Achillion Announces That Janssen Has Initiated a Phase 2a Study to Evaluate the Combination of AL-335, Odalasvir (ACH-3102), and Simeprevir for the Treatment of Genotype 1 Chronic HCV

Once Daily Triple Direct-Acting Antiviral Regimen Will be Evaluated for Treatment Durations of Four, Six or Eight Weeks

NEW HAVEN, Conn., Oct. 16, 2015 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) announced today that Alios Biopharma Inc., part of the Janssen Pharmaceutical Companies (Janssen) has initiated treatment in a phase 2a clinical trial to evaluate the safety, pharmacokinetics and efficacy of AL-335, odalasvir (also known as ACH-3102), and simeprevir in treatment-naïve patients with genotype 1 chronic hepatitis C virus (HCV) infection.

This phase 2a study is a randomized, open-label, three-arm study of AL-335, a nucleotide-based HCV NS5B polymerase inhibitor, odalasvir, an HCV NS5A inhibitor, and simeprevir, an HCV NS3/4A protease inhibitor. Patients will be randomized to one of three treatment arms and receive once daily treatment for a duration of four, six or eight weeks. The primary objective of the study is to establish the safety of the treatment regimen with secondary endpoints consisting of pharmacokinetics, the proportion of subjects achieving sustained viral response (SVR), and the effect on the viral resistance profile after treatment. The study is expected to enroll approximately 60 patients across the three treatment arms.

As previously announced on May 19, 2015, Achillion has granted Janssen an exclusive, worldwide license to develop and, upon regulatory approval, commercialize HCV products and regimens containing one or more of Achillion's HCV assets which include odalasvir (ACH-3102), ACH-3422, and sovaprevir.

Further information about the study can be found at www.clinicaltrials.gov. Study identifier: NCT02569710.

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SNAPSHOTS —Alan Franciscus, Editor-in-Chief

This month’s (October 2015) column features a variety of studies, including treatment of people with advanced liver disease, treating people who have not achieved a cure with direct acting antiviral therapy, including people who had developed RAVs.

Article:  Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease—M Charlton et al. 

Source:  Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.

Results and Conclusions

This was a phase 2 study of 337 patients with decompensated cirrhosis with genotype 1 (332 patients) and genotype 4 (5 patients) who received 12 or 24 weeks of Harvoni plus ribavirin twice daily.  None of the patients previously treated developed resistance to sofosbuvir.  People who had been previously treated with an NS5A inhibitor were excluded from the study. 

There were two groups in the study:

•  Group A, who had NOT had a liver transplant: 59 patients with Child-Pugh class B cirrhosis and 49 patients with Child-Pugh class C  cirrhosis*
•  Group B who HAD undergone liver transplantation:  111 patients without cirrhosis, 51 patients with Child-Pugh class A cirrhosis, 52 with Child-Pugh class B cirrhosis, 9 with Child-Pugh class C cirrhosis, and 6 with fibrosing cholestatic hepatitis*

 *Child-Pugh cirrhosis scoring is a system that uses various types of blood markers and liver disease progression such as ascites to evaluate a patient to establish the severity of cirrhosis and long-term patient survival.  The classes are A, B and C with A as the less severe and C as the most severe.  Cholestatic hepatitis is bile duct blockage with fibrosis.

Group A and B had 12- and 24-week treatment arms, but cure rates were similar regardless of treatment duration.

     

 The Bottom Line

In group A (those who had not received a liver transplant), the cure rate was 86% to 89%.  In group B (transplant group) the people who did not have cirrhosis or Class A cirrhosis—the cure rate was 96% to 98%.  Furthermore, in group B with class B cirrhosis (compensated) the cure rate was 85% to 88%, and those with class C cirrhosis (moderate impairment) achieved 60% to 75% cure rates. The people who had fibrosing cholestatic hepatitis achieved 100% cure rates.  There were 13 patients (4%) who discontinued treatment.  Ten patients died in the trial.  The deaths were mainly attributed to complications from hepatic decompensation or end-stage liver disease.

Editorial Comment

In the past, people with these types of severe disease progression have been very difficult to cure or even treat, but now with these ‘miracle’ drugs many people now have a second chance at life.  Now if we could just get these drugs to everyone with hepatitis C before this stage, we would eliminate the need to treat at these stages of disease severity. 

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Article:  Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent—X Forns et al.

Source:  J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.

Results and Conclusions

There were 79 HCV genotype 1 patients in the study. 

• Sixty-six patients who had been previously treated patients with an NS3/4A protease inhibitor but had not been cured. 
• Of the 13 remaining patients, 12 had discontinued treatment due to side-effect(s). 
• Thirty-four patients had NS3 resistance-associated variants (RAVs), and eight patients had NS5A RAVs. 
• Eight patients treated with the combination of grazoprevir and elbasvir plus ribavirin twice daily.

 The Bottom Line

The overall cure rates were 96% (76 of 79 patients)—this included 93% (63 of 66 patients) of the genotype 1a, one hundred percent of the patients (43 of 43 patients) who DID NOT have RAVs achieved a cure.  Ninety-one percent of those who DID have NS3 RAV’s were cured and 75% (6 of 8 patients) of those who had NS5A RAVs were cured.  Of those with cirrhosis 94% were cured with this combination. 

Editorial Comment

The addition of ribavirin to grazoprevir and elbasvir works to help cure resistance-associated variants in people who have been previously treated but who have not been cured.  It is also good strategy to treat other negative predictors to current  medications.

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Article:  Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens—D Wyles et al.  

Source:  Hepatology. 2015 Jun;61(6):1793-7. doi: 10.1002/hep.27814. Epub 2015 Apr 27.

Results and Conclusions

There were 51 genotype 1 patients enrolled in the study (Note: one patient was incorrectly typed as genotype 1, but was subsequently correctly genotyped as genotype 3).  All of the patients in this trial were previously treated with a sofosbuvir containing regimes in Gilead’s phase 1 or phase 2 studies.  The treatment duration in this study was 12 weeks. 

Breaking it down by type of prior type of non-response:

• 25 pts (49%) had previously received sofosbuvir plus pegylated interferon plus ribavirin
• 20 pts (39%) had previously received sofosbuvir plus ribavirin
• 5 pts (10%) received sofosbuvir (sugar pill/placebo) plus pegylated interferon and ribavirin
• 1 pt (2%) received GS-0938 only fourteen patients (27%) had compensated cirrhosis.

 The Bottom Line

The total number of patients who achieved a cure was 98% (50 of 51 patients).  Among those who had received a prior course of sofosbuvir 98% (44 of 45) were cured.  The only patient who did not achieve a cure was the patient who was originally misdiagnosed as a genotype 1. 

The most common side effects were fatigue, headache and diarrhea.  The patients in this trial are considered some the most difficult to treat—those who have not achieved a cure with a previous course of a direct acting antiviral medication, those with cirrhosis, and people with resistant antiviral variants (RAVs). 

Editorial Comment

The addition of ledipasvir and ribavirin to sofosbuvir increased the cure rates to 100% for genotype 1.  Excellent results!  This is a good strategy with another type of direct acting antiviral to stop the virus from replicating and escaping.

Gilead, Merck, AbbVie, Janssen, and Achillion are working on other HCV drugs that have a higher barrier to resistance to avoid the development of resistance and to work for people who are not responding to the current medications.

September 2015 Mid-Month Edition - SNAPSHOTS —Alan Franciscus, Editor-in-Chief

This month’s Snapshots is about recently published studies on all-oral therapies to treat hepatitis C in people coinfected with HIV.  We have really come a long way in such a short period of time with medications to treat a population in high need of effective therapies.    
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Article: Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1—S Naggie et al.

Source:  New England Journal of Medicine DOI: 10.1056/NEJMoa1501315

Results and Conclusions
The study included 335 patients coinfected with HIV-1 and hepatitis C genotype 1 or 4.  The median age was 52 yo (48-58 yo).  The majority of patients were White 61% (203 pts) and Black 34% (115 pts), male 82% (276), genotype 1a 75%, genotype 4 two percent, cirrhosis 20%, median CD 4+ cell count 628 (469-823), treatment naïve 45%, previously treated 55%. The treatment period was 12 weeks.  Note: I am not including the genotype 4 patients since there were only 8 patients.  

The Bottom Line
The cure rates were 96% for genotype 1a, and 96% for genotype 1b. The cure rates were similar regardless of prior response or degree of liver damage.  The most common side effects were headache, fatigue and diarrhea.  No patients discontinued treatment due to side effects.

Editorial Comment
These results are excellent across subtypes (1a/1b), races, and prior treatment responses.  Gilead has filed for marketing approval with the Food and Drug Administration.  The American Association for the Study of Liver Disease (AASLD) and the Infectious Disease Society of America (IDSA) recommend Harvoni as a treatment for HCV for people coinfected with HIV and hepatitis C.

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Article: Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial—J K Rockstroh, et al

Source:  The Lancet HIV Volume 2, No. 8, e319–e327, August 2015

Results and Conclusions
The study was conducted in people with HIV/HCV coinfection to evaluate grazoprevir/elbasvir (one pill, once-a-day) to treat HCV genotype 1, 4, and 6. The treatment period was 12 weeks. There were 218 patients in the phase 3 trial.  The trial was conducted in Europe, the United States and Australia.

The Bottom Line
The overall cure rate was 96% (210 of 218 patients).  All patients who had cirrhosis were cured.  The most common side effects were fatigue, headache and nausea. No patients discontinued treatment due to side effects.

Editorial Comment
The high cure rates and fewer side effects plus no treatment discontinuation due to treatment-related side effects equals very good news for patients.

The once-a-day combination of grazoprevir/elbasvir when approved is going to be a welcome addition to the other therapies to treat hepatitis C in people who are HIV and HCV coinfected.  

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Article: Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1—D L Wyles et al.  
Source:  New England Journal of Medicine DOI: 10.1056/NEJMoa1503153

Results and Conclusions
There were 3 different treatment groups. All the groups received daclatasvir plus sofosbuvir. Note: Since there was a small number of genotype 2, 3, and 4 patients—I omitted these results.  For this article I am just listing the genotype 1 results.    

The Bottom Line
The patient characteristics, treatment durations and cure rates are included below:

1. Naïve (untreated patients): 101 patients; median age 52 yo; male sex 91%; race: White 65%, Black 30%; genotype 1a: 70%, genotype 1b: 12%; cirrhosis 9%; median CD4+ count 520 (122-1147). Treatment duration = 12 weeks. Cure rate = 96%
2. Naïve (untreated patients): 50 patients; median age 51 yo; male 84%; race White 56%, Black 38%; Genotype 1a 70%, Genotype 1b 12%; cirrhosis 10%; treatment duration = 8 weeks.  Cure rate = 76%
3. Treatment Experienced:  52 patients; median age 57 yo; male 83%; race White 60%, Black 38%; genotype 1a 63%, genotype 1b 21%; cirrhosis 29%; treatment duration =12 weeks.  Cure rate = 98%

The most common side effects were fatigue, nausea, and headache.  No patient discontinued due to side effects.

Editorial Comment
The 12-week treatment groups had good cure rates as opposed to the 8-week treatment response group.  The treatment-experienced group #3 with a 38% Black population and a relatively high cirrhotic population achieved nearly perfect cure rates. The drawback of this combination is going to be the high price tag of the combination of these two drugs.

Note:  Another issue with treating hepatitis C in people with HIV is the potential drug-drug interactions with HIV medications.  For more information visit the AASLD/IDSA  HCV Guidelines http://www.hcvguidelines.org/full-report-view.

Finding strengths—and weaknesses—in hepatitis C's armor

Using a specially selected library of different hepatitis C viruses, a team of researchers led by Johns Hopkins scientists has identified tiny differences in the pathogens' outer shell proteins that underpin their resistance to antibodies. The findings, reported in the January 2015 issue of the Journal of Clinical Investigation, suggest a reason why some patients' immune systems can't fend off hepatitis C infections, and they reveal distinct challenges for those trying to craft a successful vaccine to prevent them. Due to concerns about the rising costs of newly available hepatitis C drugs, researchers are looking to a vaccine as a more viable and less costly option.

The systems of some people who become infected with the liver-ravaging hepatitis C virus launch a robust immune attack, producing antibodies that attach to a broad array of the germs with different genetic makeups. About one-third of these individuals successfully clear the pathogen from their bodies. However, says Justin Bailey, M.D., Ph.D., assistant professor of medicine in the Division of Infectious Diseases in the Johns Hopkins University School of Medicine, no single antibody has been found that can neutralize all strains of hepatitis C virus.

To better understand how hepatitis C viruses avoid even the most broadly neutralizing antibodies, Bailey; Stuart C. Ray, M.D., professor of medicine in the Division of Infectious Diseases in the Johns Hopkins University School of Medicine; and colleagues tested the power of 18 antibodies known to broadly attack the virus against a library of 19 viral strains that make up about 94 percent of the genetic variability of hepatitis C viruses in the most common genetic group, called genotype 1.

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Nursing Times-NHS-NICE gives backing to hepatitis C drug in latest draft guidance

“The marketing authorisation for ledipasvir-sofosbuvir recommends treatment for hepatitis C genotypes 1, 3 – in combination with ribavirin – and 4”.

“Genotypes 1 and 3 hepatitis C account for the majority of chronic hepatitis C cases in England (46% and 43%, respectively). Genotype 4 hepatitis C accounts for around 4% of cases”.

“Ledipasvir-sofosbuvir, manufactured by Gilead, is administered orally as a single tablet – with or without ribavirin – and works by inhibiting the replication of the hepatitis C virus. It prevents hepatitis C virus replication by inhibiting the NS5A and NS5B proteins”.

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New Cigna, Catamaran Hep C Pacts Put Gilead Drugs to the Test

"Since the December 2014 approval of AbbVie Inc.’s hepatitis C treatment Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets; dasabuvir tablets), at least 10 companies have disclosed exclusive or semi-exclusive deals with Gilead Sciences, Inc. that feature the manufacturer’s hepatitis C agents, Harvoni (ledipasvir/sofosbuvir) and Sovaldi (sofosbuvir). But Catamaran Corp. and Cigna Corp. this month unveiled the first outcomes-based arrangements with Gilead that industry observers say could open the door for more value-based deals around hepatitis C and other specialty agents".

"Catamaran on Feb. 3 said it would offer a new hepatitis C patient management program through its specialty pharmacy, BriovaRx, that features Gilead’s Harvoni and Sovaldi as exclusive hepatitis C treatment options (DBN 2/6/15, p. 1). Similarly, Cigna Corp., a long-term Catamaran customer, on Feb. 4 said it would offer Harvoni as the only preferred brand drug treatment for customers with hepatitis C genotype 1 infection as well as develop an outcomes-based incentive program".

"While both companies declined to provide specifics on how the deals are structured, other outcomes-based pharmaceutical arrangements between manufacturers and insurers or PBMs have tied rebate payments to agreed-upon outcomes achieved by the payers’ members. Cigna, for instance, in 2010 embarked on an outcomes-based partnership with Merck & Co. in which the drugmaker provided rebates to Cigna when its members with type 2 diabetes met goals for adherence to prescribed medications and low blood sugar levels (DBN 12/17/10, p. 1). And Prime Therapeutics LLC in 2012 signed an outcomes-based contract with EMD Serono, Inc. for its multiple sclerosis drug Rebif (interferon beta-1a) through which the drugmaker promised to pay rebates to the PBM if its members taking Rebif had a higher total cost of care than people on other MS medications. Adherence levels were also considered. Cigna inked a similar deal with EMD Serono in 2011".

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Gilead Announces SVR12 Rates From Phase 3 Study Evaluating Harvoni® for the Treatment of Chronic Hepatitis C in Patients Co-Infected With HIV

– 96 Percent SVR12 Rate for Hepatitis C Genotypes 1 and 4 Among HIV-infected Patients on Antiretroviral Therapy – 

SEATTLE--(BUSINESS WIRE)--Feb. 26, 2015-- Gilead Sciences, Inc. (NASDAQ:GILD) today announced results from a Phase 3 study, ION-4, evaluating the once-daily single tablet regimen Harvoni^® (ledipasvir 90 mg/sofosbuvir 400 mg) for the treatment of genotypes 1 or 4 chronic hepatitis C virus (HCV) infection among patients co-infected with HIV. In the trial, 96 percent (n=321/335) of HCV patients achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV infection. These data were presented in a late-breaker oral session (Session 152LB) at the 22^nd Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

“This trial provides strong evidence that people who are co-infected with HIV can achieve very high rates of hepatitis C cure with a combination direct-acting antiviral regimen,” said Susanna Naggie, MD, MHS, Director of Infectious Diseases Research at Duke Clinical Research Institute and Principal Investigator for the ION-4 study. “These high cure rates were observed in most of the historically difficult-to-treat sub-populations, including those who failed previous treatment and those with cirrhosis. We are greatly encouraged by these findings.”

ION-4 is a Phase 3, multicenter, open-label study investigating the efficacy, safety and tolerability of Harvoni treatment for 12 weeks in 335 patients with HCV genotype 1a (75 percent), 1b (23 percent) or 4 (2 percent) and HIV-1 co-infection. The study included HCV treatment-naïve (45 percent) and treatment-experienced (55 percent) patients, including patients with compensated cirrhosis (20 percent), whose HIV was suppressed using one of three HIV antiretroviral (ARV) regimens: tenofovir and emtricitabine with efavirenz (Atripla^®), raltegravir or rilpivirine (Complera^®).

SVR12 rates did not differ significantly by prior HCV treatment status, presence or absence of cirrhosis, or ARV regimen. No patients discontinued Harvoni due to an adverse event (AE). Of the 14 patients that did not achieve SVR12, two patients experienced virologic failure during treatment (likely due to non-compliance per physician reporting), 10 experienced virologic relapse post-treatment, one was lost to follow up and one died due to causes unrelated to study drug. The most common AEs reported were headache (25 percent), fatigue (21 percent) and diarrhea (11 percent).

Harvoni received regulatory approval for the treatment of chronic HCV genotype 1 infection in adults in the United States in October 2014. Based on the ION-4 trial results, Gilead plans to file a supplemental New Drug Application with the U.S. Food and Drug Administration for Harvoni to include the results from this study in the U.S. label. Harvoni received marketing authorization in Europe in November 2014, where data from a small study in HIV-HCV co-infected patients (ERADICATE) are included in the prescribing information. -

See more at: http://gilead.com/news/press-releases/2015/2/gilead-announces-svr12-rates-from-phase-3-study-evaluating-harvoni-for-the-treatment-of-chronic-hepatitis-c-in-patients-coinfected-with-hiv#sthash.MHNmiL6v.dpuf

The Global Spread of Genotype 1 —Alan Franciscus, Editor-in-Chief

The origin of hepatitis C (HCV) is unknown.  The current theory is that it may have originated in horses, but while the virus found in horses is similar to the hepatitis C virus the scientific evidence linking it to hepatitis C is far from clear.   Where the virus originated is on more solid ground—it is believed to have originated in West Africa.  Hepatitis C is spread by direct blood-to-blood contact.  So how did it develop into such a huge problem with an estimated 130-150 million people infected worldwide?  How did genotype 1 become the most common genotype worldwide?  The answer to both questions is well-known—blood transfusions and unsafe injections. 

In the study “The Global Spread of Hepatitis C Virus 1a and 1b:  A Phylodynamic and Phylogeographic Analysis,” by G Magiokinis et al., the authors used a complicated system of analysis with various models (molecular clock & the Bayesian skyline demographic).   The model tracked how genotype 1a and 1b spread throughout the world.  First it was found that genotype 1a had a steady rate of expansion from about 1906 through the 1960’s.  Moreover, it was found that from the 1960’s through the 1980’s it dramatically expanded.  This corresponds to the increase in injection drug use from the 1960’s through the present day. 

Genotype 1b on the other hand expanded at a steady rate from 1922 to the late 1940s.  Then from the 1950’s until the 1980s it showed the greatest expansion.  Thus, the highest rate of expansion of genotype 1b was ~16 years before genotype 1a.   An interesting observation was that early on in the hepatitis C epidemic it was thought that genotype 1b led to more cases of liver cancer.  A possible explanation of this is that people with genotype 1b were infected longer and were more likely to have had more disease progression.   As the authors pointed out, the connection between genotype 1b, liver cancer and the earlier spread of genotype 1b needs to be validated  in future studies. 

To validate their findings of the earlier expansion of genotype 1b, however, the authors pointed to other evidence: 

• All US military recruit samples from 1948-1955 were genotype 1b.
• Older HCV-infected individuals are “systematically” or consistently genotype 1b.

Back to why genotype 1 is the most common genotype.  The most likely reason is that genotype 1 was introduced into developed western countries and spread by the introduction of blood transfusions, plasma pooling and unsafe injections (reuse or improper needle sterilization) of medicines to treat many diseases.  In the late 1920s through the present day the epidemic of injection drug use and sharing needles and drug preparation tools is another reason for the spread of HCV genotype 1.  

One has to wonder how different it would be if genotype 2 had been ‘the genotype’ that had been the one that had greatly expanded instead of genotype 1.  Treatment of genotype 2 produced very high cure rate early on in the history of treatment.  Still with current treatments we have the potential to eradicate hepatitis C in a lifetime. If only we could increase treatment access for everyone with hepatitis C. 

Facts about genotype 1:

• Genotype 1 is the most common genotype worldwide at 83.4 million (46.2%) people.
• Genotype 1 is the most common genotype in the United States at 70% of the population with HCV.
• Genotype 1a and 1b are the most common subtypes; subtypes 1c, d, e, f, g, h, i, k and l have been identified but are uncommon.
• The current standard of care for the treatment of hepatitis C can cure 90 to 100% of people who take the medications (HARVONI and VIEKIRA PAK).  Treatment durations are usually 12 weeks but vary from 8 to 24 weeks.

http://hcvadvocate.org/news/newsLetter/2015/advocate0215_mid.html#1