Showing posts with label Bristol Myers Squibb. Show all posts
Showing posts with label Bristol Myers Squibb. Show all posts
Thursday, August 2, 2012
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.
Tuesday, April 24, 2012
J&J open to partnering with Vertex in HCV drug development...
Posted on 4/20/12 on Bloomberg.com. The growing body of evidence in HCV drug development suggests that alliances are important (unless you happen to be Gilead) especially with partners that are owned by deep-pocketed, well diversified organizations like Johnson and Johnson. Hopefully J&J can put back some luster on Vertex's non-nuc VX-222. Actually, despite it's inherent relative lower barrier of resistance, it's a good drug - QD dosing, pretty powerful, clean and low potential for drug interactions. Just needs the right partners in a regimen. TMC435 may be one of 'em - QD dosing, powerful, no need for ritonavir and thus no ritonavir baggage - sounds good on paper, anyway.
J&J Open to Expanding Hepatitis C Cooperation With Vertex
By Makiko Kitamura - Apr 20, 2012 8:09 AM PT
Johnson & Johnson (JNJ)’s Janssen unit said it may explore widening cooperation on hepatitis C with Vertex Pharmaceuticals Inc. (VRTX) that may develop in tandem with a separate partnership with Medivir AB (MVIRB) on the disease.
“We remain open to see if we can expand our collaboration,” Gaston Picchio, vice president of Janssen’s global clinical virology and hepatitic disease area, said in an interview today in Barcelona, where he’s attending the European Association for the Study of the Liver annual meeting. “Vertex has announced plans for developing interferon-free therapies. We are partners, so that puts us in a better position to be a part of that,” should studies prove to be promising.
Vertex said on April 18 that it will start enrolling patients in a mid-stage study combining three medicines, excluding interferon, a core component of the current standard of care. Vertex and competitors including Gilead Sciences Inc. (GILD), Bristol-Myers Squibb Co. (BMY) and Abbott Laboratories (ABT) are racing to develop next-generation treatments for hepatitis C that exclude interferon because of flu-like side effects.
Vertex and J&J collaborated to develop telaprevir, marketed as Incivek by Vertex in North America and as Incivo by Janssen in other regions including Europe. The drug was approved by regulators last year as a treatment for hepatitis C in combination with interferon and ribavirin.
Medivir Project
J&J, which has its headquarters in New Brunswick, New Jersey, is also developing the protease inhibitor TMC435 with Huddinge, Sweden-based Medivir, which has said mid-stage trials of the drug in interferon-free combinations with Gilead’s 7977 and with Bristol-Myers’s daclatasvir experimental drugs are starting in the second quarter.
While J&J and Medivir are also developing the TMC647 polymerase inhibitor, Vertex’s VX-222 compound in the same class of drugs is further along in development. VX-222 is one of the three drugs included in Cambridge, Massachusetts-based Vertex’s mid-stage interferon-free treatment study.
Meanwhile, J&J is also “committed” to improving the labeling of Incivo by conducting further trials that examine less frequent dosage as well as efficacy in patients also infected by the HIV virus and those who have had liver transplants, Picchio said.
To contact the reporter on this story: Makiko Kitamura in Barcelona via mkitamura1@bloomberg.net
To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net
Monday, April 23, 2012
'The Street' grades the HCV players post-EASL...
The Street's Nathan Sadeghi-Nejad grades the stocks of the big players in HCV post-EASL. It's a good read, much better than those of his peers, although my opinion on certain topics differs from his in some respects. It's helpful to know that Mr. Sadeghi-Nejad's perspective is from one entrenched in the investment community, a community notorious for knee-jerk reactions to data deemed good or bad simply based on numbers in interim data. The result is often either 'irrational exuberance' or 'irrational discouragement' causing wild fluctuations in stock price. Greater scrutiny must often be utilized to get the 'real story' behind the numbers - patient demographics, fibrosis scores, BMI, trial structure, population size, P values, etc. This is not to devalue the investment community but a call for a more discriminating eye when it comes to data analysis. Mr. Sadeghi-Nejad's analysis shows a surprising amount of discrimination. My opinion does differ from his in respect to a couple of things (he's awfully hard on Achillion, doesn't mention BI or Merck and... well, see below).
I'll go on record to challenge Mr. Sadeghi-Nejad's claim that interferon is 'dead'. That's a pretty dimissive statement. While interferon-free therapies may be an option for many patients, especially those that are treatment naive, genotype 1b, 2, 3 and 4, with moderate fibrosis, with IL28B CC/TC status. However interferon will most likely play a large role in the 'difficult to treat' population - patients presenting with advanced fibrosis/compensated cirrhosis, genotype 1a, steatosis and IL28B TT status and/or a majority of null-responders.
In fact, the data from BMS/s EMERGE trail - a head-to-head trial looking at PEG-Lambda + ribavirin vs PEG-interferon-alfa + ribavirin - was horribly under-appreciated. Not only was PEG-Lamda a good deal more effective at achieving SVR than PEG-alfa, there were also significantly less side effects. We need to see how PEG-Lambda performs with the 2nd and 3rd generation DAAs in these difficult to treat patient populations. There is definitely a need as these patients are most at risk for developing decompensated liver disease and HCC.
OK, off my soapbox now.
BARCELONA (TheStreet) -- Wow, it's been a busy few days at the European Association for the Study of the Liver (EASL) annual meeting in this beautiful Catalan capital. Investors obsessed with emerging hepatitis C therapies had plenty of new data to analyze.
Let me make one general observation about the future of hepatitis C treatment before I recap and grade each of the companies with a significant presence at the EASL meeting. Interferon -- the injectable immune system booster saddled with troublesome side effects -- is dead. The future of hepatitis C therapy belongs to interferon-free regimens. Physicians at the conference talked about interferon as if it were invented in medieval times. It's clear that any company seeking a role in hepatitis C going forward must develop or acquire an effective interferon-free regimen or face irrelevance.
Let's move to the winners and losers of EASL 2012.
Gilead Sciences(GILD_):
Grade: A-
Gilead was the big story of the conference. The company emphatically reclaimed the driver's seat in HCV, at least for now, with a combination of solid scientific results and ruthless, strategic maneuvering.
In a crowded Thursday session, anxious Wall Streeters awaited new data for Gilead's GS-7977, a once-daily nucleotide polymerase inhibitor, or "nuc." Despite impressive early data -- which prompted the undeniably expensive $11 billion Pharmasset acquisition -- subsequent results from a GS-7977 trial called ELECTRON showed the drug to have little effect in "null" responders and generated lots of investor anxiety. I was no exception. Despite my favorable disposition towards GS-7977, I wanted confirmation of the early data; most investors I spoke with shared my view.
We got what we were looking for.
An impressive 88% of treatment-naive patients in ELECTRON achieved sustained virologic response four weeks after stopping treatment (an early indication of "cure" known as SVR4) with 12 weeks of GS-7977 and ribavirin (RBV), a companion drug used in hepatitis C. Expectations leading into EASL were for an SVR4 of 70%.
At the same time, Gilead issued a press release containing preliminary data from QUANTUM, an ongoing study in treatment-naive patients also using the GS-7977 plus ribavirin combination therapy. The SVR4 rate in this study was 59%, lower than ELECTRON due to enrollment of more difficult-to-treat patients. [84% of QUANTUM patients had unfavorable "non-CC" genetics, versus 56% in ELECTRON.]
Results from the ELECTRON AND QUANTUM studies of GS-7977 were important but not the star of EASL. What got everyone really excited were data from the mid-stage study combining GS-7977 with Bristol-Myer Squibb's(BMY_) NS5A replication complex inhibitor daclatasvir. Among the patients with genotype 1 hepatitis C, GS-7977 plus daclatasvir resulted in an SVR4 rate of 100%. Yes, the combination therapy cured all treated patients. These data literally elicited high fives from several of the generally reserved hedge fund analysts in attendance. It's hard to argue with an SVR4 of 100%, but longer-term follow-up data are needed to confirm these results. Physicians traditionally use SVR12 (12 weeks) or SVR24 (24 weeks) as a final indication of cure, although recent data show a strong correlation between SVR4 and later follow up assessments.
As if that weren't enough excitement, Gilead also generated some drama at the meeting -- and elicited a "patients-not-profits" rebuke from my colleague Adam Feuerstein -- when word got out that the company had refused an offer from Bristol-Myers to collaborate on further development of GS-7977 and daclatasvir. Although Gilead insists it hasn't made a final decision, I'm guessing management will try to combine GS-7977 with GS-5885, an early-stage drug candidate in the same NS5A class as daclatasvir. Obviously, Gilead wants to keep all the profits from a highly potent, all-oral hepatitis C therapy for itself.
In GS-7977, Gilead appears to control a strong, future "backbone" for any next-generation hepatitis C regimen. I have mixed feelings about Gilead's apparent desire to deny Bristol-Myers access to the drug and therefore prevent a daclatasvir-GS-7977 regimen from reaching the market. Patients and their advocates will probably be justifiably upset that such this apparently highly effective regimen won't be developed further. I understand that. Interestingly, physicians I spoke with at the meeting didn't care either way. That surprised me; I would have expected more complaints.
As an investor, I don't fault Gilead for angling to maximize profits -- I've never subscribed to the biotechnology industry's cloying "patients first" rhetoric. However, the move does increase the company's clinical risk in hepatitis C. Even though initial GS-5885 data look clean, a problem could still emerge and daclatasvir is far more established. Essentially, management is betting that the promise (and eventually, the reality) of an "all Gilead" HCV regimen outweighs additional R&D expenses and near-term clinical risks.
That seems like a reasonable bet, and I think the stock will continue to work -- Gilead is still only trading at around 13 times estimates 2012 earnings.
Bristol-Myers Squibb:
Grade: C
Bristol-Myers had quite the Dickensian conference. The company's daclatasvir plus Gilead's GS-7977 wowed investors and physicians alike. The best of times!
Unfortunately, Gilead doesn't want to partner GS-7977; the non-nucleoside polymerase inhibitor BMS-791325 seems only modestly effective and may have toxicity issues; the protease inhibitor asunaprevir has a messy side effect profile; and adverse event rumors are haunting BMS-986094 (formerly known as INX-189), the "nuc" obtained via the $2.5 billion purchase of Inhibitex. Oh, and brivanib fails in liver cancer. The worst of times!
Gilead's refusal to collaborate raises an important observation. Consider this: Bristol-Myers hasn't made public much data about BMS-986094 since closing the Inhibitex acquisition and non-specific toxicity rumors dogged the drug at EASL. Does this explain why Bristol-Myers is trying to pressure Gilead into moving the daclatasvir-GS-7977 regimen into phase III trials? Put another way, if Bristol-Myers was confident that BMS-986094 (INX-189) could easily replace GS-7977 in a combination regimen with daclatasvir, why not play the same ruthless, "winner take all" game as Gilead?
If I was a Bristol-Myers bull, I would be worrying about the future of BMS-986094 (INX-189.)
Management better hope it can either woo or shame Gilead into collaboration (unlikely, unless something goes wrong with GS-5885) or that the Inhibitex drug plays nice with daclatasvir and the toxicity rumors are false. Otherwise, Bristol-Myers will have to open up the M&A wallet again to remain relevant in the race for next-generation hepatitis C therapies.
Abbott(ABT_):
Grade: B
Despite Wall Street skepticism, I think Abbott remains firmly in the hepatitis C game. The company presented data from two major studies, PILOT and CO-PILOT, in late-breaker sessions on Saturday afternoon.
PILOT enrolled treatment-naive patients to receive 12 weeks of ABT-450 -- a protease inhibitor that requires blood-level "boosting" with ritonavir -- in combination with the non-nucleoside NS5B polymerase inhibitor ABT-072 and ribavirin. It must be noted that all patients had favorable "C/C" genetics, making it an easy group to treat. Nonetheless, Abbott reported an impressive 91% SVR24.
One patient in PILOT suffered a late relapse after 36 weeks of follow up which dropped the SVR36 "cure" rate to 82%. These are some of the longest follow-up results yet with next-generation, all-oral regimens so the relapse was noteworthy. I'm not sure if the relapse is an isolated event, and no one I spoke with had a definitive answer. Keep the question of whether interferon-free regimens might leave patients more susceptible to late relapse in mind -- it needs to be watched closely going forward.
In Abbott's second CO-PILOT study, patients received 12 weeks of ritonavir-boosted ABT-450 and the "non-nuc" ABT-333. Patients in the two treatment-naive arms achieved SVR12 rates of 93% and 95% (These patients were a mix of easy- and hard-to-treat patients more comparable to competitors' studies). I was impressed with these data, as were most physicians at EASL. A third arm in the CO-PILOT study enrolled "non-responders" but generated only a 47% SVR12; these patients need a more robust regimen.
The downside to the CO-PILOT regimen is complexity: ABT-450 is administered once daily, as is ribavirin and ritonavir, whereas ABT-333 is dosed twice daily. Further, ritonavir has numerous drug-drug interactions. Physicians I spoke with at EASL were mixed about whether or not patients could be sufficiently compliant in the real-world setting. I doubt it. Abbott plans to co-formulate future combinations, which will include other drugs (the company also has a NS5A inhibitor.)
I plan on taking a closer look at Abbott in a future column. The company is highly dependent on sales of the rheumatoid arthritis drug Humira, which I don't like, but investors aren't assigning much value to its hepatitis C assets. Based on what I saw at EASL, that could be a mistake.
Idenix Pharmaceuticals(IDIX_):
Grade: B-
Despite having no data at EASL this year, Idenix will likely benefit from the rising tide created by Gilead and Bristol-Myers. After successfully negotiating side effect questions and a partial clinical hold, Idenix has emerged as the only smallish biotech company with both a "nuc" (IDX-184) and an NS5A inhibitor (IDX-719.) By year-end, we will see SVR4 data for IDX-184 combined with interferon and ribavirin; and early data on IDX-719.
If these results look promising, Idenix is going to be hugely attractive to large pharma companies with lackluster hepatitis C programs and an urge to catch up. Novartis(NVS_) already has a first right to license IDX-719 by year-end, but other companies might be interested regardless of the Swiss pharma giant's decision. I would be a buyer of Idenix, but keep any position on the small side.
Achillion Pharmaceuticals(ACHN_):
Grade: C-
Meh. Achillion has two NS5A inhibitors, ACH-3102 and ACH-2928, which look okay in early studies, but I'm not sure what makes these drug candidates stand out. I feel similarly unexcited about ACH-1625, a protease inhibitor, which looked decent in a confusing study that combined it with interferon and ribavirin. I'm just not convinced these are valuable assets, so I'm going to wait on the sidelines.
Vertex Pharmaceuticals(VRTX_):
Grade: D-
Out of sight, out of mind. The big loser of the EASL conference was Vertex Pharmaceuticals. The company's first-in-class protease inhibitor Incivek pioneered treatment with direct-acting antivirals in hepatitis C, but the drug now feels woefully outdated less than one year after approval. The problem is that Incivek therapy still requires patients to receive weekly injections of interferon. Remember what I noted at the top of this column -- interferon is dead -- so any drug attached to interferon is at risk of the same fate.
Vertex does have ongoing interferon-free studies that combine Incivek with ribavirin and VX-222 -- an earlier-stage "non-nuc" drug candidate -- but the combination seems like a long shot. Earlier this year, the company reported that 82% of patients in the Phase II ZENITH trial achieved an SVR4. Vertex also added to its hepatitis C portfolio recently, acquiring two "nucs" through a partnership with Alios BioPharma. Unfortunately, those compounds do not yet have any clinical data and are substantially behind the market leaders.
More from Nathan Sadeghi-Nejad
Calling Shenanigans on Amylin PharmaGilead And The Future of HIV TherapyRegeneron, Amgen And The 'Hope Creation Cycle"
Market Activity
Vertex Pharmaceuticals| VRTX
Gilead Sciences Inc| GILD
Achillion Pharmaceuticals Inc.| ACHN
Meanwhile, I expect already flat Incivek sales will decline rapidly as physicians urge patients to defer treatment until next-generation drugs reach the market. Street estimates now reflect a sequential decline in Incivek sales. If Vertex isn't able to expand use of the cystic fibrosis drug Kalydeco to a broader group of patients at premium pricing, Vertex might be a short. (I haven't done enough work to have a final opinion yet.) Either way, this wasn't a good EASL meeting for the Boston-based biotech.
Onyx Pharmaceuticals(ONXX_):
Grade: B+
EASL is not only about hepatitis C. This is a meeting that covers all liver disease, which includes liver cancer. In this regard, Onyx emerged from EASL a solid winner even though the company presented no new data.
Some investors expected positive results from a 395-patient trial of Bristol-Myers' brivanib in late-stage liver cancer. Positive brivanib data would have been bad news for Onyx, whose key asset, Nexavar, dominates the liver cancer treatment market and faces no major competitors. Fortunately, brivanib proved both a dud and a point.
In a crowded Saturday session, the same investigator who led Onyx's Phase III study presented findings from Bristol-Myers' BRISK-PS, which randomized patients who had progressed on, or were intolerant of, Nexavar to receive either brivanib or placebo. Despite positive response rate (12% versus 2%) and time to progression (4.2 months versus 2.7 months) data, brivanib showed only a slight survival benefit (9.4 months versus 8.2 months). For comparison, Nexavar improved survival by 2.8 months in the Phase III SHARP trial that led to the drug's approval.
Before I get a slew of comments on the value of any benefit in this difficult-to-treat disease, I would note that the data were not even close to statistical significance and brivanib caused meaningful toxicity, including six patient deaths attributed to the drug by study investigators.
The key takeaway here -- other than that Nexavar's leading position in liver cancer remains safe -- is that surrogate endpoints like response rate and progression-free survival do not always correlate with a survival benefit. This is particularly true in studies of solid tumors. Despite what feels like the constant media coverage of emotional demands for quick approvals based on limited data, the BRISK-PS data once again highlight the need for companies to conduct randomized studies using real endpoints.
Whew. That does it for EASL 2012, but my travels continue. This afternoon I'm off to Boston to surprise Mom for her birthday. (Let's see if she reads all the way to the end of my columns.)
Happy birthday Mom!
Disclosure: Sadeghi has no positions in any of the stocks mentioned in this article.
I'll go on record to challenge Mr. Sadeghi-Nejad's claim that interferon is 'dead'. That's a pretty dimissive statement. While interferon-free therapies may be an option for many patients, especially those that are treatment naive, genotype 1b, 2, 3 and 4, with moderate fibrosis, with IL28B CC/TC status. However interferon will most likely play a large role in the 'difficult to treat' population - patients presenting with advanced fibrosis/compensated cirrhosis, genotype 1a, steatosis and IL28B TT status and/or a majority of null-responders.
In fact, the data from BMS/s EMERGE trail - a head-to-head trial looking at PEG-Lambda + ribavirin vs PEG-interferon-alfa + ribavirin - was horribly under-appreciated. Not only was PEG-Lamda a good deal more effective at achieving SVR than PEG-alfa, there were also significantly less side effects. We need to see how PEG-Lambda performs with the 2nd and 3rd generation DAAs in these difficult to treat patient populations. There is definitely a need as these patients are most at risk for developing decompensated liver disease and HCC.
OK, off my soapbox now.
BARCELONA (TheStreet) -- Wow, it's been a busy few days at the European Association for the Study of the Liver (EASL) annual meeting in this beautiful Catalan capital. Investors obsessed with emerging hepatitis C therapies had plenty of new data to analyze.
Let me make one general observation about the future of hepatitis C treatment before I recap and grade each of the companies with a significant presence at the EASL meeting. Interferon -- the injectable immune system booster saddled with troublesome side effects -- is dead. The future of hepatitis C therapy belongs to interferon-free regimens. Physicians at the conference talked about interferon as if it were invented in medieval times. It's clear that any company seeking a role in hepatitis C going forward must develop or acquire an effective interferon-free regimen or face irrelevance.
Let's move to the winners and losers of EASL 2012.
Gilead Sciences(GILD_):
Grade: A-
Gilead was the big story of the conference. The company emphatically reclaimed the driver's seat in HCV, at least for now, with a combination of solid scientific results and ruthless, strategic maneuvering.
In a crowded Thursday session, anxious Wall Streeters awaited new data for Gilead's GS-7977, a once-daily nucleotide polymerase inhibitor, or "nuc." Despite impressive early data -- which prompted the undeniably expensive $11 billion Pharmasset acquisition -- subsequent results from a GS-7977 trial called ELECTRON showed the drug to have little effect in "null" responders and generated lots of investor anxiety. I was no exception. Despite my favorable disposition towards GS-7977, I wanted confirmation of the early data; most investors I spoke with shared my view.
We got what we were looking for.
An impressive 88% of treatment-naive patients in ELECTRON achieved sustained virologic response four weeks after stopping treatment (an early indication of "cure" known as SVR4) with 12 weeks of GS-7977 and ribavirin (RBV), a companion drug used in hepatitis C. Expectations leading into EASL were for an SVR4 of 70%.
At the same time, Gilead issued a press release containing preliminary data from QUANTUM, an ongoing study in treatment-naive patients also using the GS-7977 plus ribavirin combination therapy. The SVR4 rate in this study was 59%, lower than ELECTRON due to enrollment of more difficult-to-treat patients. [84% of QUANTUM patients had unfavorable "non-CC" genetics, versus 56% in ELECTRON.]
Results from the ELECTRON AND QUANTUM studies of GS-7977 were important but not the star of EASL. What got everyone really excited were data from the mid-stage study combining GS-7977 with Bristol-Myer Squibb's(BMY_) NS5A replication complex inhibitor daclatasvir. Among the patients with genotype 1 hepatitis C, GS-7977 plus daclatasvir resulted in an SVR4 rate of 100%. Yes, the combination therapy cured all treated patients. These data literally elicited high fives from several of the generally reserved hedge fund analysts in attendance. It's hard to argue with an SVR4 of 100%, but longer-term follow-up data are needed to confirm these results. Physicians traditionally use SVR12 (12 weeks) or SVR24 (24 weeks) as a final indication of cure, although recent data show a strong correlation between SVR4 and later follow up assessments.
As if that weren't enough excitement, Gilead also generated some drama at the meeting -- and elicited a "patients-not-profits" rebuke from my colleague Adam Feuerstein -- when word got out that the company had refused an offer from Bristol-Myers to collaborate on further development of GS-7977 and daclatasvir. Although Gilead insists it hasn't made a final decision, I'm guessing management will try to combine GS-7977 with GS-5885, an early-stage drug candidate in the same NS5A class as daclatasvir. Obviously, Gilead wants to keep all the profits from a highly potent, all-oral hepatitis C therapy for itself.
In GS-7977, Gilead appears to control a strong, future "backbone" for any next-generation hepatitis C regimen. I have mixed feelings about Gilead's apparent desire to deny Bristol-Myers access to the drug and therefore prevent a daclatasvir-GS-7977 regimen from reaching the market. Patients and their advocates will probably be justifiably upset that such this apparently highly effective regimen won't be developed further. I understand that. Interestingly, physicians I spoke with at the meeting didn't care either way. That surprised me; I would have expected more complaints.
As an investor, I don't fault Gilead for angling to maximize profits -- I've never subscribed to the biotechnology industry's cloying "patients first" rhetoric. However, the move does increase the company's clinical risk in hepatitis C. Even though initial GS-5885 data look clean, a problem could still emerge and daclatasvir is far more established. Essentially, management is betting that the promise (and eventually, the reality) of an "all Gilead" HCV regimen outweighs additional R&D expenses and near-term clinical risks.
That seems like a reasonable bet, and I think the stock will continue to work -- Gilead is still only trading at around 13 times estimates 2012 earnings.
Bristol-Myers Squibb:
Grade: C
Bristol-Myers had quite the Dickensian conference. The company's daclatasvir plus Gilead's GS-7977 wowed investors and physicians alike. The best of times!
Unfortunately, Gilead doesn't want to partner GS-7977; the non-nucleoside polymerase inhibitor BMS-791325 seems only modestly effective and may have toxicity issues; the protease inhibitor asunaprevir has a messy side effect profile; and adverse event rumors are haunting BMS-986094 (formerly known as INX-189), the "nuc" obtained via the $2.5 billion purchase of Inhibitex. Oh, and brivanib fails in liver cancer. The worst of times!
Gilead's refusal to collaborate raises an important observation. Consider this: Bristol-Myers hasn't made public much data about BMS-986094 since closing the Inhibitex acquisition and non-specific toxicity rumors dogged the drug at EASL. Does this explain why Bristol-Myers is trying to pressure Gilead into moving the daclatasvir-GS-7977 regimen into phase III trials? Put another way, if Bristol-Myers was confident that BMS-986094 (INX-189) could easily replace GS-7977 in a combination regimen with daclatasvir, why not play the same ruthless, "winner take all" game as Gilead?
If I was a Bristol-Myers bull, I would be worrying about the future of BMS-986094 (INX-189.)
Management better hope it can either woo or shame Gilead into collaboration (unlikely, unless something goes wrong with GS-5885) or that the Inhibitex drug plays nice with daclatasvir and the toxicity rumors are false. Otherwise, Bristol-Myers will have to open up the M&A wallet again to remain relevant in the race for next-generation hepatitis C therapies.
Abbott(ABT_):
Grade: B
Despite Wall Street skepticism, I think Abbott remains firmly in the hepatitis C game. The company presented data from two major studies, PILOT and CO-PILOT, in late-breaker sessions on Saturday afternoon.
PILOT enrolled treatment-naive patients to receive 12 weeks of ABT-450 -- a protease inhibitor that requires blood-level "boosting" with ritonavir -- in combination with the non-nucleoside NS5B polymerase inhibitor ABT-072 and ribavirin. It must be noted that all patients had favorable "C/C" genetics, making it an easy group to treat. Nonetheless, Abbott reported an impressive 91% SVR24.
One patient in PILOT suffered a late relapse after 36 weeks of follow up which dropped the SVR36 "cure" rate to 82%. These are some of the longest follow-up results yet with next-generation, all-oral regimens so the relapse was noteworthy. I'm not sure if the relapse is an isolated event, and no one I spoke with had a definitive answer. Keep the question of whether interferon-free regimens might leave patients more susceptible to late relapse in mind -- it needs to be watched closely going forward.
In Abbott's second CO-PILOT study, patients received 12 weeks of ritonavir-boosted ABT-450 and the "non-nuc" ABT-333. Patients in the two treatment-naive arms achieved SVR12 rates of 93% and 95% (These patients were a mix of easy- and hard-to-treat patients more comparable to competitors' studies). I was impressed with these data, as were most physicians at EASL. A third arm in the CO-PILOT study enrolled "non-responders" but generated only a 47% SVR12; these patients need a more robust regimen.
The downside to the CO-PILOT regimen is complexity: ABT-450 is administered once daily, as is ribavirin and ritonavir, whereas ABT-333 is dosed twice daily. Further, ritonavir has numerous drug-drug interactions. Physicians I spoke with at EASL were mixed about whether or not patients could be sufficiently compliant in the real-world setting. I doubt it. Abbott plans to co-formulate future combinations, which will include other drugs (the company also has a NS5A inhibitor.)
I plan on taking a closer look at Abbott in a future column. The company is highly dependent on sales of the rheumatoid arthritis drug Humira, which I don't like, but investors aren't assigning much value to its hepatitis C assets. Based on what I saw at EASL, that could be a mistake.
Idenix Pharmaceuticals(IDIX_):
Grade: B-
Despite having no data at EASL this year, Idenix will likely benefit from the rising tide created by Gilead and Bristol-Myers. After successfully negotiating side effect questions and a partial clinical hold, Idenix has emerged as the only smallish biotech company with both a "nuc" (IDX-184) and an NS5A inhibitor (IDX-719.) By year-end, we will see SVR4 data for IDX-184 combined with interferon and ribavirin; and early data on IDX-719.
If these results look promising, Idenix is going to be hugely attractive to large pharma companies with lackluster hepatitis C programs and an urge to catch up. Novartis(NVS_) already has a first right to license IDX-719 by year-end, but other companies might be interested regardless of the Swiss pharma giant's decision. I would be a buyer of Idenix, but keep any position on the small side.
Achillion Pharmaceuticals(ACHN_):
Grade: C-
Meh. Achillion has two NS5A inhibitors, ACH-3102 and ACH-2928, which look okay in early studies, but I'm not sure what makes these drug candidates stand out. I feel similarly unexcited about ACH-1625, a protease inhibitor, which looked decent in a confusing study that combined it with interferon and ribavirin. I'm just not convinced these are valuable assets, so I'm going to wait on the sidelines.
Vertex Pharmaceuticals(VRTX_):
Grade: D-
Out of sight, out of mind. The big loser of the EASL conference was Vertex Pharmaceuticals. The company's first-in-class protease inhibitor Incivek pioneered treatment with direct-acting antivirals in hepatitis C, but the drug now feels woefully outdated less than one year after approval. The problem is that Incivek therapy still requires patients to receive weekly injections of interferon. Remember what I noted at the top of this column -- interferon is dead -- so any drug attached to interferon is at risk of the same fate.
Vertex does have ongoing interferon-free studies that combine Incivek with ribavirin and VX-222 -- an earlier-stage "non-nuc" drug candidate -- but the combination seems like a long shot. Earlier this year, the company reported that 82% of patients in the Phase II ZENITH trial achieved an SVR4. Vertex also added to its hepatitis C portfolio recently, acquiring two "nucs" through a partnership with Alios BioPharma. Unfortunately, those compounds do not yet have any clinical data and are substantially behind the market leaders.
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Meanwhile, I expect already flat Incivek sales will decline rapidly as physicians urge patients to defer treatment until next-generation drugs reach the market. Street estimates now reflect a sequential decline in Incivek sales. If Vertex isn't able to expand use of the cystic fibrosis drug Kalydeco to a broader group of patients at premium pricing, Vertex might be a short. (I haven't done enough work to have a final opinion yet.) Either way, this wasn't a good EASL meeting for the Boston-based biotech.
Onyx Pharmaceuticals(ONXX_):
Grade: B+
EASL is not only about hepatitis C. This is a meeting that covers all liver disease, which includes liver cancer. In this regard, Onyx emerged from EASL a solid winner even though the company presented no new data.
Some investors expected positive results from a 395-patient trial of Bristol-Myers' brivanib in late-stage liver cancer. Positive brivanib data would have been bad news for Onyx, whose key asset, Nexavar, dominates the liver cancer treatment market and faces no major competitors. Fortunately, brivanib proved both a dud and a point.
In a crowded Saturday session, the same investigator who led Onyx's Phase III study presented findings from Bristol-Myers' BRISK-PS, which randomized patients who had progressed on, or were intolerant of, Nexavar to receive either brivanib or placebo. Despite positive response rate (12% versus 2%) and time to progression (4.2 months versus 2.7 months) data, brivanib showed only a slight survival benefit (9.4 months versus 8.2 months). For comparison, Nexavar improved survival by 2.8 months in the Phase III SHARP trial that led to the drug's approval.
Before I get a slew of comments on the value of any benefit in this difficult-to-treat disease, I would note that the data were not even close to statistical significance and brivanib caused meaningful toxicity, including six patient deaths attributed to the drug by study investigators.
The key takeaway here -- other than that Nexavar's leading position in liver cancer remains safe -- is that surrogate endpoints like response rate and progression-free survival do not always correlate with a survival benefit. This is particularly true in studies of solid tumors. Despite what feels like the constant media coverage of emotional demands for quick approvals based on limited data, the BRISK-PS data once again highlight the need for companies to conduct randomized studies using real endpoints.
Whew. That does it for EASL 2012, but my travels continue. This afternoon I'm off to Boston to surprise Mom for her birthday. (Let's see if she reads all the way to the end of my columns.)
Happy birthday Mom!
Disclosure: Sadeghi has no positions in any of the stocks mentioned in this article.
Monday, February 13, 2012
BMS completes tender offer for Inhibitex Inc...
Bristol-Myers completes Inhibitex tender offer
TRENTON, N.J. (AP) — Bristol-Myers Squibb Co. said Monday that it's completed its tender offer for the stock of Inhibitex Inc., a drug developer that Bristol is buying for $2.5 billion as part of its strategy to become a player in the hot hepatitis C drug market.
New York-based Bristol-Myers said it now has about 91 percent of outstanding shares of Inhibitex, after buying just over 77.5 million shares through midnight Friday for $26 each.
That's the last step before the merger can be executed. A Bristol-Myers spokeswoman on Monday said the company is working to quickly complete the deal but could not say when it will close.
When that happens, remaining Inhibitex shares will be canceled, their owners will be able to receive $26 per share and Inhibitex will become a wholly owned subsidiary of Bristol-Myers.
Earlier in February, the federal antitrust review period under the Hart-Scott-Rodino Antitrust act expired, satisfying a key condition of the offer.
Bristol-Myers is an important maker of medicines for viruses, including Baraclude for hepatitis B and several HIV drugs, but has nothing for hepatitis C at a time when more patients need treatment. Over 3 million Americans have the blood-borne, tough-to-treat disease, which can go undetected for many years until the liver is severely damaged. More people will be diagnosed as the baby boomer generation ages.
After a two-decade drought, the first two new hepatitis C drugs were approved last year: Victrelis from Merck & Co. and Incivek, marketed by partners Vertex Pharmaceuticals Inc. and Johnson & Johnson. Both significantly improve the cure rate over what has long been the standard of care — a mix of injections and pills with nasty, flu-like side effects that takes several months and still doesn't cure many patients.
Last month, Bristol-Myers CEO Lamberto Andreotti said his company has four experimental hepatitis C drugs in development that could be a big improvement over the pills-and-shots regimen. The Bristol compounds might also be combined with those of Inhibitex to produce an even more-effective treatment.
Inhibitex has three experimental drugs in midstage human testing, including INX-189, for treating chronic hepatitis C infections. The other two compounds are FV-100, for reducing the pain caused by shingles, and Aurexis, a biologic antibody-based drugs for treating dangerous staph infections in the blood.
Inhibitex also has other potential hepatitis C treatments in laboratory testing, and has a proprietary technology that it's licensed to Pfizer Inc. for developing a possible staph vaccine.
Tuesday, January 25, 2011
Xconomy weighs in on ZymoGenetics and what could have been....
How ZymoGenetics Coulda Been a Contender: The Big Break That Came Too Late
Luke Timmerman 1/25/11
ZymoGenetics, if it had stayed an independent company in Seattle, would be worth tens of millions of dollars more today than what it was in September when it agreed to be acquired by Bristol-Myers Squibb (NYSE: BMY).
Bristol clearly scored a big break with its new ZymoGenetics assets on December 21, about two months after it closed the books on its $885 million acquisition of the venerable Seattle biotech.
If it had still been an independent biotech, the value of ZymoGenetics would have soared that day when Cambridge, MA-based Vertex Pharmaceuticals announced that, essentially, it had failed to make ZymoGenetics’ lead drug candidate obsolete. On that day, Vertex (NASDAQ: VRTX) said it was unable to eradicate one of backbone components of hepatitis C therapy in a high profile clinical trial.
Vertex is blazing a new trail in the field with a potent new oral pill that generates unprecedented cure rates when given in combination with two standard treatments—pegylated interferon alpha and ribavirin. Vertex was hoping to raise the bar even higher, to find out if its lead molecule, telaprevir, could be combined into a new cocktail regimen that Vertex hoped would kick old-school interferon into the dustbin of history. Doctors and patients have been yearning for a way to get rid of interferon, which causes nasty flu-like symptoms that make patients feel awful for months, which discourages most patients from seeking treatment.
ZymoGenetics, knowing this well, had developed a genetically modified version of interferon, which it called pegylated interferon lambda. This new form of interferon was designed to kill the hepatitis C virus just like the older version of interferon, but without the flu-like side effects. Results from early clinical trials were so promising that ZymoGenetics was able to entice Bristol to sign a $1.1 billion partnership to co-develop the drug in January 2009.
But many on Wall Street weren’t impressed. They had fallen head over heels for Vertex’s new molecule, insisting that ZymoGenetics and Bristol were wasting their time with a new type of interferon. Vertex, they said, was coming along with a cocktail approach of new oral pills that would get rid of interferon, meaning any improvement on old-school interferon would soon be irrelevant. While many doctors, and companies like Vertex still hope it will be possible to do this, the latest clinical trial failure makes it clear that interferon will be part of the standard treatment regimen for years. That means the drug Bristol acquired from ZymoGenetics has a chance to integrate itself into a new standard of care, at a moment when awareness has never been higher among an estimated 6 million U.S. and European patients with this liver-damaging condition.
Former ZymoGenetics CEO Doug Williams, who recently took a new job as head of R&D at Weston, MA-based Biogen Idec, acknowledged in a recent interview that the failure of Vertex’s combination trial would have been a positive event for ZymoGenetics and its pegylated interferon lambda program. He stopped short of saying that Wall Street would have perceived the development in a way that would have boosted ZymoGenetics’ stock price.
“Certainly some people would have come off the fence and perhaps started to believe that interferons will be really hard to get rid of,” Williams says. “I’m certainly of the mind that it will be extremely difficult to get rid of interferon, and achieve [cure rates] currently seen.”
He added: “I gotta believe it would have been viewed as a net positive, but the degree to which it would have been reflected in the stock price, I don’t think anybody can say that.”
David Miller, the president of Biotech Stock Research in Seattle, who criticized ZymoGenetics for selling the company at a bargain price, said he believes investors would have given the company credit. An estimated 6 million patients in the U.S. and Europe have hepatitis C, and many of them are expected to start seeking treatment in 2011, now that a new wave of protease inhibitors like Vertex’s telaprevir and Merck’s boceprevir are being primed to hit the market later this year. The existing interferons from Roche and Merck made up a combined market worth more than $2 billion in 2009, even before the more-effective protease inhibitors came along to spur more interest in hepatitis C therapy.
ZymoGenetics could have seen its stock climb another $2 to $3 a share if it had still been an independent company when the Vertex news hit the wire on December 21, Miller says.
“Smart money was moving toward ZymoGenetics,” Miller says. The latest clinical trial failure of the no-interferon regimen, Miller says, “would have been huge for ZymoGenetics. People were starting to understand that interferons aren’t going anyway anytime soon. This press release (from Vertex) would have cemented that.”
Now that doctors are getting accustomed to seeing hepatitis C cure rates in the neighborhood of 70 to 75 percent of patients who take the combo regimen of the Vertex drug, plus interferon and ribavirin, it’s unlikely they will ever sacrifice even a few percentage points of effectiveness just to get rid of interferon’s side effects, Williams says. That means the bar is high for any oral pill cocktail regimen that aspires to get rid of interferon. It’s certainly possible that the combination of doses, and schedules, could coalesce to make that happen, but it will take years to figure out in clinical trials, Williams says.
Given that was what ZymoGenetics management was betting on with their new interferon, and that its thesis was essentially validated on December 21st, I had to ask Williams if he regrets selling the company for less than a billion dollars. He said no.
“I don’t look back on these sorts of decisions,” Williams says. “You make the decision you have to make at the time with the information you have available to you at the time. I feel we made the right decision at the right time.”
Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.
Luke Timmerman 1/25/11
ZymoGenetics, if it had stayed an independent company in Seattle, would be worth tens of millions of dollars more today than what it was in September when it agreed to be acquired by Bristol-Myers Squibb (NYSE: BMY).
Bristol clearly scored a big break with its new ZymoGenetics assets on December 21, about two months after it closed the books on its $885 million acquisition of the venerable Seattle biotech.
If it had still been an independent biotech, the value of ZymoGenetics would have soared that day when Cambridge, MA-based Vertex Pharmaceuticals announced that, essentially, it had failed to make ZymoGenetics’ lead drug candidate obsolete. On that day, Vertex (NASDAQ: VRTX) said it was unable to eradicate one of backbone components of hepatitis C therapy in a high profile clinical trial.
Vertex is blazing a new trail in the field with a potent new oral pill that generates unprecedented cure rates when given in combination with two standard treatments—pegylated interferon alpha and ribavirin. Vertex was hoping to raise the bar even higher, to find out if its lead molecule, telaprevir, could be combined into a new cocktail regimen that Vertex hoped would kick old-school interferon into the dustbin of history. Doctors and patients have been yearning for a way to get rid of interferon, which causes nasty flu-like symptoms that make patients feel awful for months, which discourages most patients from seeking treatment.
ZymoGenetics, knowing this well, had developed a genetically modified version of interferon, which it called pegylated interferon lambda. This new form of interferon was designed to kill the hepatitis C virus just like the older version of interferon, but without the flu-like side effects. Results from early clinical trials were so promising that ZymoGenetics was able to entice Bristol to sign a $1.1 billion partnership to co-develop the drug in January 2009.
But many on Wall Street weren’t impressed. They had fallen head over heels for Vertex’s new molecule, insisting that ZymoGenetics and Bristol were wasting their time with a new type of interferon. Vertex, they said, was coming along with a cocktail approach of new oral pills that would get rid of interferon, meaning any improvement on old-school interferon would soon be irrelevant. While many doctors, and companies like Vertex still hope it will be possible to do this, the latest clinical trial failure makes it clear that interferon will be part of the standard treatment regimen for years. That means the drug Bristol acquired from ZymoGenetics has a chance to integrate itself into a new standard of care, at a moment when awareness has never been higher among an estimated 6 million U.S. and European patients with this liver-damaging condition.
Former ZymoGenetics CEO Doug Williams, who recently took a new job as head of R&D at Weston, MA-based Biogen Idec, acknowledged in a recent interview that the failure of Vertex’s combination trial would have been a positive event for ZymoGenetics and its pegylated interferon lambda program. He stopped short of saying that Wall Street would have perceived the development in a way that would have boosted ZymoGenetics’ stock price.
“Certainly some people would have come off the fence and perhaps started to believe that interferons will be really hard to get rid of,” Williams says. “I’m certainly of the mind that it will be extremely difficult to get rid of interferon, and achieve [cure rates] currently seen.”
He added: “I gotta believe it would have been viewed as a net positive, but the degree to which it would have been reflected in the stock price, I don’t think anybody can say that.”
David Miller, the president of Biotech Stock Research in Seattle, who criticized ZymoGenetics for selling the company at a bargain price, said he believes investors would have given the company credit. An estimated 6 million patients in the U.S. and Europe have hepatitis C, and many of them are expected to start seeking treatment in 2011, now that a new wave of protease inhibitors like Vertex’s telaprevir and Merck’s boceprevir are being primed to hit the market later this year. The existing interferons from Roche and Merck made up a combined market worth more than $2 billion in 2009, even before the more-effective protease inhibitors came along to spur more interest in hepatitis C therapy.
ZymoGenetics could have seen its stock climb another $2 to $3 a share if it had still been an independent company when the Vertex news hit the wire on December 21, Miller says.
“Smart money was moving toward ZymoGenetics,” Miller says. The latest clinical trial failure of the no-interferon regimen, Miller says, “would have been huge for ZymoGenetics. People were starting to understand that interferons aren’t going anyway anytime soon. This press release (from Vertex) would have cemented that.”
Now that doctors are getting accustomed to seeing hepatitis C cure rates in the neighborhood of 70 to 75 percent of patients who take the combo regimen of the Vertex drug, plus interferon and ribavirin, it’s unlikely they will ever sacrifice even a few percentage points of effectiveness just to get rid of interferon’s side effects, Williams says. That means the bar is high for any oral pill cocktail regimen that aspires to get rid of interferon. It’s certainly possible that the combination of doses, and schedules, could coalesce to make that happen, but it will take years to figure out in clinical trials, Williams says.
Given that was what ZymoGenetics management was betting on with their new interferon, and that its thesis was essentially validated on December 21st, I had to ask Williams if he regrets selling the company for less than a billion dollars. He said no.
“I don’t look back on these sorts of decisions,” Williams says. “You make the decision you have to make at the time with the information you have available to you at the time. I feel we made the right decision at the right time.”
Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.
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