials at the Centers for Medicare and Medicaid Services (CMS) asked the public for input. Agency officials are specifically interested in clinical studies and other evidence showing that screening leads to an improvement in either short- or long-term outcomes.

Initial public comments from physicians and other health care providers were supportive of coverage. The commenters wrote that they favored screening because the condition is often asymptomatic and because there are effective treatments available.

Earlier this year, the United States Preventive Services Task Force (USPSTF) recommended that physicians offer one-time screening for hepatitis C virus (HCV) to baby boomers born between 1945 and 1965. The task force pointed to recent data showing that about three-fourths of HCV patients in the United States were born between 1945 and 1965.

A risk-based approach alone could miss a substantial number of HCV cases in the birth cohort because of lack of patient disclosure of or knowledge about risks. The one-time screening offers a chance to identify infected patients at the early stage of disease before they develop complications from liver damage, according to the USPSTF.

While age-based screening is less efficient than risk-based screening, the number of Americans who would likely benefit is greater than the number who would potentially benefit from risk-based screening, the USPSTF concluded. The task force gave the evidence associated with the recommendation a Grade B.

The Centers for Disease Control and Prevention has also endorsed universal, one-time screening of baby boomers for HCV. In August 2012, the CDC recommended an age-based approach to screening, citing the limited effectiveness of risk-based screening alone, the rising morbidity and mortality associated with HCV, and advances in treatment (MMWR 2012;61:1-18).

Comments to the national coverage analysis can be made until Oct. 5.

mschneider@frontlinemedcom.com

On Twitter @MaryEllenNY

Source

Studies in monkeys may be next step in search for HIV cure

By Julie Steenhuysen

CHICAGO | Wed Oct 30, 2013 4:22pm EDT

CHICAGO (Reuters) - A powerful infusion of HIV-fighting antibodies beat back a potent form of the virus in monkeys and kept it at bay for weeks, U.S. government scientists and a team led by Harvard University found, offering a potential next step in the battle against human HIV.

The two studies, published on Wednesday in the journal Nature, involve the use of rare antibodies made by 10 percent to 20 percent of people with HIV that can neutralize a wide array of strains.

Such antibodies latch on to regions of the virus that are highly "conserved," meaning they are so critical to the virus that causes AIDS that they appear in nearly every HIV strain.

By attaching to the virus, they make it incapable of infecting other cells.

In the past decade, scientists have tried to make vaccines that could coax the body into making these same types of HIV-specific antibodies. But finding a way to make these complex antibodies has been challenging.

"These are the Ferraris of antibodies," said Dr Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, who led the larger of the two studies.

"Nobody, including ourselves, has been able to develop a vaccine that can generate immune responses that are even close."

In the studies, the teams instead tested these antibodies as a potential treatment for people infected with HIV. Both teams used rhesus monkeys with the Simian-human immunodeficiency virus, a monkey version of HIV.

Barouch's team studied the rare antibodies harvested from HIV-infected humans that were grown in large batches and could be infused at high doses. The team tested different combinations of antibodies in 35 infected monkeys.

The one that worked best was an antibody called PGT121.

"Basically, that antibody, given either alone or in combination, resulted in a dramatic effect," Barouch said.

PEOPLE NEXT?

The antibodies reduced the virus to undetectable levels in 16 of 18 monkeys within seven days, and kept it there for one to three months. In three animals with the lowest viral load at the time of treatment, the virus did not resurface.

A smaller study by scientists at the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health, showed similar results.

Both teams say the approach should now be tested in people.

"All the data to date exist in the monkey model. We need to evaluate how these antibodies perform in humans infected with HIV," Barouch said.

His team did not test the antibody treatment in combination with antiretroviral treatments, the standard HIV drugs used by thousands of patients to control the virus.

But Barouch thinks such combinations would make sense because both treatments have different mechanisms of action.

While antiretroviral drugs only attack the machinery used by the HIV virus to make copies of itself, antibodies can directly attack free virus particles in the blood as well as in cells that are infected with the virus.

Barouch said researchers and drug companies are interested in the results, which could offer a next step toward a cure for the infection that causes AIDS.

In an interview on the Nature website, Dr Louis Picker of Oregon Health & Science University, who wrote a commentary on the research, said the study is "a baby step towards cure."

He said antiretroviral treatments, such as those made by Gilead Sciences and GlaxoSmithKline, reduce the ability of the HIV virus to replicate in the body by maybe 99.9 percent, but not 100 percent.

"This treatment on top of it may bring it to 100 percent," he said.

Still unclear is whether antibodies will also attack latent HIV cells that hide in the body and allow the virus to reappear when treatment stops.

"We haven't shown any cures," Barouch said. "However, we have shown the antibodies act not only on the virus in the bloodstream, but can also substantially reduce virus in tissues such as lymph nodes and the gut. Future research with these antibodies will help determine whether they might be part of a virus eradication or cure strategy."

(Reporting by Julie Steenhuysen; Editing by Xavier Briand)

Source

Provided by Infection Control Today

October 31, 2013

More than half of chronic hepatitis C patients studied in a new research project led by Henry Ford Hospital were not treated for the potentially fatal disease, either because they couldn't withstand current therapies or because they, or their doctors, were waiting for new treatments.

In a second, related study, Henry Ford researchers found that while the disease is not yet curable, there is a significant "lost opportunity" for hepatitis C patients to achieve the current best result of treatment.

Both studies are being presented at the annual meeting of the American Association for the Study of Liver Diseases being held in Washington, DC, Nov. 1-5.

Stuart C. Gordon, M.D., director of the Hepatology section at Henry Ford, and lead author of the first study, said it was launched because of a lack of information about the subject.

"Limited data exist concerning the clinical disposition of U.S. patients with chronic hepatitis C infection, including the reasons for lack of antiviral treatment," Dr. Gordon says. "Our goal was to add to that data."

The team collected electronic health records from four large American health systems of patients with confirmed chronic hepatitis C, a viral infection that progressively scars the liver and eventually destroys the organ and its vital functions.

Of these 4,271 patients diagnosed with the infection and still alive through the end of 2011, the median age was 57; 57 percent were male; 29 percent were black and 97 percent were insured.

• 543, or 12.7 percent, had previously achieved a sustained virologic response (SVR), meaning the hepatitis C virus was suppressed to the point that it could no longer be detected in their blood for six months after anti-viral treatment.

• 110, or 2.6 percent, were currently on anti-viral therapy.

• Of the remaining 3,618 patients, 12 percent had never been followed up within the health care system, despite clinical confirmation that they had chronic hepatitis C.

• The majority, 55 percent, were not being treated, either because of "absolute contraindications" to current therapy – meaning the risk of available treatment is too high – or because either the patient or physician were waiting for newer therapies.

• Another 12 percent of patients had chosen not to start treatment, despite a doctor's recommendation to do so.

"These results confirm that only a small proportion of chronic hepatitis C patients in American healthcare systems who were still being followed at the end of 2011 had achieved an SVR with available antiviral regimens," Gordon says. The second study sought to identify "lost opportunities" to treat hepatitis C patients and achieve SVR, now the closest thing to a "cure" for the disease.

"We looked at data regarding testing for chronic hep C, patient referral, patient visits and the start of treatment," explains Kimberly Ann Brown, MD, division head of gastroenterology at Henry Ford Hospital and lead author of the study's findings.

"In addition," Brown says, "we considered patient age, race, gender, income, marital status, psychiatric diagnoses and the number of comorbidities, or co-existing diseases."

The findings showed that of the 458 patients identified with a positive hepatitis C antibody, only 117 received confirmatory testing, were referred to a specialist and presented to the office for a visit. Of the 117 patients who came for the specialty visit, only 21, or 17.9 percent, were felt to be appropriate treatment candidates.

"This data speaks to the significant "lost opportunity" we have, not only in identifying patients with hepatitis C in our community, but also in providing them with appropriate treatment options," says Brown.

Source: Henry Ford Health System

Source

Provided by Infection Control Today

October 31, 2013

New drug therapies offer promise to some hepatitis C sufferers whose transplanted livers are threated by a recurrence of the disease, including some patients who have had no treatment options.

The encouraging findings are contained in two new studies by a collaboration of researchers across the U.S. – as well as in Spain and New Zealand – including Dilip Moonka, MD, medical director of Liver Transplant at Henry Ford Hospital. Both studies are being presented at the annual meeting of the American Association for the Study of Liver Disease being held in Washington, D.C., Nov. 1-5.

Both studies focused on the experimental anti-viral drug sofosbuvir, a direct-acting oral medication that may take the place of injectable interferon, which causes severe side effects in some patients.

The Food and Drug Administration is expected to decide in early December whether to approve its use for treating hepatitis C. Last week, the Antiviral Drugs Advisory Committee of the FDA voted unanimously in support of approval for sofosbuvir-based therapies for the treatment of chronic hepatitis C.

Chronic hepatitis C, which afflicts an estimated 3 million people in the U.S. alone, is a blood-borne viral disease that leads to scarring and deterioration of the liver. It is particularly insidious because patients usually don't develop symptoms until the scarring – or cirrhosis – is well underway.

Sofosbuvir, which belongs to a class of drugs known as nucleotide analogue polymerase inhibitors, acts at the molecular level by interfering with the RNA of the hepatitis C virus.

In the first newly released study, researchers tested it as an alternative to interferon, a naturally occurring protein that plays a role in fighting viral infections, but commonly produces a range of serious side effects.

The researchers used it in combination with ribavirin, which also inhibits the hepatitis C virus by interfering with its RNA to stem the replication of the virus and slow the progression of the disease. They sought to test the drug combination's effectiveness in preventing recurrence of hepatitis C in liver transplant recipients.

A total of 61 chronic hepatitis C patients with liver cancer were enrolled in the study and given both sofosbuvir and ribavirin daily for up to 48 weeks before liver transplant. All of the patients had well-compensated cirrhosis, meaning their bodies were still functioning without too much trouble despite liver scarring.

The researchers found that the new drug combination was both safe and effective in such patients and prevented post-transplant recurrence of the hepatitis C virus in more than 60 percent of them.

In the second newly released study, researchers focused on liver transplant recipients whose severe hepatitis C recurred after surgery and who either couldn't tolerate or didn't respond to approved antiviral therapies – leaving them with no other effective treatment options.

In such cases, experimental drugs can sometimes be tested under "compassionate use" protocols.

The researchers reported that as of April, 115 patients were approved for compassionate use of sofosbuvir combined with ribavirin and/or the antiviral drug peginterferon. At the time of their report, 63 had started treatment.

After several weeks of treatment and study, the researchers concluded that patients with severe recurrence of hepatitis C after receiving transplanted livers were able to tolerate the drug regimen, which produced strong antiviral effects.

Source

HCV in Spotlight at Liver Meeting

Meeting Coverage

Published: Oct 31, 2013 | Updated: Oct 31, 2013

42604

By Michael Smith, North American Correspondent, MedPage Today

Hepatitis C will once again have center stage at the annual meeting of the American Association for the Study of Liver Diseases, which starts Friday in Washington, D.C.

The meeting begins just a week after an FDA advisory panel recommended approval of the first new direct-acting agents against the virus since 2011 -- simeprevir and sofosbuvir.

Meeting attendees will get the latest data on them -- data that is "highly anticipated," according to Gary Davis, MD, the association's secretary.

The standard therapy for hepatitis C (HCV) for many years was pegylated interferon-alfa and ribavirin -- the first an immune system booster and the second a general antiviral medication.

In 2011, the FDA approved two drugs that act against the viral protease enzyme -- telaprevir (Incivek) and boceprevir (Victrelis).

Since then, a suite of drugs has entered the pipeline, acting against various targets in the HCV genome. Among them are simeprevir (another protease inhibitor) and sofosbuvir, which is a nucleotide analog NS5B polymerase inhibitor.

Looked at together, the drugs in the pipeline hold out the promise of getting rid of interferon entirely -- a boon since the drug is regarded as both dangerous and difficult to take.

But, Davis noted, simeprevir was recommended for use in combination with interferon and ribavirin, while for some patients sofosbuvir was also recommended for use with the older drugs.

"People are waiting for interferon-free therapy," Davis told MedPage Today. Nonetheless, he added, simeprevir and sofosbuvir will "solve some of the problems we have" with HCV therapy.

Meanwhile, he said, some of the HCV medications in the pipeline have new data that will "wow" participants, although he was unable to give details in advance of the meeting.

Participants will also hear two important lectures, he said.

Nobel laureate Bruce Beutler, MD, of the University of Texas Southwestern Medical Center in Dallas, is slated to discuss genetic approaches to finding the cause of inherited diseases.

And Anthony Atala, MD, of Wake Forest School of Medicine in Winston-Salem, N.C., will discuss tissue engineering and its application to creating new organs, Davis said.

There will also be a "lot of activity" concerning fatty liver disease, Davis said. "This is becoming a huge problem and it's thought that 10% to 11 % of the U.S. population has this," he added.

Meeting participants will be able to hear talks and view posters on the mechanisms of fatty liver disease, as well as the roles played by diet and gut bacteria.

And a special lecture on drug toxicity -- delivered this year by William Lee, MD, also of University of Texas Southwestern Medical Center -- will focus on the common over-the-counter medication acetaminophen.

The meeting usually draws between 10,000 and 12,000 participants, Davis said.

Source

October 30, 2013

Gay Men Should Be Tested for Hepatitis C

Provided by The Huffington Post

Lawrence D. Mass, M.D.

Co-founder, GMHC; author, 'We Must Love One Another or Die: The Life and Legacies of Larry Kramer'

Posted: 10/30/2013 7:54 pm

Hepatitis C is the most common blood-borne infection in the U.S., and one of the most common worldwide. One in 50 Americans is infected. It accounts for more than 50 percent of all cases of end-stage liver disease and 50 percent of cases of liver cancer, and it is the reason for more than 50 percent of liver transplants. Yet it remains severely underdiagnosed. It's estimated that upwards of 75 percent of those infected remain untested and undiagnosed, as compared with 25 percent of those with HIV. More people now die from hepatitis C than from HIV.

Those of us who struggled through the early period of AIDS understand the meaning of "Silence = Death," the motto used by the AIDS activist organization ACT UP. So when hepatitis C began to emerge among MSM (men who have sex with men), the silence that ensued seemed eerily familiar. When I first started reporting on hepatitis C in gay men nearly a generation ago, the disease was already being called "the stealth epidemic," in part because of the typically long, silent progression of the disease in its chronic form, sometimes taking 20 to 30 years from acute infection to cirrhosis of the liver, but also because of the public silence about it. If people had the disease, they mostly didn't know it, and if they did have it and did know it, they didn't go public with it. Nor did those with the disease often seek treatment, which had the reputation of being prolonged, difficult and of mixed efficacy. Since the principal risk group for the disease was injection drug users, the public wasn't exactly clamoring to know more or be more involved. There was no megacelebrity out there to help galvanize public interest and support who would admit to having hep C the way that Magic Johnson came out as having HIV. How much has changed in the intervening years?

Despite newer and often highly effective treatments that are essentially curative, not much has changed in terms of public awareness and indifference. Hepatitis C remains a stealth disease. Public health officials have long resisted the call to sound the alarm for hep C as an STI (sexually transmitted infection), citing the weak transmissibility of hep C sexually. For years, they didn't even urge that the partners of those who were hep C-positive be tested. Granted that HCV hasn't shown itself to be nearly as transmissible sexually as HIV, I expressed my concerns about what seemed to be excessive cautiousness around testing recommendations -- in the gay press, for New York magazine as well as in a public health forum co-hosted by the CDC in Atlanta.1, 2 I argued that there needed to be greater awareness of and testing for hepatitis C as an STI, especially among MSM. As the call-out in New York put it, "Hepatitis C infections are spreading beyond high-risk groups, causing a few physicians to call for widespread testing. But the medical establishment is stalling. Sound familiar?"

Why was this so controversial? Why not just test everybody who might be at risk, even if that risk were "small"? The reason I was given by CDC epidemiologists and other public health officials was that urging everyone to get tested for hep C, even all MSM, could create unwarranted alarm and would be an unjustifiable expense in view of the relative minority of cases. Also, despite the increasing numbers of cases in gay men/MSM, those numbers remain "small," and it wasn't clear that other undisclosed risk factors such as injection drug use weren't responsible, since increased rates of sexual spread weren't being observed among heterosexuals.

So where do we stand with all this now? Amidst growing reports of new cases among clusters of gay men/MSM, especially in Europe, and growing numbers of cases in MSM generally, the latest review and recommendations from USPSTF (U.S. Preventive Services Task Force) from June 25, 2013, include the following:

The Task Force reviewed recent research studies on screening for and treatment of hepatitis C infection in adults. The final recommendation statement summarizes what the Task Force learned about the potential benefits and harms of screening: (1) Adults at high risk for hepatitis C infection should be screened for the infection. (2) Health care professionals should offer 1-time hepatitis C screening to adults born between 1945 and 1965.

And who are they designating as being at "high risk"?

The most important risk factor for hepatitis C infection is the use of injection drugs. Other risk factors include having had a blood transfusion before 1992, having multiple sex partners, and getting a tattoo with an unsterilized needle.

OK, so there, they've said it: "those having multiple sexual partners." But that recommendation is absent from their final, summary recommendations. There, they define those at "high risk" to be as follows:

People who use injection drugs now or have used them in the past. Having a blood transfusion before 1992 also puts a person at increased risk. Be screened only once. Some people with ongoing risk factors, such as injection drug users, need to be screened more than once.

There's no mention in these final recommendations of those having "multiple sexual partners," which would include the majority of gay men/MSM, apparently because they are more "at risk" than at "high risk." OK, but then why not designate MSM as "at risk," even if that risk is believed to be low? Clearly, public health advisories re hepatitis C testing for MSM remain unclear.

So where does all this leave us? When it comes to hepatitis C screening, gay men must once again be proactive. If you are a sexually active gay man/MSM, if you've had sex with multiple partners over time, get tested for hepatitis C. If your doctor or health care provider declines to offer the testing based on perceived low risk and unclear public health services recommendations, seek testing from another health care provider.

References:

1. Mass, Lawrence D., "C-Sick," New York, March 29, 1999.

2. "AIDS and Hepatitis C: Lessons from AIDS," from Emerging Illnesses and Society: Negotiating the Public Health Agenda, edited by Randall M. Packard et al., Johns Hopkins University Press, 2004.

Lawrence D. Mass, M.D., is a co-founder of Gay Men's Health Crisis and wrote the first published press reports on AIDS.

Source

United States to approve potent oral drugs for hepatitis C

Nature | News

Improved treatments offer hope for eradication of viral liver infection.

Sara Reardon

30 October 2013

take-two_1_14059

Cocktails of new oral antiviral drugs to fight hepatitis C have aced clinical trials.

JAMES CAVALLINI/SCIENCE PHOTO LIBRARY

For decades, people with hepatitis C virus (HCV) have had to endure gruelling treatment regimens that include injections of the drug interferon, which can cause severe nausea and depression. But with the imminent approval of several highly effective oral antiviral drugs, and more on the way, researchers say that eradicating the infection worldwide is now a realistic goal.

Unlike previous HCV treatments, which sought to enhance the immune system with interferon and other drugs, the latest group of oral medications interferes with the virus’s ability to replicate and make proteins. A US Food and Drug Administration (FDA) board recommended two such drugs — simeprevir, made by Johnson & Johnson in New Brunswick, New Jersey, and sofosbuvir from Gilead Sciences in Foster City, California — for approval last week. When each is taken in combination with a drug called ribavirin, the treatment eliminates hepatitis C in around 80% of people.

“This is the first time in the history of humankind that we have a cure for a viral disease,” says pharmacologist Raymond Schinazi of Emory University in Atlanta, Georgia.

Findings from trials of different drug combinations are set to be released this week. A phase II study called COSMOS tested a combination of sofosbuvir and simeprevir in 197 people with HCV who had either not responded to interferon or who had advanced liver fibrosis caused by the virus. After 12 weeks of treatment, the drugs completely cleared the virus in more than 90% of participants.

Another study, led by physician Kazuaki Chayama at Hiroshima University in Japan, treated 220 people with a combination of daclatasvir and asunaprevir, two new drugs from Bristol-Myers Squibb in New York. The cocktail cured 85% of participants. Eric Hughes, lead global medical researcher at the company, says that it plans to submit the drugs for FDA approval in 2014.

Stopped short

Despite such encouraging results, larger studies of drug combinations involving multiple drug companies seem to be unlikely. Charlotte Edenius, vice-president of development at Medivir, a drug company in Stockholm that collaborated with Johnson & Johnson on the COSMOS study, says that Gilead and Johnson & Johnson do not plan to work together for a phase III trial. Similarly, a Bristol-Myers Squibb spokesperson says the company has no plans to collaborate with Gilead on larger trials of a combined sofosbuvir–daclatasvir therapy, despite a phase II trial completed earlier this year in which the drug pairing cured all 41 participants.

Even without phase III trials or FDA approval for this approach, David Thomas, a hepatitis C researcher at Johns Hopkins University in Baltimore, Maryland, expects that some physicians will begin prescribing such combinations 'off-label' for difficult-to-treat cases.

And, he says, the impressive cure rates achieved in clinical trials suggest that potent drug combinations could eradicate HCV worldwide — at least in theory. The virus does not have an animal reservoir, meaning that it is not harboured by other animals, and it is not easily spread between people, except through blood. Improved screening of blood supplies used for transfusions and better patient-screening techniques have already greatly cut transmission rates over the last 15 years. Emergence of drug-resistant virus strains could be a hurdle, adds Thomas, but they might be rare because the latest antiviral drugs are so potent in combination.

Price problem

Hepatologist Rajender Reddy at the University of Pennsylvania in Philadelphia sees a second stumbling block: getting such treatments to people who need them. Many of the roughly 170 million people worldwide who carry hepatitis C will not be able to afford the drugs, he says. There is also little incentive for drug companies to lower costs — unlike antiviral therapies for HIV, which must be taken for a patient's lifetime, HCV treatment is given for only 12 weeks.

Identifying HCV carriers is also challenging, because most people do not know that they have the disease until they develop severe cirrhosis or liver cancer — sometimes decades after being infected. Mandatory screening of at-risk populations such as the elderly and drug users would need to be a major part of an eradication effort, says virologist Charles Rice of Rockefeller University in New York. Crucial too is education to prevent people from contracting the disease in the first place. Even the most effective oral drugs do not raise a lasting immune response against the virus, and people can be reinfected.

That is why the search for a preventative HCV vaccine continues, with the most promising ones currently in phase II clinical trials. “Even if we have all the drugs we need — which is still an open question — it will be decades, if not a century, before it’s gone,” says Rice.

Journal name: Nature

DOI: doi:10.1038/nature.2013.14059

Source

Changes to Incivek (telaprevir) product labeling

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FDA approved changes to the Incivek (telaprevir) product labeling to include results from trial C211 (OPTIMIZE) to support a twice daily dosing regimen. In addition new contraindications were added for anticonvulsant medications (carbamazepine, phenobarbital and phenytoin) and other revisions to the section 7 Drug Interactions. Below is a summary of the changes

  • Section 2: Dosage and Administration of telaprevir were updated throughout the label: from 750 mg three times a day to 1125 mg twice daily.
  • The anticonvulsant medications carbamazepine, phenobarbital, and phenytoin were moved from the Drug Interaction section (Section 7, Table 5) to the Contraindications section (Section 4, Table 3)
  • Section 6: Adverse Reactions was updated as follows:

Additional Data from Clinical Trials

In the analysis of an additional study (Trial C211), the safety profile of combination treatment with INCIVEK 1125 mg twice daily was similar to the safety profile for patients receiving combination treatment with INCIVEK 750 mg every 8 hours (q8h) [see Clinical Studies (14.2)]. No new safety findings were identified.

  • The analgesic medications alfentanil and fentanyl were added in section 7 Drug Interactions Table 5 as potential drug interaction drugs when used with telaprevir. Specifically, careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when telaprevir is co-administered with alfentanil or fentanyl, including extended-release transdermal or transmucosal preparations of fentanyl.
  • Section 12 Clinical Pharmacology was updated with information regarding the twice daily dosing regimen.

Telaprevir total exposure (AUC24h,ss) was similar regardless of whether the total daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125 mg twice daily.

Additionally the data from interaction trials with carbamazepine and phenytoin were included.

  • Section 12.4 Microbiology was updated as follows:

In the C211 Phase 3 clinical trial, there were no differences in the types of emerging variants between subjects receiving telaprevir 1125 mg twice daily and subjects receiving telaprevir 750 mg every 8 hours. Similar proportions of subjects in both treatment groups had telaprevir-resistant variants at the time of failure.

  • Section 12.5 Pharmacogenomics was updated to include the sustained virologic response rates at 12 weeks post treatment (SVR12) for the twice daily dosing regimen as follows:

In Trial C211, all subjects were prospectively tested for IL28B variants; there were no clinically relevant differences in SVR12 responses between q8h and twice-daily dosing within the genetic subgroups.

Trial rs12979860 Genotype SVR, n/N (%) SVR, n/N (%)
C211 (treatment-naïve)   T12 Twice Daily/PR T12 q8h/PR
  C/C 97/105 (92%) 92/106 (87%)
  C/T 139/206 (67%) 141/208 (68%)
  T/T 38/58 (66%) 37/57 (65%)
  • Section 14 Clinical Studies was updated to include results from Trial C211 (OPTIMIZE)

Trial C211 was a randomized, open-label, Phase 3 trial conducted in treatment‑naïve subjects. Enrolled subjects received 12 weeks of either INCIVEK 750 mg every 8 hours [T12 (q8h)/PR] or INCIVEK 1125 mg twice daily [T12 (twice daily)/PR] in combination with peginterferon alfa‑2a and ribavirin. The trial was designed to compare twice-daily dosing [T12 (twice daily)/PR] versus q8h dosing [T12 (q8h)/PR] of INCIVEK. At week 12, INCIVEK dosing ended and subjects continued on peginterferon alfa‑2a and ribavirin treatment. The total treatment duration was determined based on the subjects’ individual on-treatment viral response. If a subject achieved undetectable HCV RNA < 25 IU/mL (target not detected) at week 4, the total treatment duration was 24 weeks. Otherwise, the total treatment duration was 48 weeks.

The 740 enrolled subjects had a median age of 51 years (range: 18 to 70); 60% of the subjects were male; 21% had a body mass index ≥ 30 kg/m2; 5% were Black; 2% were Asian; 85% had baseline HCV RNA levels ≥ 800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had HCV genotype 1a; and 43% had HCV genotype 1b.

Table 11 shows the response rates for the T12 (twice daily)/PR group and the T12 (q8h)/PR groups by treatment outcomes. The overall SVR rates were similar at 74% [T12 (twice daily)/PR; 274/369] and 73% [T12 (q8h)/PR; 270/371], respectively.

Table 11: Response Rates: Trial C211

Treatment outcome

T12 (twice daily)/PR

N = 369% (n/N)

T12 (q8h)/PR

N = 371% (n/N)

SVR

74% (274/369)

73% (270/371)

Undetectable HCV RNA (target not detected) at week 4a

69% (256/369)

67% (250/371)

SVR in subjects with undetectable HCV RNA (target not detected) at week 4

86% (221/256)

85% (213/250)

SVR in subjects who did not have undetectable HCV RNA at week 4

47% (53/113)

47% (57/121)

Outcome for Subjects without SVR

26% (95/369)

27% (101/371)

On‑treatment virologic failureb

10% (38/369)

10% (36/371)

Relapsec

8% (23/300)

6% (19/293)

Otherd

9% (34/369)

12% (46/371)

T12 (twice daily)/PR: INCIVEK 1125 mg twice daily for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks; T12 (q8h)/PR: INCIVEK 750 mg every 8 hours for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks

a   Subjects with planned total treatment duration of 24 weeks.

b   On‑treatment‑virologic failure includes subjects who met a protocol‑defined virologic stopping rule and/or who had detectable HCV RNA at the time of their last dose of study drug and had viral breakthrough.

c   Relapse was defined as having less than 25 IU/mL at the planned end of treatment followed by HCV RNA ≥ 25 IU/ml at the last observation within the SVR follow-up visit window.

d   Other includes subjects with detectable HCV RNA at the planned end of treatment but who did not have viral breakthrough, and subjects with a missing SVR assessment during planned follow-up.

SVR rates were similar for the T12 (twice daily)/PR and T12 (q8h)/PR groups across subgroups determined by sex, age, race, ethnicity, body mass index, HCV genotype subtype, IL28B genotype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups. 

  • Fifty-four and 49 subjects in T12 (twice daily)/PR and T12 (q8h)/PR groups, respectively, had cirrhosis at baseline. The SVR rate in these subjects was 54% (29/54) in the T12 (twice daily)/PR group and 49% (24/49) in the T12 (q8h)/PR group. In the T12 (twice daily)/PR group, 52% (28/54) of subjects with cirrhosis achieved undetectable HCV RNA (target not detected) at week 4; their SVR rate was 68% (19/28). In the T12 (q8h)/PR group, 59% (29/49) achieved  undetectable HCV RNA (target not detected) at week 4; their SVR was 59% (17/29). The SVR rate for subjects assigned 48 weeks of treatment was 38% (10/26) in the T12 (twice daily)/PR group and 35% (7/20) in the T12 (q8h)/PR.

  • Thirty-five subjects were Black/African Americans. The overall SVR among Black/African American subjects was 50% (10/20) in the T12 (twice daily)/PR group and 60% (9/15) in the T12 (q8h)/PR group. Among these subjects, 46% (16/35) were assigned to 24 weeks of treatment and of those 88% (14/16) achieved SVR.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration


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Gileads’ CEO Discusses Sofosbuvir During Q3 2013 Earnings Call

Gilead Sciences' CEO Discusses Q3 2013 Results - Earnings Call Transcript

Excerpt from page 4

“And finally, as all of you are aware, we had a successful FDA advisory committee last week. The panel [ph] voted unanimously in favor of approval of sofosbuvir with ribavirin for the treatment of genotype 2 and 3 hepatitis C infected patients and approval of [indiscernible] course of sofosbuvir pegylated interferon with ribavirin for the treatment of genotype 1 and 4 hepatitis C infected patients.

In addition, the majority of panel members were in favor of broadening the indication to improve genotype 1 treatment experienced patient in the label. [indiscernible] the use of sofosbuvir plus ribavirin in the pre-transplant setting quotations with ACC. At the advisory committee meeting, new data were presented from the VALENCE study which indicated that treatment-naïve and treatment experience genotype 3 hepatitis C infected patient was so faster by providing with 24 weeks with SVR rate of 84%.

We are naturally excited about bringing sofosbuvir to the market and we feel like panel members commented that this is a historic moment, for which every employee at Gilead is proud of. We look forward to working with FDA to complete the review of the sofosbuvir NDA and ultimately launch the product.

Meanwhile the clinical development program of the sofosbuvir [indiscernible] dose combination is also proceeding rapidly. Three phase 3 studies IN-1, IN-2 and IN-3 explore the utility of the fixed dose combination both treatment, naïve treatment experience genotype 1 hepatitis C infected patients, with and without ribavirin, therefore treatment durations of eight, 12 and 24 weeks, we anticipate having data from these studies that we have about towards the end of this year and into early next year as we are on track for NDA, MAA filings in the second quarter of 2014.

The development of sofosbuvir in combination with ribavirin for genotype 2 infected patients in Japan is progressing. The single-arm phase 3 study with 12 weeks treatment duration was fully enrolled in September and we are on track to submit the marketing application in Japan towards the middle of 2014. This is a significant opportunity as genotype 2 infected patients in Japan constitute over 25% of the total and sofosbuvir and ribavirin will be the first on oral interferon free option for these patients.

In addition, the phase 3 program after fixed dose combination of sofosbuvir/ledipasvir with and without ribavirin genotype 1 hepatitis C infected patients was initiated in September 2013 that we anticipate this study to be fully enrolled by the end of this year. This two-arm study in three [indiscernible] genotype 1 infected both treatment, naïve treatment experienced patients, randomized to a 12-week course of the fixed dose combination with and without ribavirin.

Finally, the potentially pan-genotypic interferon and ribavirin free regimen, the combination of sofosbuvir [indiscernible] GS-5816 is advancing to phase 2 development, two studies in treatment naïve and treatment experienced patients in various genotypes are fully enrolled, and depending on the emerging data, we should be in a position to initiate phase 3 studies in the second half of 2014.

More information on our programs will be presented at the annual AASLD meeting which will commence this week in Washington DC. Over 50 abstracts were submitted on Gilead's various liver disease programs and importantly, new data will be presented on the safety and efficacy of sofosbuvir,

Ribavirin in HIV core affected patient and in the post liver transplant setting.

In summary, very rapid progress has been made across all our therapeutic areas in all other programs. Our pipeline provides us with numerous opportunities with continued growth, both short-term and longer-term. We want to take this opportunity to thank all of our employees for their continued hard work and dedication.

So with that, we will now open the call for questions. Operator?”

Continue reading the full transcript here ……

The Rise and Fall of a Revolutionary Drug

Provided by The Motley Fool

By Brian Orelli | More Articles
October 29, 2013

One of the best drug launches in history has become one of the fastest run downs.

Approved in May 2011, Vertex Pharmaceuticals' (NASDAQ: VRTX ) hepatitis C drug Incivek hit $457 million in sales in its second full quarter on the market. Many drugs never hit $457 million in annual sales at their peak.

Less than two years later, sales are down to $86 million in the most recent quarter. You can't say I didn't warn you.

Ironically, what made Incivek so popular to begin with is also what caused the crash. Hepatitis C is a slowly developing disease, so there's a limited downside to patients waiting a few years to be treated if the virus isn't doing much damage to the liver yet.

Doctors could see that Incivek and Merck's (NYSE: MRK ) Victrelis were working well in clinical trials, so they cut back on the prescribing the standard of care at the time -- Roche's Pegasys or Merck's Pegintron with a generic called ribavirin -- because they only cured about half the patients and make many people feel like they have the flu.

Once Incivek was approved, the warehoused patients were prescribed Incivek, which had a little better data than Merck's Vicrelis, and sales skyrocketed.

Rinse and repeat
But then doctors heard about the next generation of drugs and started warehousing again. Doctors are going to prescribe Johnson & Johnson's (NYSE: JNJ ) simeprevir and Gilead Sciences' (NASDAQ: GILD ) sofosbuvir, which both look like they're going to get approved this year after getting unanimous endorsements from their respective advisory committees. The large number of drugs in clinical trials also siphoned off some patients.

Vertex has seen the writing on the walls, so the biotech is cutting 370 positions, about 15% of its workforce, to conserve cash while it ramps up its cystic fibrosis business. Vertex also has a next-generation hepatitis C drug, VX-135, but it'll take a few years to get approved -- if side effects don't kill it first -- so it doesn't make sense to keep the hepatitis C sales force on the payroll.

All those workers can find new homes at Johnson & Johnson or Gilead Sciences. At least until doctors start warehousing again.

These two biotechs should have longer legs
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