- Category: Experimental HCV Drugs
- Published on Tuesday, 06 May 2014 00:00
- Written by HIVandHepatitis.com
Idenix Pharmaceuticals' hepatitis C virus NS5A inhibitor samatasvir (formerly IDX179) plus Janssen's HCV protease inhibitor simeprevir (Olysio) and ribavirin produced early sustained virological response rates of about 80% in a small study presented at the 49th EASL International Liver Congress last month in London. Another study showed that the company's HCV polymerase inhibitor candidate IDX21437 looks good in preclinical studies and is a potential once-daily partner for samatasvir in interferon-free regimens.
Eric Lawitz from the Texas Liver Institute and fellow investigators presented findings from the HELIX-1 study, a randomized, double-blind Phase 2 trial that included 93 previously untreated chronic hepatitis C patients, most (about 90%) with HCV subtype 1b and the rest with genotype 4. About half were women, about 75% were white, and the mean age was about 52 years. About one-third had the favorable IL28B CC gene variant.
Participants were randomly assigned to receive samatasvir at doses of 25, 50, 100, or 150 mg, plus 150 mg simeprevir and weight-based ribavirin for 12 weeks.
At 4 weeks post-treatment, sustained virological response (SVR4) rates for genotype 1b patients were 80%, 83%, and 75% in the 25, 50, and 100 mg dose groups, respectively, falling to just 47% in the highest dose arm. Among the 10 genotype 4 patients, 7 (70%) achieved SVR4.
Treatment was generally safe and well-tolerated, with no serious adverse events or discontinuations for this reason. The most common side effects were fatigue, headache, insomnia, pruritus (itching), and nausea. 14% developed anemia (a side effect of ribavirin) and some had elevated bilirubin (associated with simeprevir).
"The safety and efficacy results support future studies of samatasvir in combination with selected anti-HCV DAAs including studies with the Idenix nucleotide prodrug IDX24137," the investigators concluded, adding that it is unclear why efficacy dropped off at the highest samatasvir dose
Idenix scientists also presented preclinical data on IDX21437, a pan-genotypic nucleotide HCV NS5B polymerase inhibitor, which is a prodrug of IDX20803.
The researchers concluded that IDX21437 demonstrated activity against HCV genotypes 1-6, has a high barrier to resistance, has low potential for drug-drug interactions, has a long half-life in liver tissue supporting once-daily dosing, and showed minimal toxicity in cell culture and animal studies.
These findings indicate that IDX21437 is a "good candidate for combination therapy with DAAs acting via different mechanisms" and "support the potential for once-daily use with samatasvir, an NS5A inhibitor, as a potent, pan-genotypic HCV combination regimen in future clinical studies," they summarized.
Below is an edited excerpt from an Idenix press release describing the findings from a Phase 1/2 proof-of-concept study of IDX21437. The company is also testing a next-generation nucleotide prodrug, IDX21459.
Idenix Announces Promising Clinical Data and Continued Progress in Nucleotide Prodrug Development Programs for the Treatment of Hepatitis C
- Idenix Reports Positive Proof-of-Concept Data for Lead Nucleotide Prodrug, IDX21437
- Idenix on Track to Initiate All-Oral Pan-Genotypic Phase II Combination Clinical Study of IDX21437 and Samatasvir in mid-2014
- Idenix Initiates Phase I Clinical Trial of Follow-on Nucleotide Prodrug, IDX21459
Cambridge, Mass. -- April 7, 2014 -- Idenix Pharmaceuticals, Inc. (Nasdaq:IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced continued progress of the Company's program to develop nucleotide prodrug inhibitors for the treatment of hepatitis C virus (HCV) infection. Idenix is reporting potent antiviral activity of mean maximum 4.2-4.3 log10 IU/mL reductions for patients infected with HCV genotype 1, 2 or 3 receiving 300 mg once daily of IDX21437 in the seven-day proof-of-concept portion of a phase I/II clinical trial. Based on this progress, the Company's goal is to initiate a combination clinical trial of IDX21437 and samatasvir, a pan-genotypic NS5A inhibitor, in mid-2014. In addition, Idenix has selected a follow-on uridine-based nucleotide prodrug, IDX21459, from its ongoing nucleotide discovery program and initiated enrollment for the healthy volunteer portion of a phase I clinical trial.
"As more all-oral regimens become available to treat hepatitis C, an increased number of patients will be diagnosed and treated. It will be important to have simple, short duration options for our patients. These early data for IDX21437 support its potential to be part of future treatment combinations." said Professor Edward Gane, MD, Deputy Director and Hepatologist, New Zealand Liver Transplant Unit, Auckland City Hospital in New Zealand, and a clinical investigator in the IDX21437 proof-of-concept study. "Nucleotide-based treatment combinations are favored because of safety, efficacy, high barrier to resistance and low drug-drug interaction potential and we look forward to seeing further results from studies with IDX21437."
"We are very pleased with these positive data for IDX21437 and we are excited to have two nucleotide prodrug candidates in the clinic," said Ron Renaud, Idenix's President and Chief Executive Officer. "With the initiation of the phase II study of IDX21437 and samatasvir later this year, we will be one of a few companies with an all-oral, pan-genotypic, nucleotide-based combination approach in the clinic. We believe this regimen has the potential to play a significant role in advancing HCV care for the benefit of patients, physicians and payers."
IDX21437: Topline 7-Day Phase I/II Clinical Results
In January 2014, Idenix initiated the seven-day proof-of-concept portion of a phase I/II clinical trial for IDX21437. The trial completed enrollment of 44 treatment-naive, genotype (GT) 1, 2 or 3 HCV-infected patients. Patients were randomized to receive once-daily doses of placebo, 50 mg, 150 mg, or 300 mg of IDX21437 for seven days. The topline clinical results include:
- IDX21437 was well-tolerated with no observed pattern of adverse events or laboratory abnormalities.
- Treatment with IDX21437 exhibited potent pan-genotypic activity in a dose-dependent manner:
- In GT 1 HCV-infected patients (n=8), the mean maximal viral load reduction was 4.2 log10 IU/mL in the 300 mg arm.
- The mean maximal viral load reduction of 4.3 log10 IU/mL was achieved in GT 2 and 3 HCV-infected patients in the 300 mg arm (n=10).
More detailed findings are expected to be presented at a future scientific meeting.
Based on these findings, the 300 mg dose of IDX21437 has been chosen for the anticipated phase II combination study with samatasvir.
IDX21459: Phase I Clinical Program
In April 2014, Idenix initiated enrollment for the healthy volunteer portion of a phase I clinical trial of IDX21459 in Europe. This portion of the study is expected to enroll approximately 50 healthy volunteers and will evaluate once-daily doses of IDX21459 ranging from 10 mg - 300 mg. The proof-of-concept portion of the study is expected to enroll a total of 40 treatment-naive, genotype 1 HCV-infected patients who will receive once-daily doses of placebo, 50 - 300 mg of IDX21459 for seven days. IDX21459 has shown a favorable preclinical profile including potent, pan-genotypic activity and favorable safety with respect to cardiac, mitochondrial and genotoxicity assessments.
Additional Nucleotide Candidates
Idenix's primary efforts in nucleotide development will continue to focus on its lead candidate, IDX21437, and follow-on prodrug candidate, IDX21459, as well as earlier-stage nucleotide prodrugs. An important objective for the discovery program is to identify nucleotides offering distinct resistance profiles that can be combined with one of the Company's current nucleotide clinical candidates to treat HCV. Idenix also announced today that the Company has elected not to continue its clinical development program for HCV nucleotide prodrug, IDX20963, previously placed on clinical hold by the U.S. Food and Drug Administration (FDA).
IDX21437, Idenix's lead uridine-based nucleotide prodrug inhibitor, has completed the single-dose and seven-day proof-of-concept portions of a phase I/II clinical trial. Extensive preclinical testing for IDX21437 has demonstrated favorable antiviral activity across genotypes 1-6 and a safety profile which supported advancement into clinical trials. Based on this progress, the Company's goal is to initiate an Idenix-sponsored combination clinical trial of IDX21437 and samatasvir in mid-2014.
Samatasvir is an NS5A inhibitor with low picomolar, pan-genotypic antiviral activity in vitro. To date, samatasvir has been safe and well-tolerated after single and multiple doses of up to 150 mg in healthy volunteers up to 14 days duration, and in HCV-infected patients up to 12 weeks duration. Samatasvir has demonstrated potent pan-genotypic antiviral activity in HCV-infected patients with mean maximal viral load reductions up to approximately 4.0 log10 IU/mL across HCV genotypes 1-4 in a proof-of-concept, three-day monotherapy study.
Under a non-exclusive collaboration with Janssen Pharmaceuticals, Inc., Idenix is evaluating all-oral, direct-acting antiviral HCV combination regimens including samatasvir, simeprevir (TMC435), a once-daily protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, and TMC647055/r, a once-daily non-nucleoside polymerase inhibitor boosted with low-dose ritonavir being developed by Janssen. In this program, Idenix is conducting two ongoing phase II 12-week clinical trials, HELIX-1 and HELIX-2.
K Gupta, M Seifer, I Serra, et al. Favorable preclinical profile of IDX21437, a novel uridine nucleotide prodrug, for use in a direct-acting antiviral (DAA) regimen for HCV. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract P1244.
E Lawitz, M Rodriguez-Torres, T Nguyen, et al. A Phase II Study of Samatasvir (IDX719) in Combination with Simeprevir and Ribavirin in Treatment-Naive HCV-Infected Subjects with Genotypes 1b and 4 (HELIX-1 Study). 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract P1222.
Idenix Pharmaceuticals. Idenix Announces Promising Clinical Data and Continued Progress in Nucleotide Prodrug Development Programs for the Treatment of Hepatitis C. Press release. April 7, 2014.