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New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist
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From Jules Levin
Highlights yesterday at AASLD include a Merck poster reporting on their new HCV protease inhibitor 5172, where with 7 days monotherapy 400mg once daily the mean maximal reductions from baseline of HCV RNA viral load were 5.4 and 3.98 log reductions in genotype 1 (n=6) and of note genotype 3 (n=6). There was no on-treatment viral rebound, 5 genotype 1 patients had decreases in viral load below the limit of detection during the study, drug was 'generally well tolerated with no serious adverse experiences, discontinuatios due to adverse events, or safety lab abnormalities. As I reported yesterday PSI-7977 a nucleotide from Pharmasset looks good, R7128, a nucleoside from Roche & Pharmasset looked good after 12 weeks treatment in naives with peg/rbv a high percent of patients achieved undetectable viral, of note no drug resistance was seen in R7128, this is an important benefit of nucleosides & nucleotides, Pharmasset also reported prior to conference data showing potency of PSI-938, a nucleotide & they will conduct a study of the 2 nucleotides in combination as oral therapy without peg/rbv. There will be several studies reported here at AASLD looking at 2 oral therapies: by Gilead with & without ribavirin, by BMS with their protease & NS5A inhibitor, and by Boerhinger ingelheim. These are noteworthy & show that the field is moving ahead. Today are late breaker posters & orals on new HCV drugs.
In yesterday's 2 oral sessions at 3pm doses of 200mg bid and 400mg bid of ANA598, a NNRTI for HCV, + peg/rbv study results were presented out to 12 weeks with 75% using 400mg, 73% with 200mg and 63% with peg/rbv alone achieving undetectable viral load. Those patients with IL28B CC genotype, the gene that is associated with better response to peg/rbv: 100% receiving 200mg bid (n=4) and 82% taking 400mg bid achieved undetectable viral load at week 12. Patients in the study received a loading dose of 800mg ANA598 at beginning of dosing in study. Patients with CT & TT polymorphisms had lower rates of undetectable viral load at week 12: 73% with 200mg bid, about 68% (see pics below) with 400mg bid and 43% with peg/rbv alone. However at 200mg bid safety & tolerability was comparable to peg/rbv placebo arm 38% in 200mg ANA598, 34% on peg/rbv alone) but at 400mg bid rash had an increase in incidence & severity with 50% (n=17) of patients on ANA598 having a grade 1 rash, compared to 34% (n=11) in peg/rbv alone group; 3% (n=1) on 400mg ANA598 had grade 2 rash compared to 0 in peg/rbv group and 200mg bid group; grade 3 rash: 3% (n=1) on 200mg bid, 9% (n=3) on 400mg bid, 0 on peg/rbv. There were no grade 4 rashes in any of 3 treatment groups. Only 1 patient discontinued due to rash, this patient experienced a grade 3 rash on 400mg bid ANA598.
The Roche/Genentech HCV protease inhibitor RG7227 (danoprevir) had 12 weeks data presented from phase 2 study in genotype treatent-naives in combination with pegasys/rbv. Boosted danoprevir with low dose ritonavir is the treatment now being moved forward by Roche in studies. This presentation reviewed the ALT elevations some patients experienced on danoprevir: grade 4 elevations - 0 on danoprevir 300mg bid, 1 patient (n=72) on 600mg bid, and 3 (n=50) on 900mg bid. The elevations were reported to be asymptomatic, occurred between 6 and 12 weeks of dosing, were reversible upon discontinuation of danoprevir, and one case was associated with elevated bilirubin, "modeling of available data confrms relationship between danoprevir exposure (AUC) and likelihood of ALT elevations. Resistance was detected only in genotype 1a failures none in genotype 1b, "Danoprevir otherwise was well-tolerated. That's why danoprevir is now being moved ahead in further studies with low-dose ritonavir, and at lower doses of danoprevir, this dosing scheme allows for PK (lower danoprevir AUC & Cmax) such that these ALT elevations would not be expected to be seen and so far there have been no reports of these ALT elevations at the new dosing approach. They showed the new study scheme that will examine the new dosing approach: the Dauphine Study will look at danoprevir 200mg, 100mg and 50 mg bid with each dose boosted by 100mg ritonavir for 24 weeks all i combination with Pegasys/rbv, and an arm looking at danoprevir/r 100/100+peg/rbv for 12 weeks. But this study presented today showed the potency of danoprevir even unboosted, boosted would be expected to be more potent. At week 12 88% taking 300mg bid+peg/rbv, 89% taking 600mg bid+peg/rbv and 92% taking 900mg bid+peg/rbv achieved undetectable viral load compared with 43% taking peg/rbv alone.
In this oral session IMO-2125, a TLR agonist, study in null-responders was presented by Idera Pharmaceuticals. 75% of subjects receiving 0.16 to 0.48 mg/kg/wk x 4wk had ≥1log10 decrease in viral load. "Proof of concept achieved in null responders". "There was IMO-2125 dose-dependent immune activation: Increase in NK cells and helper and cytotoxic T cells; Increase in antiviral cytokines and chemokines; Dose-dependent induction of endogenous interferon-α. "Reduction in viral load correlates with IFN-αinduction". "Proof of concept achieved in null responders: Supports further development and studies in other populations". "Ongoing studies: Twice-weekly dosing; Combination with ribavirin in treatment-naïve patients".
From press release: Idera Pharmaceuticals, Inc. (Nasdaq: IDRA) announced today the presentation of data from a Phase 1 clinical trial evaluating IMO-2125, a novel immune modulator, in null-responder patients with chronic hepatitis C virus (HCV) infection. The oral presentation, entitled "IMO-2125, a TLR9 Agonist, Induces Immune Responses which Correlate with Reductions in Viral Load in Null-Responder HCV Patients" (Abstract #33), is being made by Maribel Rodriguez-Torres, M.D., of Fundacion de Investigacion in Santurce, Puerto Rico at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
"The data presented from this trial support the target product profile of IMO-2125 as a novel immune modulator with the potential to be used as a key component of HCV treatment"
"Null-responder patients are the most difficult HCV patients to treat and represent an area of significant need as there are currently no approved treatment options for these patients," said Dr. Rodriguez-Torres. "The data presented show that IMO-2125 induced a broad immune response including induction of endogenous interferons. This suggests that IMO-2125 may provide an alternative to the recombinant interferon component of HCV treatment."
This Phase 1 clinical trial evaluated 51 null-responder HCV patients; 41 patients received IMO-2125 monotherapy at five dose levels and 10 patients received placebo once per week for four weeks. Most of these patients were infected with HCV genotype 1 and had the CT or TT IL28B gene alleles. IMO-2125 was well tolerated at all dose levels. IMO-2125 induced a broad immune response with dose-dependent increases in serum concentrations of antiviral proteins and activation of cellular immune responses. Across the three highest dose levels, seventy-five percent of patients achieved a 1 log10 or greater decrease in viral load at least once during the treatment period. Consistent with the proposed mechanism of IMO-2125, induction of higher serum concentrations of interferon-alpha correlated with greater decreases in HCV viral load. Additional patients are being enrolled in this Phase 1 trial to evaluate twice-weekly dosing of IMO-2125.
"These data demonstrate that in the trial once-weekly dosing of IMO-2125 in null-responders induced a distinctive pattern of immune activation and achieved dose-dependent viral load reductions," said Robert Arbeit, M.D., VP of Clinical Development of Idera Pharmaceuticals. "To optimize the dosing schedule and maximize antiviral activity we are continuing the trial to evaluate twice-weekly dosing of IMO-2125."
R7128 is a nucleoside from Roche & Pharmasset, today's data in combination looked good, showed good percentages of patients undetectable, no resistance. See pic below. PSI-7977 is one of two nucleotides from Pharmasset, looks good, see pic below. MK-7009 a protease inhibitor from Merck showed potency in combination with peg/rbv with 80% SVR rate after 48 weeks therapy but there was vomiting among some of the patients in the study, the presenter said they were moving into phase 2b.
R7128
PSI-7977
ANA598
Danoprevir
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