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.

Medivir and BMS partner for TMC435 and daclatasvir Phase II trial ...

Medivir press release dated on 6-29-12. Medivir/Janssen will partner with Bristol Myers Squibb for a 180 patient open-label phase II combination trial combining the protease inhibitor TMC435 with BMS's NS5A inhibitor daclatasvir both with and without ribavirin. The patient population will consist of genotype 1a and 1b treatment naive and null responder subjects. Of note in genotype 1a subjects, ribavirin will be included in both the 12 and 24 week arms. Given the  recent change in inclusion criteria in the COMMAND-3 trial, this isn't surprising. Genotype 1b subjects will be randomized to arms either with or without ribavirin. Subjects in the high-need category with F3/F4 fibrosis scores will make up approximately 35% of the population of the trial. 

Medivir announces an interferon-free phase II combination trial with TMC435 and daclatasvir to commence shortly

29-Jun-12

· The phase II interferon-free combination study with TMC435 and daclatasvir will evaluate treatment-naïve or previous null responder patients with HCV genotype 1a and 1b

· The study will include approx. 180 patients and will evaluate a combination of TMC435 and daclatasvir, with or without Ribavirin, in four different cohorts for 12 or 24 weeks of treatment

Stockholm, Sweden - Medivir AB (OMX:MVIR), the research-based pharmaceutical company focused on the development of high-value treatments for infectious diseases, announces that a phase II combination study with the investigational compound TMC435 and Bristol-Myers Squibb’s investigational compound daclatasvir will start in July. This study is part of the clinical collaboration agreement between Janssen R&D Ireland and Bristol-Myers Squibb Company (NYSE:BMY) announced on 2 December 2011 and on 18 April 2012.

TMC435 and daclatasvir (BMS-790052)
TMC435, a once daily potent NS3/4A protease inhibitor (PI) in phase III clinical development for the treatment of chronic genotype-1 hepatitis C virus (HCV) infection, will be investigated in an interferon free phase II trial in combination with Bristol-Myers Squibb´s investigational NS5A replication complex inhibitor, daclatasvir (BMS-790052), also in phase III development.

The purpose of this study is to assess the efficacy and safety of TMC435 and daclatasvir in combination with or without Ribavirin in chronic genotype-1 hepatitis C infected patients who are treatment-naive or null responders to previous Peginterferon alfa/Ribavirin therapy.

Study design
In this open label phase II study the potential to achieve sustained viral response (SVR), 12 (SVR12) and 24 (SVR24) weeks post treatment in treatment-naïve and null responder patients infected with HCV genotype 1a and 1b will be evaluated. Patients with advanced liver disease (F3/F4) will be allowed up to approx. 35% of the total treated population.

Cohort one and two will include patients with genotype 1b where TMC435 and daclatasvir will be dosed with or without Ribavirin for 12 weeks with a 36 weeks follow-up or for 24 weeks with a 24 weeks follow-up.

Cohort three and four will include patients with genotype 1a where TMC435, daclatasvir and Ribavirin will be dosed for 12 or 24 weeks with a 24 weeks post treatment follow-up.

For additional information from these recently updated studies, please see www.clinicaltrials.gov

For more information about Medivir, please contact:

Medivir Rein Piir, EVP Corporate Affairs & IR Mobile: +46 708 537 292
M:Communications medivir@mcomgroup.com
Europe: Mary-Jane Elliott, Amber Bielecka, Hollie Vile +44(0)20 7920 2330

About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The World Health Organization estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is TMC435, a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.

In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialisation of TMC435 in the Nordic markets, once approved.

Medivir’s first product, the unique cold sore product Xerese®/Xerclear®, is launched in collaboration with GlaxoSmithKline to be sold OTC under the brand name ZoviDou in Europe, Japan and Russia.

Are HCV NS5A inhibitors as potent as we thought?

Posted on 6/20/12 on Pharmalot.com. Commentary on a change in protocol in BMS's COMMAND-3 trial for it's NS5A inhibitor daclatasvir by Pharmalot's Ed Silverman. BMS has restricted future enrollment for the trial to include only genotype 1b - a big statement in that 80% of genotype 1 (the most dominant genotype of HCV in the US) are of the 1a subtype. Does this mean there has been some virologic breakthrough in genotype 1a subjects in the COMMAND-3 trial? Hard to say, but the change in inclusion criteria has cast some doubt on the NS5A class. We'll have to wait for further data to see how this plays out. 

Bristol Hep C Trial Change Has Big Implications

By Ed Silverman // June 20th, 2012 // 8:02 am

Is a promising new class of drugs for treating hepatitis C going to be limited because patients with the most common genotype of the virus are likely to develop resistance to the medications? This is the possibility raised by a Wall Street analyst after learning that Bristol-Myers Squibb last week altered the protocol for a clinical trial for its daclatasvir antiviral, which is believed to be the most potent in the forthcoming NS5a class of hepatitis c treatments.

According to ClinicalTrials.gov, the drugmaker changed the protocol to its COMMAND-3 trial, which compares its drug in combination with interferon and ribavirin to Incivek, a protease inhibitor sold by Vertex Pharmaceuticals, along with interferon and ribavarin. What was the change? Bristol-Myers restricted future enrollment to patients who have only genotype 1b HCV, rather than all genotype 1 patients (see this and this).

“This effectively eliminates from the trial the most common HCV genotype in the US – 75 percent of HCV is genotype 1 in the US, 80 percent of genotype 1 is genotype 1a,” Sanford Bernstein analyst Tim Anderson writes in an investor note. “This change, some three months after the study started enrollment, suggests that some form of virologic failure has emerged in the patients with these genotypes… The NS5a class, as a whole, might be limited by the propensity to rapidly develop virological resistance, and by significant differences in potency from one viral genotype to another.”

He adds that the change in the protocol has “major strategic and tactical implications” for the hot and fast-growing hepatitis C market. How so? Several drugmakers are developing NS5a treatments and the possibility that these drugs generate resistance to the virus may prompt changes in how different types of medications are combined and, consequently, alter various corporate strategies for drug development, alliances and dealmaking.

Take Gilead Sciences. The drugmaker is developing an NS5a, which has the code name of GS5885, as well as another that is a nucleotide inhibitor, or nuke, which Gilead calls GS7977 and believes could be the cornerstone of the first all-oral regimen for hepatitis C. Gilead, you may recall, acquired GS7977 last fall as part of its $11 billion acquisition of Pharmasset, a bet that has transformed the investor view of the drugmaker (back story).

Two months ago, results of a study that combined daclatasvir with GS7977 suppressed hepatitis C in most patients four weeks after completing treatment, raising hopes about the prospects for a therapy that does not involve an injectable medication. But further collaboration between the two drugmakers appeared uncertain, because Gilead indicated a preference for developing its own NS5a drug with GS7977 (see this).

However, as Anderson notes, the Gilead NS5a drug is less potent than daclatasvir, which “increases the risk for Gilead of sticking with GS5885. On the Bristol side, their ‘go-it-alone’ strategy may be developing a hole, increasing the urgency of incorporating daclatasvir into an all-oral combination with a potent resistance-fighting nuke such as GS7977. This collaboration appears to have become more important to both parties,” he writes.

Both drugmakers recently declined comment on this topic, although late last month, Bristol-Myers ceo Lamberto Andreotti renewed a call for Gilead to jointly develop their hepatitis C medications. We asked Bristol-Myers about the change in the trial protocol and will update you with any reply that we receive.

Looking ahead, Anderson sees greater potential for combination therapy that relies on three drugs, instead of two, including GS7977 from Gilead, since the response to NS5a drugs suggests there can be limitations to at least one of the agents that developers would want to use in a one-two punch. And he believes Gilead’s prospects for creating one “super-regimen” for all subtypes with GS7977 and GS5885 alone, or even with ribavirin, have fallen.

As for other drugmakers, the questions concerning the NS5a drugs may result in slightly extended utility for Incivek as well as Victrelis, another protease inhibitor that is sold by Merck. This also suggests additional jockeying surrounding the NS5a drugs being developed by Achillion Pharmaceuticals and Idenix Pharmaceuticals, since larger drugmakers may decide to adjust their strategies and portfolios in response to the changing dynamics of this class of treatments.

“All this incremental insight about the limitations of different classes means the portfolios of the committed participants in the field will likely need to be larger than previously anticipated,” Anderson opines. “If, indeed, the field migrates to a three-mechanism standard, then smaller companies with one or more relatively isolated drugs, will be even more compelled to accept offers from buyers, and those buyers are likely to also require even more compounds than they have today, increasing the pressure on them to secure the few remaining independent assets.”

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

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

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


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

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

David Paul Morris/Bloomberg News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BMS and Tibotec team up HCV antivirals for phase II trial....

The HCV development partnership space is jumpin'! Medivir/Tibotec now has two partnerships, one with Gilead/Pharmasset in combination with their nuc PSI-7977 and now with BMS's daclatasvir. The question of what happens to the development of BMS's peg lambda is still a bit of a mystery.

December 02, 2011 07:30 AM Eastern Time

Bristol-Myers Squibb Enters Clinical Collaboration Agreement with Tibotec Pharmaceuticals for Phase II Combination Study in Patients Chronically Infected with Hepatitis C

NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that it has entered into a clinical collaboration agreement with Tibotec Pharmaceuticals, one of the Janssen Pharmaceutical Companies, to evaluate the utility of daclatasvir (BMS-790052), Bristol-Myers Squibb’s investigational NS5A replication complex inhibitor, in combination with Tibotec Pharmaceuticals' investigational NS3 protease inhibitor, TMC435, for the treatment of chronic hepatitis C virus (HCV).

Under the agreement the companies will evaluate the potential to achieve sustained viral response 12 and 24 weeks post treatment in patients with HCV genotype 1 in a study with three treatment regimens: an oral, once-daily treatment regimen of daclatasvir and TMC435 with pegylated-interferon alpha plus ribavirin; an oral, once-daily treatment regimen of daclatasvir and TMC435 with ribavirin and an oral, once-daily treatment regimen of daclatasvir and TMC435 alone. The study is planned to start in the first half of 2012.

“Bristol-Myers Squibb is dedicated to developing innovative treatment options for patients with serious diseases like HCV,” said Brian Daniels, senior vice president, Development. “We are pleased to work with Tibotec to advance the scientific understanding for the potential for an all-oral regimen of direct acting antivirals, which would be an important advancement for patients with HCV. This is a continuation of our leadership in forging partnerships to advance combination antiviral therapy.”

About daclatasvir (BMS-790052)

Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir is the first NS5A replication complex inhibitor to be investigated in clinical trials and is currently in Phase III development. Daclatasvir is part of a portfolio of investigational compounds that the company is developing for the treatment of hepatitis C.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the compound described in this release will move from early stage development into full product development, that clinical trials of this compound will support a regulatory filing, or that the compound will receive regulatory approval or become a commercially successful product. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2010, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

Contacts

Bristol-Myers Squibb
Media:
Jennifer Fron Mauer, 609-252-6579
jennifer.mauer@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com
or
Teri Loxam, 609-252-3368
teri.loxam@bms.com

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The Motley Fool on the J&J/Pharmasset partnership....

J&J's Been Busy

http://www.fool.com/investing/general/2011/07/07/jjs-been-busy.aspx

Brian Orelli
July 7, 2011

When it comes to virus inhibition, Johnson & Johnson (NYSE: JNJ ) has been getting around. Last week, the health-care giant signed a partnership with Gilead Sciences (Nasdaq: GILD ) to combine their HIV drugs. And yesterday, Johnson & Johnson announced it was hooking up with a different partner, Pharmasset (Nasdaq: VRUS ) , to create a hepatitis C drug combo.

The duo plan to run a phase 2 trial combining the companies' experimental drug candidates: PSI-7977 from Pharmasset and TMC435 from Johnson & Johnson. They'll start in patients that have already failed a round of treatment, but if the drugs show success, the companies will surely move into treatment-naive patients.

The press release didn't mention any financial details. Maybe they're waiting to see if they're compatible before putting a name on their relationship.

Like the HIV market, the future of hepatitis C treatment is a cocktail that's hopefully capable of curing everyone. Incivek and Victrelis from Vertex Pharmaceuticals (Nasdaq: VRTX ) and Merck (NYSE: MRK ) , respectively, are combined with older medications to help boost the cure rate from around half of the treated patients to as much as 79%.

But that still leaves room for improvement. And the older medications -- Merck's PegIntron and Roche's Pegasys -- have to be injected and have unpleasant side effects. Going to an all-oral regimen is the ultimate goal.

Hepatitis C drugmakers with limited compounds are scrambling to partner up to avoid being left behind. Pharmasset has a similar deal combining PSI-7977 with a drug from Bristol-Myers Squibb (NYSE: BMY ) . Merck and Roche have also hooked up to test their drug candidates.

Gilead has six hepatitis C compounds in clinical trials that it can mix or match to find the right combo on its own, which might explain why Johnson & Johnson didn't hit up its HIV partner for another go around in hepatitis C.

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

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

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

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

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

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

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

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

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

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

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

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

Bristol Myers Squibb's BMS-790052 and BMS-650032 combo opens up new possibilites at EASL...

Wow. And I said it couldn't be done, that the possibilities were remote at best for an interferon-free DAA combination to cure HCV. Well, I'll gladly step up and dig in to my slice of Humble Pie, because this really is terrific news that quite possibly will open up a brand new treatment paradigm that sheds the side effect-laden burden of interferon, at least in some patients. BMS unleashed their Phase II data at EASL on the combination of their NS5A inhibitor BMS-790052 protease NS3 inhibitor BMS-650032 in patients that had been previously treated with the current standard of care therapy, peglyated-interferon plus ribavirin for 48 weeks. Out of the 11 patients who took took the drug combo without the inteferon component, five cleared virus at the end of treatment, and four of those remained undetectable 24 weeks after 24 weeks. In a similar patient population that received the drug combo plus peg and riba, 9 out 10 patients were cured. That's some potency right there. From a business perspective, it looks like the company is being extremely proactive in looking at partners to help fill the void between the pending launch of the first generation of DAA agents and BMS-790052 + BMS-650032. Pharmasset, which just announced positive two week data on their own interferon-free two drug combo PSI-938 and PSI-7977, might be looking mighty sexy to BMS at this point.


Bristol-Myers Squibb Co. (BMY)’s cocktail of two experimental drugs cured four hepatitis C patients in the first success for a therapy that excludes often-toxic existing drugs.

The combination had a higher rate of success when paired with the current standard treatment in the 21-person trial, curing nine of 10 patients, researchers said today at the Berlin meeting of the European Association for the Study of the Liver. The study points to the next generation of drugs for the evasive virus, said Mark Thursz, a professor of hepatology at Imperial College London and vice-secretary of EASL.

Bristol-Myers, based in New York, is among about a dozen companies trying to make better drug combinations that either include interferon, a decades-old shot that causes flu-like symptoms and only works in half of patients, or that replace interferon entirely. At stake is leadership in a market that Jefferies International Ltd. estimates may total $15 billion a year by 2019.

“This is perhaps one of the most exciting developments this year,” Thursz said in an interview. “For some patients who are not going to tolerate interferon, this is the light at the end of the tunnel.”

Bristol-Myers plans to begin the last trials required for regulatory approval this year, Douglas Manion, the drugmaker’s head of neuroscience and virology research, said in an interview.

Toughest-to-Treat

Today’s trial studied the Bristol-Myers drugs, BMS-790052 and BMS-650032, in patients for whom existing therapies hadn’t been successful, “the toughest-to-treat population,” Manion said.

Ten patients got the two drugs together with interferon and generic ribavirin. All showed no sign of the virus 12 weeks after the treatment was over. One patient had signs of virus at 24 weeks and was again virus-free in another follow-up test 35 days later.

Of 11 patients who took the Bristol-Myers combination alone, five had cleared the virus from their bodies at the end of treatment. Four remained virus-free after 24 weeks.

Patients may start treatment earlier if they aren’t faced with the toxic side effects of traditional hepatitis C drugs, said Howard Liang, a Boston-based analyst for Leerink Swann & Co., in an interview.

“If you have an interferon-free regimen, the market expands fairly dramatically,” Liang said.

Side Effects

Side effects of the existing interferon regimen are often severe enough to force patients to take time off work, said Charles Gore, president of the Geneva-based patient advocacy group World Hepatitis Alliance.

Roche Holding AG (ROG) of Basel, Switzerland, sells a version of interferon under the brand name Pegasys, while Merck & Co. of Whitehouse Station, New Jersey markets a form called PegIntron.

Merck, Vertex Pharmaceuticals Inc. (VRTX) and Johnson & Johnson are expected to bring the first new hepatitis C drugs in a decade to the market this year. About 90 percent of patients who responded quickly to treatment with Johnson & Johnson (JNJ) and Vertex’s telaprevir were cured, Cambridge, Massachusetts-based Vertex said in two studies last year. Three-quarters of all patients were cured. Patients who responded quickly to Merck’s boceprevir showed similarly high cure rates in studies last year, with about two-thirds of all patients being cured.

The Vertex and Merck trials included people who hadn’t yet been treated, an easier-to-cure group than those in today’s smaller study. By comparison, about 30 percent of those who hadn’t responded to previous treatment were cured after trying telaprevir plus standard therapy, researchers said.

Seeking Partners

Merck is seeking partnerships to gain its own hepatitis C drug combinations, Patrick Bergstedt, general manager of the infectious diseases franchise, said in an interview.

“We’re behind the others,” Bergstedt said. “We need to partner to fill the gap.”

Bristol-Myers expects an “element of consolidation” as companies use acquisitions, partnerships and research and development collaborations to gain their own hepatitis C drug combinations, Manion said. After signing a development deal with Princeton, New Jersey-based Pharmasset Inc. (VRUS) in January, Bristol- Myers is “talking to pretty much every company out there,” he said.

“This is like trying to redesign a car as you’re rolling down the road at 100 miles per hour, because the data are coming so fast,” he said. “What an exciting time.”

To contact the reporter on this story: Naomi Kresge in Frankfurt at nkresge@bloomberg.net

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