The Street.com: Bristol-Myers Missing Hep C Data Raises Red Flags, May Boost Gilead, Idenix

Posted on 5/7/12 on The Street.com. The Street.com's Nathan Sadeghi-Nejad is picking up some signals that BMS might be having trouble with his polymerase inhibitor INX-189 (now BMS-094) acquisition from Inhibitex. Namely, Sadeghi-Nejad points to a chemical called 1-naphthol that is a byproduct of in the metalbolization of  BMS-094 that is toxic to hepatocytes. Details below. 

Bristol-Myers Missing Hep C Data Raises Red Flags, May Boost Gilead, Idenix

Nathan Sadeghi-Nejad
05/07/12 - 07:00 AM EDT

NEW YORK (TheStreet) -- Since my return from the European Association for the Study of the Liver (EASL) conference two weeks ago, I have been unable to get over the strange behavior of executives at Bristol-Myers Squibb(BMY). As I discussed in my EASL wrap-up, investors should view with suspicion Bristol-Myers' complaints about Gilead Sciences'(GILD) refusing to collaborate on a late-stage study of the hepatitis C drugs GS-7977 and daclatasvir partnership. Then there's Bristol-Myers' odd and prolonged silence about INX-189 -- the nucleoside polymerase inhibitor, or "nuc," acquired in the $2.5 billion Inhibitex deal.

I suspect something is wrong with Bristol-Myers' INX-189, which has since been renamed by the company as BMS-094. The red flags are popping up everywhere. If I'm right about Bristol-Myers being in trouble, Gilead's lead in the race to develop all oral therapies for hepatitis C will expand and Idenix Pharmaceuticals'(IDIX) hepatitis C drugs become more attractive.

Let's examine the details:

1. New BMS-094 data should have been available by EASL. In mid-January, Bristol-Myers completed enrollment in a Phase II trial of BMS-094 in genotype 2/3 patients, an easier-to-treat subpopulation of hepatitis C. By the time the hepatitis C world gathered in Barcelona for EASL in April, Bristol-Myers likely had four-week and 12-week on-treatment viral response data from this study. These results will provide an important first look at BMS-094's efficacy and safety, yet Bristol-Myers said nothing about the data at EASL.

2. Bristol-Myers passed on a second chance to provide insight on BMS-094 during the company's first-quarter earnings conference call. At least 16 weeks have now passed since the study completed enrollment. By now, Bristol-Myers should have four-week sustained virologic response (SVR4) data, an early indication of cure.

Yet on its April 26 conference call, Bristol-Myers executives once again declined to provide a meaningful clinical update on BMS-094. Instead, Chief Scientific Officer Elliot Sigal spoke in generalities about the drug.

"We feel that there are multiple doses that are safe for human testing from 50 to 200 [mg]," said Sigal , referring to BMS-094. "We will be getting more experience with 200 [mg] throughout this year. We will have safety data on a range of doses of 50 to 100 [mg], which we will at least have internally and hopefully talk about towards the end of the year." [Emphasis mine.]

3. BMS-094 produces a toxic metabolite. At a scientific conference in 2010, Inhibitex presented preclinical data on the metabolic pathway for BMS-094, then known as INX-189. The first step in this metabolic pathway yields a byproduct called 1-naphthol, a chemical that is toxic to hepatocytes, or liver cells. (My source for the background data is a 1984 paper published in Biochemical Pharmacology.) To be fair, the clinical importance of 1-naphthol at BMS-094's potential clinical doses remains unclear. However, two other nucs in clinical development -- Gilead's GS-7977 and Idenix' IDX-184 -- do not produce 1-naphthol. As an investor, the presence of this toxic byproduct should be a big concern until proven otherwise.

4. BMS-094 has shown potential toxicity across multiple organ systems. Data presented in 2009 indicate that BMS-094 (again, known then as INX-189) has a relatively low CC50, a measure of cytotoxicity, across lymphoid, bone marrow, kidney, and liver cells. Bulls will, reasonably, counter by citing the drug's potency and resulting therapeutic index, an indicator of drug safety equivalent to the ratio of the drug's in vitro efficacy measured via the EC50 relative to CC50. For BMS-094, the
therapeutic index is widest in lymphoid tissue and narrowest in the bone marrow, with liver in the middle. Again, this single data point isn't a smoking gun, but it does raise another red flag.

5. BMS-094 appears far less effective at lower doses than Gilead's GS-7977. After three days of dosing at 200 mg once daily, BMS-094 reduces median viral load by roughly 3.0 log. That's less than the 3.7 log viral load reduction seen with a 400 mg once-daily dose of Gilead's GS-7977 after three days, although in the same ballpark and therefore comparable and competitive.

At a 100 mg once-daily dose, however, BMS-094's impact is far less impressive, with a 1.15 log reduction in viral load. This brings BMS-094's effect size closer to Idenix's nuc IDX-184, which gets criticized for lackluster efficacy. [I think the jury is still out on the Idenix nuc. Management claims the drug's effect size will improve over time. That's possible, since BMS-094 gains some efficacy with an additional few days of dosing.]

If Bristol-Myers can't dose BMS-094 safely at 200 mg, the drug may not be competitive with Gilead's GS-7977. (Gilead's GS-7977 studies use a 400 mg once daily dose.) Importantly, none of Bristol-Myers' ongoing or publicly listed BMS-094 studies use the 200 mg once-daily dose. Not a good sign.

6. Bristol-Myers had limited safety data for BMS-094 when it purchased Inhibitex. Investors frequently cite a partnership or acquisition as validation of the smaller company's technology. I often disagree with the validation hypothesis, and that's true in this case. It seems very unlikely that Bristol-Myers had meaningful non-public safety data for BMS-094 prior to the company's January purchase of Inhibitex for $2.5 billion. This limited visibility might not raise a red flag, but I think it makes the validation defense less compelling.

Bristol-Myers is a big company so the investment impact of potential trouble in its hepatitis C drug pipeline is unclear. Most analyst models don't yet include forecasts for significant sales from the company's experimental hepatitis C drugs. The anticoagulant Eliquis, which has an FDA approval decision date in late June, is by far Bristol-Myers' most important near-term driver. [I expect Eliquis to receive approval, and consensus earnings estimates look achievable but not necessarily low.]

Nonetheless, failure of a high-profile program like BMS-094 would certainly knock the shine off Bristol-Myers' 17-timesearnings multiple, which exceeds most of the company's peer group. I think it's worth considering Bristol-Myers as a short, butI wouldn't make it a big position.

Failure or problems with Bristol-Myers' nuc would likely have a more significant impact on Gilead and, potentially, Idenix. Bothcompanies stand to benefit should BMS-094 stumble. Idenix would have a more attractive asset in IDX-184. I think it's worth taking a small long position in Idenix at current prices.

I think Gilead has more to gain from possible Bristol-Myers problems. Gilead would expand its lead in the race to develop an all oral regimen for HCV, and would gain significant negotiating leverage in any development partnership discussions. Given the potential for multiple positive catalysts over the next year -- including likely FDA approval of the Quad HIV pill this summer -- I am inclined to be long Gilead. I would not be an aggressive buyer of the stock until or unless it dips meaningfully below
$50 per share.

Disclosure: Sadeghi has no positions in any of the stocks mentioned in this article

'The Street' grades the HCV players post-EASL...

The Street's Nathan Sadeghi-Nejad grades the stocks of the big players in HCV post-EASL.  It's a good read, much better than those of his peers, although my opinion on certain topics differs from his in some respects. It's helpful to know that Mr. Sadeghi-Nejad's perspective is from one entrenched in the investment community, a community notorious for knee-jerk reactions to data deemed good or bad simply based on numbers in interim data.  The result is often either 'irrational exuberance' or 'irrational discouragement' causing wild fluctuations in stock price.  Greater scrutiny must often be utilized to get the 'real story' behind the numbers - patient demographics, fibrosis scores, BMI, trial structure, population size, P values, etc.  This is not to devalue the investment community but a call for a more discriminating eye when it comes to data analysis.  Mr. Sadeghi-Nejad's analysis shows a surprising amount of discrimination. My opinion does differ from his in respect to a couple of things (he's awfully hard on Achillion, doesn't mention BI or Merck and... well, see below).


I'll go on record to challenge Mr. Sadeghi-Nejad's claim that interferon is 'dead'. That's a pretty dimissive statement. While interferon-free therapies may be an option for many patients, especially those that are treatment naive, genotype 1b, 2, 3 and 4, with moderate fibrosis, with IL28B CC/TC status. However interferon will most likely play a large role in the 'difficult to treat' population - patients presenting with advanced fibrosis/compensated cirrhosis, genotype 1a, steatosis and IL28B TT status and/or a majority of null-responders.  


In fact, the data from BMS/s EMERGE trail - a head-to-head trial looking at PEG-Lambda + ribavirin vs PEG-interferon-alfa + ribavirin - was horribly under-appreciated. Not only was PEG-Lamda a good deal more effective at achieving SVR than PEG-alfa, there were also significantly less side effects.  We need to see how PEG-Lambda performs with the 2nd and 3rd generation DAAs in these difficult to treat patient populations. There is definitely a need as these patients are most at risk for developing decompensated liver disease and HCC. 


OK, off my soapbox now. 


BARCELONA (TheStreet) -- Wow, it's been a busy few days at the European Association for the Study of the Liver (EASL) annual meeting in this beautiful Catalan capital. Investors obsessed with emerging hepatitis C therapies had plenty of new data to analyze.

Let me make one general observation about the future of hepatitis C treatment before I recap and grade each of the companies with a significant presence at the EASL meeting. Interferon -- the injectable immune system booster saddled with troublesome side effects -- is dead. The future of hepatitis C therapy belongs to interferon-free regimens. Physicians at the conference talked about interferon as if it were invented in medieval times. It's clear that any company seeking a role in hepatitis C going forward must develop or acquire an effective interferon-free regimen or face irrelevance.


Let's move to the winners and losers of EASL 2012.

Gilead Sciences(GILD_):

Grade: A-

Gilead was the big story of the conference. The company emphatically reclaimed the driver's seat in HCV, at least for now, with a combination of solid scientific results and ruthless, strategic maneuvering.

In a crowded Thursday session, anxious Wall Streeters awaited new data for Gilead's GS-7977, a once-daily nucleotide polymerase inhibitor, or "nuc." Despite impressive early data -- which prompted the undeniably expensive $11 billion Pharmasset acquisition -- subsequent results from a GS-7977 trial called ELECTRON showed the drug to have little effect in "null" responders and generated lots of investor anxiety. I was no exception. Despite my favorable disposition towards GS-7977, I wanted confirmation of the early data; most investors I spoke with shared my view.

We got what we were looking for.

An impressive 88% of treatment-naive patients in ELECTRON achieved sustained virologic response four weeks after stopping treatment (an early indication of "cure" known as SVR4) with 12 weeks of GS-7977 and ribavirin (RBV), a companion drug used in hepatitis C. Expectations leading into EASL were for an SVR4 of 70%.

At the same time, Gilead issued a press release containing preliminary data from QUANTUM, an ongoing study in treatment-naive patients also using the GS-7977 plus ribavirin combination therapy. The SVR4 rate in this study was 59%, lower than ELECTRON due to enrollment of more difficult-to-treat patients. [84% of QUANTUM patients had unfavorable "non-CC" genetics, versus 56% in ELECTRON.]

Results from the ELECTRON AND QUANTUM studies of GS-7977 were important but not the star of EASL. What got everyone really excited were data from the mid-stage study combining GS-7977 with Bristol-Myer Squibb's(BMY_) NS5A replication complex inhibitor daclatasvir. Among the patients with genotype 1 hepatitis C, GS-7977 plus daclatasvir resulted in an SVR4 rate of 100%. Yes, the combination therapy cured all treated patients. These data literally elicited high fives from several of the generally reserved hedge fund analysts in attendance. It's hard to argue with an SVR4 of 100%, but longer-term follow-up data are needed to confirm these results. Physicians traditionally use SVR12 (12 weeks) or SVR24 (24 weeks) as a final indication of cure, although recent data show a strong correlation between SVR4 and later follow up assessments.

As if that weren't enough excitement, Gilead also generated some drama at the meeting -- and elicited a "patients-not-profits" rebuke from my colleague Adam Feuerstein -- when word got out that the company had refused an offer from Bristol-Myers to collaborate on further development of GS-7977 and daclatasvir. Although Gilead insists it hasn't made a final decision, I'm guessing management will try to combine GS-7977 with GS-5885, an early-stage drug candidate in the same NS5A class as daclatasvir. Obviously, Gilead wants to keep all the profits from a highly potent, all-oral hepatitis C therapy for itself.

In GS-7977, Gilead appears to control a strong, future "backbone" for any next-generation hepatitis C regimen. I have mixed feelings about Gilead's apparent desire to deny Bristol-Myers access to the drug and therefore prevent a daclatasvir-GS-7977 regimen from reaching the market. Patients and their advocates will probably be justifiably upset that such this apparently highly effective regimen won't be developed further. I understand that. Interestingly, physicians I spoke with at the meeting didn't care either way. That surprised me; I would have expected more complaints.

As an investor, I don't fault Gilead for angling to maximize profits -- I've never subscribed to the biotechnology industry's cloying "patients first" rhetoric. However, the move does increase the company's clinical risk in hepatitis C. Even though initial GS-5885 data look clean, a problem could still emerge and daclatasvir is far more established. Essentially, management is betting that the promise (and eventually, the reality) of an "all Gilead" HCV regimen outweighs additional R&D expenses and near-term clinical risks.

That seems like a reasonable bet, and I think the stock will continue to work -- Gilead is still only trading at around 13 times estimates 2012 earnings.

Bristol-Myers Squibb:

Grade: C

Bristol-Myers had quite the Dickensian conference. The company's daclatasvir plus Gilead's GS-7977 wowed investors and physicians alike. The best of times!

Unfortunately, Gilead doesn't want to partner GS-7977; the non-nucleoside polymerase inhibitor BMS-791325 seems only modestly effective and may have toxicity issues; the protease inhibitor asunaprevir has a messy side effect profile; and adverse event rumors are haunting BMS-986094 (formerly known as INX-189), the "nuc" obtained via the $2.5 billion purchase of Inhibitex. Oh, and brivanib fails in liver cancer. The worst of times!

Gilead's refusal to collaborate raises an important observation. Consider this: Bristol-Myers hasn't made public much data about BMS-986094 since closing the Inhibitex acquisition and non-specific toxicity rumors dogged the drug at EASL. Does this explain why Bristol-Myers is trying to pressure Gilead into moving the daclatasvir-GS-7977 regimen into phase III trials? Put another way, if Bristol-Myers was confident that BMS-986094 (INX-189) could easily replace GS-7977 in a combination regimen with daclatasvir, why not play the same ruthless, "winner take all" game as Gilead?

If I was a Bristol-Myers bull, I would be worrying about the future of BMS-986094 (INX-189.)

Management better hope it can either woo or shame Gilead into collaboration (unlikely, unless something goes wrong with GS-5885) or that the Inhibitex drug plays nice with daclatasvir and the toxicity rumors are false. Otherwise, Bristol-Myers will have to open up the M&A wallet again to remain relevant in the race for next-generation hepatitis C therapies.

Abbott(ABT_):

Grade: B

Despite Wall Street skepticism, I think Abbott remains firmly in the hepatitis C game. The company presented data from two major studies, PILOT and CO-PILOT, in late-breaker sessions on Saturday afternoon.

PILOT enrolled treatment-naive patients to receive 12 weeks of ABT-450 -- a protease inhibitor that requires blood-level "boosting" with ritonavir -- in combination with the non-nucleoside NS5B polymerase inhibitor ABT-072 and ribavirin. It must be noted that all patients had favorable "C/C" genetics, making it an easy group to treat. Nonetheless, Abbott reported an impressive 91% SVR24.

One patient in PILOT suffered a late relapse after 36 weeks of follow up which dropped the SVR36 "cure" rate to 82%. These are some of the longest follow-up results yet with next-generation, all-oral regimens so the relapse was noteworthy. I'm not sure if the relapse is an isolated event, and no one I spoke with had a definitive answer. Keep the question of whether interferon-free regimens might leave patients more susceptible to late relapse in mind -- it needs to be watched closely going forward.

In Abbott's second CO-PILOT study, patients received 12 weeks of ritonavir-boosted ABT-450 and the "non-nuc" ABT-333. Patients in the two treatment-naive arms achieved SVR12 rates of 93% and 95% (These patients were a mix of easy- and hard-to-treat patients more comparable to competitors' studies). I was impressed with these data, as were most physicians at EASL. A third arm in the CO-PILOT study enrolled "non-responders" but generated only a 47% SVR12; these patients need a more robust regimen.

The downside to the CO-PILOT regimen is complexity: ABT-450 is administered once daily, as is ribavirin and ritonavir, whereas ABT-333 is dosed twice daily. Further, ritonavir has numerous drug-drug interactions. Physicians I spoke with at EASL were mixed about whether or not patients could be sufficiently compliant in the real-world setting. I doubt it. Abbott plans to co-formulate future combinations, which will include other drugs (the company also has a NS5A inhibitor.)

I plan on taking a closer look at Abbott in a future column. The company is highly dependent on sales of the rheumatoid arthritis drug Humira, which I don't like, but investors aren't assigning much value to its hepatitis C assets. Based on what I saw at EASL, that could be a mistake.

Idenix Pharmaceuticals(IDIX_):

Grade: B-

Despite having no data at EASL this year, Idenix will likely benefit from the rising tide created by Gilead and Bristol-Myers. After successfully negotiating side effect questions and a partial clinical hold, Idenix has emerged as the only smallish biotech company with both a "nuc" (IDX-184) and an NS5A inhibitor (IDX-719.) By year-end, we will see SVR4 data for IDX-184 combined with interferon and ribavirin; and early data on IDX-719.

If these results look promising, Idenix is going to be hugely attractive to large pharma companies with lackluster hepatitis C programs and an urge to catch up. Novartis(NVS_) already has a first right to license IDX-719 by year-end, but other companies might be interested regardless of the Swiss pharma giant's decision. I would be a buyer of Idenix, but keep any position on the small side.

Achillion Pharmaceuticals(ACHN_):

Grade: C-

Meh. Achillion has two NS5A inhibitors, ACH-3102 and ACH-2928, which look okay in early studies, but I'm not sure what makes these drug candidates stand out. I feel similarly unexcited about ACH-1625, a protease inhibitor, which looked decent in a confusing study that combined it with interferon and ribavirin. I'm just not convinced these are valuable assets, so I'm going to wait on the sidelines.

Vertex Pharmaceuticals(VRTX_):

Grade: D-

Out of sight, out of mind. The big loser of the EASL conference was Vertex Pharmaceuticals. The company's first-in-class protease inhibitor Incivek pioneered treatment with direct-acting antivirals in hepatitis C, but the drug now feels woefully outdated less than one year after approval. The problem is that Incivek therapy still requires patients to receive weekly injections of interferon. Remember what I noted at the top of this column -- interferon is dead -- so any drug attached to interferon is at risk of the same fate.

Vertex does have ongoing interferon-free studies that combine Incivek with ribavirin and VX-222 -- an earlier-stage "non-nuc" drug candidate -- but the combination seems like a long shot. Earlier this year, the company reported that 82% of patients in the Phase II ZENITH trial achieved an SVR4. Vertex also added to its hepatitis C portfolio recently, acquiring two "nucs" through a partnership with Alios BioPharma. Unfortunately, those compounds do not yet have any clinical data and are substantially behind the market leaders.

More from Nathan Sadeghi-Nejad
Calling Shenanigans on Amylin PharmaGilead And The Future of HIV TherapyRegeneron, Amgen And The 'Hope Creation Cycle"
Market Activity
Vertex Pharmaceuticals| VRTX
Gilead Sciences Inc| GILD
Achillion Pharmaceuticals Inc.| ACHN
Meanwhile, I expect already flat Incivek sales will decline rapidly as physicians urge patients to defer treatment until next-generation drugs reach the market. Street estimates now reflect a sequential decline in Incivek sales. If Vertex isn't able to expand use of the cystic fibrosis drug Kalydeco to a broader group of patients at premium pricing, Vertex might be a short. (I haven't done enough work to have a final opinion yet.) Either way, this wasn't a good EASL meeting for the Boston-based biotech.

Onyx Pharmaceuticals(ONXX_):

Grade: B+

EASL is not only about hepatitis C. This is a meeting that covers all liver disease, which includes liver cancer. In this regard, Onyx emerged from EASL a solid winner even though the company presented no new data.

Some investors expected positive results from a 395-patient trial of Bristol-Myers' brivanib in late-stage liver cancer. Positive brivanib data would have been bad news for Onyx, whose key asset, Nexavar, dominates the liver cancer treatment market and faces no major competitors. Fortunately, brivanib proved both a dud and a point.

In a crowded Saturday session, the same investigator who led Onyx's Phase III study presented findings from Bristol-Myers' BRISK-PS, which randomized patients who had progressed on, or were intolerant of, Nexavar to receive either brivanib or placebo. Despite positive response rate (12% versus 2%) and time to progression (4.2 months versus 2.7 months) data, brivanib showed only a slight survival benefit (9.4 months versus 8.2 months). For comparison, Nexavar improved survival by 2.8 months in the Phase III SHARP trial that led to the drug's approval.

Before I get a slew of comments on the value of any benefit in this difficult-to-treat disease, I would note that the data were not even close to statistical significance and brivanib caused meaningful toxicity, including six patient deaths attributed to the drug by study investigators.

The key takeaway here -- other than that Nexavar's leading position in liver cancer remains safe -- is that surrogate endpoints like response rate and progression-free survival do not always correlate with a survival benefit. This is particularly true in studies of solid tumors. Despite what feels like the constant media coverage of emotional demands for quick approvals based on limited data, the BRISK-PS data once again highlight the need for companies to conduct randomized studies using real endpoints.

Whew. That does it for EASL 2012, but my travels continue. This afternoon I'm off to Boston to surprise Mom for her birthday. (Let's see if she reads all the way to the end of my columns.)

Happy birthday Mom!

Disclosure: Sadeghi has no positions in any of the stocks mentioned in this article.

Presidio Pharmaceuticals announce new HCV pan-genotypic non-nuc polymerase inhibitor....

Posted on MarketWatch, 4/21/12.  Presidio releases pre-clinical profile of it's new novel pan-genotypic non-nuc polymerase inhibitor PPI-393 at EASL. It will be a very competitive environment for HCV drugs just getting started in development given the high bar set with interim SVR data presented for the 2nd generation HCV drugs at EASL.  New drugs in development will have to offer a significant advantage in respect to resistance profile, dosing, tolerability and efficacy to compete. 

PRESS RELEASE

April 21, 2012, 2:00 a.m. EDT

Presidio Pharmaceuticals Announces a New Clinical Candidate, PPI-383, a Novel Pan-Genotypic Non-Nucleoside Polymerase Inhibitor for HCV

Pre-Clinical Profile to be Presented at the 47th European Association for the Study of the Liver (EASL) Meeting

SAN FRANCISCO, Apr 21, 2012 (BUSINESS WIRE) -- Presidio Pharmaceuticals, Inc. announced today that PPI-383, a novel non-nucleoside polymerase inhibitor to treat hepatitis C virus (HCV), has been nominated for clinical development and will be profiled by Richard Colonno, Ph.D., Chief Scientific Officer, in poster 1173 at the 47th Annual EASL meeting being held in Barcelona, Spain on April 21st, 2012.

PPI-383 is a potent, pan-genotypic inhibitor of HCV discovered at Presidio, which exhibits a favorable pharmacokinetic and safety profile in multiple animal species following oral dosing. PPI-383 binds to the Palm II pocket of the HCV polymerase (NS5B) and possesses excellent biochemical and pharmaceutical properties critical to successful drug development, including a potential for once-daily oral dosing and minimal potential for drug-drug interactions. PPI-383 is currently undergoing further preclinical evaluation to support initiation of clinical studies alone and in combination with PPI-668 next year.

PPI-383, identified through an extensive medicinal chemistry effort, exhibits EC50s of 8.3 and 2.2 nM in HCV 1a and 1b replicon assays, respectively. PPI-383 is also active against other major HCV genotypes (2a, 3a and 4a) in stable replicon cell assays (EC50s of 4.4-11.7 nM). "The selection of PPI-383 underscores Presidio's continued commitment to generate best-in-class compounds for treating HCV," commented Dr. Colonno, who added, "It is an excellent complement to our lead NS5A inhibitor, PPI-668, currently completing Phase 1b clinical studies. We intend to develop oral, combination regimens that possess potent, pan-genotypic activity." The distinct mechanism of action of PPI-383 will potentially allow its use in combination regimens with all other classes of HCV inhibitors.

Poster 1173, entitled "Identification and Characterization of PPI-383, a Next Generation HCV NS5B Non-Nucleoside Inhibitor with Potent Activity Against all Major HCV Genotypes" will be presented by Dr. Colonno on Saturday, April 21st, 2012 at the Centre Convencions Internacional Barcelona (CCIB) from 8:00 AM to 5:00 PM.

About HCV

Chronic hepatitis C is a persistent, potentially progressive inflammatory liver disease caused by chronic infection with the hepatitis C virus (HCV). Worldwide, there are an estimated 130 to 170 million persons with chronic HCV infection, with over 350,000 deaths occurring each year.

The current standard treatment for hepatitis C in the United States, for patients with HCV genotype-1 infection, is combined administration of pegylated-interferon-alfa, ribavirin, and an HCV protease inhibitor. This multi-drug treatment is characterized by incomplete efficacy for HCV genotype-1 patients, variations in efficacy according to patients' underlying human genetic factors, no established efficacy for patients infected with other HCV genotypes, severe side effects in some patients, and dosing inconveniences. In countries where the current HCV protease inhibitors are not yet regulatory-approved, standard treatment is only pegylated-interferon-alfa plus ribavirin, which is less effective.

There is a continuing need for all oral, more consistently effective and better tolerated antiviral combinations for HCV infection, regardless of HCV genotype, patient genetic factors, or disease stage.

About Presidio

Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics. For more information, please visit our website at: www.presidiopharma.com .

SOURCE: Presidio Pharmaceuticals, Inc

New York Times on GS-7977 + daclatasvir combo - will it make it to market?

Posted on 4/19/12 via the New York Times. For those of you even casually following the HCV drug development data being presented at EASL, you've no doubt heard that the combination of Gilead's nuc GS-7977 + BMS's NS5A inhibitor daclatasvir wowed just about everyone by reporting 100% SVR in genotype 1 treatment-naive patients with this combination without the support of ribavirin and pegylated interferon. There are certain caveats that I'll go into later regarding the study, but even with those, the results are flat out astounding. The problem appears to be that BMS and Gilead haven't thus far agreed to collaborate on this combination. Gilead seems the most unwilling - they've got their own pipeline of drugs to combine with GS-7977 and their data from GS-7977 + ribavirin garnered an 88% SVR in a similar patient population. With downward pressure on drug costs and and the pressure to increase drug access, it would seem like the more economically appealing option is for Gilead to go to market for the treatment naive population with GS-7977 + a generic drug (ribavirin). After all, 88% SVR with greatly improved tolerability over current therapy with much improved dosing options is nothing to sneeze at. In regards to the tougher-to-treat patients (i.e. null responders, partial responders, advanced fibrosis, steatosis, co-infection), it looks like Gilead  has enough confidence in it's own pipeline and co-formulation ability to not have to rely on the often-difficult-to-manage partnership agreement. No doubt this will be interesting to watch and see what unfolds. 


Collaboration on Hepatitis Drugs Lags
By ANDREW POLLACK
Published: April 19, 2012

A combination of two pills proved extremely effective in treating hepatitis C in a small trial, raising hopes among researchers that the disease will be curable without an injected drug that has debilitating side effects.

David Paul Morris/Bloomberg News

But the combination might not find its way to the market because one pill is owned by Gilead Sciences and the other by Bristol-Myers Squibb. The companies have not agreed to collaborate, to the chagrin of some doctors.

“The only appropriate motivation should be what is the best and fastest way to get cures, not what is best for the shareholders,” said Dr. Scott Friedman, chief of liver diseases at the Mount Sinai School of Medicine in New York, who was not involved in the trial.

Dr. Douglas J. Manion, a senior vice president for Bristol-Myers, said his company was “keen” on working with Gilead but that “thus far, they have been unwilling to engage in that collaboration.”

Norbert W. Bischofberger, executive vice president for research and development at Gilead, said his company wanted to wait several months for data on other treatment options before deciding what path to take.

“We told them it’s too early to jump wildly into this collaboration,” he said.

Both executives spoke separately by telephone from the International Liver Congress in Barcelona, Spain, where data on the drug combination was presented.

Gilead and Bristol are among the leaders of one of the most heated races in the pharmaceutical industry — to develop an all oral treatment for hepatitis C, a liver-damaging virus that infects three million to four million Americans.

New pills introduced last year by Vertex Pharmaceuticals and Merck have sharply improved the cure rate, to about 60 to 80 percent. But those drugs must still be used alpha interferon, which is injected weekly for up to a year and can cause flulike symptoms.

Many companies are trying to develop combinations of pills — similar to those used to treat H.I.V. — that would eradicate the virus without the need for interferon.

Results from several companies presented at the Barcelona conference have given doctors confidence that this will indeed be possible, with the first such combinations reaching the market perhaps by 2014.

Dr. Melissa Palmer, who was a practicing liver specialist until last fall, said that the trials were small and patients were usually not followed long enough to see if they were truly cured.

“It’s going to be important to wait a longer time to see if these results are sustainable,” said Dr. Palmer, who is now a consultant to investors.

Nonetheless, investors were busily predicting from the Barcelona data which companies will capture the billions of dollars a year in possible sales. Besides Gilead and Bristol, some mentioned Abbott Laboratories, which also presented strong preliminary data.

Gilead, a leader in drugs for AIDS, paid $11 billion a few months ago to acquire Pharmasset, based on very preliminary data on its hepatitis drug, now called GS-7977. Subsequent data was not as good and Gilead’s stock sank.

But the data announced on Thursday appeared to restore confidence in 7977. Shares of Gilead gained 12 percent to $52.25. Shares of Bristol rose 1 percent to $33.93.

All 29 of the patients with the strain of the virus that is most common in the United States had no detectable virus in their blood four weeks after finishing 24 weeks of treatment with GS-7977 and Bristol’s pill, daclatasvir. The figure was 28 out of 30 patients with two other virus strains. Each pill was taken once a day.

Doctors usually wait 12 to 24 weeks after finishing treatment to declare a cure, since there can be relapses.

Dr. Bischofberger said that before deciding whether to work with Bristol on a larger trial, Gilead wanted to wait a few months for data showing whether the same two drugs would work with only 12 weeks of treatment instead of 24.

He said he also wanted to see whether Gilead could improve results of using GS-7977 with ribavirin, a drug that is part of the existing treatment.

A combination of GS-7977 with ribavirin, which is generic, would be far less expensive than a combination with daclatasvir, he said, because new hepatitis drugs are expected to cost tens of thousands of dollars for a course of treatment.

A combination with ribavirin would also mean that Gilead would not have to split revenues with Bristol, making it easier to recoup the money it spent to buy Pharmasset.

Dr. Bischofberger said that once both 7977 and daclatasvir won approval, doctors could use them together, so patients would not be shortchanged if the companies did not collaborate.

Gilead interim ELECTRON and QUANTUM SVR4 data...

Posted 4/19/12 on ClinicaSpace.com - Good news for patients, providers and of course Gilead today at EASL. Not so great for interferon, at least regarding it's place in HCV therapy where it increasing looks like it will be niched to specific special populations.  Gilead's Phase II ELECTRON trial looking at 12 weeks of GS-7977 + RBV posted a SVR4 rate of 88% in genotype 1 patients. Three other arms - including the very-hard-to-treat null responder patients - will be presented later this week. QUANTUM, also a Phase II trial, looking at 12 and 24 week regimens of GS-7977 + RBV in genotype 1, 2 and 3 patients with and without cirrhosis. Data was available only for the 12 week genotype 1 arm, 4 weeks post therapy (SVR4), which garnered a 59% SVR4. It's not clear how many of the 17 patients in the analysis were cirrhotic, but I'm sure that information is forthcoming. It will be interesting to see that breakdown, and if the cirrhotic patient would benefit from 12 additional weeks of GS-7977 + RBV. 

Gilead Sciences, Inc. (GILD)-Bristol-Myers Squibb Company (BMY)'s Experimental Hepatitis C Drug Cured 88% Post-Therapy

4/19/2012 7:22:40 AM

BARCELONA, Spain, Apr 19, 2012 (BUSINESS WIRE) -- Gilead Sciences, Inc. GILD -0.15% today announced interim data from the Phase 2 ELECTRON study examining the investigational once-daily oral agent GS-7977 plus ribavirin (RBV) in treatment-naive patients with genotype 1 chronic hepatitis C virus (HCV) infection. Of the 25 patients who completed 12 weeks of treatment with the GS-7977-based regimen, 88 percent of patients (n=22/25) remained HCV RNA undetectable four weeks after completion of treatment. Three patients experienced viral relapse. These findings are being presented this week during a poster session (Poster #1113) at the 47th Annual Meeting of the European Association for the Study of the Liver (International Liver Congress 2012) in Barcelona, Spain.

"These preliminary results suggest that 12 weeks of therapy with once-daily oral GS-7977 and ribavirin may be enough to cure hepatitis C in many genotype 1 patients, including those who are currently not candidates to receive interferon," said Professor Edward Gane, MD, Deputy Director and Hepatologist, New Zealand Liver Transplant Unit, Auckland City Hospital in New Zealand, and principal investigator of the ELECTRON study. "Further investigation of GS-7977 in a variety of patient populations and combinations will be important in assessing the drug's potential as part of an all-oral regimen for hepatitis C."

Results from three additional arms of the ELECTRON study examining GS-7977-based therapy in various patient populations are also being presented this week at the International Liver Congress. These include null responder genotype 1 patients, and genotype 2 and genotype 3 patients, both treatment-naive and prior non-responders.

Overall, GS-7977 was well tolerated and exhibited a favorable safety profile. No patients experienced viral rebound during treatment. No patients discontinued therapy due to an adverse event. The most common adverse events were fatigue, dizziness and headache, and two grade 3/4 laboratory abnormalities were reported.

Gilead today also announced interim results from a second Phase 2 trial (QUANTUM) examining a 12- and 24-week duration of GS-7977 plus RBV in treatment-naive patients. Twenty-five patients were randomized to the 12-week treatment arm: 19 genotype 1 patients; four genotype 3 patients; and two genotype 2 patients. Two genotype 1 patients discontinued therapy prematurely during the 12-week treatment period. At the four-week post-treatment time period, data were available for 17 genotype 1 patients. Of these, 10/17 (59 percent) remained HCV RNA undetectable. Seven patients (41 percent) experienced viral relapse. Additionally, seven of the patients who have reached the eight week post-treatment time period, and who achieved SVR4, remain HCV RNA undetectable.

The overall safety and efficacy profile of GS-7977 was consistent with that seen in ELECTRON. No patients experienced viral rebound while on treatment and no patients discontinued therapy due to an adverse event.

Eleven of the 25 patients (44 percent) in ELECTRON and three of 19 patients (16 percent) in QUANTUM had the IL28B C/C genetic polymorphism. Each of the three patients who relapsed in the ELECTRON study had a different IL28B polymorphism (C/C, C/T or T/T). The seven patients who relapsed in the QUANTUM study either had IL28B C/T (n=4) or IL28B T/T (n=3) genetic polymorphisms. Patients in both studies will continue to be observed to determine sustained virologic response rates at weeks 12 and 24 of follow-up (SVR12 and SVR24).

"The early results from these studies confirm that GS-7977 has the potential to become the cornerstone of an efficacious, all-oral combination regimen for many patients with chronic hepatitis C infection," said John McHutchison, MD, Senior Vice President, Liver Disease Therapeutics, Gilead Sciences. "We look forward to more data unfolding as our trials progress and we expect to initiate additional studies with GS-7977 in combination with other oral antivirals in our pipeline in the coming months. Our goal is to develop a short, simple, safe and effective single tablet regimen for HCV patients throughout the world."

About ELECTRON

ELECTRON is an ongoing Phase 2 randomized open-label clinical study evaluating GS-7977 for the treatment of chronic HCV infection. The primary endpoint of the trial is the safety and tolerability of GS-7977 400 mg once-daily for 8 or 12 weeks, with and without RBV and/or Peg-IFN in HCV patients with genotypes 1, 2 or 3. Study populations include treatment-naive non-cirrhotic patients and those who have failed prior interferon based therapies or "null" responders.

About QUANTUM

QUANTUM is a Phase 2 randomized double-blind placebo-controlled clinical study evaluating GS-7977 for the treatment of chronic HCV infection. The current active arms of the trial are examining GS-7977 400 mg once-daily plus RBV for 12 or 24 weeks in cirrhotic and non-cirrhotic treatment-naive HCV patients with genotypes 1, 2 and 3. The results announced today are for the cohort of patients who have received and completed 12 weeks of therapy with GS-7977 plus RBV (n=25).

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility that the proportion of patients who maintain a sustained virologic response 12 and 24 weeks post-treatment will not be as favorable as the sustained virologic response rates reported in this press release and the possibility of unfavorable results from additional arms of the ELECTRON and QUANTUM studies and subsequent clinical trials involving GS-7977 and RBV. As a result, GS-7977, including in combination with other oral antivirals in Gilead's pipeline, may never be successfully commercialized. Further, Gilead may make a strategic decision to discontinue development of the compounds if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. In addition, Gilead may be unable to develop an all-oral antiviral regimen for HCV genotype 1 patients or a pangenotypic regimen for all HCV patients. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Annual Report on Form 10-K for the year ended December 31, 2011, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

SOURCE: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Susan Hubbard, 650-868-5215 (Investors)
shubbard@gilead.com
Patrick O'Brien, 650-522-1936 (Investors)
pobrien@gilead.com
Cara Miller, 650-576-7849 (Media)
cmiller@gilead.com

Bristol-Myers Squibb and Medivir/J&J expand on Direct Acting Antiviral agreement...

Posted on 4/18/12 on Bloomberg.com - A good day for Medivir/J&J's late stage HCV protease inhibitor TMC435 as both companies inked a deal with BMS looking at mixing and matching Direct Acting Antivirals with TMC435 in interferon-free regimens for treating chronic Hepatitis C. Expect to see more data on both TMC435 and BMS's arsenal of DAA's this week from EASL. 

Bristol-Myers Expands Hepatitis C Accord With J&J, Medivir
By Makiko Kitamura - Apr 18, 2012 5:27 AM PT

Bristol-Myers Squibb Co. (BMY) agreed to conduct two trials of experimental hepatitis C treatments in collaboration with Medivir AB (MVIRB) and Johnson & Johnson. (JNJ) Medivir shares rose as much as 5.7 percent in Stockholm.

The companies will conduct a late-stage trial of Bristol- Myers’ daclatasvir and J&J and Medivir’s TMC435, depending on the outcome of a mid-stage study, Stockholm-based Medivir said today in a statement. A drug interaction study of TMC435 with Bristol-Myers’ BMS-986094 will also be conducted, they said. That expands a collaboration between J&J and Bristol-Myers announced Dec. 2, Medivir said.

The Bristol-Myers drug in the second study entered the company’s pipeline with the acquisition of Inhibitex Inc. for $2.5 billion in February. TMC435 is a protease inhibitor, which blocks the action of the protease enzyme the hepatitis virus needs to replicate, directly stopping it from spreading. BMS-986094 is a nucleotide polymerase inhibitor, which works differently to block the virus’ ability to replicate in the body.

“We see the expanded clinical collaboration as a strong validation of TMC435, especially as we know of no other competing protease inhibitors running interferon-free combination trials with other direct-acting antivirals externally,” which include polymerase inhibitors, said Hans Jeppsson, an analyst at Danske Bank, in a note to investors today.

Medivir shares rose 4.6 percent to 73.25 kronor at 2:17 p.m. in Stockholm, giving the company a market value of 2.29 billion kronor ($339 million).

Drug Combinations
Other nucleotide polymerase inhibitors include Gilead Sciences Inc.’s 7977 compound, which was gained through the company’s acquisition of experimental hepatitis C-treatment maker Pharmasset Inc. for $10.8 billion in November. Bristol- Myers, based in New York, and Medivir are also testing their experimental treatments in combination with Gilead’s 7977.

Drugmakers are exploring cocktails of hepatitis C treatments that exclude interferon, a component of the current standard of care, because of the injectable therapy’s side effects.

Hepatitis C affects as many as 170 million people globally, putting them at risk of developing liver cancer, according to the World Health Organization. The disease is most commonly transmitted through contaminated blood transfusions, organ transplants, contaminated syringes and needle-injected drug use, according to the WHO.

To contact the reporter on this story: Makiko Kitamura in London at mkitamura1@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

Bloomberg BusinessWeek on Gilead's GS-7977 and critical upcoming data from EASL...

Article posted 4/12/12 on Bloomberg BusinessWeek - All investor eyes on Gilead regarding their EASL data for GS-7977 both in combo with RBV in treatment-naive patients and in combo with BMS's daclatasvir +/- ribavirin. No pressure, though. *cough*


Gilead Bets on Hepatitis C Data to Back Pharmasset Deal

Gilead Sciences Inc. (GILD) (GILD), after paying $10.8 billion for the developer of an experimental hepatitis C drug, will soon give investors a better sense of whether its largest-deal ever is going to pay off.

Beginning next week, Gilead will release data from dozens of patients who have tried the medicine, providing the most complete evidence yet about its prospects for treating 170 million people who are infected with the virus globally. Trial results reported in 10 people in February spurred wild swings in the company’s stock price.

Gilead, the world’s largest maker of HIV drugs, has fallen 10 percent in the past four years, and is facing the loss of half of its revenue from patent expirations on AIDS medicines beginning in 2018. Despite that, 26 analysts (GILD) advise buying the shares, and seven suggest holding them.

“They will be there as one of the key players to treat a very large unmet medical need in hepatitis C, and one of the first players,” said Joshua Schimmer, a Leerink Swann & Co. analyst. “You can make a very strong case that Gilead shares are worth owning through the volatility.”

The purchase of Pharmasset Inc., announced Nov. 21, was designed to add a heavyweight product to diversify Gilead in an area -- infectious disease -- where the Foster City, California- based biotechnology company has expertise and an established sale force.

The company became a leader in AIDS treatments by finding the right combinations of drugs to help change the disease from a quick killer into one that’s manageable. Researchers say hepatitis C also may be attacked with drug cocktails. It’s a matter of finding “the right recipe,” said Mani Subramanian, a Gilead vice president of clinical research.

Liver Meeting
Investors are looking to results to be reported beginning at next week’s European Association for the Study of Liver meeting in Barcelona to define what role Gilead’s hepatitis C drug, known as 7977, will play in a developing market for new medicines that is expected to reach $20 billion.

In data reported on Feb. 2, four weeks of Gilead’s medicine seemed to eradicate the virus in 10 patients who hadn’t responded to prior rounds of therapy, boosting the company’s stock market value (GILD). On Feb. 17, when some patients relapsed, Gilead shares fell the most in 11 years.

“You have to be kind of astounded by it,” Leerink Swann’s Schimmer said in a telephone interview.

One key study weighs the performance of Gilead’s 7977 in tandem with an experimental product from Bristol-Myers Squibb Co. (BMY) (BMY) when used by all types of patients. Others will report on 7977’s effectiveness in those who have never been treated.

Bristol-Myers Compound
Bristol-Myers’s compound, BMS-790052, hinders a protein called NS5A that creates a scaffolding around the virus, securing it so it can replicate, Gilead’s Subramanian said. His company’s drug integrates itself into the virus’s replicating process, preventing it from churning out copies.

The new hepatitis C drugs also promise to work more quickly and be safer than the current standard of care that combines an antiviral called ribavirin with interferon, an injectable immune-boosting protein, studies have shown.

“We’re very excited about this Bristol-Myers study,” Subramanian said in an interview at the company’s headquarters. “We’ll know whether you even need ribavirin if you have a NS5A in the mix.”

Proving the worth of Bristol-Myers’s product in combination with 7977 could also help Gilead down the line when GS-5885, its own NS5A inhibitor, is put before the U.S. Food and Drug Administration for approval. The product is now in the second of three phases of trials generally required for clearance.

Ribavirin Combination
Gilead is expected to report at the Barcelona conference how 7977 works in combination with ribavirin after 12 weeks of therapy in those who haven’t had other treatments before, so- called naïve patients. This will help establish which patients can be cured, or not, without interferon.

If Gilead’s hepatitis C drug is approved, at the end of 2013 at the earliest, it may add $3 billion to $4 billion in revenue by 2018, said Michael Yee, an analyst with RBC Capital Markets in San Francisco. That would help replace sales from Atripla, the most widely used HIV medicine, and Truvada, a component of Atripla, he said. The medicines generated $6.1 billion in 2011 sales, or 73 percent of Gilead’s revenue.

“The company did have very steady revenue and earnings growth, but they’re looking to accelerate that,” Yee said. “The growth potential of the company has significantly changed, with higher risk and higher reward.”

No Death Knell
The finding last month that some patients have relapsed shouldn’t be looked at as a death knell for the developing product, Gilead’s Subramanian said.

The data “means one of two things,” he said in an interview. “Do you need longer duration, or more drugs?”

Geoff Porges, an analyst with Sanford C. Bernstein & Co. in New York with a market perform rating on Gilead, isn’t so sure.

The failure of 7977 to cure people who had previously been treated “shocked the world,” and means Gilead won’t dominate the field as some had expected, he wrote in a note to clients. “It changes the treatment landscape,” he wrote, and “highlights the vulnerability of Gilead’s stock to any stumbles.”

Subramanian remains philosophical about the hepatitis c therapies: “It’s like cooking,” he said. “At some point we’ll figure out the right recipe.”

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

BMS-Gilead EASL data leak spurs speculation...

Posted 4/9/12 on The Street. From the sounds of it, embargoed data showing the EOT response with daclatasivr and GS-7977 combo was mistakenly published on the EASL website over the weekend, showing an encouraging 97% EOT response in tx-naive genotype 1 patients and 90% in genotype 2 and 3 subjects. An analyst picked this up and sent a research report to his clients. It's unclear at this time whether this was the arm with ribavirin or without... further speculation on my part says that if it is indeed without ribavirin, we need to keep a close eye on the relapse rates. EOT is, unfortunately, not SVR. 

Bristol-Gilead Hep C Drug Data Leaks
Adam Feuerstein

04/09/12 - 09:29 AM EDT

Updated with a corrected research report from Jefferies, noting that the end-of-treatment response to daclatasvir and GS-7977 was actually 97%, not 93%.

BOSTON (TheStreet) -- An early peek at data from a closely watched mid-stage study combining hepatitis C drugs from Bristol-Myers Squibb(BMY) and Gilead Sciences(GILD) has leaked in advance of the European Association for the Study of the Liver (EASL) annual meeting.

Ninety-seven percent of genotype 1 hepatitis C patients treated with Bristol's daclatasvir and Gilead's GS-7977 has undetectable viral levels after 12 weeks of treatment. For genotype 2/3 patients, the 12-week response rate was 90%, according to a research note published Monday by Jefferies analyst Thomas Wei.

Wei called the end-of-treatment response to daclatasvir-GS-7977 "encouraging" and "positive."

These data from Bristol and Gilead were supposedly embargoed by EASL and were therefore not made available to the public when research abstracts for the EASL meeting were posted online on April 4.

In an email to clients Monday, Jefferies said the Bristol-Gilead abstract was "briefly posted" on EASL's web site over the weekend before being taken down.

Officials with EASL have not responded to questions regarding the leak of the research abstract.

Interim results from a phase II study combining Bristol's NS5a inhibitor daclatasvir (BMS-52) with Gilead's GS-7977 in genotypes 1, 2, and 3 is the most highly anticipated data presentation at the EASL meeting this year. The study is important because it will be one of the first glimpses at the Hep C-killing potency of these two classes of direct-acting antivirals combined into a single, all-oral therapy.

Early cure rates from the dacalatasvir-GS-7977 study -- defined as the percent of patients with undetectable viral loads four weeks after cessation of treatment -- will be presented at the EASL meeting, which takes place April 18-22.

--Written by Adam Feuerstein in Boston.

The Street - "Winners, Losers From EASL Hep C Data Dump"

Article posted on 4-4-12 on The Street.com. The author is right - the data people really want to see (tx-naive arm of ELECTRON; QUANTUM and GS-7977 + daclatasvir) won't be available until 4-21 after the Late Breaker sessions. After all, EASL has to fill seats for five days and Barcelona isn't just up the street for most of us. These leaves room for speculation - LOTS of speculation in the case of Idenix, which saw it's market cap take a hit after an analyst speculated that because nuc mericitabine (RG7128) under-performed in the JUMP-C study, it's distant cousin IDX184 would likely do the same.  The Idenix CEO quickly retorted that such comparisons are unfounded. We'll see - amazing the power of the Wall Street analyst in this market place. 

Adam Feuerstein
04/04/12 - 03:20 PM EDT
Updated with new information, including comments from the CEO of Idenix Pharmaceuticals.

BOSTON (TheStreet) -- The European Association for the Study of the Liver (EASL) finally released hepatitis C drug research abstracts Wednesday ahead of its closely followed conference in two weeks. But investors looking for clear winners and losers in the race to develop new all-oral hepatitis therapies came away disappointed.

As with all things hepatitis C, the EASL abstract "data dump" raised more questions than provided answers, in part because a lot of the data investors most wanted to see remains under wraps.

Still, Wall Street loves to make snap judgments, so Abbott(ABT) shares rose less than 1% to $61.60 on strong results from a small mid-stage study of a three-drug, all-oral regimen, which resulted in hepatitis C cure rates greater than 90%.

Abbott's gain was Gilead Science's(GILD) pain, causing the latter's shares to fall 2% to $47.13. Further hurting Gilead Wednesday was the absence of new data on GS-7977, the hepatitis C drug acquired in the $11 billion Pharmasset purchase. EASL chose not to make GS-7977 data available Tuesday, withholding for presentation at the meeting itself.

EASL also kept under wraps data from an important study combining Bristol-Myers Squibb's(BMY) daclatasvir with Gilead's GS-7977. A Bristol spokesperson did confirm, however, that interim results tracking early cure rates from this study will be presented at the EASL meeting.

The biggest loser Wednesday appears to be Idenix Pharmaceuticals(IDIX), with shares down 12% to $8.99 but not because of any new information released on its hepatitis C drugs. Instead, investors appear to be worried about the future of Idenix's lead drug IDX184 based on poor results released today on a similar drug being developed by Roche.

EASL's International Liver Congress is being held April 18-22.

More details on the hepatitis C research abstracts made public Wednesday:

Abbott: Today's results come from a phase II study of its own all-oral Hep C regimen consisting of protease inhibitor ABT-450, a ritonavir booster and the non-nuke polymerase inhibitor ABT-333. The study enrolled treatment naive genotype 1 patients as well as treatment-experienced non-responders. Patients were treated for 12 weeks.

In the treatment-naive patients, SVR12 or hepatitis C "cure" rates were 93% and 95% for the low- and high-dose arms, respectively. These are some of the strongest cure rates seen for new hepatitis C therapies, particularly for regimens that exclude injectable interferon. The high cure rates are even more impressive given that a majority of the patients enrolled were diagnosed with the more difficult-to-treat genotype 1A subtype.

In patients who failed to respond to previous treatment, the Abbott all-oral regimen resulted in a cure rate of 47%.

One looming concern about the Abbott hepatitis C regimen is convenience. As formulated now, patients must take one pill once per day and another two pills twice per day. For a relatively short treatment duration of 12 weeks, remembering to take a total of five pills per day may not be a problem, unless competing companies develop equally effective and simpler therapies.

Idenix: A Roche study combining the nucleoside polymerase inhibitor mericitabine, a protease inhibitor danoprevir and ribavirin proved to be relatively unsuccessful, with a cure rate of 41% overall (71% in genotype 1b patients and just 26% in the harder-to-treat genotype 1a patients.)

This study has nothing to with Idenix except that the company's own nucleoside polymerase inhibitor IDX184 is perceived by some investors to be similar to that of Roche's mericitabine. This raises concerns that any future combination regimen pairing IDX184 with a protease inhibitor may result in similarly poor cure rates.

Idenix CEO Ron Renaud calls comparisons between IDX184 and mericitabine "ridiculous," adding that data already presented shows '184 to be more like GS-7977 than mericitabine. "Comparing '184 to mericitabine, I don't know where that comes from," says Renaud. "It's just conjecture and assumptions being made by some… All we can do is continue to generate good data. We remain as optimistic about '184 as we've ever been." Hepatitis C data not yet released by EASL but expected at the meeting:

Gilead Sciences: Data from two separate but similar studies (ELECTRON and QUANTUM), both involving the two-drug combination of GS-7977 plus ribavirin in treatment-naive genotype 1 patients.

Gilead has said results from the QUANTUM study could be announced in a press release early in the second quarter i.e. before the start of the EASL meeting. Investors are sure to scour the EASL web site Thursday for any early patient data that may give a hint about the later '7977 results. Much is riding on the outcomes from these treatment-naive patient studies because '7977's potency was cast in doubt due to poor results in so-called "null responder" patients.

Bristol-Myers Squibb: Interim results from a phase II study combining Bristol's NS5a inhibitor daclatasvir (BMS-52) with Gilead's GS-7977 in genotypes 1, 2, and 3 is the most highly anticipated data presentation at the EASL meeting this year. The study is important because it will be one of the first glimpses at the Hep C-killing potency of these two classes of direct-acting antivirals combined into a single, all-oral therapy.

If this study is successful, Bristol is expected to swap out GS-7977 for its newly acquired nuke INX-189, gained from the Inhibitex acquisition. Gilead may also capitalize on the study by combining GS-7977 with its own NS5a inhibitor.

--Written by Adam Feuerstein in Boston.

Abbott Laboratories releases data on PILOT & CO-PILOT studies...

The EASL madness begins! An article posted today on Wall Street Journal.com below on Abbott's (or soon-to-be spin-off AbbVie) PILOT and CO-PILOT studies looking at protease inhibitor ABT-450 and polymerase inhibitors ABT-072 and ABT-333.  These studies are remarkable for a couple of reasons in my view:

• Interferon-free regimens, at least for certain populations, is really a reality.
• An SVR12 of at least 90% (in the tx-naive, no complications populations) is the new 75% of last year.
• The majority of large pharma companies now in the HCV marketplace is astounding. Competition will be fierce.
• The prospects of a Novir-boosted HCV PI is questionable, especially with 4 severe adverse events attached to it. 
• The drug to really, really beat is Ribavirin. Don't say I didn't tell you so. 

This EASL is going to be a big one for HCV drug development - stay tuned!

Abbott Drugs Suppress Hepatitis C Virus In 2 Studies

--Abbott is testing several experimental hepatitis C drugs

--More than 90% of patients with no prior treatment in one study had suppressed virus 12 weeks after treatment

--Abbott is targeting launch of hepatitis C regimen in 2015

(Adds details of a Bristol-Myers study in final paragraph; updates stock prices.)


   By Peter Loftus
   Of DOW JONES NEWSWIRES

Experimental drugs from Abbott Laboratories (ABT) suppressed the hepatitis C virus in most patients in two small, midstage studies.

The results unveiled Wednesday could reinforce Abbott's position as a key player in an industry race to bring the next generation of drugs to what is expected to be a multibillion-dollar market for hepatitis C therapies. The drugs' safety and efficacy, however, need to be confirmed in additional studies.

"The Abbott data are clearly impressive from an efficacy perspective," said ISI Group analyst Mark Schoenebaum.

Abbott shares rose 36 cents, or 0.6%, to $61.50 in recent trading, and earlier set a 52-week high of $62.57.

Abbott has said it could begin selling a new hepatitis C regimen in 2015, and sales could eventually exceed $2 billion annually. The drugs would be sold by the pharmaceutical business that Abbott plans to split off into an independent company later this year, to be named AbbVie.

Summaries of the Abbott studies and studies of other liver-disease drugs were posted online Wednesday by the European Association for the Study of the Liver, or EASL, in advance of its annual scientific meeting in Barcelona in mid-April. Some EASL study results won't be released until the conference begins in two weeks, including data for key drugs from Gilead Sciences Inc. (GILD) and Bristol-Myers Squibb Co. (BMY).

Gilead, Bristol-Myers, Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. (MRK) are among several companies developing hepatitis C drugs to tap a market that research firm Decision Resources predicts will hit $16 billion in 2015, up from just $1.7 billion in 2010.

Hepatitis C is a viral disease that attacks the liver, and is believed to afflict about 180 million world-wide, with more than 4 million in the U.S., according to the National Institute of Allergy and Infectious Diseases. At-risk groups include people who had blood transfusions before 1992, when a screening test for the virus was developed.

Abbott is developing several potential hepatitis C drugs. One of them, ABT-450, is a so-called protease inhibitor, which is the same class of drugs as two that went on sale last year, Merck's Victrelis and Vertex's Incivek, which is marketed outside the U.S. by Johnson & Johnson (JNJ) as Incivo.

The protease inhibitors advanced treatment of hepatitis C, but there is still room for improvement because current treatments require an injectable drug, interferon, that can be difficult for patients to tolerate. Abbott and other companies want to develop all-oral regimens that eliminate the need for interferon.

In addition, Abbott is developing two polymerase inhibitors, ABT-072 and ABT-333, which have different mechanisms of action than the protease inhibitors.

The two studies released Wednesday each focused on ABT-450. One, titled "Co-Pilot," involved 50 patients who were given the following: one of two different dose levels of ABT-450, combined in the same pill with Abbott's Norvir boosting agent; ABT-333; and an existing drug called ribavirin that is part of the current standard of care for hepatitis C. The regimen amounted to several pills taken daily.

The study tested safety and tolerability of a 12-week regimen of the drugs in people with the most common form of hepatitis C, known as genotype 1. Patients in the study either hadn't previously received any treatment or didn't respond to prior treatment.

In the treatment-naive patient groups, more than 90% had a sustained virologic response 12 weeks after the end of treatment, a measure known as SVR12. Sustained virologic response is roughly equivalent to being virus-free or having nearly undetectable viral levels.

In the patients who didn't respond to prior treatment, 47% achieved SVR12 in the Abbott-funded study.

The second, smaller study--called "Pilot"--combined ABT-450 boosted by Norvir, ribavirin, and ABT-072. All 11 patients had received no prior therapy. This group of patients had a subtype of the virus that generally responds well to an interferon-based regimen and thus considered among the easier forms to treat.

Ten of the 11 patients achieved a sustained virologic response 24 weeks after stopping treatment, for an SVR24 rate of 91%. One patient relapsed.

"We're showing a sustained, post-treatment response from 12 to 24 weeks out" from the end of treatment, said Scott Brun, divisional vice president of infectious disease development at Abbott.

In both studies, the most common adverse events included headache, fatigue and nausea, and most were mild. In the larger "Co-Pilot" study, four patients had severe adverse events including fatigue and vomiting. There were no deaths in either study.

Abbott is conducting larger mid-stage studies testing various combinations of the three experimental drugs used in the smaller studies, Brun said. Abbott hopes to move some combination of the drugs into late-stage testing next year.

Abbott has developed ABT-450 in collaboration with Enanta Pharmaceuticals.

Shares of some of Abbott's rivals in the hepatitis C field declined Wednesday. Idenix Pharmaceuticals Inc. (IDIX) dropped 14% to $8.77; Gilead was off 1.85% at $47.21; Vertex was down 2.5% at $40.73, and Bristol-Myers was down 0.6% at $33.66.

A summary of a Bristol-Myers study posted Wednesday by EASL showed that a regimen of the drugs daclatasvir and asunaprevir helped 90.5% of hepatitis C patients who hadn't responded well to prior therapy achieve sustained virologic response 12 weeks post-treatment. Some 64% of patients who were ineligible for interferon-containing regimens or who discontinued prior therapy for intolerance achieved SVR 12 with the Bristol regimen.

-By Peter Loftus, Dow Jones Newswires; 215-982-5581; peter.loftus@dowjones.com

EASL 2012 International Liver Conference abstracts now online...

Click here to load up on all the fun!

EASL abstracts to be available online April 4, 2012...

Posted on 3/22/12 on The Street.com. EASL will now allow full access to clinical data abstracts online on April 4, 2012. 

EASL Backs Down, Will Publicly Disclose Key Hep C Data
By Adam Feuerstein    03/22/12

BOSTON (TheStreet) -- The European Association for the Study of the Liver, better known as EASL, has backed down and will no longer unfairly and selectively disclose potentially stock-moving hepatitis C clinical data ahead of its important and closely followed conference next month.

In a total reverse of its previous policy, EASL said Thursday that research abstracts for its International Liver Congress, taking place April 18-22 in Barcelona, would be made publicly available online on April 4. Clinical data in the abstracts will not be under embargo, meaning journalists will be allowed to report on them.

"EASL is making these changes in light of recent criticism of its proposed policy, which suggests 'selective distribution' of officially accepted clinical data in advance of the Congress would make our proposed embargo policy untenable," EASL said in a statement issued Thursday.

The EASL meeting is where Gilead Sciences, Bristol-Myers Squibb, Abbott, Idenix Pharmaceuticals, Vertex Pharmaceuticals and Merck are among the companies expected to present new clinical data on experimental hepatitis C therapies. Therefore, the meeting is as vitally important to hepatitis C doctors and patients as it is to investors.

Yet under its old policy, EASL wanted to provide an advance look at potentially market-moving hepatitis C drug data to the medical society's members or registered attendees of the EASL meeting -- a group which includes hedge fund/mutual fund portfolio managers and sell-side analysts, all of whom can pay for early access.

EASL had planned to selectively distribute hepatitis C drug research abstracts to these folks today. The same documents were not going to be made available to the public, which meant that a select group of investors would have had access to potentially stock-moving clinical data while a majority of investors were to be kept in the dark.

In columns published Tuesday and Wednesday, I criticized EASL's abstract distribution policy as being misguided, unfair and quite frankly unworkable. Smarter medical and scientific groups like the American Society of Clinical Oncology (ASCO) realized years ago that trying to compartmentalize research abstracts was futile. Information cannot be selectivity disclosed and expected not to leak, especially information that will weigh on the market valuations of biotech and drug firms involved in new hepatitis C drug research.

EASL, to its credit, has now admitted the unfairness of its policy and took the necessary corrective steps.

In its statement Thursday, EASL said it "accepts that we must address this issue, and we acknowledge the efforts of several individuals to draw this to our attention."

--Written by Adam Feuerstein in Boston.

The Street.com: EASL Gives Wall Street's Privileged Investors Sneaky Preview to Key Hep C Data

Article posted on The Street.com on 3/20/12. Spring is in the air, and that means that one of the most important meetings in HCV drug development - EASL - is right around the corner.  The Street author Adam Feuerstein is none too pleased on EASL's rather elitist approach to disseminating important data ahead of time to only a chosen, privileged few. He's right - and he's also right that EASL's attempt at keeping this data embargoed until the actual start of the conference is pert near impossible.  The time has come for reform and revolution. I'd be right there on the front lines, but there's too much good stuff on TV. 

EASL Gives Wall Street's Privileged Investors Sneaky Preview to Key Hep C Data

By Adam Feuerstein    03/20/12 - 10:45 AM

Update: After this column was published, EASL announced a delay in the release of research abstracts for the International Liver Congress to Tues. March 27.

BARCELONA (TheStreet) -- Investing in hepatitis C drug stocks is a suckers bet this week because the European Association for the Study of the Liver, better known as EASL, has rigged the game so that Wall Street's privileged investors get a sneak peek at new clinical data ahead of an important and closely followed conference next month.

EASL's International Liver Congress, taking place April 18-22 in Barcelona, is the must-follow medical meeting of the spring. Gilead Sciences, Bristol-Myers Squibb, Abbott, Idenix Pharmaceuticals, Vertex Pharmaceuticals and Merck are among the companies rolling out new clinical data on experimental hepatitis C therapies.

But if you want an advance look at potentially market-moving hepatitis C drug data, you'll have to be an EASL member or a registered attendee of the EASL meeting -- a group which includes hedge fund and mutual fund portfolio managers and sell-side analysts, all of whom can pay for early access.

EASL plans to selectively distribute hepatitis C drug research abstracts to these folks on Thursday. The same documents will not be made available to the public. That means a select group of investors will have access to potentially stock-moving clinical data while a majority of investors will be kept in the dark.

Journalists registered to cover the EASL meeting will also be granted early access to hepatitis C research abstracts but they are barred by EASL's restrictive embargo rules from writing about any new data until the start of the April meeting.

EASL's abstract distribution policy is misguided, unfair and quite frankly unworkable. Smarter medical and scientific groups like the American Society of Clinical Oncology (ASCO) realized years ago that trying to compartmentalize research abstracts was futile. Information cannot be selectivity disclosed and expected not to leak, especially information that will weigh on the market valuations of biotech and drug firms involved in new hepatitis C drug research.

That's why most medical and scientific groups made research abstracts freely available to everyone in advance of major conferences.

Jacqui Sisto, an EASL spokesperson, explained via email that selective disclosure of research abstracts "ensures the integrity of the International Liver Congress." Really? EASL appears to be corrupting its most important meeting, not making it more honest.

Pharmasset Announces the Expansion of the ELECTRON Trial in Chronic Hepatitis C

Pharmasset adding arms to it's genotype 2/3 ELECTRON trial looking at shorter durations of therapy in addition to inteferon-free monotherapy for it's PSI-7977 nucleotide analog. Nucs traditionally have a very high barrier to resistance in comparison to non-nucs, but with a virus capable of making every possibly mutation of itself in the course of a day, is nuc monotherapy without an immune system modulator or another viral life cycle-specific inhibitor enough, even in the relatively easy-to-treat G2 and 3 virus? If it's not, what are the odds of a PSI-7977 resistant quasispecies developing and the corresponding fitness level compared to wild type of those variants? Guess we'll find out soon enough. If anyone can shed further enlightenment, please do.

PRINCETON, N.J., June 8, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) and two arms of interferon-sparing therapy: one for 8 weeks of PSI-7977 plus peginterferon and ribavirin (Peg-IFN/RBV) in patients with HCV genotype 2 (GT2) or 3 (GT3) and one for 12 weeks of PSI-7977 plus Peg-IFN/RBV in patients with HCV genotype 1 (GT1) prior null responses.

"The combination data reported at EASL demonstrated that SVRs were achievable with two oral DAAs in the absence of peginterferon and ribavirin," stated Bill Symonds, PharmD, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine, "We continue to explore the potential for removing peginterferon and ribavirin from the HCV treatment regimen. Given the encouraging data we are seeing in ELECTRON, we have decided to expand the study to investigate PSI-7977 monotherapy, as well as shorter treatment regimens based on the promising data we reported at EASL from PROTON."

Pharmasset anticipates reporting results from the first four arms of the trial (n=40) during the second half of 2011. We have submitted a number of abstracts to the 2011 American Association for the Study of Liver Diseases (AASLD) meeting, including data from the ELECTRON and PROTON trials.

About the Trial

The ELECTRON trial is an exploratory study of PSI-7977 for the treatment of chronic HCV infection. Part 1 of the trial is evaluating 12-week regimens of PSI-7977 400mg QD in combination with ribavirin (RBV) only, and in separate arms with abbreviated durations of Peg-IFN for 4, 8, or 12 weeks in treatment-naive patients with HCV GT2 or GT3. The primary endpoint of the trial is the safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without Peg-IFN. On May 11, 2011, Pharmasset announced the completed enrollment of Part 1 of ELECTRON in patients with HCV GT 2 or GT 3:

* PSI-7977 400mg with RBV for 12 weeks (no peginterferon);
* PSI-7977 400mg with RBV for 12 weeks; Peg-IFN weeks 1-4 only;
* PSI-7977 400mg with RBV for 12 weeks, Peg-IFN weeks 1-8 only;
* PSI-7977 400mg with Peg-IFN and RBV for 12 weeks.


In Part 2 of ELECTRON, Pharmasset will enroll an additional 30 patients into exploratory regimens of monotherapy and abbreviated durations of total therapy. Following on the first four Cohorts of ELECTRON a 5th cohort will be added to explore 7977 400mg monotherapy in treatment-naive patients with HCV GT2 or GT3:

* PSI-7977 400mg monotherapy for 12 weeks.


With the previously reported 100% SVR12 in naive GT2/3 subjects in PROTON, a 6th and 7th cohort will be added to ELECTRON to explore shorter treatment durations in both GT2/3 naive subjects and HCV GT1 subjects who have documented null responses (less than 2 log(10) IU/mL reduction in HCV RNA after 12 weeks of Peg-IFN/RBV):

* PSI-7977 400mg with Peg-IFN/RBV for 8 weeks
* PSI-7977 400mg QD with Peg-IFN/RBV for 12 weeks.


About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in three Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in two Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.

Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 865-0693

Forward-Looking Statements

Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 and our Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.

SOURCE Pharmasset, Inc.

A bit more info on Novartis' cyclophilin inhibitor...

An article appearing on Pharmiweb about the approval of Telaprevir and Boceprevir, but also comments on alisporivir, also known as DEB025 which Novartis licensed from fellow Swiss firm Debiopharm in February 2009.

THE Food and Drug Administration (FDA) has approved Vertex Pharmaceuticals Inc.'s (VRTX) hepatitis C drug telaprevir and Merck’s hepatitis C drug, boceprevir.

Both drugs are protease inhibitors (PIs) and are designed to block an enzyme that helps the hepatitis C virus replicate. Hepatitis C is a liver disease caused by infection with the hepatitis C virus, which is transmitted through contaminated blood. The infection can cause liver failure and liver cancer.

The move follows the presentation and publication of new data on the drugs at the recent annual meeting of the European Association for the Study of Liver Disease (EASL) held in Berlin. Also presented at the meeting was data on Novartis' novel investigational oral agent alisporivir. This data was described as “fantastic” by EASL vice secretary Mark Thursz, professor of hepatology at Imperial College, London, while Robert Flisiak from the Medical University of Bialystok, Poland, told the congress as he presented the data: “This novel agent has the potential to be an important component of future hepatitis C treatment.” The availability of novel agents such as alisporivir and the protease inhibitors marks a new era in the treatment of hepatitis C infection. More than 30 potential hepatitis C agents are currently in R&D pipelines. Professor Thursz said that the new PIs offered unprecedented levels of sustained virological response and would be used initially with the current standard of care, pegylated interferon-alpha plus ribavirin. However, with so many potential novel treatments for hepatitis C on the horizon, he envisaged a time when standard of care for hepatitis C would be an interferon-free regimen. Boehringer’s HCV polymerase inhibitor BI 207127 has been fast-tracked by the FDA in combination whilst Bristol-Myers Squibb is trialling its PI, BMS 650032, in combination with the NS5A inhibitor BMS 790052.

Novartis’ alisporivir shows significant promise if its phase II data from the ESSENTIAL study, presented at EASL, is repeated in a phase III trial, which is now underway. The ESSENTIAL study involved 300 previously untreated patients infected with genotype 1 HCV. Of those treated with alisporivir, plus standard of care (pegylated-interferon alfa 2a/ribavirin), 76% achieved superior viral cure compared to 55% of patients on standard care alone 24 weeks after stopping treatment.

The study’s principal investigator, Stefan Zeuzem from Goethe University Hospital in Frankfurt, said: “Hepatitis C is difficult to treat and current therapies are effective only in about half of patients with the most prevalent genotype. These results are exciting because a large majority of patients achieved sustained viral response with alisporivir.”

Alisporivir is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the hepatitis C virus directly, alispirovir, targets host proteins that the hepatitis C virus uses for replication. A Phase IIb trial looking at the potential of the agent in HCV patients with genotypes 2 and 3 is also underway. The host proteins are needed for replication in all types of HCV infection so there is potential for the agent to have broad activity; there are six variations of HCV.

An international Phase III study is evaluating the efficacy and safety of alisporivir combined with standard care in previously untreated HCV G1 patients. The Phase II study showed that serious adverse events occurred in 6.9% of patients treated with alispirovir and standard care compared to 5.5% of patients treated with standard care alone. Prof Flisiak reported a higher rate of bilirubin (32.9% versus 1.4% in the alisporivir-treated group compared to standard care alone) but this was transient and reversible and associated with the initial loading dose. Final data from the Phase III ESSENTIAL-2 is expected in March 2013.

Novartis medical director Nikolai Naoumov said: “The data is very encouraging because it has produced a significant response in the most common form of HCV which can be very difficult to treat and with a reasonable safety profile. If the results of Phase III and other studies are also encouraging, this agent could offer a paradigm shift in clinical practice by being able to treat a number of genotypes and patients who have not responded to standard care.” Novartis in-licensed alisporivir, also known as DEB025, from fellow Swiss firm Debiopharm in February 2009.

Read more: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=40176#ixzz1Lo0stbq3

Original article here: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=40176

Conatus Pharmaceuticals - Phase II data on Hepatitis C MMP inhibitor CTS-1027 to be presented at EASL

Privately-held Conatus Pharmaceuticals will have two posters on the Phase II trial of it's inhibitor of matrix metalloprotease (MMP) activity, CTS-1027 - the only MMP inhibitor currently in development for HCV at this time.

Conatus Pharmaceuticals Inc. today announced the acceptance of two poster presentations of Phase 2 clinical trial data of CTS-1027 for the treatment of hepatitis C virus-infected patients at the 46th annual meeting of the European Association for the Study of the Liver (EASL) to be held in Berlin, Germany, on March 30 to April 3, 2011.

Specifically, abstract 562 entitled: 24-WEEK TREATMENT WITH CTS-1027 IN COMBINATION WITH RIBAVIRIN REDUCES HCV-RNA IN TREATMENT NAIVE GENOTYPE-1 PATIENTS will be presented.

In addition, abstract 549 entitled: UNIQUE PATTERN OF VIROLOGIC RESPONSE IN PATIENTS WITH GENOTYPE-1 HCV: A PHASE II STUDY OF CTS-1027 IN COMBINATION WITH PEGINTEFERON/RIBAVIRIN (SOC) IN NULL RESPONDERS will also be presented.

"This will be the first public disclosure of these exciting clinical results and represents a significant step forward to raise awareness of CTS-1027 for the treatment of HCV," said Alfred P. Spada, Ph.D., Senior Vice President, Research and Development at Conatus.

"CTS-1027 is a first-in-class oral, small molecule inhibitor of host matrix metalloprotease (MMP) activity. There are no other drugs under development for HCV that operate by the same mechanism of action. Most other approaches to treat HCV infection are direct-acting anti-viral drugs whose activity is directed against virus proteins or enzymes with the objective of reducing the production of virus in infected cells. CTS-1027 by comparison is distinctly different in that its activity is hypothesized to facilitate the immune clearance of virus-infected cells and decrease the frequency of new infections, both of which are of key importance in curing HCV infections," said Steven J. Mento, Ph.D, President and CEO of Conatus.

Conatus Pharmaceuticals Inc. is a privately-held biopharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease and oncology. Conatus' lead drug candidate, CTS-1027 is in multiple Phase 2 clinical trials for the treatment of hepatitis C virus (HCV). Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the sale of Idun to Pfizer.

SOURCE Conatus Pharmaceuticals Inc.

EASL: Telaprevir in combination with Peg-INF2a and RBV increased SVR rates in treatment-naive patients regardless of race or ethnicity

Some impressive Telaprevir TVR) treatment naive pooled analysis data to be presented at the upcoming EASL meeting in Berlin, looking at SVR rate differences between race and ethnicity in the ADVANCE and ILLUMINATE trials. Specifically, differences between the TVR arms and Peg-inf2a/Ribavirin (PR). Most impressive were the differences in SVR, relapse and viral failure in Black/African American subjects. In the TVR + PR for 12 weeks, then PR for another 12 or 36 weeks depending on viral response, total SVR was 61%, relapse was 13% and viral failure was 9%. Compare this to the 48 week PR control arm, which showed 25% SVR, 36% relapse and 46% viral failure. Total TVR-related SVR was still lower than non-Black/African Americans (61% vs 75%, respectively) but the improvement from the current standard of care (48 weeks of PR) is significant and encouraging. See the full poster abstract here: http://www1.easl.eu/easl2011/program/Posters/Abstract222.htm

TELAPREVIR IN COMBINATION WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN INCREASED SUSTAINED VIROLOGIC RESPONSE RATES IN TREATMENT-NAïVE PATIENTS REGARDLESS OF RACE OR ETHNICITY

G.M. Dusheiko1*, M.W. Fried2, R. Reddy3, D.R. Nelson4, N. Bzowej5, N. Adda6, C.I. Wright6, L. Bengtsson6, S. George6, S.L. Flamm7

1Royal Free and University College, London, UK, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, 3University of Pennsylvania School of Medicine, Philadelphia, PA, 4University of Florida, Gainesville, FL, 5California Pacific Medical Center, San Francisco, CA, 6Vertex Pharmaceuticals Incorporated, Cambridge, MA, 7Northwestern University, Chicago, IL, USA. *g.dusheiko@medsch.ucl.ac.uk

Background and aims: ADVANCE and ILLUMINATE were Phase 3 randomized studies that evaluated the safety and efficacy of telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R) in treatment-naïve genotype 1 HCV patients. In this pooled analysis, we evaluated the effect of race or ethnicity on the response to treatment with telaprevir-based therapy.

Methods: Patients who received 12 weeks of response-guided telaprevir-based therapy for a total treatment duration of 24 or 48 weeks (ADVANCE N=903 and ILLUMINATE N=540) were compared to ADVANCE patients who received 48 weeks of PR alone (N=361). Race and ethnicity were self-reported and were not mutually exclusive. Ethnicity was not reported in 13 patients as the question was not allowed per local regulations.

Results: Efficacy outcomes are presented in the Table. The most common ( ≥ 25% in any subgroup) adverse events in patients who received telaprevir-based therapy were: fatigue, pruritus, nausea, headache, anemia, rash, influenza-like illness, insomnia, neutropenia, and diarrhea. Discontinuations of all drugs during telaprevir phase were: due to adverse events (7% in T12PR and 4% in PR), rash events (1% in T12PR and 0% in PR) and anemia events (1% in T12PR and < 1% in PR).

View table here: http://www1.easl.eu/easl2011/program/Posters/Abstract222.htm

Conclusions: Telaprevir-based therapy provided a substantial improvement in SVR rates in Black/African American and Hispanic/Latino patient populations known to achieve lower SVR rates when treated with PR alone. Low rates of discontinuations of all drugs due to adverse events, rash and anemia events were observed across all subgroups during the telaprevir phase.