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Hep C Discussion Forum -> Hep C News -> A "new?" NS5B - "AL-355"
Post Info TOPIC: A "new?" NS5B - "AL-355"
Canuck


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RE: A "new?" NS5B - "AL-355"
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Too bad Janssen pulled trialing their ¾ simi out of this triplet, combined with Achillions  (new) 5B "AL-355" and their 5A "odal", for further study, because as a triple (called JNJ-4178) it had some really impressive "preliminary" results for (basically TN) GT1's (and for other GT's as well) - but, as you will see in further bits of data below, it was being shown to be falling down for GT3's and for some of the GT2's (2c's specifically I believe), not pan enough to compete on the pan market, but still ... a shame to see a perfectly good triple not being further explored even if it only serves the needs of "select" GT's for whom it appeared to work on SO well. (The 100% parts of their results certainly impressed me, given the short durations!)

http://www.natap.org/2017/AASLD/AASLD_17.htm

___________________________________________________

Achillion Announces Presentation of Data From OMEGA-1 Phase 2b Trial With Odalasvir, AL-335, and Simeprevir (JNJ-4178) at the 2017 Liver Meeting

- 98.9% SVR12 achieved following six weeks of therapy for patients with chronic HCV genotypes 1, 2, 4, 5, or 6 -

NEW HAVEN, Conn., Oct. 23, 2017 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) reported today Phase 2b data on JNJ-4178, the triple combination consisting of odalasvir, AL-335, simeprevir, following presentations at the 2017 Liver Meeting(TM) organized by the American Association for the Study Liver Diseases (AASLD), held in Washington D.C., on October 20 - 24, 2017.

SVR12 data from OMEGA-1, a global open-label Phase 2b study of the efficacy and safety of JNJ-4178 in non-cirrhotic patients with HCV genotypes 1, 2, 4, 5 and 6, were presented at the conference by Dr. Stefan Zeuzem, Professor of Medicine and Chief of the Department of Medicine I at the Goethe University Hospital, Frankfurt, Germany.

The results showed that 98.9% (181/183) of patients treated with JNJ-4178 for 6 weeks achieved SVR12, while 97.8% (178/182) of patients treated with JNJ-4178 for 8 weeks achieved SVR12, with both arms meeting the pre-specified endpoint of statistical non-inferiority compared to historic controls. The triple combination was generally well-tolerated in both arms of the study, with the most frequent adverse events being headache and fatigue. Further information on the study can be found at www.clinicaltrials.gov (NCT02765490).

Achillion announced on September 11, 2017, the termination of the worldwide license and collaboration arrangement on hepatitis C with Janssen Pharmaceuticals, Inc. (Janssen), one of the Janssen Pharmaceutical Companies of Johnson & Johnson. The notice followed the decision by Janssen to discontinue the development of the investigational hepatitis C treatment regimen JNJ-4178.

______________________________________________________

 

*NOTE: In this below, of the GT's, the only GT1's who did NOT do well, were the ones who did NOT get the triple. (Being on the double alone did not bode well for GT1's, and, in general for the GT3's - the GT3's did not fare well on the triple, period).

 

 

Apr 22, 2017

 

Achillion Announces Additional Phase 2 Results Including 100% SVR24 for Genotype 1 HCV After 6-Weeks of Once Daily JNJ-4178

Ongoing Janssen global Phase 2 program with JNJ-4178, (odalasvir, AL-335, and simeprevir) focused on treatment durations of six and eight weeks for HCV genotype 1, 2, 4, 5, and 6 patients

AMSTERDAM, the Netherlands, April 22, 2017 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) announced today the presentation of updated results from the ongoing phase 2 '604 Study' being conducted by Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies (Janssen). These results were presented as an oral presentation during the European Association for the Study of the Liver (EASL) 2017 International Liver Congress in Amsterdam. These results demonstrate that the triple combination of simeprevir, odalasvir and AL-335 has the ability to shorten treatment duration, offer high efficacy and be generally well tolerated in those whose disease is caused by hepatitis C virus (HCV) genotype 1 (GT1), one of the most prevalent causes of hepatitis C globally.

"The goal of the Janssen HCV development program is to optimize treatment outcomes by providing a novel, simplified therapeutic option with high efficacy, safety, and a shorter treatment duration to address a broad range of patients living with HCV. Importantly, in this study 100% SVR12 was achieved despite the presence of NS5A polymorphisms, which can reduce the efficacy of other HCV regimens, that were observed at baseline," commented David Apelian, M.D., Ph.D., chief medical officer at Achillion. "The clinical community has expressed the need for more simplified treatment options, and these data with JNJ-4178 highlight the potential of this once daily regimen to achieve SVR24 for genotype 1 patients after only six weeks of therapy."

Study results, presented by principal investigator Dr. Edward Gane, professor of medicine at the University of Auckland and chief hepatologist at Auckland City Hospital, included expanded safety and efficacy data and were made in a presentation entitled "Short duration treatment with AL-335 and odalasvir, with or without simeprevir, in treatment-naïve patients with hepatitis C virus (HCV) genotype 1 infection." It reports that 100% of patients receiving treatment for six or eight weeks with a triple combination of once-daily AL-335 800 mg and simeprevir 75 mg with odalasvir 50 mg every other day achieved a sustained viral response 24 weeks after the completion of treatment (SVR24).

Summary of Phase 2 '604 Study' Design and Interim Results

The oral presentation features clinical trial data examining the safety, pharmacokinetics and efficacy of six and eight weeks of treatment with AL-335 and odalasvir with or without simeprevir to treat HCV in treatment naïve subjects across a range of HCV genotypes and stages of liver disease.

Data from this study demonstrate that JNJ-4178, the three-drug combination of simeprevir, odalasvir and AL-335, was highly effective in treatment naïve patients with HCV genotype 1 infection without cirrhosis, achieving 100% SVR24 for treatment durations of both 6 and 8 weeks. The two-drug regimen of odalasvir and AL-335, a combination regimen not anticipated to move forward, achieved 84% SVR24 for treatment duration of 8 weeks in patients with HCV genotype 1 without cirrhosis. The three-drug regimen of simeprevir, odalasvir and AL-335 in HCV genotype 3 patients without cirrhosis achieved an SVR12 of 77% following 12 weeks of therapy, and is also not anticipated to move forward. Genomic sequencing results indicate that despite the presence of multiple NS5A mutations observed at baseline there was no apparent impact on SVR rates.

The all-oral combination regimens containing odalasvir and AL-335, with or without simeprevir, were generally safe and well tolerated. Treatment results from the 604 Study' are summarized in the table below. Based on these data, JNJ-4178 is being further investigated for the treatment of HCV genotypes 1, 2, 4, 5, and 6.

Dose

HCV Genotype

Dosing
Duration
(weeks)

Number (%) with undetectable HCV RNA at SVR24*

AL-335
(mg QD)

ODV 
(mg)

SMV
 (mg QD)

400

50 QD

100

1

8

20/20 (100%)

800

50 QOD

75

1

8

20/20 (100%)

800

50 QOD

75

1

6

20/20 (100%)

800

50 QOD

--

1

8

21/25 (84%)

800

50 QOD

--

1

12

7/8 (88%)

800

50 QOD

75

3

8

0/5 (0%)

800

50 QOD

75

3

12

10/13 (77%)**

QD: every day; QOD: every other day; RNA: ribonucleic acid; SVR: sustained virologic response. *All results SVR24, with the exception of genotype 3 which is SVR12 **One patient did not attend SVR12 follow-up.

Ongoing Phase 2b Triple Combination Development Program

Janssen has initiated a multi-center, randomized, open-label Phase 2b study of JNJ-4178, the triple combination of once-daily odalasvir 25mg, AL-335 800mg, and simeprevir 75mg for treatment durations of six and eight weeks. Designated OMEGA-1, this trial has now completed enrollment of more than 365 treatment-naïve and treatment-experienced, non-cirrhotic patients chronically infected with HCV genotype 1,2,4,5 and 6. Results from this trial are anticipated during the second half of 2017. In addition, the 604 Study' is ongoing and will assess the triple combination JNJ-4178 in patients with compensated cirrhosis.

Additional Studies Supporting Global Development Program

In addition to the OMEGA-1 and '604 Study,' a number of supplemental clinical trials are being conducted by Janssen including those assessing special populations, certain drug-drug interactions, the bioavailability of a fixed dose combination, and providing for long-term follow-up of patients, all supporting the global development of JNJ-4178.

Further information on clinical studies being conducted with JNJ-4178 can be found at http://www.clinicaltrials.gov.

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Canuck


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From the recent 2017 Liver Meeting ... they're still "talking" about the trial results from the triple combo trials using NS5B "AL-355"/ NS5A odal and NS3/4A simi ... even though we have heard Janssen is "finished" (with an "early out") in pursuing further trials with this triple ... it's hard to fathom they are scrapping a (ho-li-cow)"new" 5B" (and this triple) from further phase 3 trials ... why? This article seems to focus on potential weaknesses in leaving GT2's behind?? (as opposed to earlier thoughts about this combo's potential weaknesses in leaving GT3's behind)?? Wonder what the actual problems are (in fact) that are stopping phase 3 trials??????? We'll have to study up some more on the the actual trial data to keep speculating on where the problem(s) lie. Is it a marketing issue or the combo itself? Hate to see any good triple (if it is good as another triple"choice") being "left" behind!

 

New three-drug HCV regimen shows nearly 100% response in 6, 8 weeks

Helio- October 26, 2017

WASHINGTON - A novel triple therapy combination correlated with nearly perfect SVR12 rates in most patients treated for 6 or 8 weeks, according to findings presented at The Liver Meeting 2017.

"There is evidence that any shortening of treatment for hepatitis C may have potential to improve patient compliance, convenience, and tolerability," Stefan Zeuzem, MD, of J. W. Goethe University, Frankfurt am Main in Germany, said. "The doses were chosen from a prior phase 2a study."

Zeuzem and colleagues presented findings for a three-drug combination called JNJ-4178 that includes the NS5B inhibitor AL-335 (Achillion) at 800 mg, the NS5A inhibitor odalasvir (Achillion) at 25 mg, and Olysio (simeprevir, Janssen) at 75 mg once daily. Researchers followed eligible participants for 24 weeks after the end of treatment.

SVR12 served as the primary endpoint, and adverse events, laboratory abnormalities, electrocardiogram or echocardiogram, and pharmacokinetics served as secondary endpoints.

The study included 183 patients treated for 6 weeks and 182 treated for 8 weeks. HCV genotypes 1a and 1b comprised approximately 70% of the cohort, with genotypes 2 and 4 comprising about one-quarter and a small proportion having genotype 5 HCV. "We extended the genotypes to the phase 2b study," Zeuzem said. "All genotypes but genotype 6 were enrolled. They were allowed to be enrolled."

For the 8-week arm, 178 of 182 patients reached the primary endpoint, according to Zeuzem. In the 6-week arm, 181 of 183 patients reached SVR12. Zeuzem noted that these findings translated to an overall 98.9% SVR12 rate. "This of course also meets the non-inferiority to historical controls," he said.

SVR12 rates were above 98% in every genotype except genotype 2, Zeuzem added. "Specifically, genotype 2c infection patients experienced relapses most frequently," he said.

There were no grade 4 adverse events reported, no premature discontinuations of the study drug, and no laboratory abnormalities observed, according to Zeuzem. "There were typical adverse events, fatigue, headache, but nothing special in particular," he said. "Extensive and thorough cardiac evaluation did not reveal any evidence for cardiotoxicity."

There is some debate about the role of resistance variants in patients who failed to reach SVR12, particularly those with genotype 2 disease, according to Zeuzem. Most of the variants were found in patients with genotype 2c.

"Six and 8 weeks of treatment with [JNJ-4178] resulted in SVR rates of 99% and 98%, respectively," Zeuzem concluded. -  by Rob Volansky

For more information:

Zeuzem S, et al. Abstract 65. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Zeuzem reports consulting for AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck/MSD.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Canuck


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Ya, we'll see, as Janssen IS going to "complete" and wrap up these current trials - the proposed "completion" dates for these trials (some in Canada - get that! - who'da thunk it!) was supposed to be Oct 2017 maybe - so, it may be some time yet before we get to read their results data. But, if memory serves, these trials were some of their shorter treatment time duration trials?, some 6 and 8 week durations included (I think), so, being that I also recall from prior trials that the effect for GT3's was fairly dismal, or kinda disappointing (and for maybe another GT as well) - those two factors alone (leaving any GT's behind and them exploring these short duration trials) may make the results of these two study completions (or further phase 3's) a foregone conclusion (as far a good business sense for Janssen) - perhaps the thought is scrap it, we can't compete/not potent enough for GT3's/ or pan enoughto capture all GT's to compete - this is what i am guessing anyway. Still, I was very interested to know how good their "new" NS5B (AL-355) was going to be, as compared to Gileads NS5B (sof) - that was and is an exciting thought!, and just in general how this triple combo preformed in the long run. But if they are already leaving 3's behind ... well, it is hard to compete in the short pan world - who knows, maybe we will see one pharma acquiring another's drug(s), just like we have seen them gobble up each others stuff before. We "triple" people like to see more triple trials of NS5A's, 5B's and 3/4A combos, potentially exciting to have choices! 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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robertsamx


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Hi C.   I had read this a few weeks ago. They are just a little late to the party. After all the R/D and taking it to a phase 2 trial, I bet if the phase 2 trial numbers are good they most likely will do a phase 3 and at least put it out there as a option. They could price it low just to try to recoup there R/D cost. It just depends on the phase 2 results. Interesting to keep an eye on this one!   RC



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 M-68, 3 Treatments)( SOF-RIBA 2014)(SOF-RIBA-PEG 2016)(HCC 2016) (LIVER TRANSPLANT 8-2017)(VOSEVI-RIBA 2017)   SVR-12. 3-13-18   
Canuck


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hm, so the other shoe has dropped - Janssen has had enough? (in the competition of which pharma can create and make the highest selling biggest/bestest pan).

The potential use of their combo - simi (NS3/4A)/odal (NS5A), and AL-355 (their "new" NS5B), has ceased for Janssen (formerly Idenix).

Janssen to discontinue development of HCV therapies - September 11, 2017 - Helio

Janssen announced it will discontinue further development of the investigational hepatitis C regimen JNJ-4178, a direct-acting antiviral combination of AL-335, odalasvir and the company's simeprevir regimen Olysio, according to a press release.

"Going forward, our hepatitis R&D efforts will focus on chronic hepatitis B, where a high unmet medical need still exists," Lawrence M. Blatt, PhD, Global Therapeutic Area Head, Infectious Disease Therapeutics at Janssen, said in the release. "Our scientists are energized by this challenge and our research ambition is to achieve a functional cure of hepatitis B which affects over a quarter of a billion people globally."

Janssen will complete the ongoing phase 2 studies for JNJ-4178 as planned. According to the press release, Janssen made the decision in response to the increasing availability of highly effective DAA therapies for HCV.

"At Janssen," Blatt continued, "we focus our research and development on areas of greatest unmet medical need where we can combine our excellent internal science with the best available external innovation to bring optimized solutions and maximum benefit to patients." - by Talitha Bennett 



-- Edited by Canuck on Saturday 16th of September 2017 05:57:38 AM

__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Canuck


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Oh, darn. C.



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HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Tig


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NO! Put it back, Chuck... wink 



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Canuck


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Tig found and posted this very interesting one - it's aptly under "clinical trials", but I don't want to loose track of this new NS5B, so borrowed Tig's find to be over here as well, so it can be seen as new "news" as well! Hope that's OK Tig. smile

 Janssen 2a trial

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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