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4.1.5 Direct-Acting Antiviral Combos

4.1.5 Direct-Acting Antiviral Combos

At this point in time, our Direct Acting Antivirals (DAAs) are usually combined in trials with pegIFN and RBV, but a serious search is being conducted for all-oral treatments without interferon and its side-effects. Here are some of the not-just-interferon-based combo trials that have been taking place:

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4.1.5a Protease-Polymerase Combos

R1626 + VX-950: A study presented at EASL conference in April of 2007 combined the polymerase inhibitor R1626 (R1479) and the protease inhibitor VX-950 (Telaprevir/Incivek-approved in 2011). Although the latter as monotherapy was very potent, new HCV resistant strains developed quickly. Combining VX-950 with standard treatment prevented resistance. The researchers have shown in vitro that R1626 and VX-950 are not cross-resistant, that R1626 may be more of a barrier against resistance than VX-950, and believe that combining the two can also prevent resistant strains of the virus from emerging. In test tubes, each product cleared the mutant strains left by the other.

ITMN-191 + R7128 (INFORM-1): Probably the most exciting news at the EASL conference in 2009 was the report from the study combining two oral HCV drugs—a milestone in HCV drug development. The Phase I INFORM-1 study enrolled 57 treatment-naïve patients in Australia and New Zealand, combining the protease inhibitor ITMN-191 (aka R7227) with the polymerase inhibitor R7128. More cohorts (arms) were added for non-responders and null responders, for twice a day dosing, and for higher doses of ITMN-191. It is especially unusual because it does not include interferon. Results from the first 4 cohorts showed the combination is safe and effective, even without IFN, in treatment-naive HCV patients.

The original INFORM-1 protocol consists of four dosage cohorts—A, B, C and D—with a total of six dosing groups:

  • Cohort A consists of two dosing groups, Group A and Group B. Group A patients take 500 mg 2x/day of R7128 alone for 3 days, then combine it for 4 days with 100 mg every 8 hours of ITMN-191. Group B patients take 100 mg every 8 hours of ITMN-191 alone for three days and then 4 days combined with 500 mg 2x/day of R7128.
  • Cohort B patients (Group C) receive the same doses of R7128 and ITMN-191 as in Cohort A, but for 14 days in combination.
  • Cohort C has two dosing groups: Group D and Group E. Group D patients take 1000 mg twice daily of R7128 and 100 mg of ITMN-191 every 8 hours. Group E patients receive 500 mg twice daily of R7128 and 200 mg every 8 hours of ITMN-191.
  • Cohort D (Group F) patients take 1000 mg twice daily of R7128 and 200 mg of ITMN-191 every 8 hours.

The new design includes three more dosage cohorts, as follows:

  • Cohort E: Treatment-experienced genotype 1 patients take the combination of both ITMN-191 (600 mg) and R7128 (1000 mg), or placebo, twice-daily.
  • Сohort F: Null-responder genotype 1 patients. Null response is having less than a 2.0 log10 drop in RNA at week 12, and/or less than a 1.0 log10 decline at week 4. Patients take ITMN-191 (900 mg) plus R7128 (1000 mg), or placebo, twice daily.
  • Cohort G: Treatment-naive patients take the combo twice-daily of ITMN-191 (900 mg) and R7128 (1000 mg), or placebo.

Patients receiving the combination of R7227 and R7128 for 14 days—without pegIFN or RBV—had an average drop in viral levels of 4.8 to 5.2 log10, with the highest doses. Adding R7128 to R7227 resulted in 63% of patients dropping to undetectable. 25% in the highest dosage groups tested undetectable at 14 days. (EASL Conference 2009)

BI 201335 + BI 207127: BI 201335 is an NS3/4A protease inhibitor produced by Boehringer Ingelheim Pharmaceuticals. It has been shown to be effective in previous trials. The company announced results from its SOUND-C1 non-interferon trial, which tested a combination of its protease inhibitor, its polymerase inhibitor and ribavirin. 17 patients were treated. 2 of the patients, both GT-1a with a high baseline viral load, experienced breakthrough. On the 29th day of treatment, all patients were put on standard therapy plus BI 201335, the protease inhibitor. All eventually tested undetectable. (natap.org AASLD 2010)

BI 201335 was administered with SOC to 429 GT1 subjects, both treatment-naïve and treatment-experienced, in the SILEN-C1 Phase II trial. The best results were seen in the 240 mg daily dose arm, in those who had an extended rapid viral response (at weeks 4, 8 and 20), showing a 93% SVR with only 24 weeks of SOC. Interestingly, a 3-day lead-in treatment with SOC alone produced higher rates of breakthrough. 4-12% dropped out due to adverse events. The US FDA has granted fast-track designation to approve the marketing of this drug combined with SOC, and also of the IFN-free combination of this protease inhibitor BI 201335 with BI 207127, their polymerase inhibitor, for G1 patients. Phase II trials of the IFN-free combo, with and without RBV, have begun. (EASL Conference 2011)

The company has begun to recruit 1,875 HCV+ subjects, starting with North America, for a Phase III trial which will investigate BI 201335 plus pegIFN/RBV in both treatment-experienced and –naive HCV+ GT1 patients. There are currently three Phase III trials enrolling patients in the US, Canada, Taiwan and Korea. Results from the Phase III studies are expected in the first half of 2013.
(www.natap.org/2011/HCV/04301103.htm 27 April 2011)

ABT-450 + ABT-333 or ABT-072
Abbott announced data from its clinical trial suggesting patients could achieve an SVR without IFN and with shorter treatment time, hopefully in 90% of subjects. 44 treatment-naïve subjects were enrolled and given ABT-450r (ABT-450 boosted with ritonavir) plus either ABT-333 or ABT-072 and RBV (ribavirin) during 12 weeks. All patients still being treated at 12 weeks had an EVR, and of the 10 patients who have been tested 24 weeks after finishing the 12-week trial, 9 achieved an SVR. The FDA has granted fast-track status to the regimen. It is expected to be available to the public by 2015. The company is developing a 4-in-one pill including ABT-450r, 2 polymerase inhibitors, and RBV.
(www.pharmpro.com/News/2011/10/Business-Abbott-Announces-Positive-Data-from-Mid-Stage-t 24 Oct 2011 and
www.nature.com/nm/journal/v17/n12/full/nm1211-1526.html 6 Dec 2011)

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4.1.5b Danoprevir + Ritonavir+ PegIFN/RBV

Danoprevir (RG7227 or ITMN-191) is an NS3/4A serine protease inhibitor. Abbot’s Ritonavir (RTV or Norvir) is an HIV protease inhibitor that inhibits a liver enzyme called CYP3A4. CYP3A4 metabolizes the “good” protease inhibitors, weakening them. RTV lets the “good” protease inhibitors work longer, so a lower dose of them can be just as effective. This drug is already FDA-approved for use in HIV/AIDS. It has been used in co-infected patients, and is being used in trials to “boost” some Hep C protease inhibitors in patients infected with only HCV.

This trial was designed for GT1 patients who had no response to previous therapy with pegIFN/RBV plus Danoprevir.

24 patients were treated for 12 weeks with danoprevir/ritonavir/pegIFN/RBV, and some continued for 36 weeks of pegIFN/RBV alone. The rapid response rate for GT1b patients was 88%, with only 6% breakthough cases by week 12. Unfortunately breakthrough was 50% for GT1a patients by week eight.

The researchers plan to add another drug in GT1 null responders, such as mericitabine (RG7128)

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4.1.5c Clemizole

Clemizole, produced by Eiger BioPharmaceuticals, is an inhibitor of the virus’ NS4B-RNA binding. This recently-discovered binding has become a target for new drugs, since the binding is needed for the virus to replicate. Clemizole is being investigated in all genotypes, in several clinical trials, as a substance to boost standard of care medications, making them more effective and decreasing resistance, since it targets the interaction between NS4B and the HCV-RNA. Adding clemizole to protease inhibitors may allow them to be used at lower doses, while keeping the desired antiviral effect and avoiding the side-effects caused by the protease inhibitors such as rash and anemia. “Clemizole has the potential to be an ideal component of future anti-HCV cocktails," said the company’s founder, Dr. Jeffrey Glenn, M.D., Ph.D.
(www.therapeuticsdaily.com Jul. 01, 2010)

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4.1.5d BMS-650032 + BMS-790052 Combos

BMS-650032 + BMS-790052
Bristol-Myers presented results from their protease + NS5A inhibitor trial. The results at 12 weeks after finishing quadruple therapy showed 100% of the patients testing undetectable, with no resistant variants emerging in the 21 null-responders who took part in the trial. (19 had unfavourable IL28B genotypes.) The patients received SOC plus BMS-650032 (an HCV NS3 protease inhibitor) and BMS-790052 (an HCV NS5A replication complex inhibitor). This may be the future of HCV therapy, and new hope for non-responders. Null responders have a 30% response rate to SOC plus telaprevir, so treatment is still needed for the other 70%.

In a later, Phase IIb no-IFN trial, 10 GT1b non-responders were treated with BMS-650032 + BMS-790052 and in the 9 patients who finished the treatment all tested undetectable from week 8 to the present. The other patient—a 60 year old woman—dropped out at week 2 because of remaining HCV+ and because of a high level of bilirubin and gastroenteritis that may have been caused by the drug(s). Interestingly, her virus was undetectable 24 weeks after her planned end of treatment.

The drugs, also called asunaprevir (protease inhibitor) and daclatasvir (NS5A inhibitor) were given orally. The dose of asunaprevir was reduced because of elevated liver enzymes occurring in a different study. The patients were treated for 24 weeks and observed for the following 24 weeks. There was a case of grade 3 fever which was considered serious. "The adverse event profile compares favourably with historical experience with peginterferon and ribavirin," said the study’s author.
(Hepatology 2011; 54(4): Abstract LB-4. Nov 14, 2011 www.medpagetoday.com/MeetingCoverage/AASLD/)

UPDATE: Recent study results from the above Phase II trial in 21 non-responder genotype 1 patients showed that 9 of 10 patients in the pegIFN/RBV/asunaprevir/daclatasvir arm, still tested undetectable after 24 weeks. This is the first study to show sustained response without using interferon. More trials are in progress.

BMS-790052 + GS-7977 (Formerly PSI-7977)
Bristol-Myers Squibb and Pharmasset are collaborating on a clinical trial combining BMS-790052, an NS5A inhibitor, and GS-7977, a polymerase inhibitor. It is encouraging that two companies are collaborating in developing combinations of therapies. This is a real step forward.

Pharmasset has begun a Phase IIa study with the combination of BMS-790052 and GS-7977, hoping that these drugs can provide an all-oral treatment without interferon side effects. The company will study several 24-week regimens of the two drugs, which have been shown to work well with PegIFN/RBV. (A combination of BMS-790052 plus BMS-650032 resulted in high response rates in previous non-responders. See 4.1.5d) The subjects will be treatment-naïve genotype 1, 2 and 3. Some arms of the trial will include a lead-in period of 1 week with GS-7977 by itself, and then combining it with BMS-790052. Other arms will add RBV to the trial drugs.

BMS-790052 + TMC435
Bristol Myers-Squibb and Tibotec have agreed to work together to investigate the benefits of combining the NS5A inhibitor daclatasvir (BMS-790052) with the NS3 protease inhibitor, TMC435 in a Phase II trial expected to start in the first part of 2012. Researchers will be looking for SVR at 12 and 24 weeks post treatment in GT1 patients. There will be 3 once-a-day treatment arms: 1) daclatasvir/TMC435/pegIFN/RBV; 2) daclatasvir/TMC435/RBV; or 3) only daclatasvir/TMC435. Their goal is to find an all-oral treatment for hepatitis C.
(www.businesswire.com Dec. 02, 2011)

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4.1.5e GS-7977 + PSI-938

GS-7977 (formerly PSI-7977) has been combined with standard treatment in genotypes 1, 2 or 3 patients and is involved in two Phase IIb studies, including one IFN-sparing study with genotype 2 or 3 patients. PSI-7977 is being used in a 14-day combination study with the guanine nucleotide analog PSI-938.

Trial arms with PSI-938 are on hold due to elevated enzymes at higher doses. GS-7977 is not suspected.

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4.1.5f ABT-450 + ABT-333

Abbott is recruiting GT1 treatment-naïve subjects for a Phase II of ABT-450 with Ritonavir (ABT-450/r) combined with ABT-333 and Ribavirin (RBV).
(http://clinicaltrials.gov/ct2/show/NCT01306617?term=abbott+hepatitis+c&rank=3 )

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4.1.5g IDX184 + IDX375

IDX184, a nucleotide prodrug polymerase inhibitor, seemed to be safe and easily tolerated in healthy volunteers in single doses up to 100 mg. Previous studies in HCV-infected chimpanzees showed viral load reduction. There was a study which enrolled treatment-naïve genotype 1 subjects, who were taking 25, 50, 75 and 100 mg of IDX184 daily. (EASL 2009)

IDX375: Idenix has enrolled about 78 subjects, both healthy and treatment-naïve GT1 patients, to test the effect of several doses of IDX375, a non-nucleoside polymerase inhibitor as monotherapy. Dose escalation will be tried in healthy subjects. The trial is being carried out in Belgium and Moldova. Dosing is for 3 days, with a 25-day follow-up.
(http://apps.who.int/trialsearch/trial.aspx?trialid=ISRCTN80501908 7 June 2011)

In 2009, a Phase II trial of IDX375 combined with pegIFN/RBV was administered to treatment-naïve GT1 patients, who were to take pegIFN/RVB + IDX184 or a placebo once daily for 14 days and continue with pegIFN/RBV for another 14 days. The study was done in the US and Argentina.

The company has also done in vitro trials combining IDX375 with some of their other direct-acting antivirals such as IDX184 and IDX320 (a protease inhibitor which proved toxic). Some trials showed that these combinations can significantly improve suppression of HCV compared to single agents or double combinations

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4.1.4f BIT225

Hepatitis C FAQ

4.2.0 Other Therapies