Sofosbuvir (GS-7977) in HIV/HCV co-infected patients...

Posted 9/17/12 on Hep Mag.com. A small interferon-free Phase Ib 7-day trial of Sofosbuvir (GS-7977) plus ribavirin in 19 HIV/HCV co-infected patients yielded some impressive initial results in a population that is definitely in need of more anti-HCV options. Sofosbuvir showed no difference in viral kinetics vs non co-infected patients, no new safety signals, no HIV viral breakthrough and no added side-effects. Hopefully the larger Phase III trial in this population will be equally impressive in its results. 

Sofosbuvir (GS-7977) Shows Promise in HIV/Hep C-Coinfected People

Gilead Sciences' experimental NS5B polymerase inhibitor sofosbuvir (GS-7977) was just as likely to rapidly reduce hepatitis C virus (HCV) levels in people coinfected with HIV, compared with those living with HCV but not HIV, in a small seven-day study presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco. The clinical trial, which enrolled HCV/HIV-coinfected and HCV-monoinfected patients residing in Puerto Rico—75 percent of whom had difficult-to-treat genotype 1 HCV infection—also noted that side effects were no different or more severe among those with living with both viruses. After a week of sofosbuvir treatment, used without other hep C medications, HCV viral loads dropped by an average of 4 log (99.99 percent). Additionally, nearly 60 percent of patients achieved undetectable HCV viral loads during the study, with 15 percent maintaining undetectable levels seven days after treatment was discontinued. Sofosbuvir appeared to work equally well against the different HCV genotypes in the study and did not hinder the effectiveness of the antiretroviral regimens being used to suppress HIV. A Phase III clinical trial of sofosbuvir plus ribavirin enrolling people living with HCV and HIV began in July and is currently recruiting volunteers.

The Street.com: Rethinking Idenix Pharma in Wake of Bristol's Hep C Blow Up...

Posted 8/6/12 on The Street.com. The Streets's Nathan Sadeghi -Nejad weighs in on the current - and seemingly hyperactive - HCV drug development space. He's right, the last couple of weeks have been a whirlwind of surprises - Novartis giving Idenix the rights to it's HCV drugs back, BMS's BMS-094 seemingly taking it's last breath, Gilead co-formulating it's nuc with it's NS5A inhibitor just to name a few.  BMS has had a rough time of it in the HCV drug development space. It's $885 million purchase of ZymoGenetics with it's Peg Lambda seemed like a great move in 2010, before the advent of the idea of potential interferon-free therapy (I still think Peg Lambda may be a surprise dark horse - I'm still cautious on the potential 'interferon free' except in certain cases), Then consider the $2.5 billion purchase of Inhibitex, whence the doomed BMS-094 nuc came from leaving BMS's NS5A inhibitor without a BMS-owned partner. It's other late-stage HCV drugs aren't much to sneeze at. Ouch. Sadeghi-Nejad makes some other observations (Gilead - yes. Idenix - nuc is too close to BMS-094, maybe a toxicity issue but no safety signals to support. Vertex nuc looks powerful, but too far from market to mean much) that you may or may not agree with. Definitely a good read if you're watching the HCV drug development race.

Rethinking Idenix Pharma in Wake of Bristol's Hep C Blow Up

By Nathan Sadeghi-Nejad - 08/06/12 - 7:00 AM EDT
Tickers in this article: IDIX BMY GILD VRTX

NEW YORK (TheStreet) -- Last week, Bristol-Myers Squibb(BMY) confirmed my previously reported suspicions by abruptly halting a Phase II trial of BMS-094 (formerly INX-189) -- a nucleotide polymerase inhibitor, or "nuc," for the treatment of hepatitis C. One patient in the study experienced major cardiovascular toxicity, forcing Bristol-Myers to stop dosing BMS-094.

The company has provided few follow-up details but it appears as if BMS-094 is dead.

That means Bristol-Myers' $2.5 billion acquisition of Inhibitex (from where BMS-094 originated) has proven to be a complete zero in less than seven months. I'm not sure if that's a mergers-and-acquisition disaster record, but it's probably close.

The demise of BMS-094 has also reshaped the Hep C landscape. Let's review who still stands and where. For some assistance, I turned to John Tucker, a scientific analyst with BioMedTracker, a division of Sagient Research. Tucker recently published an excellent overview on Hep C drugs in development and he's been all over BMS-094 and its implications.

At this point, combining a "nuc" with an NS5A inhibitor and the generic antiviral drug ribavirin seems to be the most promising "all oral" Hep C regimen in clinical development. This makes Bristol-Myers' daclatasvir, an NS5A inhibitor essentially useless on its own. The company's other later-stage hep C drug candidates -- the non-nucleoside polymerase inhibitor BMS-791325 and the protease inhibitor asunaprevir -- have only modest efficacy or toxicity issues, or both.

Bristol-Myers may continue to beg but I'm convinced Gilead Sciences(GILD) has no interest in a daclatasvir partnership. As I noted recently, Gilead's nuc-NS5A combination -- GS-7977 and GS-5885 -- has made rapid clinical progress and will start pivotal trials this year. In sum, the BMS-094 blowup leaves Bristol-Myers up a proverbial creek in Hep C. Although this failure has little long-term financial impact, Bristol-Myers' apparent inability to foresee this compound's risks raises concerns about the company's R&D and business development capabilities.

Gilead emerges a big winner. I have long believed Gilead would be first to market with an all-oral Hep C regimen, but Bristol-Myers has handed the company a much bigger lead. (I also still doubt the size of the commercial market for Hep C, but that's another issue.)

I initially considered Idenix Pharmaceuticals(IDIX) and its nuc IDX-184 a winner emerging from the BMS-094 blowup. Now, I'm less sure.

IDX-184 has a chemical structure that is similar to both BMS-094 and Pharmasset's PSI-938, another Hep C nuc that was killed off by toxicity problems last year. More specifically, the active moiety of IDX-184 -- the part of the molecule that makes the drug work -- appears to be similar to the active moieties of both BMS-094 and PSI-938. That could be a big problem.

Chemists often attach nonessential atoms to a drug candidate in an attempt to change the compound's overall physiological behavior. As the drug is metabolized in the body, those byproducts are cleaved and the working core of the drug -- the active moiety -- is unveiled.

The byproducts are usually innocuous, but not always. For example, it's not clear whether the side effects that killed BMS-094 were caused by the active moiety or by 1-naphthol, a toxic metabolite of the drug. Similarly, PSI-938's fatal flaw remains unclear. This worries me, and it should worry Idenix bulls.

Idenix does have a very reasonable defense. Management contends IDX-184 is nearly entirely targeted to the liver and metabolized poorly in other cell types. Further, IDX-184 seems to be more slowly metabolized by the liver than BMS-094. These factors certainly lessen the risk of toxicity. Thus far, Idenix has treated roughly 60 patients for 12 weeks with IDX-184 and observed no safety signals, including no cardiovascular side effects.

That's encouraging, but I would prefer to overpay for Idenix after there are more data on IDX-184. I would reduce or eliminate long exposure to Idenix until the drug's safety has been more completely established.

Two more Idenix red flags that make me cautious: First, Novartis(NVS), Idenix's partner for nearly a decade, ended the relationship last week. I understand that Novartis wasn't much of a collaborator so walking away might actually be a net positive for Idenix. But I still tend to view pharma-biotech breakups as a negative, although in this case a bit less so.

Second, Idenix completed a major secondary offering only two days after the Novartis breakup. Idenix sold 22 million shares at $8.00 per share or 28% below recent highs. Although I generally support equity issuances at management's discretion, the company still had at least $90 million in the bank. Shareholders should feel justifiably frustrated at this seemingly unnecessary rush dilution of the existing investor base. I worry that the timing signals dark clouds on the horizon.

Right before the Bristol-Myers news, Vertex Pharmaceuticals(VRTX) announced impressive early clinical data for ALS-2200, a nucleotide analogue licensed from Alios BioPharma. After seven days of dosing, the eight treated patients showed a median 4.54 log reduction in viral load. That's near complete eradication of virus, for those of you unfamiliar with the logarithmic scale.

Unfortunately for Vertex, ALS-2200 has not cleared any meaningful long-term safety hurdles and the drug remains years behind Gilead's compounds. I would put Vertex on the "watch and wait" list, but that's it.

As I have discussed before, it's hard for me to get excited about the other Hep C players. Abbott(ABT) has a seemingly decent trio of drug candidates in later-stage development, but the impending spin off of AbbVie -- Abbott's pharma business -- makes the new company nearly completely dependent on the multi-blockbuster rheumatoid arthritis drug Humira.

Johnson & Johnson's(JNJ) TMC-435 looks solid but lacks an obvious companion unless the company partners with Gilead or physicians, on their own, decide to combine TMC-435 with Gilead's GS-7977 into an "off label" all-oral Hep C regimen -- an idea that BioMedTracker's Tucker believes is a real possibility. Finally, everyone wants me to like Achillion Pharmaceuticals, but there is no shortage of NS5A or protease inhibitors -- the company has two NS5As and a protease inhibitor -- so I can't get that excited.

Ironically given the longstanding investor skepticism, Gilead appears likely to dominate the Hep C market over the next decade. I still worry the company vastly overpaid for Pharmasset, but that concern will be meaningful only if something goes wrong and investors are looking for a cudgel with which to beat management. Otherwise, it's time for investors to start thinking logically about the real size of the Hep C treatment market. It's going to be hard for any company to make big money if there aren't enough Hep C patients to treat.

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

BMS halts development of Phase 1 anti-HCV nuc, BMS-986094...

Posted 8/2/12 on MedPage Today.com. BMS halts development of its investigational nuc BMS-986094 for treatment of chronic HCV after one of the patients the 200mg arm of the  phase 1 trial suffered heart failure. It is unknown at time of publishing whether the drug was directly linked to the drug and all patients involved with the trial are undergoing full assessment.  This effectively makes GS-7977, Gilead's nucleotide analog one of the only nucs currently in advanced development unscathed by toxicity and certainly adds to it's luster, at least in the short term. 

Safety Issue Halts Study of BMS HCV Drug

By Michael Smith, North American Correspondent, MedPage Today
Published: August 02, 2012

Bristol-Myers Squibb has suspended treatment "to protect patient safety" in a phase IIb trial of an investigational oral drug for hepatitis C.

A spokeswoman for the company said the decision was made after one of the patients getting 200 mg of the compound, dubbed BMS-986094, suffered heart failure.

Bristol-Myers Squibb is not giving further details on the patient's condition, according to Cristi Barnett, the company's associate director of public affairs.

In an email to MedPage Today, Barnett said it's still not clear what caused the heart failure or whether it's related to the study drug. To try to clarify the issue, BMS is doing "an immediate assessment of all patients receiving 094 at any dose," Barnett said.

"This assessment includes full physical exams and histories, and cardio ECHO imaging and ECGs for all patients," Barnett said. "Any clinically significant cardiac ECHO abnormality will then be reviewed by a consulting cardiologist as soon as possible."

The drug is a nucleotide NS5B polymerase inhibitor and was acquired by the company when it paid $2.5 billion in January to purchase Inhibitex, the original developer. It was first known as INX-08189.

It's one of several under development -- both Gilead Sciences of Foster City, Calif., and Vertex Pharmaceuticals of Cambridge, Mass., have competitors in the field.

The range of potential treatments for the virus, blamed for about 15,000 deaths annually in the U.S., has been expanding dramatically with the recent development of so-called direct-acting agents.

Two HCV protease inhibitors -- telaprevir (Incivek) and boceprevir (Victrelis) -- are already on the market, but they are indicated for use with pegylated interferon-alfa and ribavirin, which aim at stimulating the immune system rather than targeting the virus directly.

The goal has been to develop all-oral combinations of direct-acting agents that would eliminate the need to use interferon and ribavirin.

BMS-986094 was being tested in a two-part dose-ranging study, dubbed AI472-003, among patients with HCV genotypes 2 or 3 who had not been previously treated. Genotypes 2 and 3 are regarded as being easier to cure than genotype 1.

The first part of the 12-week study was double-blinded and included 90 patients in four treatment arms. In the comparator arm, patients were treated with pegylated interferon-alfa and ribavirin, plus an oral placebo.

In the remaining arms, patients got interferon and ribavirin plus 25, 50, or 100 mg of BMS-986094.

The second part of the study, planned to include 120 patients, was open label for 12 weeks and had five arms.

In two arms, patients took either 100 or 200 mg of BMS-986094, combined with ribavirin. In two others, they took the same doses of the drug, this time combined with daclatasvir, the company's investigational NS5A replication complex inhibitor.

Finally, in the fifth arm, they took 50 mg of BMS-986094 and both daclatasvir and ribavirin.

BMS urges HCV combo study with Gilead Sciences...

Lovingly pinched from the mighty NATAP.org. BMS calling out Gilead to collaborate at the at the Sanford Bernstein Strategic Decisions Conference in New York, after the success of Gilead's GS-7977 and Bristol's daclatasvir combination in HCV treatment-naive patients presented at EASL. Gilead seems content to use their own, proprietary NS5A inhibitor in combo with GS-7977 thus far, however. 

Bristol urges combo hepatitis C study with Gilead

By Ransdell Pierson

Thu May 31, 2012


(Reuters) - Bristol-Myers Squibb Co renewed calls for biotechnology company Gilead Sciences Inc to test one of its hepatitis C drugs in late-stage trials alongside Bristol's own promising medicine, following impressive results from a mid-stage trial that combined the experimental products.

Bristol's daclatasvir is from a new class of drugs known as NS5A inhibitors. Gilead's GS-7977 is a nucleotide polymerase inhibitor. Both are designed to block enzymes essential to replication of the hepatitis C virus.

Bristol-Myers Chief Executive Lamberto Andreotti, speaking on Thursday at the Sanford Bernstein Strategic Decisions Conference in New York, said patients and both drugmakers stand to benefit if combined Phase III trials of the two medicines are pursued.

"We have a different point of view about whether to enter Phase III (trials) with that combination," Andreotti said. "We believe, for both patients and companies, it is better to move forward" in the short term.

But Andreotti said Gilead instead seemed intent on looking "in-house" -- focusing on combinations of its own products. Gilead officials could not immediately be reached to comment.

Andreotti said there was a "huge, unmet need" for better treatments among an estimated 170 million to 180 million people worldwide believed to be infected with the virus. Transmitted by blood transfusions, sexual contact or shared drug needles, the virus invades the liver and can steadily destroy the organ over decades. It is the most common reason for liver transplants in the United States.

Data from the mid-stage trial combining Gilead's GS-7977 and Bristol's daclatasvir showed a 100 percent response rate in previously untreated patients with the most common form of hepatitis C.

Shares of Gilead jumped 11 percent on April 19 when the data were released, showing the profound benefits of combining its 7977 -- acquired through Gilead's $11 billion purchase of Pharmasset -- with daclatasvir.

At the time, Bristol said Gilead had balked at further collaboration on the combination under study, which was begun while 7977 was owned by Pharmasset.

The results of the mid-stage study were accomplished without interferon, an injected drug that causes flu-like symptoms and other side effects that often lead patients to discontinue or delay treatment. Nor did the study use ribavirin, an older antiviral drug that is also currently part of all treatment regimens.

Instead of working with Bristol-Myers, Gilead is forging ahead with a study of 7977 in combination with its own experimental NS5A inhibitor. In the meantime, Bristol-Myers is testing daclatasvir with a drug similar to 7977 that it acquired with its $2.5 billion purchase of Inhibitex, as well as with other experimental drugs in its development pipeline.

In other remarks at the Sanford Bernstein meeting on Thursday, Andreotti said he expects some form of U.S. healthcare reform to emerge, even if the U.S. Supreme Court rules against extensive reforms approved by Congress and signed into law by President Obama.

The High Court is expected next month to render a decision on the sprawling legislation, which would greatly expand healthcare coverage to uninsured Americans but require bigger fees and rebates from drugmakers and medical device makers.

Andreotti said the enacted reforms "started out on the right foot" but became too complicated for Bristol-Myers and the American people.

The Bristol-Myers CEO said he expects rapidly declining sales of Plavix, a blood-clot preventer which has long been the company's biggest product, due to loss of U.S. patent protection earlier this month and ensuing competition from a number of cheaper generics. The pill, sold in partership with French drugmaker Sanofi, had revenue last year of more than $7 billion -- making it one of the world's top-selling medicines.

Despite expected plunging sales of Plavix, Andreotti said Bristol-Myers has no plans to "downsize" its research spending, having already closed down many company facilities in previous cost-cutting efforts.

Bristol-Myers will adjust future R&D spending in accordance with company performance, and expects significant sales gains to come from Asia but not from Europe, Andreotti said.

He said the company plans over the next few years to concentrate on developing medicines to treat cancer, viral infections and blood clots -- calling those therapeutic areas "the three pillars" of company growth.

(Reporting By Ransdell Pierson; Additional reporting by Bill Berkrot; Editing by Maureen Bavdek and Gunna Dickson)

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

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

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.

Post-Scripps Conference Download "New Treatments in Chronic Liver Disease"

I attended the Scripps Clinic 'New Treatments in Chronic Liver Disease' conference this past weekend in La Jolla, CA.  There were three sessions focusing just on HCV - 'Management of Chronic Hepatitis C in the DAA Era'; 'Controversy - Should We Treat IL28B CC Patients Without DAAs?' and the 'New Directions for HCV Therapy (2012 - 2014)'.  Adrian Di Bisceglie MD, Paul Pockros MD and Anna Lok, MD - all three superstars of Hepatology - did the honors. Below are some of the highlights (for me, anyway) in terms of the future of HCV treatment. Reductionism at its most subjective.

·        The future of Interferon & Ribavirin:

o   Interferon will likely be with us for at least the next 5 years, but may be regulated to patients that are tough to treat (i.e. cirrhotics, G1a)

o   Ribavirin will be a mainstay of therapy for the majority of patients.

o   A nuc may be able to replace RBV in a small subset of patients in combination therapy (PI +nuc + nonnuc, for example) The subset of patients were characterized as G2 & G3, non-cirrhotic, low BMI, non-smoking and/or post-transplant / dialysis patients and perhaps G1b with CC allele). 

o   The  economic ramifications of this strategy where examined. if a generic like RBV worked just as well as a nuc, then why use two or more DAAs where the cost of treatment will likely be much higher?

·        Ribavirin dose reduction with current therapy:

o   Docs doing CDCs every two weeks. When patient drops below 10 g/Dl, theydrop RBV down to 600.  If that doesn’t provide enough EPO is added.

o   Approval of EPO an issue – may take three weeks, what do we do then?

o   One doctor on the panel said “we don’t know how how we can go with RBV. Can we stop RBV for a couple of days until the patient normalizes? We don’t know.”

o   Another doctor on the panel replied that the current data on stopping RBV is “inadequate” (very vociferous on this).  Referenced the HCV Target registry Mike Fried was involved in to take a closer look at this issue.  Cautioned against this until the data is more clear.

·         New treatment notables: 

o   GS-7977 + RBV (no INF)  much less likely to cause anemia than current DAA therapy. Referenced a slide from the ELECTRON study that showed only an average of a 2 g drop in hemoglobin, no reduction in absolute neutrophil count. Also much less propensity for DDIs than current DAA therapy.

o   All agreed that the data they are most anxiously awaiting is the G1 treatment naïve data from the ELECTRON trial with GS-7997 + RBV (to be presented at EASL)

o   Doctor on the panel referenced ELECTRON demographics – G1a, no cirrhosis. “We need to see VERY high SVR rates in this INF-free trial in this population. I’m looking for 100% SVR”.

o   Resistance will always be a concern given the error-prone, highly replicative capacity of the virus. Less of a concern with the polymerase inhibitors because of the higher barrier to resistance.

o   Future much more certain for polymerase inhibitors and protease inhibitors than cyclophilin inhibitors at this point.

o   Less danger of drug-drug interactions with upcoming therapies – good news for post-transplant, dialysis and HIV/HCV co-infected patients.

·         Timeline predictions on evolution of HCV therapy:

o   Q4 2013/ Q1 2014 – Quad therapy vs new triple therapy options (PI + nuc/nonnuc + PEG/RBV)

o   Q4 2013/Q1 2014 IFN-free regimens for G2/3 and perhaps G1b (w/ CC allele)        and for those intolerant to IFN. (PI +nuc/nonnuc/NS5A w/+ RBV)…. Maybe w/out RBV for small segment of patients.

Original article: The REAL drug to beat in Hepatitis C treatment: Ribavirin

An article I authored and recently published online thanks to the great folks at GastroHep.tv, a multi-media, cutting edge online resource for the Gastroenterology and Hepatology community. 



The REAL Drug to Beat in Treating Hepatitis C: Ribavirin

by Chris Barnes

By now, most of us are aware – some of us painfully so – that the Hepatitis C drug development market is red hot. Investors and developers alike need a scorecard to keep track of who is buying who and for what potential blockbuster drug in the race to make it big in treating Hepatitis C.  All of this hullabaloo is for good reason – the CDC estimates there are over 170 million people infected with Hepatitis C worldwide[1], a vast majority of them don’t know that they have it.  That is paradoxically both an enormous and lucrative problem. This means there are a lot of potential patients for pharmaceutical companies to treat with blockbuster anti-HCV drugs.

The names of the compounds in development are like alphabet soup – GS-7977, VX-222, BMS-790052, BI-201335, TMC 435, BL-8020… protease inhibitors, polymerase inhibitors, cyclophilin inhibitors… the list goes on and on. This is a good thing for both drug makers and patients. Drugs to treat Hepatitis C are becoming more potent and more tolerable.  And the race for the next blockbuster drug means there is no shortage of drugs and drug classes to choose from.  Drug developers may even realize the holy grail of Hepatitis C treatment – an all oral, interferon-free regimen consisting of 2-4 pills a day. That’s right, no shots, no interferon. This would potentially make treatment for Hepatitis C infinitely more tolerable for patients.

So the HCV drug development biz is booming… but the hottest drug to beat in Hepatitis C?  Ribavirin.  A cheap, generic anti-viral. It turns out that even with all the advances drug makers are realizing in interferon-free drug combinations, ribavirin is critical to the success in curing patients of Hepatitis C.   The trouble is that no one is really sure how ribavirin works. All we know is that treatment response rates are infinitely higher when it is part of a Hepatitis C antiviral regimen.[2][3][4]

Researchers are busy trying to find out just what makes ribavirin tick, but let’s look at a few of the current theories on how the drug works:

Ribavirin may cause something called ‘error catastrophe’ in the lifecycle of the HCV virus.[5]Ribavirin is a nucleoside analog – this means that ribavirin can fool the virus into thinking that it’s one of the building blocks needed for the virus to replicate. So when the virus tries to replicate itself, it picks ribavirin as a building block instead of the real thing. This mucks up the replication process leading to ‘error catastrophe’ – in other words, the virus is no longer able to make copies of itself.
Inosine monophosphate dehydrogenase (IMPDH). That’s a tongue-twister to be sure, but it’s also a cellular enzyme the human body makes and the HCV virus needs. Ribavirin may inhibit this enzyme, which consequently shuts down the energy supply the Hepatitis C virus requires to survive and replicate.[1]
The Hepatitis C virus is sneaky. It has a peculiar knack for evading the body’s immune system[2], so anything that might disrupt that ability would be very valuable to an anti-HCV regimen. It turns out that ribavirin may have this unique ability by helping the body mount a specific anti-viral response to the Hepatitis C virus, which is essential in fully clearing the virus. [3]
While ribavirin’s exact mechanism of action remains a mystery, there is one thing we do know for certain – we need ribavirin to fight Hepatitis C. Paring ribavirin with the above new antiviral compounds currently in development – called Direct Acting Antivirals  or DAAs -  that target and disrupt numerous points in the lifecycle of the virus, lead to significantly better cure rates then just using the DAAs alone. While interferon may go the way of the buffalo, it appears that the lowly, unsexy ribavirin is here to stay.  This makes ribavirin the REAL drug to beat in the Hepatitis C drug development marketplace.

References

[1] Perz JF, et al. The contribution of hepatits B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529-38

[2] Vertex Pharmaceuticals, Inc. (2010)  Vertex adds ribavirin in additional treatment arm in ongoing phase II VX-222 & Telaprevir combo trial. [Press Release] Retrieved from http://viralmatters.blogspot.com/2010/11/vertex-adds-ribavirin-in-additional.html

[3] Hezode, Christopher, et al. (2009) Telaprevir and Peginterferon with or without Ribavirin for chronic HCV Infection. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa0807650

[4] Smith, M. (2012). New Combo KOs HCV Without Interferon, Ribavirin  [Online article] Retrieved from: http://www.medpagetoday.com/InfectiousDisease/Hepatitis/30739

[5] Maag D, et al. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl. Acad. Sck. 2001; 98: 6895-900

More difficult-to-treat patients relapse in Gilead GS-7977 hepatitis C trial...

Posted on 3/6/12 on Reuters.com: Two more G1 null responder patients relapsed on 12 weeks of Gilead nuc GS-7977 + PEG and RBV. Investors are spooked, but really shouldn't be.  GS-7977 + PEG & RBV is a powerful drug combo, but given the head-spinning replicative capacity of this virus and it's lack of a proof-reading mechanism, 12 weeks is probably not long enough to quash the virus in a null responder patient and will probably require more than just one DAA targeting more than just one cycle of the virus's replicative process. The most intriguing part of this is the speculation of just what the 'Rescue Protocol' involves in terms of added drugs to GS-7977 and duration of therapy.

More patients relapse in Gilead hepatitis C trial

Tue Mar 6, 2012 5:17pm EST

(Reuters) - Two more patients in a 10-patient segment of a mid-stage trial testing Gilead Sciences Inc's experimental hepatitis C drug GS-7977 had the virus return within four weeks of treatment, researchers said on Tuesday.

The company, which recently paid nearly $11 billion to acquire the drug and its developer, Pharmasset, said last month that six out of 10 patients with a prior "null response" to standard hepatitis C therapy saw the virus return within four weeks of treatment with a combination of GS-7977 and the antiviral drug ribavirin.

The latest results from the mid-stage trial bring to eight the number of patients who have relapsed.
One patient has not reached the four-week point and the other showed a response to the drug, Dr. Edward Gane from New Zealand's Auckland City Hospital and the study's lead investigator said here at the Conference on Retroviruses and Opportunistic Infections.

The trial segment he updated involved patients infected with genotype 1 hepatitis C -- the most common, but also the most difficult to treat, subset of the disease.

"The majority of null responders have relapsed post treatment," Dr. Gane said, adding that such patients will likely need either a longer duration of therapy or combination treatment with other direct-acting antiviral agents.

He said the relapsed patients will be offered a "rescue protocol" in the form of another trial of GS-7977 in combination with a different experimental drug.

Shares of Gilead have dropped 18 percent since the company's announcement of the trial results, which suggested that an all-oral treatment for hepatitis C may be further away than many had hoped.

Dr. Gane said ongoing pivotal-stage trials of GS-7977 "should establish that interferon-free treatment is not a dream. It's a reality that should be here within the next five years."

Current hepatitis C drug regimens require injections of interferon, which causes severe flu-like symptoms and cannot be tolerated by some patients.

GS-7977 is designed to block an enzyme essential to the replication of the hepatitis C virus. It is one of a new class of treatments designed to be given without injections of interferon, which helps boost the body's immune system but can also cause debilitating flu-like side effects.

Gilead has said it expects to announce at the end of this month results from a mid-stage trial of GS-7977 in previously untreated hepatitis C patients.

Hepatitis C is a liver-destroying disease that affects some 170 million people worldwide. Untreated, it can lead to cirrhosis, liver cancer and the need for a liver transplant.

Seeking Alpha: Addressing Vertex/Gilead Confusion...

Posted 3-1-2012 on Seeking Alpha.com: More on HCV drug development investment 'irrational exuberance', the author making a case that investors have given Vertex the bum's rush and should take another look. 

Addressing Vertex / Gilead Confusion
March 1, 2012
Contributor: Prohost Biotech

Hepatitis C virus (HCV) treatments are moving stocks of HCV developers up and down in a chaotic way that makes no sense. While Vertex’ (VRTX) Incivek sales have been breaking the record of drug sales, investors who have been fed immature and unconfirmed knowledge that Pharmasset’s oral HCV therapeutics combination will render Incivek obsolete caused a sell-off in VRTX. Investor logic that patients would definitely prefer all oral drugs over a combination that has injectable alfa interferon is undisputable, that’s we too are waiting for a successful all oral HCV treatment, which has yet to emerge.

With the media stressing that Pharmasset was the firm that will put the magic combination on the market, Pharmasset's stock doubled from over $20 in January 2010, to around $45 at the end of December. In 2011, the stock rallied again from $45 in January to $135 in August, split 2 to 1 and started climbing back from around $66 to $72. The firm was then acquired by Gilead (GILD), which paid an additional 67% premium over its obese market price, i.e., around over $130 per share.

This scenario does not make sense to us. Contrary to the market’s culture, investors, for one reason or another, sold a real present to buy a future designed on mere speculation. They sold VRTX, a company that had a marketed HCV drug, which is the first ever to represent a cure for the life-threatening HCV infection and whose sales have been actually generating record revenues to buy into Pharmasset’s oral combination while still in mid-trial and requires more lengthy experimentation before confirming the all-oral combination’s safety and long-term efficacy.

Just before concluding the acquisition deal, on December 16, 2011, Pharmasset surprisingly announced its decision to discontinue all treatment arms with a regimen containing its drug PSI-938 because of laboratory abnormalities associated with liver function in subjects receiving the drug at a dose of 300 mg/day. This news surprised investors, especially Gilead’s shareholders who began to question the value of the deal with Pharmasset. The news did not alter Gillead’s decision to acquire the company. After the acquisition, Gilead’s stock experienced a temporary retreat. Many investors believed that $11 billion was an unprecedented high amount of money to be paid for molecules that have yet to complete clinical trials, confirming their superiority as described by the media since 2009. Investors’ temporary negative reaction toward the deal was the only understandable action in this story.

It did not take time for GILD to fiercely rebound after the firm announced its financial results. The stock was up to $56, matching its new high for the past three years. Less than two months later, though, other trial results with Pharmasset’s combination on HCV genotype 1 patients with a prior “null” response to an interferon-containing regimen demonstrated that the majority of patients experienced viral relapse within four weeks of completing 12 weeks of treatment with what has become Gilead’s combination of GS-7977 plus ribavirin (RBV). GILD tumbled, trading now at around $45, after loosing around 15% of its value.

In the mean time, Vertex is generating millions of dollars selling its selective HCV protease inhibitor. Its stock, though, remained boxed - sold every time it makes an attempt to rally even though Vertex is also trying its own all-oral combination. The stock remained boxed even after data from two treatment arms of the Phase 2 ZENITH study evaluating an interferon-free (all-oral) treatment regimen of the non-nucleoside polymerase inhibitor VX-222 in combination with INCIVEK (telaprevir) tablets and ribavirin in people with genotype 1a or 1b hepatitis C who were new to treatment have demonstrated promising safety and efficacy and after learning that the data from this study will be used to design a Phase 3 program with the goal of submitting a New Drug Application (NDA) to the FDA for the first interferon-free regimen for genotype 1 (1a and 1b) patients by the end of 2014 or beginning of 2015.

Investors didn’t even bother considering the fact that Vertex and its collaborator Alios BioPharma are conducting Phase 1 studies of two structurally-distinct nucleotide polymerase inhibitors, ALS-2200 and ALS-2158. Vertex has begun the first seven-day viral kinetic studies of ALS-2200 and ALS-2158 in people with genotype 1 hepatitis C, whose safety and viral kinetic data expected in the second quarter of 2012. Positive results would enable the initiation of Phase 2 studies in the second half of 2012 to evaluate multiple interferon-free combination regimens of ALS-2200, ALS-2158, INCIVEK, VX-222 and/or ribavirin.

What continued to make no sense at this stage is that investor pessimism with Gilead's all-oral combination that erased 15% of GILD price, did not transform into optimism for VRTX, which was cremated by the enthusiasm for Gilead’s drug that investors are now experiencing doubt about. It looks as if investors are sensitized to not appreciate the firm that introduced the first HCV cure and the first approved cystic fibrosis drug that works at the root cause of the disease, knowing in fact that Vertex has plans ready to bring breakthrough treatments to all cystic fibrosis patients.

Gilead is a great firm and at the end of the day it will probably succeed in bringing an HCV breakthrough treatment to the market. But this does not mean that Vertex will not succeed reaching the same goal. Vertex is also a great firm that has already changed the way chronic life-threatening diseases have been treated. Gilead has a lot of current and upcoming good news and so does Vertex. The HCV market is huge. It requires more than one, or two treatments to satisfy its needs.

Disclosure: We are long both firms.

In 2015, Gilead's GS-7977 Plus Ribavirin Will Earn Decision Resources' Proprietary Clinical Gold Standard Status for the Treatment of Non-Responder Patients with Hepatitis C Virus...

Press release posted 2/28/12 on Marketwatch.com. Although their output is always of exceptional high-quality, Decision Resources' ability to pick a 'whip-your-head-right-around, spill-your-coffee-and-read-at-all-costs' attention-grabbing headline in hopes that you'll buy their product, is unprecedented in the market analysis marketplace. That's the type of unexpurgated crassness we'd like to see more of.  You have to love them. Apparently, the oracles at DR have already decided that they will award GS-7977 plus RBV the "Decision Resources' Proprietary Clinical Gold Standard" for treatment of non-responders in 2015. That's some unshakable confidence, let's hope they're right because no one is going to let them forget this press release. Despite the puffery, some interesting analysis is to be gleaned from this press release. They've obviously been doing some serious homework. DR expects that "the overall HCV drug market will experience significant growth, expanding from almost $1.7 billion in 2010 to $14.4 billion in 2015 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Thereafter, the market will decrease to $11.2 billion in 2020, owing to a decline in the size of the treatment-eligible population due to declining prevalence and effective new regimens." Compelling reason enough on why the HCV drug development marketplace is red hot at the moment.  


In 2015, Gilead's GS-7977 Plus Ribavirin Will Earn Decision Resources' Proprietary Clinical Gold Standard Status for the Treatment of Non-Responder Patients with Hepatitis C Virus

* GS-7977 Plus Ribavirin Will Displace the Current Proprietary Clinical Gold Standard, Telaprevir in Combination with Peg-IFNa/Ribavirin, According to Findings from Decision Resources


BURLINGTON, Mass., Feb 28, 2012 (BUSINESS WIRE) -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that, based on clinical data and the opinions of interviewed thought leaders, telaprevir (Vertex's Incivek, Johnson & Johnson's Incivo) in combination with peg-IFNa (Roche's Pegasys or Merck's Victrelis) and ribavirin (Roche's Copegus; Merck's Rebetol; generics) has earned Decision Resources' proprietary clinical gold standard status for the treatment of non-responder patients with hepatitis C virus (HCV). Owing to its competitive advantages in safety and tolerability as well as delivery, the interferon-free combination of Gilead's GS-7977 (formerly PSI-7977) plus ribavirin will displace telaprevir plus peg-IFNa/ribavirin and earn proprietary clinical gold standard status for HCV non-responders in 2015, following its launch for the indication in 2014 in the United States.

Decision Resources' analysis of the hepatitis C virus drug market also finds that surveyed U.S. gastroenterologists and managed care organization (MCO) pharmacy directors agree that the percentage of genotype-1 null responders achieving sustained virologic response is one of the attributes that most influences their decisions regarding prescribing and formulary status determinations, respectively, in HCV non-responders.

"Clinical data and the opinions of interviewed thought leaders indicate that several emerging regimens utilizing novel, HCV-specific direct-acting antivirals have advantages over sales-leading telaprevir plus peg-IFNa/ribavirin on this attribute," said Decision Resources Analyst Seamus Levine-Wilkinson, Ph.D.

According to insights from surveyed U.S. gastroenterologists and MCO pharmacy directors, the absence of interferon-free treatment options for HCV is one of the greatest unmet needs in HCV. Clinical data and the opinions of interviewed thought leaders indicate that GS-7977 has demonstrated the potential to significantly fulfill this unmet need.

The findings also reveal that surveyed U.S. gastroenterologists indicate that they would prescribe the quadruple regimen of Bristol-Myers Squibb's NS5A inhibitor daclatasvir (BMS-790052) plus Bristol-Myers Squibb's protease inhibitor asunaprevir (BMS-650032) plus peg-IFNa/ribavirin to 41 percent of their HCV non-responder patients. Decision Resources' forecast for this quadruple regimen is more conservative due to anticipated reimbursement restrictions, positioning in later lines of therapy, competition from IFN-free regimens and competition asunaprevir will face from other protease inhibitors.

The launch of novel HCV-specific agents will increase the size of the drug-treated population mainly as a result of re-treatment of prior non-responders as well as increased referral and drug treatment rates. The overall HCV drug market will experience significant growth, expanding from almost $1.7 billion in 2010 to $14.4 billion in 2015 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Thereafter, the market will decrease to $11.2 billion in 2020, owing to a decline in the size of the treatment-eligible population due to declining prevalence and effective new regimens.

Decision Resources' Robust Market Forecast and Opportunities Analysis

Decision Resources provides a comprehensive view of what is happening in a specific drug market now and in the decade ahead. The research includes analysis of the unmet need and near-term drug development opportunities that exist within a drug market powered by primary research from physicians and payers. The robust market forecast and opportunities analysis is comprised of the Pharmacor 2012 advisory service and the DecisionBase 2012 report series.

About Decision Resources

Decision Resources ( www.decisionresources.com ) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources Group company.

About Decision Resources Group

Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com .

All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

SOURCE: Decision Resources

     
        Decision Resources
        Christopher Comfort, 781-993-2597
        ccomfort@dresources.com

Wall Street Journal - "Medivir Vies For Spot In Narrow Hepatitis C Market"

Posted 2/27/12 in the Wall Street Journal: Now here's a corporate leader with some confidence, bordering on cockiness, which, arguably is what coporate leaders should have copious amounts of. Even if it's bluster. Medivir Executive Vice-President of Corporate Affairs Rein Piir tells Dow Jones that "there is nothing in development that's better than TMC435, which is currently in global Phase III trials and which Medivir expects to launch by the end of next year." This puts TMC435, if he's right, to be potentially the first 2nd generation DAA to hit the market, at least ex-US. 
 
By Simon Varcoe
    Of DOW JONES NEWSWIRES

LONDON (Dow Jones)--Hepatitis C, a harrowing infection that leads to the inflammation of the liver, is a virus of pandemic size that has attracted the attention of some of the world's biggest drug makers.

But Sweden's small biotech Medivir AB (MVIR-B.SK) says it intends to be a major player in treating the disease, and predicts the market will ultimately have room for just four or five products.

"It is simply a question of which drug will have the biggest share of the market", Medivir's executive vice-president of corporate affairs Rein Piir told Dow Jones Newswires in an interview.

And in protease inhibitor TMC435, Piir believes Medivir has found its winner.

Piir says there is nothing in development that's better than TMC435, which is currently in global Phase III trials and which Medivir expects to launch by the end of next year.

Danske Banke analyst Hans Jeppsson agrees.

Jeppsson regards TMC435 as being the best-in-class protease inhibitor, which prevents viral replication by inhibiting the activity of protease enzymes. Final judgment will need to await results from two combination trials the drug is currently undergoing, he adds.

Around 170 million people are infected worldwide with Hepatitis C, a disease that can be transmitted sexually, through shared needles or through infected blood transfusions.

Thousands of people in Japan were infected with Hepatitis C between the 1970s and 1990s due to tainted blood clotting agents and the country remains one of the most hepatitis C-dense in the world. Due to the high numbers of hepatitis C sufferers in Japan, the country is "as important commercially" to Medivir as Europe, Piir says.

Other countries with a high prevalence of Hepatitis C include Egypt, where around 20% of blood donors are anti-HCV positive, and areas of Italy.

Medivir's Piir believes that the future treatment of Hepatitis C will involve a combination of protease inhibitors; inhibitors of nucleotides, which are molecules that, when joined together, make up the structural units of RNA and DNA; and inhibitors of NS5A, a non structural viral protein found in Hepatitis C.

NS5A inhibitors currently in development include Bristol-Myers Squibb's (BMY) BMS790052, and Gilead Sciences Inc's (GILD) GS-7977. However, Gilead recently reported that a majority of patients in a clinical trial of GS-7977 had experienced a relapse in their disease after being treated with the product, raising questions about the market potential of the drug and the wider class of NS5A inhibitors.

A protease inhibitor currently used to treat HCV genotype 1 infection, the most common and hardest-to-treat type of Hepatitis C is Vertex Pharmaceuticals' (VRTX) and Johnson & Johnson's (JNJ) telaprevir, though, unlike TMC435, it must be administered in combination with pegylated interferon alpha and the antiviral drug ribavirin. Its safety profile has also been criticized, whereas TMC435 has to-date been generally safe and well tolerated, according to Medivir.

The Swedish biotech floated on the Nasdaq OMX Stockholm index in 1996 and currently has a market capitalization of around SEK2.1 billion ($320.2 million).

-By Simon Varcoe, Dow Jones Newswires; +44-20-7842-9449; simon.varcoe@dowjones.com

Gilead Sciences announces viral relapse in 12 week GS-7977 + RBV ELECTRON arm...

Gilead press release on 2/17/12. The press release that shook the HCV drug development world. Gilead announced that they had data for 8 out of 10 previous null-responder subjects  randomized to the 12 week GS-7977 + RBV arm in the ELECTRON trial. Out of the 8 patients, 6 developed viral relapse. Data on the other two patients is forthcoming. So, this counts out GS-7977 + RBV for 12 weeks as effective therapy for previous null responders. The questions that remain are: can therapy extended past 12 weeks do the job? (say 24, 36 or even 48)?  Does this regimen require the addition of one or more additional DAAs that target differing parts of the HCV replication process? Or the addition of interferon? Or both of the latter? This is clearly not a reason to panic (although, judging from the stock drop today, shareholders did do just that) but it did answer 'no' to an important question this study was designed to answer - is 12 weeks of GS-7977 + RBV enough to achieve an SVR in the null responder patient population?  Gilead will look at multiple combinations of treatment durations and drug combinations to find the one that achieves the best results. Gilead also has an excellent portfolio of HCV drugs that inhibit differing parts of the HCV replication process to pair with GS-7977.  So panic is definitely not warranted.


It is a warning to analysts who touted an inteferon-free GS-7977 + RBV as the answer to all patient types. Such statements were misleading to their investors. We can learn from the early research days of HIV. I don't want to say "I told you so", but "I told you so". The HCV virus is a highly replicating virus with no proof-reading mechanism capable of making every possible mutation of itself in the course of a day. As in HIV, one drug will not be able to stop the virus from replicating and will select out the mutations that are resistant to the drug and are most fit to survive in the presence of drug. It will take more than one drug targeting more than one part of the viral replication process to do the trick, and may also require the generalized immune response triggered by exogenous interferon as much as we'd like to see that go away. 

Gilead Announces Data for Genotype 1 Null Responder Hepatitis C Patients Enrolled in ELECTRON Study


– Viral Relapse Seen Post Treatment with GS-7977 Plus Ribavirin –

– Awaiting Data for Treatment-Naïve Genotype 1 Patients –
Press Release: Gilead Sciences, Inc.
.

FOSTER CITY, Calif.--(BUSINESS WIRE)--

Gilead Sciences, Inc. (NASDAQ:GILD - News) announced today that the majority of hepatitis C genotype 1 patients with a prior “null” response to an interferon (IFN)-containing regimen enrolled in the ongoing ELECTRON study experienced viral relapse within four weeks of completing 12 weeks of treatment with GS-7977 plus ribavirin (RBV). Ten patients were randomized to this arm of the ELECTRON study and data are available for eight of the 10 patients at this time. Among these eight patients, six have experienced viral relapse. Two patients have not relapsed; however, they have only reached the two week post-treatment time point.

“These data answer an important question about the use of GS-7977 and ribavirin for the treatment of genotype 1 null responder patients, suggesting that additional direct acting antivirals may be necessary to effectively treat this patient population,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. “We will continue to explore a number of therapeutic approaches to address this significant unmet medical need, including combinations with other oral antivirals.”

GS-7977 is a nucleotide analog polymerase inhibitor that is currently being studied for the treatment of chronic hepatitis C. A number of ongoing Phase 2 and Phase 3 studies are evaluating the safety and efficacy of the compound with and without RBV and/or pegylated interferon (Peg-IFN) in patients with genotypes 1-6 who are treatment naïve, treatment experienced, or have had a “null” response to Peg-IFN.

Genotype 2 and 3 data from the ELECTRON study were presented at the 62nd annual meeting of the American Association for the Study of Liver Diseases (The Liver Meeting 2011). Data from the genotype 1 null responder arm of the study will be presented at an upcoming scientific conference.

Results from ongoing studies in genotype 1 treatment-naïve patients will be available in the coming months. The first data evaluating GS-7977 plus RBV for 12 weeks in genotype 1 naïve patients will come from an arm of the QUANTUM study with 25 patients at the end of the first quarter of 2012. This will be followed in the second quarter by data from the ELECTRON study involving 25 patients and, early in the third quarter, data on GS-7977 and RBV treatment for 24 weeks from an arm of the QUANTUM study will become available.

Conference Call

 Gilead will host a conference call today, February 17, 2012 at 8:00 a.m. Eastern Time, to discuss these study results. To access the live call, please dial 1-866-825-1709 (U.S.) or 1-617-213-8060 (international). The conference passcode number is 71588571. Telephone replay is available approximately one hour after the call through 11:59 p.m. Eastern Time, February 20, 2012. To access, please call 1-888-286-8010 (U.S.) or 1-617-801-6888 (international). The conference passcode number for the replay is 64278864. The information provided on the teleconference is only accurate at the time of the conference call, and Gilead will take no responsibility for providing updated information.

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 of unfavorable results from the ELECTRON and QUANTUM studies, including in genotype 1 treatment-naïve patients, as well as other clinical trials evaluating GS-7977 with or without RBV and/or Peg-IFN or in combination with other antivirals; the anticipated timing for receiving clinical data and making regulatory filings; and Gilead’s ability to develop an all-oral antiviral regimen for HCV genotype 1 patients or a pangenotypic regimen for all HCV patients. As a result, GS-7977 may never be successfully commercialized. Further, Gilead may make a strategic decision to discontinue development of GS-7977 if, for example, it believes commercialization will be difficult relative to other opportunities in its pipeline. 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 Quarterly Report on Form 10-Q for the quarter ended September 30, 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.

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Contact:.
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Gilead Sciences, Inc.
Susan Hubbard, 650-522-5715 (Investors)
Amy Flood, 650-522-5643 (Media)

BioCryst releases preclinical results for HCV nucleoside inhibitor BCX5191

Posted 2/15/12 on Business Wire -  BioCryst announce pre-clinical results for their once-a-day (concieveably) pan-genotypic polymerase inhibitor BCX5191, with first in-human study planned for Q4 2012. The authors of the press release invoke "GS-7977" in comparsion to BCX5191 in terms of internal comparative preclinical studies.

BioCryst Announces Promising Results from Preclinical Studies of BCX5191 for Hepatitis C


•BCX5191: Planning to file for first–in-human studies during the fourth quarter 2012
•BioCryst to discuss study outcomes during its 2011 results call February 16 at 11:00 a.m. ET

RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)--BioCryst Pharmaceuticals, Inc. (NASDAQ: BCRX) today announced favorable preclinical results for BCX5191, a novel adenine nucleoside analog targeting viral RNA polymerase for the potential treatment of hepatitis C.

“Based on our internal comparative preclinical studies of BCX5191 with the most advanced nucleotide analog in clinical development, GS-7977, we believe BCX5191 has the potential to be the backbone of best-in-class oral treatment regimens for hepatitis C patients.”

.BioCryst has successfully completed in vitro and in vivo studies in which BCX5191 exhibited potent and selective pan-genotypic antiviral activity against the hepatitis C polymerase enzyme. BCX5191 showed no inhibition of human RNA polymerase and no evidence of toxicity from standard in vitro screens.

Human liver cells rapidly and efficiently convert BCX5191 into its active triphosphate form. BCX5191 does not require prodrug technology to achieve bioavailability. BCX5191 inhibits the viral RNA polymerase enzyme across genotypes 1-4 at sub-micromolar concentrations (0.05-0.36 µM) and is active in replicon cell assays for genotypes 1a and 1b.

In preclinical models, BCX5191 demonstrates high oral bioavailability, and the drug is actively transported into the liver. Following a single oral dose in rats, liver BCX5191 triphosphate levels exceed the IC50 values for genotypes 1-4 through 24 hours. At Cmax, the drug triphosphate level is more than 100 times the IC50. This pharmacokinetic profile is expected to support once-daily dosing in clinical studies.

“BCX5191 has met stringent preclinical criteria to advance to IND-enabling studies. We expect this program to be ready to file for first-in-human studies during the fourth quarter of 2012,” said Dr. William P. Sheridan, Senior Vice President & Chief Medical Officer of BioCryst Pharmaceuticals. “Based on our internal comparative preclinical studies of BCX5191 with the most advanced nucleotide analog in clinical development, GS-7977, we believe BCX5191 has the potential to be the backbone of best-in-class oral treatment regimens for hepatitis C patients.”

Additional BCX5191 non-clinical experiments are ongoing or planned, including Good Laboratory Practices (GLP) non-clinical safety studies and in vitro evaluation of BCX5191 in combination with ribavirin.

Conference Call and Webcast

BioCryst's leadership team will host a conference call and webcast on Thursday, February 16, 2012 at 11:00 a.m. Eastern Time to discuss financial results and recent corporate developments, including results from the BCX5191 hepatitis C program. To participate in the conference call, please dial 1-877-303-8027 (United States) or 1-760-536-5165 (International). No passcode is needed for the call. The webcast and accompanying slides can be accessed by logging onto www.BioCryst.com. Accompanying slides will be available on the BioCryst website several hours prior to the call. Please connect to the website at least 15 minutes prior to the start of the conference call to ensure adequate time for any software download that may be necessary.

About Hepatitis C

Hepatitis C is a contagious liver disease that results from infection with the hepatitis C virus (HCV), which is the most common virus that infects the liver and can lead to life-threatening liver problems, such as liver damage, cirrhosis, liver failure or liver cancer. There are an estimated 170 million individuals worldwide who are chronically infected with HCV, and about 3 to 4 million people are infected annually. In the United States, there are approximately 4 million people who have chronic hepatitis C.

About BioCryst

BioCryst Pharmaceuticals designs, optimizes and develops novel small-molecule pharmaceuticals that block key enzymes involved in infectious diseases, inflammatory diseases and cancer. BioCryst currently has three novel late-stage compounds in development: peramivir, a neuraminidase inhibitor for the treatment of influenza, BCX4208, a purine nucleoside phosphorylase (PNP) inhibitor for the treatment of gout, and forodesine, an orally-available PNP inhibitor for cancer, which is being developed by Mundipharma under a global license agreement. Utilizing crystallography and structure-guided drug design, BioCryst continues to discover additional compounds and to progress others through preclinical and early development to address the unmet medical needs of patients and physicians. For more information, please visit the Company's website at http://www.biocryst.com/.

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding future results, performance or achievements. These statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performances or achievements expressed or implied by the forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Some of the factors that could affect the forward-looking statements contained herein include: that there can be no assurance that our compounds will prove effective in clinical studies; that development and commercialization of our compounds may not be successful; that we or our licensees may not be able to enroll the required number of subjects in planned clinical trials of our product candidates and that such clinical trials may not be successfully completed; that BioCryst or its licensees may not commence as expected human clinical trials with BCX5191; that ongoing and future preclinical and clinical development may not have positive results; that we or our licensees may not be able to continue future development of our current and future development programs; that our development programs may never result in future product, license or royalty payments being received by BioCryst; that BioCryst may not reach favorable agreements with potential pharmaceutical and biotechnology partners for further development of BCX5191; that our actual cash burn rate may not be consistent with our expectations; that BioCryst may not have sufficient cash to continue funding the development, manufacturing, marketing or distribution of its products and that additional funding, if necessary, may not be available at all or on terms acceptable to BioCryst. Please refer to the documents BioCryst files periodically with the Securities and Exchange Commission, specifically BioCryst's most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and current reports on Form 8-K, all of which identify important factors that could cause the actual results to differ materially from those contained in our projections and forward-looking statements.


BCRXW

Contacts

BioCryst Pharmaceuticals

Robert Bennett, 919-859-7910 (investors)

or

WCG

Catherine Kyroulis, 212-301-7174 (media)