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IDX184 a weak nuke?
  (1) IDX184 Monotherapy 3 days - Idenix Pharmaceuticals Successfully Completes Proof-of-Concept ...

Idenix Reports Advancement of HCV Development Pipeline: new NS5A & 'next-generation' nucleotides - (01/09/12)

Idenix Reports Positive Interim Data for HCV Nucleotide Inhibitor, IDX184 - (01/09/12)

Idenix Update Slides - IDX184 Nucleotide, new IDX719 NS5A (slides attached from investor call this morning), 2 new nucleotides in development (IDX19368/IDX19370) - (01/09/12)

Interim Phase IIb Data Encouraging; Can a Weak Nuke Be Part of the Future?

from Katherine Xu, William Blair Securities

Before the markets opened on Monday, January 9, Idenix reported 28-day interim data for the first 31 hepatitis C (HCV) treatment-naïve genotype 1 (GT1) patients from the ongoing 12-week Phase IIb study of its lead nuke (nucleotide polymerase inhibitor) candidate IDX184 in combination with PEG-interferon plus ribavirin (P/R).

· So far so good on safety: Data Safety Monitoring Board (DSMB) has concluded that there is no hepatoxicity and recommended the study to continue. Management noted that IDX184+P/R demonstrated a safety profile consistent with that of P/R alone and no serious adverse events (SAEs) were observed. There was no evidence of hepatoxicity and 90% of the patients had normalized liver enzymes to date, with median exposure to IDX184+P/R of approximately 8 weeks. There were two discontinuations due to AEs, nausea and severe anemia.

· Rapid virologic response (RVR) and 8-week response rate in line with the other weak nuke, Roche's mericitabine (figure 2). Treatment with IDX184+P/R led to RVRs of 63% and 73% for the IDX184 50 mg dosed daily (QD) and 100 mg QD cohorts, respectively. In addition, 94% and 87% of patients in the IDX184 50 mg QD and 100 mg QD cohorts, respectively, had undetectable virus with a median of 8 weeks on treatment. As a comparison, Roche's (RHHBY $43.34) mericitabine demonstrated a 62% RVR, and 80%-87% EVR (early virological response at 12 weeks) in the PROPEL study. We note that both IDX184 and mericitabine are weaker nukes that led to about 1 log viral load drop in 3-day monotherapy studies. A stronger nuke, such as PSI-7977 of Pharmasset that led to close to 4 log drop at 3 days, had demonstrated close to 100% RVR and EVR when in combination with P/R.

· The interim data and the DSMB decision have been submitted to the FDA, and the partial clinical hold could be removed in Februray. Idenix submitted both the interim data from the first 31 patients in the study as well as the DSMB's recommendations to the U.S. Food and Drug Administration (FDA) requesting the removal of the partial clinical hold on IDX184 and continuation of the Phase IIb study. The FDA could respond within 30 days. With such data and the positive recommendation from the DSMB, we believe that it is highly likely that the partial clinical hold will be removed.

· Full safety and efficacy data from the study is likely to be presented at the upcoming 2012 International Liver Congress (EASL, Barcelona, Spain; April 18-22, 2012).

The acquisitions of Pharmasset by Gilead (GILD $42.78; Outperform) and Inhibitex by BristolMyers Squibb (BMY $33.91) showcase the value of potent nukes. How should a weaker nuke such as IDX184 position for the future?

· An IDX184+R combination will likely not suffice.
It has been demonstrated that nukes are a preferred class for a Holy Grail-like regimen because nukes have high genetic barrier to resistance and are pan-genotypic. Pharmasset (VRUS $131.37; Market Perform) further demonstrated in 2011 that if a nuke is potent enough, there is no need for another potent agent from a different class; a generic partner of ribavirin will suffice. Such demonstration significantly increased strategic value of potent nukes. In the case of IDX184, which appears to be much weaker in potency than PSI-7977 of Pharmasset or INX-189 of Inhibitex, we do not believe an IDX-184+R combination would suffice to produce high SVRs (sustained virological response, or cure rate), such as 90%.

· IDX184+MK5172?

Merck's Victrelis is currently on the market as a distant second to Vertex's (VRTX $34.05; Outperform) Incivek. Behind Victrelis, the most notable in Merck's HCV pipeline is MK-5172, a pan-genotypic protease inhibitor (PI). We note that MK-5172 could drop viral load by over 5 logs in both GT 1 and GT 2/3 patients, the highest potency demonstrated for any DAAs to date. The compound can also overcome the typical PI resistance with its high potency and high pharmacologic barrier to resistance. We believe that MK-5172, although extremely potent, may still select for fit mutations due to lower genetic barrier to resistance as compared to the nukes. In our opinion, MK-5172 could pair with another nuke to form a strong pan-genotypic, QD, Holy Grail combination. With MK-5172's high potency, a MK-5172+IDX184 combo might be sufficient with IDX184 contributing modest potency and high barrier to resistance. Furthermore, Merck needs to find a partner for MK-5172, and IDX184 is now the only nuke left in the field that is in Phase II development.

· IDX184+IDX179? Idenix has its own NS5a inhibitor candidate IDX179 that has just entered the clinic, with initial viral kinetic data available in mid-2012. IDX179 looks to be a potent, pan-genotypic compound that is more active across genotypes as compared to the first-generation NS5a inhibitors such as BMS-790052. Could a weak nuke IDX184 and a second-generation NS5a inhibitor IDX179 form a combo that produces sufficiently high SVR? We note that the leaders in the race, Gilead and Bristol-Myers Squibb, also have the nuke+NS5a combos: PSI-7977+GS-5885, and INX-189+BMS-790052; these two combos might be stronger than the IDX184+IDX179 combo.

· What is Roche doing with mericitabine? Roche is conducting a few combination studies with its nuke mericitabine, including mericitabine+danoprevir (ritonavir-boosted) with or without R, and mericitabine+Victrelis+P/R. Compared to mericitabine, IDX184 is once daily, of much lower dosage (100 mg QD vs. 1000 mg BID), and could have synergy with R as IDX184 is a guanosine analog. Roche's moves might provide insight to Idenix as to how to position a weak nuke for the future.

Brief history of the IDX184 clinical hold. In September 2010, IDX184 was placed on full clinical hold by the FDA based on three SAEs related to liver toxicity observed in the Phase I drug-drug interaction (DDI) study of IDX184 and the company's protease inhibitor (PI) IDX320. In February 2011, the full clinical hold on IDX184 was converted by the FDA into partial clinical hold and Idenix discontinued the development of IDX320, based on the company's conclusion that the observed toxicity in the DDI study was likely caused by IDX320.

Review: Design of the current Phase IIb study (figure 1). Initiated in July, the 12-week Phase IIb study plans to enroll and randomize 100 treatment-naïve, genotype 1 (GT1) patients to receive the combination of P/R with either 50 mg QD or 100 mg QD of IDX184; the study design does not include a placebo+P/R control arm (figure 1). Following the initial combination therapy, patients will receive either an additional 12 or 36 weeks of P/R, dependent upon a response-guided protocol assessment of early rapid virologic response (eRVR). The study also stratifies patients according to IL28B status as well as liver histology. The primary objective is safety, tolerability and sustained virological response (SVR). Due to the partial clinical hold on IDX184, the study includes two formal interim safety reviews: 1) after the first 30 patients complete 28 days of treatment and 2) after the first 60 patients complete 28 days of treatment.

Pipeline update: Proofofconcept data from NS5A inhibitor IDX179 expected in second quarter; IND filing of nextgeneration

nukes IDX19368 and IDX19370 expected by mid2012

In January 2012, Idenix initiated a Phase I study evaluating IDX179 in healthy volunteers; proof-of-concept data from the pan-genotypic NS5A inhibitor are expected by second quarter 2012. The company also commented that it is on track to file an investigational new drug (IND) application for its preclinical nuke candidates, IDX19368 and IDX19370, by mid-2012 and initiate proof-of-concept studies by year-end 2012

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