April 13, 2012

GS-7977 Phase 3 in Genotype 2/3 Started, in Gt1 Soon waiting for QUANTUM results, nucleotides & Other HCV Drugs

Provided by NATAP

CORRECTION: The analysts reporting online is wrong regarding the BMS' NS5A+ GS7977 with or without ribavirin study. The presentation at EASL will report on the 24 week study, so the analysts report from the leaked abstract that the 12-week data is End Of Treatment is not correct. The 97% reported in the online leaked abstract is after 12 weeks on treatment that is of 24 weeks duration. There is a lagging cohort of this study that looks at 12 weeks total therapy, but this part of the study started later so results will be reported later.

From jules: Nucleotides are considered an important component of an HCV therapy regimen because they are potent & are not associated with developing drug resistance easily at all. Its worth repeating that the recent Gilead announcement that in a small study of null responders patients had undetectable viral load at the end of 12 weeks treatment with GS7977+RBV but virologically failed after stopping therapy has been misinterpreted in that observers think this is a bad commentary on this class of drugs. NOT, this is not the case. First, the patients were all undetectable after 12 weeks treatment, at the end of therapy, this is a great sign. Second, the therapy was ONLY 7977+RBV, essentially 1 drug in the hardest to treat patient population. HELLO, although 100% were cured in genotype 2/3 with the same therapy, this is the hardest to treat patients. Three, add more drugs to the regimen and/or longer duration of therapy to 24 weeks & I anticipate we will see very good results. This is in the context that at EASL next week Abbott is presenting 95% SVR rates in gt1 with 2 oral drugs, interferon-free ABT450 (a protease) plus a NNRTI (either ABT072 or ABT333, 2 studies), and at the end of 12 weeks treatment we heard preliminarily, a leak, that the 2 oral drug interferon-free regimen of BMS' NS5A+ GS7977 produced 97% undetectable viral load at the end of treatment. We are also poised to see soon results from the combination of TMC435+GS7977, TMC435 is the potent Tibotec protease. Bot these these NS5A+protease combinations are being studied with & without ribavirin & are interferon-free. Interestingly the Abbott protease ABT450 is boosted with low dose ritonavir & so is the Roche protease danoprevir which also appears to be very potent, so does boosting with low dose ritonavir provide a special significance related to potency & a barrier to resistance as it does in HIV? I suspect it does, lets wait for more info on this. There will be oral presentations on ATOMIC, PROTON, ELECTRON at EASL. QUANTUM study results expected soon after EASL. GS7977 is a nucleotide, it is the furthest along in development (phase 3 in gt2/3 & about to enter phase 3 in gt1), showed an average 4.5 to 5 log reduction in viral load with monotherapy over 7-14 days, while INX189 the Inhibitex nucleotide acquired by BMS showed an average viral load reduction of 4.25 logs after 7 days monotherapy and this nucleotide is further back in clinical development. Alios' 2 nucleotides were acquired by Vertex & we expect the first early clinical data this Spring, very soon. So, put this information together. Several years ago I predicted we would see 100% cure rates. NS5A inhibitors are an important class of drugs because they also are very potent with BMS' showing up to over 5 logs viral load reduction in monotherapy in gt1b and 3.3 logs in gt1a, this NS5A is in phase 3 clinical development now, there are additional NS5A inhibitors in earlier stages in development by other companies including Abbott, Achillion, Gilead, Presidio, Idenix & Merck. There are numerous potent new HCV protease inhibitors in development for which we will see updates at EASL next week including from Roche, Boerhinger Ingelheim, Abbott, Tibotec, Merck with BI & Tibotec in phase 3 now & Merck in 2b & Abbott & Roche about to enter phase 3, in addition to the 2 protease inhibitors that were approved last year boceprevir & telaprevir. There are numerous NNRTIs in development; there is a potent cyclophillin inhibitor from Novartis in phase 3 with updates in gt1 and gt2/3 at EASL.

BMS-790052, a First-in-Class Potent Hepatitis C Virus NS5A ... www.natap.org/2010/AASLD/AASLD_58.htm Nov 3, 2010 - Background: NS5A plays a central role in hepatitis C virus (HCV) replication. BMS-790052 is a first-in-class and potent NS5A inhibitor

PSI-938 and PSI-7977 as monotherapy and in combination & INX189 Monotherapy

ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 ... www.natap.org/2011/EASL/EASL_07.htm Apr 3, 2011 - PSI-938 and PSI-7977 as monotherapy and in combination were ... Of note, PSI-7977 monotherapy produced HCV RNA reductions over 7 days

INX189 Monotherapy at Higher Dose 200mg

AASLD: Antiviral Activity and Safety of INX-08189, a Nucleotide Polymerase Inhibitor, Following 7-Days of Oral Therapy in Na•ve Genotype-1 HCV Patients - (11/07/11)

Pharmasset Announces the Initiation of an Interferon-Free Phase 3 ... www.natap.org/2011/HCV/110111_02.htm Nov 1, 2011 - The final design of the trial will be based on emerging data from ongoing studies, including ELECTRON and QUANTUM

Pharmasset Initiates QUANTUM, a Phase 2b Interferon-Free Trial of ... www.natap.org/2011/HCV/091611_02.htm Sep 13, 2011 - The QUANTUM trial will evaluate interferon-free regimens of PSI-7977 400mg QD and PSI-938 300mg QD with and without ribavirin over 12 or

Pharmasset Announces Intent to Amend QUANTUM Trial - PSI938 ... www.natap.org/2011/HCV/121611_02.htm Dec 16, 2011 - 16, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that the company will amend the design of the QUANTUM

(dec 2011) PSI7977 stays intact; PSI7977+R up for testing in GT 1 patients with data out late first quarter 2012. To date, over 400 patients have been exposed to PSI-7977 for 12 weeks or longer, and no notable safety signals have been identified. The goal of the QUANTUM study is to test whether the PSI-7977+R regimen for 12 weeks could also achieve the same near-100% SVR in genotype 1 (GT 1) patients as it did in GT 2/3 patients, and if 12 weeks of PSI-7977+R treatment is not sufficient, whether 24 weeks will be. The SVR data will be available during late first quarter or early second quarter 2012, by our estimation. We believe this will be the decisive data for Gilead and Pharmasset to have a pan-genotypic, all-oral regimen in hand to take into full blown Phase III studies.

Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes - (03/31/11)

PSI-7977 400 mg with PEG/RBV Provides 93% SVR Across HCV GT ... www.natap.org/2011/hepDART/hepDART_02.htm Dec 4, 2011 - Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes - (03/31/11) Gilead Sciences to Acquire Pharmasset,

Pharmasset Announces Further Expansion of ELECTRON Trial in ... www.natap.org/2011/HCV/101011_01.htm Oct 10, 2011 - "We look forward to reporting SVR12 results from Part 1 and interim data from the PSI-7977 monotherapy arm of ELECTRON on Sunday,

PSI-7977: ELECTRON Interferon is not required for Sustained ... www.natap.org/2011/AASLD/AASLD_07.htm - Translate this page PSI-7977: ELECTRON Interferon is not required for Sustained Virologic Response in Treatment-Na•ve Patients with HCV GT2 or GT3. Reported by jules Levin

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