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FT Novartis/Alcon article
http://www.ft.com/cms/s/2/d44d926c-f776-11dd-81f7-000077b07658,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html
Novartis/Nestle may see cycle of negotiations over Alcon option rights in 4Q 2009
By Sasha Damouni, James Avallone and Nadia Damouni
Published: February 10 2009 13:35 | Last updated: February 10 2009 13:35
This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
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Negotiations between Novartis (NYSE:NVS) and Nestle (VTX:NESN) over their option rights – allowing Novartis to acquire the remaining stake Nestle owns in Alcon (NYSE:ACL) – may see another cycle of negotiations in the fourth quarter, two industry attorneys speculated.
Last April, Nestle, the world’s largest foods producer, sold 24.85% of Alcon’s issued and outstanding capital for USD 143.18 each share, Pharmawire reported. Nestle and Novartis have a put and call option rights agreement in place for the remaining 52% of Alcon shares Nestle owns from January 2010 to July 2011. The Basel pharma giant’s call option is at a fixed price of USD 181 per share. During this time, Nestle has the option to sell its remaining Alcon stake at a 20% premium of the average share price during the week before the sale, not exceeding USD 181 per share.
The first attorney said the probability of another cycle of negotiations would be closer to the fourth quarter of this year or beginning of 2010, when the markets may have stabilized. ”Certainly from Novartis’s perspective it makes no financial sense to pay USD 181 a share for a stock that is trading at USD 85 to 90 right now,” the first attorney said. The second attorney, who is familiar with situation, commented that ”a lot can happen” between now and fourth quarter and at the end of the year the USD 181 price tag may again look attractive to Alcon. The company closed at USD 82.89 on 5 February.
Despite some industry banker conjecture that Novartis would counter Pfizer’s (NYSE:PFE) USD 68bn deal with Wyeth (NYSE:WYE) or bid for Netherlands-based Crucell (NASDAQ:CRXL), an industry banker in Europe said he was aware that Novartis was keeping its dry powder open for an Alcon M&A purchase. The banker believed the put and call agreement would not hinder a deal happening before 2010.
In addition, Novartis announced this month that it launched a USD 5bn two-tranche bond offering in the US. The first tranche consists of a USD 2bn five-year bond with a coupon of 4.125%; the second includes a USD 3bn 10-year bond with a coupon of 5.125%. The company stated that the offering ”enhances the financial flexibility of Novartis through this access to new sources of funding.” It said the proceeds would be used for general corporate purposes. The second industry attorney said in order for Novartis to proceed with an acquisition of Alcon, the parties would have to waive the restrictions in the agreement that prevent Novartis from acquiring shares outside of that agreement. A spokesperson for Novartis said the company’s strategy for 2009 has not changed from 2008, with bolt-on acquisitions as its core focus. He would not comment on the company’s powder for acquisitions or upcoming debt maturities.
Last year, Novartis made a number of bolt-on acquisitions, including Protez Pharmaceuticals, Nektar Therapeutics and the remaining stake in Speedel Holding. In a recent SEC filing, Novartis reported that as of 31 December 2008 it had cash, short-term deposits and marketable securities of USD 6.12bn.
Cary Rayment, president and CEO of Alcon, told this news service he had no insight on the deal structure. He was willing to comment on the company’s potential to make acquisitions, which included products or companies that make strategic sense. When asked, Rayment declined to discuss specifics about whether Alcon would look at filling its pipeline with companies or products involved in wet age-Related macular degeneration (AMD), a leading cause of blindness in the elderly, or uveitis (an inflammation of the uvea).
Alcon terminated a 2500-patient Anecortave Acetate Phase III trial for AMD in July 2008. Anecortave Acetate is still in development for open-angle glaucoma, however, according to an Alcon press release.
When considering the medical device market, ophthalmology is ranked high in the eyes of companies with cash. Within medical device M&A, the other two areas of active consolidation have historically been in the cardiovascular and orthopedics spaces, a managing director at a prominent private equity firm said. Ophthalmology was the one area where he forecasted ”tremendous activity.” Other firms have already realized and acted on the importance of this market, with diversified healthcare company Abbott Laboratories (NYSE:ABT) paying a sizeable premium for Advanced Medical Optics (NYSE:EYE) in January of USD 2.8bn.
Most diseases of ophthalmology are age-related and as a result of a demographic shift, there is also an explosive amount of innovation in venture capital portfolios, the managing director added. He stated that considering that Alcon is sitting on USD 2.7bn in cash, the company could be seeking to make its own acquisitions. ”They are most likely going to acquire private companies with interesting technologies and fast-growing revenue,” he said, citing privately-held Lux Biosciences and EyeGate Pharma as potential targets.
Lux, with a Phase III uveitis drug Luveniq, is open to different types of transactions, CEO Dr Ulrich Grau told this news service. He emphasized that the company is not putting up a ”for sale” sign up, but is currently in discussions with various potential parties over ”the technicalities of our assets.”
Grau said Alcon is considered a premiere ophthalmology company with a stronghold in both devices and drugs. Despite this, he believed Alcon would not exclude itself from looking to innovate and said it would be worthwhile for the company to make acquisitions.
EyeGate CEO Stephen From said ophthalmology is one of the last areas in the life sciences where there is a substantial unmet medical need and is a market that could produce further potential blockbusters. He specifically commented on dry-AMD, which comprises most of the AMD market, and spoke about the fact that there is no therapeutic approved for diabetic macular edema.
EyeGate, a company developing a platform of medicine to treat diseases of the eye using its non-invasive, iontophoretic drug-delivery system, would be very attractive to any of those firms in the ophthalmology space, From said. Still, he noted the company is not at the stage yet for a takeout, and is currently in partnership discussions.
Yet the managing director at the private equity firm said Alcon’s cash on its balance sheet could also be an attractive feature to Novartis, and as a result would not stop the Swiss-giant from pulling the trigger on making a play for Alcon sooner rather than later.
Even though Grau admitted he is not privy to the Novartis/Nestle put and call option rights, he said it was his thinking that both firms are working at how they can, in the interim, arrive at a collaboration within the confines of their agreement.
Alcon develops prescription drugs for eye diseases such as glaucoma as well as allergy and non-steroid anti-inflammatory drugs, over-the-counter contact lens solutions, medical devices and products for ophthalmic surgery. Novartis currently has its own contact lens business, and along with Genentech, sells Lucentis for age-related macular degeneration.
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Copyright The Financial Times Limited 2009
i am not so sure. the pancreatitis issue is still unresolved. didn't the FDA ask for additional data back in December?
the obesity space is probably under heightened scrutiny following the failure of the entire CB-1 class of drugs.
Also, Vivus reported disappointing results as well. Orexigen's results were also mediocre.
great article on BIIB/ELN
14-Jan-09 14:22 Biogen Idec identified by deal-makers as likely 2009 takeover target; could acquire Elan - analysis
Story Biogen Idec (NASDAQ:BIIB) and Elan (NYSE:ELN) will likely be acquired in one fell swoop towards the end of 2009, in the opinion of three sources that were involved in Biogen’s auction process more than a year ago.
The sources agreed that Biogen, in the eyes of large pharma and other biotech companies, remains one of the last standing great assets in the market. The shortlist of other biotech targets include Amgen (NASDAQ: AMGN), Genentech (NYSE:DNA), which is currently being targeted by Roche, and Gilead Sciences (NASDAQ:GILD) - the latter would represent a hefty USD 45bn deal for a company that primarily focuses on HIV/AIDS.
Although Celgene (NASDAQ:CELG) is on everyone’s “wish list”, one of the sources said it is growing incredibly fast and has become too expensive. “You pass Biogen and then [targets] drop dramatically to that USD 1bn to USD 2bn size,” this source said. “We are not seeing the wave coming. It’s past us and we may be on the back end of it,” he said.
Despite Biogen’s attractiveness, these sources identified the various challenges that cropped up during the company's initial sale process that started in October 2007 – namely the collaboration agreements between Biogen’s co-marketing partners, Genentech and Elan.
At the time, buyers were disallowed from signing confidentiality agreements with the partners. Elan’s agreement with Biogen was considered the greater concern. The Irish-based pharmaceutical company has a 50% interest in the Tysabri collaboration with Biogen. Under the terms of the Biogen/Elan collaboration agreement, if a third party acquires control of Biogen, Elan has several options: the right to acquire for fair value the 50% economic interest in Tysabri currently held by Biogen; under certain circumstances, the ability to sell its 50% economic interest in Tysabri; or, to continue with the existing agreement. Elan also may consider restructuring the agreement in connection with a third party's acquisition of Biogen.
Now bidders are jostling the idea of taking a shot at both Elan and Biogen and cutting out this change of control barrier. The first source pointed out that Elan has a meager USD 3bn market cap, while Biogen’s market cap continues to skirt around USD 12bn to USD 14bn, some USD 10bn less than a projected deal transaction during its process. Biogen and Elan’s shares also dropped precipitously last year after the announcement of the potentially fatal brain infection, progressive multifocal leukoencephalopathy, or PML, occurred in four patients associated with the multiple sclerosis (MS) drug Tysabri.
Still, the sources hardly dismiss Tysabri, describing it as a preeminent drug for MS. “I don't see a scenario where one gets done and not the other. I think over time, if one goes, both will get done,” said the first source.
Both this source and a second source said a Biogen/Elan acquisition will, in their view, be a 2009 event. The second source said the pressure on Biogen is increasing and expects a deal to occur later in the year as both Biogen and Elan assess their own respective strategies.
The first source noted that the credit markets are starting to thaw and the assumption is a party will acquire Biogen rather than it being a merger of equals. Potential bidders that this news service had identified during the initial auction included Novartis, Pfizer, Bristol-Myers Squibb, Merck, Johnson & Johnson and Eli Lilly.
During an investor presentation at the JPMorgan Healthcare Conference Wednesday, Biogen’s President and CEO, Jim Mullen, confirmed that all standstill agreements that were signed by prospective suitors were effectively removed.
A third source familiar with the situation said obviously Biogen's biologics capabilities are still very interesting to many players. However, he said in order to achieve a premium valuation, a bidder would need to put significant value on Tysabri. “People would want to wait and see how the whole PML situation plays out… and see how the drug penetration continues in any further PML cases over the few months at least,” said this source.
Also during this time period, Biogen will be receiving more data on its pipeline, which would enable suitors to see if there is anything of value there and start allocating a price. However, he still considered Tysabri as the most significant driver for the company. Simultaneously, a suitor vying an interest in both Biogen and Elan would also have to be prepared for the additional risk associated with Elan’s Alzheimer drug, bapineuzumab.
Wyeth and Elan’s bapineuzumab, a monoclonal antibody targeting beta-amyloid plaques associated with Alzheimer’s disease, produced disappointing Phase II clinical data in July 2008, causing Elan shares to lose almost a third of their value and Wyeth shares to drop to a four-year low. Bapineuzumab, one of the more closely watched drugs in 2008, failed to achieve statistical significance in the trial and also showed an increased risk of serious side effects.
But what appears to be a more prevalent theme is the likelihood of Biogen acquiring Elan ahead of a possible three-way deal, said a person familiar with the situation. “Biogen would really like to buy Elan,” said the person.
Elan announced Wednesday that it had retained Citigroup to conduct a review of strategic alternatives. The range of alternatives that will be assessed could include a minority investment or strategic alliance, a merger or sale, according to a company release.
When asked by an investor during a breakout session at the JPMorgan conference whether Biogen would be interested in acquiring the co-rights on Tysabri, Mullen said Biogen remains “very bullish” on the MS drug and believes it continues to be a big product. However, he pointed out that Biogen has to take a step back and see how the current process unfolds at Elan. “We are catching up with the news as much as you are," he told investors.
Even more interesting among the investment community is the lack of initiatives that has been disclosed to place the roughly USD 2bn cash and marketable securities that Biogen holds. A spokesperson for Biogen said the company continues to look at all options to utilize its cash position but that the “economic situation continues to weigh in that mix”.
During its 3Q filings, Elan reported it had USD 444m in cash and USD 1.76bn in long term debt. Its current debt has no maintenance or leverage covenants and refinancing does not commence until 2011. However, total debt does exceed total assets, which accounted for USD 1.67bn over the same quarter.
Shane Cooke, Elan’s CFO told this news service that following the company’s strategic review announcement, investors have not pushed the company for one particular strategy, namely a sale. Rather they are asking for the timing rationale behind the announcement. “No-one has a preconceived outcome,” Cooke said.
Elan’s CEO Kelly Martin told investors Wednesday that the timing of the announcement coincides with a series of factors that were discussed internally over the last year-and-a-half to two years between the board and senior management. The big driver was bapineuzumab along with the “enormity of task on the commercial side.”
Posed with the question surrounding Biogen’s significant cash position, Shane responded: “There are lots of options, and we will see what we will do.” He would not comment to this news service on a three-way tie up between Biogen/Elan and a prospective suitor.
As for the change of control provisions under the Elan and Biogen collaboration agreement, Cooke said the latter agreement has some “teeth to it” due to the various stipulations the partners have over Tysabri. He said Wyeth’s agreement on bapineuzumab was not so much of an issue as it contains standard change of control provisions.
Cooke said the review will also evaluate partnerships as one option. However, he noted that the company did not decide to enter the process to assess the pipeline “piece by piece.”
Although Elan and Biogen may have different balance sheets today, initial bid-ask discrepancies asked from Biogen management in 2007 appears to have finally decreased, commented the second source. He said arguably bidders know Tysabri even better, and although considered an immensely important drug, there “is no longer this gigantic upside that people thought was so far removed”.
by Sasha Damouni and Nadia Damouni
Source Pharmawire
Pharmawire - regulatory article:
14-Jan-09 16:54 Funding for comparative effectiveness studies likely to come during health reform debate, sources say
Story * First funds more likely to come through stimulus package, rather than part of SCHIP
* Funds of USD 1.3bn could fund studies that would guide reimbursement decisions
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Legislators will likely free up funding for comparative effectiveness studies as part of any healthcare reform package this year, but the short-term impact on drug makers will likely be minimal, healthcare policy experts said.
However, they noted that the long-term impact will likely create "winners and losers" in drug development. These studies are used to assess the cost effectiveness of different treatment options - looking at, for instance, whether a generic drug would work just as well as a newer agent for a particular disease.
Support for these studies has been building over the past year in order to control rising healthcare costs and reign in Medicare spending. Bruce Fried, a partner at law firm Sonnenschein, Nath & Rosenthal, noted that the Congressional Budget Office recently included funding for comparative effectiveness research in its list of budget options.
He noted that one proposal being discussed on the Hill would allocate USD 100m for these studies starting in 2010 - going up to USD 400m in 2014. All together, the proposal would allocate USD 1.3bn by 2019, he said.
"The savings would be realized by not paying for treatments that are less effective," said Fried, who previously served as director of the Center for Health Plans and Providers at the agency now known as the Centers for Medicare and Medicaid Services. "Those treatments that are found to be less effective than others are going to receive less payment."
Congressional Democrats will probably use the upcoming economic stimulus bill to get the ball rolling, according to Dan Mendelson, president of Avalere Health and former associate director for health at the Office of Management and Budget. Mendelson said he expects funding of more than USD 10m to be included in the stimulus package and allocated for further research into comparative effectiveness.
While specific drugs and devices haven't been singled out, regulators will likely look first at the therapeutic areas with the highest spending, Fried noted. "They're going to go after the low-hanging fruit," he said.
Private insurers will also use this work to guide reimbursement decisions, he said, adding, "There are going to be winners and losers."
Former FDA chief counsel Daniel Troy, who is now general counsel at GlaxoSmithKline, also predicted last year that a democratic administration would usher in a comparative effectiveness mandate. "The pressure there is extreme," he said at a conference on cancer drug development.
"The trend is essentially moving in conjunction with personalized medicine," said Robert B. Nicholas, a partner at law firm McDermott Will & Emery and former chief counsel to Vice President Al Gore.
Nicolas noted that Congress is likely to provide funding and other incentives to managed care companies and drug makers to perform the studies themselves - rather than charge a particular government office with that task. Comparative effectiveness studies are costly to conduct and take time to yield data, he added.
A rumor has circulated Washington in recent days that the reauthorization of the State Children's Health Insurance Program (SCHIP) may have some comparative effectiveness language in it, according to Jeff Chertack, vice president for health policy at Ogilvy Public Relations Worldwide.
While the House version - which was released yesterday - does not appear to have this language, the Senate version is still an open question, Fried noted.
Yet Fried was also skeptical that comparative effectiveness would be tacked onto SCHIP. "They've been fairly constrained in adding on extraneous issues," he said. "They want to pass SCHIP quickly [and] comparative effectiveness is not without controversy."
Nicolas agreed. "To the extent that [SCHIP] could become controversial, that would make it harder [to pass]," he said.
More likely, Mendelson said, will be a piecemeal strategy that pushes the issue forward for the next two years. While the creation of a new federal agency to monitor the issue is possible, Mendelson said he thought it was more likely that legislation would dramatically increase funding for the Agency for Healthcare Research and Quality (AHRQ) and house comparative effectiveness under that agency's roof.
"The implication for the companies is that this will change the way drugs are evaluated post-market," Mendelson said.
by Beth Herskovits and Marc Longpre
Source Pharmawire
articles for the new year!
by Kimberly Ha and Elizabeth Krutoholow
Source Pharmawire
09:11 Eli Lilly and Amgen: KRAS testing in colorectal cancer sees swift clinical adoption ahead of likely FDA re-labeling of Erbitux and Vectibix
Story * FDA label revisions for Lilly's Erbitux and Amgen's Vectibix likely
* ODAC panel member said she believes current retrospective data is adequate to support a label change
* Change in practice guidelines for KRAS testing already at the community physician level, not just academic centers
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Eli Lilly and Amgen's cancer drugs will see rapid adoption of routine KRAS gene testing for patients with advanced colorectal cancer, ahead of a likely FDA decision to relabel the drugs for use in only a subset of patients, according to physicians and industry executives.
Approximately one-third of patients with advanced colorectal cancer have mutated KRAS status.
There has been a wealth of research which suggests that patients with advanced colorectal cancer who have a mutation of the KRAS gene do not confer any benefit with treatments that inhibit the epidermal growth factor receptors (EGFR), said Nancy Roach, founder of the Colorectal Cancer Coalition.
These drugs include Lilly's Erbitux and Amgen's Vectibix - both which target the EGFR receptor - and have significant toxicities. Erbitux causes a severe, acne-like skin rash in certain patients, which ironically, acts as a predictive biomarker that the patient is responsive to the drug.
Numerous physicians from a number of different hospital networks throughout the US told this news service that KRAS testing is not only being conducted at academic centers, but that community physicians are also adopting the new practice guidelines ahead of the FDA's formal rulemaking decision.
"We’re not waiting for the FDA when there is fairly strong evidence to support testing patients for KRAS mutations," said Dr Wells Messersmith, director of gastrointestinal medical oncology at University of Colorado in Denver.
He added that academic centers in particular are using KRAS mutation testing as a prerequisite before using these drugs.
“We’re already doing KRAS testing for our patients at the University of Kansas Cancer Center,” said Dr Stephen Williamson, director of the oncology division there.
Right now, reimbursement is not a problem, he added. "Diagnostics are cheap and these drugs are expensive," said Dr Justin Stebbing, an oncologist at Imperial College London.
The National Comprehensive Cancer Network updated its colorectal cancer guidelines last year to include KRAS testing. More recently, the American Society of Clinical Oncology (ASCO) also recommended that patients test their tumors for KRAS gene status before treatment with Erbitux or Vectibix.
Dr Jean Grem, a voting panel member at the recent FDA ODAC meeting that discussed the KRAS issue, said she believes there is enough data in front of the agency to support relabeling these drugs with KRAS testing. "I have a feeling [that the FDA] probably will relabel. We don’t know for certain, but it seems this is widely adapted," said Grem.
"The FDA label is - I don’t want to say irrelevant - but the change in practice has already happened for most academic centers, and is growing steadily in private practice," said Messersmith.
Dr Stephen Little, the CEO of DxS, a personalized medicine company that has a KRAS test available, noted that a label change seems inevitable, because the FDA will likely accept the current retrospective studies - if they’re conducted properly - without requiring further prospective data. "But I don’t know if we will get formal guidance [on that issue]," he added.
Grem agreed that the FDA will likely discuss the importance of prospective data, and more of those studies will probably be conducted. But she added that the consensus at the ODAC panel was that the current retrospective data was adequate to support a label change. Grem already started conducting KRAS testing on her patients as soon as the data came out at last spring. "I think at the FDA, they were using the meeting as a forum to discuss the issue of how good the data has to be."
Physicians in private practice are also conducting KRAS testing, said Grem, who also noted that since the KRAS data garnered a lot of publicity at last year's ASCO meeting - testing is already being widely conducted not just at academic centers, but on a broader community level.
However, physicians stressed that just because a patient has normal KRAS status, and no gene mutation, it is not a guarantee that they will see a benefit. “Just because you have the normal KRAS status doesn’t mean you will benefit from these agents either. But it’s a definite way of screening out patients who will not benefit from treatment,” said Williamson.
"You’d be sparing a patient toxicities when they have no chance of benefit," said Grem.
Hi Dew, thanks for all those posts on Orexigen. I never liked Contrave. I think following all the failed CB-1 class of drugs, the FDA is just not ready to approve an obesity drug yet.
Maybe they're scared they'll send the wrong message to the public.
Also, I think Arena, Vivus, are probably also in the same boat.
I don't think Orexigen's Contrave will see FDA approval. Didn't their CEO leave for personal reasons as well? Nobody has partnered with them yet either - Arena has been screaming partnership since forever - and nobody is partnering.
I think also the insomnia class of drugs, like Neurocrine's indiplon - nobody has partnered with them either. I think you might have already mentioned it earlier on this board - but who cares if they get it approved - who will they be competing against? Lunesta? They're going to need to partner to sell this to primary care physicians.
Allos therapeutics - does anyone know why this stock fell so much today? did a fund just crash and burn. i thought they announced orphan drug status for one of their drugs today.
is their drug legit? they seem to be going after a really small market with the lead indication in some niche leukemia or lymphoma indication.
any help appreciated. thanks.
i agree. Somaxon also has an unpartnered sleep drug. merck scrapped their drug a couple of years ago, the one partnered with lundbeck. neurogen ran into problems with their insomnia drug adipilion.
insomnia drugs aren't getting partnered these days. too high of a risk at the FDA.
also, cardiovascular drugs are also taking a beating lately. i wonder when the agency will announce anything on prasugrel.
still waiting...
i don't know his track record, so can't say. It seems more like Biocentury or the pinksheet though. he doesn't really get into the fundamentals, or the science. or trial design, etc.
i think they do. or sometimes ppl (like me) repost on boards. or you can find some on yahoo msg boards. i think their free trial is like 2 wks or something. hope that helps.
i use Pharmawire. their track record on likelihood of drug approvals, PDUFA dates and partnership/M&A insider info is great.
www.pharmawire.com
happy thanksgiving! hope everyone had a fantastic holiday!
You're right. idenix have been quite vocal about their partnership discussions on 899 for quite some time now. i was surprised they haven't signed anything yet - if the compound is in fact as great as they say.
but then again, given the lack of attractive compounds in the industry that are unpartnered, i'm sure they'll still get a good deal - even in these markets.
is the IDX899 partnership already priced into the stock. do you think it will move much? they're trading at 5.79/share right now.
maybe they'll do a quick pop and drop on the same day.
there's another company dev an HIV NNRTI - named Ardea Biosciences. have you looked at their compound - they've released more coformulation data than IDX. but i suspect their NNRTI is less potent.
From your rationale - the partner for 899 has to be GILD. that's the logical suitor, at least. but you're right - we just have to sit tight and wait around for another 6 wks! :)
i wonder if all this talk and push for biomarkers is actually doing more harm in terms of drug development costs. it must be so much costlier to conduct biomarker trials. that will prob slow down R&D in the short term ??
also, tarceva phase III SATURN trial results testing as maintainence therapy in NSCLC is coming out soon in Q408. might run into some issues with pt selection, like EGFR mutations. that should be interesting. but it should only work in a small population regardless. i wonder if there is really much value in tarceva as maintenencen therapy in NSCLC.
what do you think about Amgen buying someone like genzyme? is that crazy?
also, couldn't gilead buy vertex or another HCV company. they're not in HCV, but they're huge in HIV . so doesn't that make sense to do a deal like that?
i still think all these mid-cap HCV companies, Intermune, Pharmasset, Anadys, Idenix will all get acquired by Roche, schering, or another large pharma in the next 12-18 mths.
03-Nov-08 13:00 Idenix in advanced partnership discussions on IDX-899 with more than one party, CFO says
Story Idenix is "far down the path," and in advanced partnership discussions with more than one party on IDX-899, said CFO Ronald Renaud. A deal should be in place by year-end, he added.
Idenix began informal discussions with all major HIV players about a year ago but, once the company amassed proof of concept data, the discussions became more serious, Renaud noted. "We don't have a specific deal in mind. There is no good benchmark for HIV partnering," he said.
IDX899 is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that is currently undergoing Phase I/II clinical trials.
Gilead is the "lead suspect," according to an analyst who cited the fact that Sustiva, an NNRTI that is part of the company's triple combination regimen, will go off patent in 2013. Merck, Bristol-Myers Squibb and perhaps GlaxoSmithKline could also be potential partners for IDX-899, the analyst noted.
While Novartis owns 56% of the company, the company has already publicly stated that it is not involved in the HIV space, which is why the company is shopping IDX-899 around, according to the analyst.
Although there has been criticism on the company's lack of co-formulation studies with IDX-899, the rationale was that Idenix did not want to spend USD 5m-10m conducting formulations trials when it is unknown who would ultimately partner the compound, rendering some studies useless, Renaud said.
Renaud noted that the company's expectation is early demonstration of safety and efficacy. The compound has a high barrier to resistance, and its 100 mg pill is potent enough for once-daily dosing. The company's strategy is to forge a deal early on to make sure the compound is partnered with a critical mass of drugs, he added.
The data thus far is promising for combination, Idenix CEO Dr Jean-Pierre Sommadossi said at a recent investor conference.
"Essentially, there would probably be about 18 months of more studies before Phase III trials," Renaud said. "We will continue with the formulation that we have until Phase III."
When asked whether the company would entertain new bidders, Renaud noted that the release of proof of concept data in September indeed caused new bidders to contact the company. "It's never too late, if it's a good offer," he added.
However, since the company is in advanced discussions, if a bidder came in today, it would have to quickly get up to speed. "We have to close before year end. That's our major goal for the year," he said.
A physician speculated that the recent decline in share price is likely due to the fact that the company's hepatitis C virus (HCV) pipeline is still pre-clinical and investors are waiting for validation in a difficult area.
The company is also developing three different classes of direct antivirals to combat HCV - a protease inhibitor, a non-nucleoside inhibitor and a nucleoside inhibitor, which the company hopes can be combined to form a new treatment paradigm.
IDX-184, the company's lead HCV nucleoside polymerase inhibitor, has already completed Phase I studies and will go into proof of concept studies in the coming weeks. The candidate is active against all genotypes, Sommadossi said. Because of costs and timing, the company will only take one protease inhibitor into the clinic. Idenix has completed seven-day toxicology studies with its two protease inhibitors.
"It is clear that we will make a decision in the next two months on which candidate will forward into IND," said Renaud.
by Kimberly Ha and Sasha Damouni in San Francisco and Elizabeth Krutoholow in New York
Source Pharmawire
i agree. the timing of everything was too close for comfort. it's really far out now.
have they got their Byetta monotherapy decision yet? it should be in 4Q08 right? i wonder if they'll get that addition - if not, then i think it's just more bad news for LLY.
also, AMAG's decision is coming up - what are their chances here?
i personally don't think they're going to get approved anytime soon, like like SVNT and puricase. i think the fDA is too risk averse right now. but at least they didn't ask amag to run an additional trial.
thoughts appreciated.
17:54 Decision on AMAG's ferumoxytol could come as soon as next month after manufacturing, clinical questions are addressed - executives
Story * Data shows safety advantage even over oral iron
* Drug could interfere with emergency MRIs, one physician suggested
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AMAG Pharmaceuticals is anticipating approval as soon as next month for its high dose, rapid infusion iron replacement product ferumoxytol, according to insiders at the company.
The drug, which is being studied for anemia associated with chronic kidney disease, received a complete response letter from the FDA on 20 October. A spokesperson noted that the agency's concerns relate to manufacturing processes as well as clinical questions.
Yet the company does not need to conduct additional trials and expects the agency to issue a decision within two to six months of its complete response, according to an executive.
The company is prepared to launch the product in 1Q09 and has already hired 80 drug representatives, the spokesperson said, adding that AMAG is not looking for a partner in the US and believes it can target the 4,700 dialysis centers here with its own sales team.
At the meeting of the American Society of Nephrology, investigators reiterated that the product is safe and has convenience benefits.
Dr Brigitte Schiller, a nephrologist and clinical medical director at Satellite Healthcare, noted that dialysis patients typically require two grams of iron - which could mean at least 10 infusions with Watson's InFed or Ferrlecit or American Regent's Venofer or Dexferrum. The maximum dose with each of these products is about 200mg, she said, and each infusion can take up to 15 minutes.
Ferumoxytol, in contrast, delivers 510mg of iron in about a minute. Patients receive two infusions during a one-week period.
Schiller noted that there were no safety signals in the any of the trials, which compared ferumoxytol to oral iron. "Oral iron is a very safe drug," she said. And even still, "when we compare it to the oral iron, the oral iron is actually looking worse."
Adverse events such as diarrhea, nausea, edema, vomiting and constipation were more common in the oral iron group, according to a poster presentation for which Schiller was an investigator. Hypotension was the only adverse event that occurred more frequently in the ferumoxytol group (2.1% compared to 0.3%).
Dr Louis Brenner, senior vice president at AMAG, noted that comparing the drug to oral iron sets a higher safety bar than comparing it to IV iron, which is known to cause anaphylactic reactions. "The threshold for a new product is safety," he said. While he acknowledged that using IV iron would have set a higher bar for efficacy, "the efficacy story with oral iron is fairly well told and it’s more about safety," he said, adding that oral iron is the standard of care outside the dialysis population.
Ferumoxytol is also being studied for additional indications, including other causes of anemia as well as a magnetic resonance imaging agent. One nephrologist in private practice questioned whether using ferumoxytol for iron replacement would interfere with a patient's ability to undergo MRI - and said that he would hesitate to limit diagnostic options for patients.
In an interview, Brenner conceded that its magnetic properties could be a concern for emergency MRIs, but noted that most MRIs are planned. He added that ferumoxytol only has a 15-hour half-life and then "most of it is gone."
Schiller agreed. "I don't think it’s magnetic enough to influence MRIs."
This news service previously reported that IV iron has seen increased use as safety questions have dogged erythropoiesis-stimulating agents (ESAs), the standard of care for anemia in both nephrology and oncology. Many physicians believe that adding iron to ESAs can help lower ESA doses and increase ESA responsiveness.
ESAs include Amgen's Aranesp and Epogen and Johnson & Johnson's Procrit.
AMAG has a market cap of USD 440m.
by Beth Herskovits in Philadelphia
Source Pharmawire
SGP - boceprevir
what do you guys think about boceprevir coming out from AASLD? some physicians think the additional anemia with boc isn't an issue. but this is cut and paste from a rodman analyst report:
he thinks boc is headed for 'no man's land'
Close Competitor Boceprevir Likely Headed for No Man’s Land Recall that Schering-Plough Corp. (SGP, Not
Rated) is developing its own investigational oral HCV protease inhibitor, boceprevir, which is the TVR competitor
closes in development. In data presented at EASL in April, SVR12 were surprisingly high, 57% and 55%, for the
two arms with or without a 4-week lead-in of standard therapy, respectively. Although less impressive than the
61% SVR12 demonstrated by telaprevir in PROVE 1, the data showed that boceprevir could be competitive.
Prompted by these surprising positive results, Schering-Plough (SP) began recruiting patients for two Phase III
clinical trials with boceprevir. One study, HCV SPRINT-2, will evaluate boceprevir in previously untreated (naïve)
patients, and the other, HCV RESPOND-2, in patients who failed prior treatment (relapsers and nonresponders),
however, both include a 4-week lead-in with standard therapy. In line with recent insights we gained at AASLD on
likely short duration treatment regimens that will be explored, we believe boceprevir headed down the wrong path.
Were boceprevir to be approved, the 4-week lead-in period of standard therapy, which SP believes is important for
to achieve steady state levels of P+R to reduce the selection and expansion of resistant strains after the addition of
a protease inhibitor, poses a significant problem. With the potential evaluation of RVR at week 4, we believe
hepatologists may choose instead to re-initiate therapy for RVR negative CHC patients with a TVR-based therapy
instead of risking an evaluation 12 weeks into therapy that could also show positive HCV RNA, as treatment with
boceprevir could preclude patients from subsequently being treated with TVR. Further, the viral kinetics of
boceprevir therapy at week 4 (week 8 overall) are largely unknown. Experts we consulted are in agreement that
evaluating virological response at week 8 does not provide useful decision-making information. As a result, we
believe boceprevir is headed for the “no man’s” land of future HCV treatment regimens. The likely evolution of HCV
treatment toward shorter duration therapy at best could relegate boceprevir to TVR-failures, or at worst, prompt SP
to scrap its Phase III plans and evaluate more optimal doses of boceprevir further solidifying TVR’s first-mover
entry into the market.
pharmawire article on MDVN - by kimberly ha.
22:00 Medivation: some experts skeptical of Dimebon's chances of attaining FDA approval
Story Medivation's Dimebon is still under scrutiny, and the drug's chances of attaining FDA approval are questionable, according to a number of industry specialists interviewed by Pharmawire.
An FDA consultant, who has been following Dimebon's development for years, said Medivation has made the claim on mitochondrial pore inhibition. "I’ve been following that drug for years," he said. "But I’m still skeptical on the Russian trial. The data is too good to be true."
From his review of the Russian literature on the drug's mechanism of action, the papers claim that Dimebon has five different mechanisms of action, including memantine-like effects. It works on the NMDA receptor, and also has mitochondrial pore protective properties, the consultant said.
The consultant added that although the company has stated the drug's mechanism of action is due to mitochondrial pore inhibition, he has not seen anything yet in terms of reported literature.
He also said that he was 'amazed' of news that Pfizer had partnered with Medivation on Dimebon in September, and was 'doubtful that the drug works.' The company is also conducting trials in South America, in addition to the US, he added.
"I hope when the [final] results come out, they will reveal the mechanism of action. My worry is they will throw all the data together," he added.
He was also skeptical of the data from treatment-naïve patients in the Russian Phase II study.
The consultant said he also predicted the previous failures, Neurochem’s Alzhemed and Myriad’s Flurizan. On Myriad, he said the company ran an open-label trial, and did not conduct an adequate Phase II trial. “I was skeptical on Flurizan because their Phase II trial was a subgroup analysis,” he added.
Medivation is currently enrolling patients for a six-month confirmatory Phase III study to determine the safety and efficacy of Dimebon in the treatment of mild-to-moderate Alzheimer's disease. It is a six-month study enrolling 525 patients in the United States, Europe, and South America. The study started in May 2008, with an estimated enrolment of 525 patients. The trial has an estimated primary completion data of July 2010, according to clinicaltrials.gov.
One physician affiliated with Pfizer, who has seen Dimebon’s data said, “there are all these sorts of problems with the Russian study,” and difficulty knowing whether the trial endpoint was really done to standard protocol. He agreed that the patients on in the Russian Phase II trial were of younger age, and were treatment naïve.
The same physician said almost every patient in the US who has Alzheimer’s will be on a cholinesterase inhibitor. He said "it just seems like a losing proposition" to try to test this drug on treatment-naïve patients, or patients who are not on medication, as anyone in the US who has Alzheimer’s who is not taking a cholinesterase inhibitor is probably someone who tried it and they dropped it because they had side–effects, or have become so demented that there is no effect anymore.
Exclusion criteria for the Phase III US trial include: anti-dementia drugs including cholinesterase-inhibitors or NMDA receptor antagonists within 90 days, according to clinicaltrials.gov.
“You’d have to wonder, you’ll have an odd population. To pick out people with a diagnosis of AD in the US and say I’m going to run a drug trial in people who don’t take cholinesterase inhibitors, it’s unethical,” the physician said.
He went on to say that the only population the drug company would get would be people who do not want to take cholinesterase inhibitors and that will be non-representative of the overall population. “I don’t know why any company would want to do that in the US.” He said. “Maybe for people who can’t tolerate, or have GI side effects from cholinesterase inhibitors.”
The physician also added that he has seen the data, and "there are some funny things about the data." He explained that some of the trajectories on the cognitive endpoints look positive, but on some other time trajectories on other endpoints, there does not appear "too much on anything." He questioned why, if Dimebon worked, there would be an effect on one cognitive instrument and not on another endpoint.
A researcher who used to work for the Department of Mental Health, said "thank God" Dimebon does not hit the histamine receptors. He added that Pfizer's leading anticholinesterase candidate, Aricept, increases blood pressure, and increases circulation to the brain, and anti-histamines should do the opposite.
When asked whether Dimebon and Pfizer’s Aricept could be combined in one pill, the researcher said that could create a psychedelic. He hypothesized that Dimebon’s proposed mechanism of action may be due to a blocking of the pathways and the cause of dendritic branching may be due to an asphyxiation effect, or a reduction of oxygen flow to the brain. It appears that Dimebon causes dendritic branching, but the neurogenesisis is just on the dendritic level and not the axonal or cell body type level, he added.
“So the branching is just dendrites,” the researcher said. “And you have dendrites branching out, obviously you will get psychoactive activation.”
Dr William Potter, who serves on the FDA's Psychopharmacologic Drugs Advisory Committee, and vice president for translational neuroscience at Merck, said from a scientific view, the industry should find a drug that could potentially block amyloid formation.
“The ideal thing to test from a scientific target is BACE,” said Potter. “But it’s been very difficult for the industry or anyone to generate the ideal compound. Just a very hard target.”
The company did not comment to this story as of press time.
However, CEO David Hung told investors at a conference in New York in September that the company is seeking approval for Dimebon as a symptomatic treatment of Alzheimer’s, and not a disease modifying therapy. Medivation will not be conducting autopsies on the Russian Phase II trial patients, Hung also added at the same conference.
The company has stated publically that "Dimebon is an orally-available, small molecule that has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer’s disease and Huntington’s disease…based on clinical and preclinical data generated to date, Medivation believes that Dimebon works through a novel mechanism of action improving mitochondria function."
Medivation has a current market cap of USD 561m.
by Kimberly Ha in New York
Source Pharmawire
pharmawire article from yesterday: on the FDA advisory panel today, imaging agents in AD.
by Kimberly Ha and Elizabeth Krutoholow
22-Oct-08 16:39 FDA advisory panel with Bayer, GE Healthcare tomorrow to discuss imaging biomarkers in Alzheimer's will affect disease modification drug trials
Story * FDA to discuss controls, clinical utility, phase III trial design for amyloid imaging markers in Alzheimer’s * Markers would fill unmet medical need in identifying patients with amyloid plaque build-up * Potential to be used in clinical trials for patient selection and in early intervention * Binding properties need to be validated in phase III trials
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Bayer, GE Healthcare and Avid Radiopharmaceuticals will meet with the FDA advisory panel tomorrow to discuss the development of new imaging markers for use in Alzheimer’s disease (AD). The Advisory Committee Meeting is aimed at providing specific recommendations based on clinical utility towards the design of Phase III diagnostic imaging studies in AD.
There are some key concerns before approval of these imaging agents, several key opinion leaders said, including the validation of the binding properties of these new imaging agents to beta-amyloid, a key structural hallmark of this neurological disorder.
There is no single test that accurately diagnoses AD, and physicians have to rely on a variety of assessments, ranging from cognitive to laboratory tests to make a ‘probable’ diagnosis. A definitive diagnosis can only be made upon autopsy, upon examination of brain tissue for the presence of amyloid plaques and neurofibrillary tangles.
The neocortical amyloid-beta plaque deposits, or ‘amyloid plaques,’ occur early in the disease, years before the onset of clinical symptoms. The availability of a non-invasive, imaging biomarker capable of detecting amyloid-beta in the brain to facilitate early and accurate in vivo disease detection of AD is a major unmet medical need.
The current imaging agent used is a PET tracer called Pittsburgh Compound-B (PIB), the first compound to non-invasively monitor the brains of people with Alzheimer's. However, the agent has a relatively short half-life of 20 minutes, which hinders its potential use as a routine clinical diagnostic agent. It has not been validated in a prospective study comparing imaging results to histopathological measurements of amyloid plaque in the brain.
New agents in development, with an approximate half-life of two-hours, all hope to be indicated for PET imaging of amyloid plaque pathology in the brain to aid in the evaluation of patients with signs or symptoms of cognitive impairment. They could also be used to monitor patient response to disease modifying drugs in development. Dr G. William Rebeck, associate professor of neurology at Georgetown University Medical Center, who will be presenting at tomorrow’s FDA panel, said the problem is PET tests are expensive, and not every clinic has access to a PET scanner. The current accuracy of diagnosing AD is between 90-95%, if it is a referral. “Do you need an expensive routine test to get that last few percent? Probably not.”
But for the cases where there is something unusual, and an individual presents atypical symptoms, they may want to get a PET scan, added Rebeck. Companies will also have to conduct more validation studies, and time seems to be their only limitation, as they have to wait for patient autopsies, he added.
“The thing that I worry about is a number of clinical trials are coming up negative. If there is not something encouraging, people will lose interest in conducting these expensive trials,” said Rebeck.
Dr William Hall, director of the Center for Healthy Aging at the University of Rochester School of Medicine, said a lot of theories have come and gone. The fundamental unanswered question of whether amyloid is in fact the culprit remains unknown. “We might be barking up the wrong trees right now,” he said.
“A biomarker is not the same as the cause of the disease. It might be along for the ride, which complicates current research,” Hall said.
These new imaging agents will be a ‘huge boom’ for clinical trials, Rebeck said. From a research standpoint, it will be a very interesting reagent to use because researchers will be able to see how much amyloid accumulates before the symptoms, and dementia sets in.
Bayer is developing a new F-18 labelled PET tracer called BAY 94-9172, and GE Healthcare is developing GE-067. Avid Radiopharmaceutical’s AV-45 also shows high affinity specific binding to amyloid pathology.
"We expect a lot of failed biomarkers," said Dr Daniel Skovronsky, CEO of Avid Radiopharmaceuticals. It's a turning point for the field as a whole, and there is a push from the industry and the FDA, he said.
Skovronsky said radiopharmaceutical agents are quite safe when using tracer doses, and a few micrograms are given per imaging session. These agents are unlikely to be toxic, and the FDA recognizes the safety of these compounds. Although it is easier to conduct trials for imaging agents, compared to therapeutics - one challenge that remains is the establishment of a clear reference standard.
When asked about the possibility of developing a control or standard of truth so that autopsy is not required, Skovronsky explained that this is one of the challenges of being a leader in the space, but Avid is ready to surmount this hurdle, he said.
Dr Gregory Jicha, assistant professor of neurology, University of Kentucky, Sanders-Brown Center on Aging, said there is such a huge push to try to get the FDA to accept a biomarker as a surrogate marker for the disease state. “It’s not just to make money, but is intrinsically linked to all of the clinical trials [regarding disease modifying drugs],” he added.
If we can get the FDA to accept this as a diagnostic for the disease state - all we have to do is come up with drugs to influence the biomarker for drug approval. 40% of normal people have significant amyloid deposition in their brain. It isn’t just prion disease, but patients with dementia with Lewy bodies also have a similar abundance of amyloid and as extensive in AD.
Dementia with Lewy bodies is a type of dementia characterized by abnormal levels of Lewy bodies, a nervous system protein.
It will be very difficult to get physicians to accept biological data as an indicator of an underlying disease process, said Jicha. He gave the example of a recent patient who was 50-years old, reported memory complaints and tested positive on both the PET scan and CSF test, but did not meet the clinical diagnosis of AD. Upon further diagnosis, her physician, who was the director of a major Alzheimer’s Center, told her she had anxiety, said Jicha.
A cyclotron, a type of particle accelerator, is used to create radioactive elements which are essential if clinics want to use PIB as an imaging agent. The University of Kentucky could not use PIB in studies, as it did not have this machine, but is now gearing up to potentially use Abbott’s imaging compound in future clinical trials.
Imaging biomarkers and a CSF assay may be used together for better specificity. “But it will be pretty costly to do all these studies on everyone who walks through the door,” said Jicha, who rarely does a PET or CSF test. A referral consultation has a diagnostic accuracy of 90% or better in many cases.
Skovronsky suggested that using a sequence of several biomarkers would be ideal in the screening process. If a cheap, easy, and sensitive diagnostic could be developed, even if it were nonspecific, it could be used as a screening test to identify appropriate patients for imaging, which would be more specific, he said.
A major issue is APOE allele testing in people. The American Academy of Neurology advises against this genetic test, said Jicha, as there is no current treatment, but it can increase the diagnostic certainty. “The argument is telling patients if we have a way to change the outcome. Otherwise you’re just giving patients bad news,” said Jicha.
Yet physicians said that these new imaging agents will hopefully be used to help screen patients who may be at risk for Alzheimer’s, and show mild cognitive impairment, but have not progressed to AD. Patients who report positive CSF, PET, and APOE status tests, but report no cognitive functional decline may be good candidates for PET scans, said Jicha. “The move towards biomarkers is not just to make money for companies, but to open the door to treat people in a pre-dementia state,” he said.
According to studies by the Mayo Clinic, Jicha said the prevalence of MCI in the population over age 65 is about 20%. These companies have to opportunity to increase the market significantly, as one-fifth of the population over 65 could take the medication and these imaging tests.
There may also be false positives, such as individuals who test PIB positive, due to amyloid deposits in their brains, but do not have dementia. There is also the possibility of PIB binding in other conditions, such as prion diseases, although it is very rare, said Rebeck.
Dr David Holtzman, Head of the Department of Neurology at Washington University School of Medicine in St. Louis, said there is already strong evidence that PIB is imaging amyloid protein from several publications. “I think with amyloid imaging and ancillary CSF tests, we can identify now those who have AD pathology in vivo without a biopsy.”
Amyloid imaging is currently not approved for anything other than research use, said Holtzman. Rebeck also agreed that a negative amyloid PET scan would be useful to rule out AD as a current diagnosis for the elderly subject presenting for evaluation of clinically identified progressive cognitive impairment - one of the key questions raised at tomorrow’s panel.
Dr Richard Frank, vice president of medical affairs and clinical strategy at GE Healthcare, said the company’s lead molecule, GE-067, targets insoluble forms of amyloid. GE has also performed research on soluble oligomers, which led to the subsequent collaboration with Eli Lilly.
“There has been a lack of clarity from the FDA and the companies are hoping to understand the regulatory pathway after the meeting tomorrow,” Frank said.
While many critics question the use of such a diagnostic as there are no disease modifying agents on the market, there are many benefits of such a test, said Frank. The imaging of amyloid beta plaques would confirm that the patient is a proper candidate for a disease modifying therapy in development.
The diagnostic could ultimately play a critical role in early intervention. The current treatment paradigm in AD is analogous to treating a cardio patient with statins after they have already had two heart attacks and implanted stents. He likened amyloid imaging to serum cholesterol levels, and said that patients need to be treated earlier before they show memory loss.
Imaging agents may also be useful after initiation of therapy to ensure the patient is gaining some benefit, that is to say, they are receiving the right drug at the right dose. If the post-treatment test does not show improvement, the regimen could be individualized, that is to say the dose could be increased, dose in intervals could be shortened, or the drug could be changed, Frank said.
Dr Edward Zamrini, director of clinical trials for the Center for Alzheimer's Care at the University of Utah Hospital, said amyloid imaging is a tremendous advance, although there is no ultimate proof that the presence of amyloid plaques is equal to the degree of clinical pathology.
However, aggregate data and science are moving toward molecular diagnosis rather than symptomatic diagnosis, said Zamrini. Imaging the tau tangles in conjunction with amyloid plaques would also provide better positioning, and there is a clinical initiative to correlate clinical progression with an amyloid imaging agent.
“I don’t think there are any major hurdles. The one thing is what you do with an individual who is PIB positive, who is not demented,” said Rebeck. Although there is a growing body of literature supporting imaging agents such as PIB, more validation studies need to be conducted before clinical adoption, physicians agreed.
The FDA advisory meeting tomorrow is a historic step, and shows the urgency to develop an imaging agent for use in AD, as the agency normally doesn't hold a committee this early in the development process. “The impetus for this meeting is the unmet clinical need, and the push from the medical community to develop new therapeutics. PET is the fastest growing piece of imaging,” said Skovronsky.
“It’s a whole new approach to treating this disease,” said Rebeck. But the important thing to remember is we’re talking about a biomarker, not a cure, added Hall.
I know - and there was that report by the PinkSheet. I'm sure you guys heard. the potential cancer risk with prasugrel. Lets see what will happen...
what do you think will happen to prasugrel? I'm not too sure. severe label restrictions probably.
plavix is going generic soon anyways. guess that's why LLY was pressed to buy IMCL.
you think it'll happen next year?? BIIB are pretty cheap now but the tysabri news might be putting them at bay. thoughts??
pharmawire - Novartis' MS oral drug.
17:14 Novartis' oral MS drug FTY720 comes under physician scrutiny; side-effects affecting patient enrollment in US trial - analysis
Story Novartis' oral multiple sclerosis drug FTY720 (fingolimod) is under scrutiny in light of recent adverse events which are affecting ongoing patient enrollment in Phase III US trials, physicians said.
While EU and global trials have finished enrollment, US placebo-controlled trials are still far from meeting that goal, said Dr Daniel Kantor, assistant professor of neurology and director of the Comprehensive Multiple Sclerosis Center at the University of Florida. Kantor said the enrollment process was a year behind what he had expected.
"We were all very excited about FTY720, but the company is having a lot of problems enrolling patients in the trial," he said.
Earlier this year, two patients developed a serious infection, one of whom died from a disseminated varicella infection. The other developed a life-threatening herpes encephalitis infection. "I was astounded when the company told me [the cases] were not related to the drug, and that regular people had this [disease]," said Kantor.
Dr Daniel Wynn, director of clinical research at Consultants in Neurology in Chicago, agreed that the main concerns surrounding FTY720 are safety issues, which have been stalling the trials.
The concerns center around the drug's effect on the lymphoblastic cardiac and pulmonary receptors, as the compound appears to decrease lung functions and slow a patient's heart rate. A couple of patients developed severe opportunistic infections, and the patient with the herpes infection died after developing a disseminated intravascular coagulation, Wynn explained.
Novartis representatives were not available for comment.
Wynn said he did not believe that all the safety issues that the company found have been made public. "There are less patients who want to go into the trial and fewer doctors who are putting people into these trials," he said.
Many hospitals conducting this trial are relatively inexperienced, and many have few patients, Wynn said, adding that data analysis becomes far more complicated - and accuracy decreases - as enrollment declines. Side effects might also go under-reported, he added.
Although oral MS drugs may be easier to take than current injectables and infusion treatment, patient compliance may be worse, said Kantor, who drew a parallel with the current lack of compliance with oral high blood pressure medications. These new oral MS drugs will likely be used in newly diagnosed MS patients who have not been treated with injectables yet, he added. Other patients could include individuals who cannot tolerate the current drugs on the market.
"Most patients do well on standard MS therapies, and I'm not sure patients will be switching straight away to oral medicines," Kantor said.
The new oral MS drugs will most likely be used in conjunction with current therapies, physicians said. Yet some physicians, such as Kantor, noted that in light of the concerns that a combination of Biogen Idec's Tysabri and Avonex could lead to progressive multifocal leukoencephalopathy (PML) - a typically fatal brain infection - neurologists may now be more hesitant to combine MS drugs. "There’s no data looking at FTY720 in combination. After what happened with Tysabri and Avonex, I’m not sure that physicians are going to feel that comfortable," Kantor said.
FTY720 will likely have the highest efficacy among oral therapies, physicians agreed. "But with that strength will come side effects. That is going to be very concerning to physicians and patients," Kantor said.
Dr Patricia O'Looney, director of biomedical research programs at the National Multiple Sclerosis Society, said that many patients will transition to oral therapies once they become available. But she noted that some advanced stage patients can lose their ability to swallow, and there will always be a need for non-oral therapies for this group of patients.
"Whether the oral therapies will be as effective as Tysabri, or other IVs, still remains unknown," she noted.
Dr Keith Edwards, a neurologist and director of Empire Neurology in New York, noted that FTY720 appears to increase the risk of sinus infections, but it is unclear whether the two cases of serious infection - herpes encephalitis and disseminated zoster - were definitely drug related. The drug may be so effective that a lower dose (0.5 mg) may work, without causing the excessive immunosuppressive issues, he suggested.
Kantor noted that FTY720 will carry an absolute contraindication for use with pregnant women. The drug can cause fetal malformation, as a result of the drug's mechanism of action, he added. MS is a disease that affects young women, and data from animal studies suggest that precautions should be made for patients who may be pregnant.
Dr Timothy Vollmer, medical director of the Rocky Mountain MS Center, noted that FTY720 is an immunosuppressant. Although the drug differs from traditional chemotherapy, it could still cause infections. "These are problems with all immunosuppressants, whether they're selective or non-selective," he said.
Unlike Tysabri, FTY720 is more of a general immunosupressant, and can cause not only PML, but acute infections as well, Vollmer noted. Viral infections could be even more of a concern than PML, Wynn noted.
Vollmer added that the tolerability of FTY720 will be negated if patients have to go to a different physician every week to check for its effect and safety on major organs. "It will be a very challenging drug for clinicians and patients to use," Vollmer said.
When asked whether the drug will be rejected at the FDA, Vollmer said 5,000 patients are currently on it. The agency wants to get 3,000 patient exposures with new MS drugs. FTY720 will likely be shown to be substantially more effective than current first-line agents, but the larger issue is how the FDA will view the drug's safety profile in terms of other organ toxicities, he noted.
"That’s a tough call," Vollmer said regarding approval, pointing to skin cancer cases that also arose during studies. Approval will depend on whether Novartis can convince the FDA, based on the natural history of the illness, whether side-effects are coincidental, said Vollmer.
There are at least two other oral drugs in development, including Biogen Idec's BG-12 and Teva's laquinimod.
by Kimberly Ha and James Avallone
upcoming events this month:
Event Date Brand Name Event Originator Licensee(s) Therapeutic Categories Pharma Class
14-Oct-08 Femara (Litigation) Motion Hearing (Mylan case) Novartis AG Cancer
Aromatase Inhibitors
14-Oct-08 Cinryze (Product) PDUFA expected Lev Pharmaceuticals, Inc. Cardiovascular
Enzyme Inhibitors
15-Oct-08 Acapodene (Product) FDA guidance expected GTx Inc. GTx Inc.
Ipsen SA (formerly known as Beaufour IPSEN)
Cancer
Hormonal disorder
Selective Estrogen Receptor Modulators
15-Oct-08 Ranexa (Product) (Licensing) PDUFA expected CV Therapeutics, Inc CV Therapeutics, Inc
Quintiles Transnational Corp.
The Menarini Group
Cardiovascular
Cardiovascular Agents
Sodium Channel Inhibitors
15-Oct-08 Tricor (Litigation) Telephone Conference (Teva case) Solvay SA Cardiovascular
Metabolism
Lipotropics (Fibric Acid Derivatives)
17-Oct-08 Protonix (Litigation) Status Conference (Teva case) Wyeth (formerly known as American Home Products Corporation) Gastrointestinal
Proton Pump Inhibitors
18-Oct-08 Acapodene (Product) Phase III results expected GTx Inc. GTx Inc.
Ipsen SA (formerly known as Beaufour IPSEN)
Cancer
Hormonal disorder
Selective Estrogen Receptor Modulators
19-Oct-08 Promacta (Product) PDUFA expected GlaxoSmithKline plc GlaxoSmithKline plc
Immunomodulation
Blood Formation Products (Erythropoietins)
19-Oct-08 ferumoxytol (Product) PDUFA expected AMAG Pharmaceuticals, Inc. (formerly known as Advanced Magnetics, Inc.) 3SBio Inc.
Cytogen Corporation
Blood and forming organs
Diagnostic
Genito-urinary
Imaging Contrast Agents
20-Oct-08 Pulmicort (Litigation) Motion Hearing (Teva case) AstraZeneca PLC Respiratory
Corticosteroids-Inhalation / Nasal
21-Oct-08 Myozyme (Product) FDA Advisory Committee meeting Genzyme Corporation Metabolism
Enzyme Replacements/Modifiers Anti-cystine Agents
21-Oct-08 Telavancin (Product) FDA decision expected Theravance Inc Astellas Pharma Inc. (formerly Yamanouchi Pharmaceutical Co., Ltd.)
Infectious disease
Respiratory
Antibacterials (Glycopeptide Antibacterials)
22-Oct-08 XL184 (Licensing) Opt-in date for GSK Exelixis Inc. Cancer
Central Nervous System
Tyrosine Kinase Inhibitors
VEGFR2 Inhibitors
23-Oct-08 Allegra (Litigation) Telephone Conference (consolidated) Sanofi-Aventis SA Sciele Pharma, Inc.
Allergy
Dermatological
Antihistamines (Histamine1 (H1) Blocking Agents, Mildly/Non-sedating)
24-Oct-08 picoplatin (Product) Phase II results expected Poniard Pharmaceuticals Poniard Pharmaceuticals
Cancer
Antineoplastics
Cancer Agents
24-Oct-08 deforolimus (Product) Phase III results expected Ariad Pharmaceuticals Merck & Co., Inc.
Cancer
Antiangiogenic Agents
Antineoplastics
Receptor Protein Kinase Interactions
26-Oct-08 CP-690550 (Product) Phase IIb results expected Pfizer Inc. Immunomodulation
Immune Suppressants (Immune Suppressants (Non-TNF Inhibitors))
26-Oct-08 ARRY-797 (Product) (Licensing) Phase II results expected Array BioPharma, Inc. Cancer
Antineoplastics
27-Oct-08 alogliptin (Product) PDUFA expected Takeda Pharmaceutical Company Limited (formerly Takeda Chemical Industries) PPD Inc. (Pharmaceutical Product Development Inc.)
Metabolism
Antidiabetic Agents (Dipeptidyl Peptidase-4 (DPP-4) Inhibitors)
28-Oct-08 Isentress (Product) Phase III results expected Merck & Co., Inc. Infectious disease
HIV Integrase Inhibitors
28-Oct-08 Prevnar (Product) Phase III results expected Wyeth (formerly known as American Home Products Corporation) Infectious disease
Vaccines / Antisera
28-Oct-08 Orencia (Product) Phase II/III data Repligen Corporation Gastrointestinal
Immunomodulation
Proteins
29-Oct-08 R788 (Product) (Licensing) Phase IIa results expected Rigel Pharmaceuticals, Inc. Cancer
Immunomodulation
Tyrosine Kinase Inhibitors
29-Oct-08 PF-4383119 Phase II results expected Pfizer Inc. Genentech Inc
Musculoskeletal
CNS, Miscellaneous
29-Oct-08 Puricase (Product) Phase III results expected Savient Pharmaceuticals Inc. (formerly Bio-Technology General Corp) Musculoskeletal
Antigout
29-Oct-08 INCB18424 (Product) Phase II results expected Incyte Corporation (formerly Incyte Pharmaceuticals, Incyte inc, Incyte Genomics) Blood and forming organs
Cancer
Dermatological
Immunomodulation
Molecular Target Inhibitors (Multitargeted Kinase Inhibitors, Bcr-Abl/c-kit Receptor Tyrosine Kinases)
30-Oct-08 Vimpat (Product) PDUFA expected UCB S.A. Central Nervous System
Musculoskeletal
Anticonvulsants
Sodium Channel Interactions
31-Oct-08 interleukin-21 (Product) Phase II results expected ZymoGenetics, Inc. Novo Nordisk A/S
Cancer
Antineoplastics
31-Oct-08 Gardasil (Product) sBLA decision expected Merck & Co., Inc. Beijing Wandong Medical Equipment Co. Ltd. (MRI operation)
C & M Communication
Cancer
Genito-urinary
Immune Stimulants (Vaccines to Prevent Papillomavirus Disease)
31-Oct-08 Effient (Product) PDUFA expected Eli Lilly and Company Eli Lilly and Company
Cardiovascular
Platelet Aggregation Inhibitors (Adenosine Diphosphate P2Y12 Inhibitors)
31-Oct-08 Stalevo (Product) Phase III results expected Orion Corporation Novartis AG
Central Nervous System
Catechol O-methyltransferase (COMT)
Dopamine Precursors
31-Oct-08 Remodulin (Product) Phase III results expected United Therapeutics Corporation Goldshield Group plc
Grupo Ferrer Internacional SA
Nova-Tex, Ltd.
Orphan Australia Pty Ltd
Paladin Labs Inc.
Cardiovascular
Prostacyclin Receptor Agonists
31-Oct-08 Treanda (Product) PDUFA expected Cephalon, Inc. Eisai Co., Ltd.
SymBio Pharmaceuticals Limited
Cancer
DNA Damaging Drugs
31-Oct-08 Ranexa (Product) (Licensing) PDUFA expected CV Therapeutics, Inc CV Therapeutics, Inc
Quintiles Transnational Corp.
The Menarini Group
Cardiovascular
Cardiovascular Agents
Sodium Channel Inhibitors
31-Oct-08 milnacipran (Product) PDUFA expected Cypress Bioscience, Inc. Cypress Bioscience, Inc.
Forest Laboratories Inc
Central Nervous System
Serotonin / Norepinephrine Reuptake
31-Oct-08 Provenge (Product) Phase III results expected Dendreon Corporation Cancer
Vaccines / Antisera
31-Oct-08 asenapine (Product) PDUFA expected Schering Plough Corporation Pfizer Inc.
Central Nervous System
Receptor Interactions
31-Oct-08 TriLipix (Product) FDA decision on NDA expected Abbott Laboratories Cardiovascular
Dyslipidemics (Fibrates)
31-Oct-08 IDX184 Phase I results expected Idenix Pharmaceuticals Inc Infectious disease
Hepatitis C Agents
Inhibitors
thanks Dew!
does anyone know anything about this?
Swiss news agency, Swisster, reporting that Roche secured the financing for the purchase of DNA @ $89 and that their still could be a higher offer at $96.75.
true false??
pharmawire article - 02-Oct-08 21:07 Genentech: Roche financing is 'not a problem', insider says
Story Roche does "not have a problem" with financing the USD 43.7bn bid for Genentech, according to an insider at Roche. Despite reports that Roche is facing difficulties securing the funds, the insider confirmed it has not been a problem. "To me, it's a done deal. It's just a matter of time," he added. An industry executive, who claimed knowledge of the situation, also said that he heard Roche had already secured financing.
The Swiss-based pharmaceutical currently holds 56% of California-based Genentech, which rejected a USD 89 per share bid from Roche in mid-August.
An industry banker with knowledge of the situation said that Roche has lined up a committed credit facility of USD 40bn. The banker said he had heard that Genentech’s special committee, which rejected Roche’s proposal on 13 August, is fighting over the offer price and has come to a disagreement with its financial advisor, Goldman Sachs. The committee's asking price is USD 130 per share, but a more realistic offer will be USD 115 per share, the industry banker said.
But a second industry banker said the process is moving “very slowly” given Wall Street’s meltdown, as compared to previous predictions of a deal being wrapped up expeditiously. He added that Roche had not lined up the financing yet, and is continuing to have discussions with banks. "In this market, you should continue discussions. If they have been talking to Wachovia, then they have a problem," he added.
Regardless, he believed a deal would be struck. “I don’t know if Roche can really go back to what it used to be," the second banker said. He did not believe Roche would walk away from the deal, in light of the current market conditions.
The Roche insider said the main reason for the Swiss drug-maker to move ahead with a Genentech acquisition, instead of maintaining the current partnership model, is due to the fact that Roche will lose its exclusive rights to Genentech's products outside the US in 2015. Roche currently holds the right of first negotiation for external US rights to all drugs in Genentech’s pipeline. The right of first negotiation on drugs ex-US is the most important element of the current Roche/Genentech relationship, the insider said.
Meanwhile, he disagreed that proposing to acquire Genentech was a maneuver to ward off other potential bidders, in light of the recent M&A market frenzy in the sector. Rather, the merger will lead to a significant amount of sales and marketing synergies, he added.
Still, the merger is likely to result in redundancies on both sides in terms of employees, who will likely leave by their own will, due to the potential culture clash, the industry executive and the Roche insider warned. "One of the things Roche has done brilliantly is leaving Genentech alone," the industry executive commented.
The industry executive further said maintaining Genentech's innovative culture after the deal will be tough. "I don’t know if the deal is good or bad for the industry. What I do know, it won’t help the Genentech culture survive," he said.
An oncology executive also agreed that the deal will cause redundancies, and said, "if I was at Genentech, I would be looking over my shoulder to see who is left." The executive, who is in contact with a number of internal sources at Roche, said from his knowledge, the mood has been different over the last few weeks.
Roche is known for being conservative in nature, particularly in terms of its R&D protocol, the oncology executive said. "I think the industry is still surprised over this announcement," he added.
by Kimberly Ha, Nadia Damouni and Sasha Damouni
Source Pharmawire
BIDDER Roche Holding AG
TARGET Genentech Inc
Intel. Type Cross Border
Other
Takeover situations
Countries Switzerland
USA
Intel. Grade Strong evidence
Intel. ID 706908
11:28 Medical device industry is likely to face the same proposals for restrictions on direct-to-consumer (DTC) advertising as pharma, industry sources say
Story The medical device industry is likely to face the same proposals for restrictions on direct-to-consumer (DTC) advertising as the pharmaceutical industry, industry sources said.
Recent hearings on Capitol Hill concerning the practice of DTC advertising from medical device companies was a clear signal that the industry will be forced to deal with an issue that had so far been limited to pharmaceutical advertising, the sources said.
Sources admitted it had become nearly impossible to predict the legislative priorities for 2009, considering the economic meltdown and the uncertainty of the upcoming presidential and congressional elections. But they also said it was clear that device companies would be included in any discussion of DTC advertising practices within the pharmaceutical industry and that it was possible the sector would be dealt with before the larger pharmaceutical companies.
The Senate Special Committee on Aging heard testimony last month to consider recommendations on whether increased regulation of the practice is needed for devices such as heart stents, replacement hips, and other implanted devices.
The practice of advertising devices directly to consumers is fairly new, and relatively small compared to pharmaceutical companies, according to AdvaMed, the trade association representing medical device manufacturers. According to the organization, device companies spent just USD 116m in 2005 on DTC ads, while pharmaceutical companies spent USD 4.1bn.
But the focus on device manufacturers like Medtronic, Boston Scientific, Johnson & Johnson, and Abbott comes, at least in part, because of the dramatic increase in the practice over the last decade, according to Dr William Boden, professor of medicine and public health at the University of Buffalo.
Boden pointed out that there were only two producers of drug-eluting stents a few years ago, and companies only began to spend on advertising when several other players entered the market. Cordis Corporation, a Johnson & Johnson company, debuted an ad for its Cypher stent on Thanksgiving last year, he said. Companies like Stryker and Johnson & Johnson both currently use celebrities Jack Nicholas and Mike Krzyzewski to promote artificial hips.
The Committee on Aging has a history of getting the ball rolling towards considering legislation, according to an industry source involved in this issue in Washington. The source pointed out that hearings led by Sen. Larry Craig (R-ID) eventually led to the FDA reform bill that was defeated in 2007.
The source said that the hearings had drawn significant attention, and he expected it to be revisited next year. He said the device industry in particular was at risk because of the complexity of devices such as heart stents, and that they were more permanent than drugs. Boden agreed, and said for that reason he expects broadcast advertising to be targeted rather than print. Boden also recommended a two-year ban on advertising following a product's approval by the FDA.
John Kamp, executive director of the Coalition for Healthcare Communications, said Sen. Herb Kohl (D-WI) had written to Rep. Bart Stupak (D-MI) in the hope he would take up the issue. Kamp said he expects the issue to stick, and said he would not be surprised if the device manufacturers were included in legislation next year originally aimed at pharmaceutical companies.
Kamp pointed to comments from Rep. Rahm Emanuel (D-IL) indicating the Ways and Means Committee may look at a proposal to strip device and pharmaceutical companies of their tax write-off for advertising spending. Kamp said he expects the proposal to come up next year, though said it would almost certainly be challenged in the courts.
“It’s another indication that DTC is likely to be the subject of a lot of discussion and possibly legislation in 2009,” Kamp said.
A spokesperson for AdvaMed, however, argued for the continued use of device advertising. “The idea that a patient would undergo a complex and invasive procedure based on an advertisement, or that a physician would agree to perform them if inappropriate for the patient, is difficult to imagine,” the spokesperson said via email.
by Marc Longpre
Source Pharmawire
wait, is Cortex the company with the worst management team of all time? these are the guys that tried to bring that AD drug to market right? or am i wrong..there was another company that has notorious management - the company that tried to use copper/zinc inhibition to treat AD.
Eli Lilly in talks to buy ImClone: sources
Wed Oct 1, 2008 6:30pm EDT Email | Print | Share| Reprints | Single Page | Recommend (-) [-] Text [+]
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PHILADELPHIA (Reuters) - ImClone Systems Inc (IMCL.O: Quote, Profile, Research, Stock Buzz) is in talks to be acquired by Eli Lilly and Co (LLY.N: Quote, Profile, Research, Stock Buzz), sources familiar with the situation said on Wednesday, after ImClone had rebuffed a sweetened takeover offer from Bristol-Myers Squibb Co (BMY.N: Quote, Profile, Research, Stock Buzz).
Eli Lilly has offered to buy ImClone, which makes the cancer drug Erbitux, for $6.1 billion, or $70 a share, topping Bristol-Myers's offer of $62 per share for the 83 percent of ImClone it does not already own, The Wall Street Journal reported.
A $70 per share offer would mark a 7.1 percent premium over ImClone's closing stock price of $65.35 on Wednesday.
"The strategic fit isn't obvious, other than Lilly has a decent cancer franchise and is trying to get more into biotech," said Les Funtleyder, analyst for Miller Tabak & Co.
Cancer is one of the three main areas of research focus at Eli Lilly, along with diabetes and neuroscience. Eli Lilly's has a robust oncology business, but its largest product, Gemzar, loses patent protection in 2012.
Like other major pharmaceutical companies facing competition from generic drug rivals, Eli Lilly also faces the risk of slower growth due to the pending patent expiry of its schizophrenia drug Zyprexa.
"The fact that Erbitux is a biologic is good for the long term in terms of patent protection and Lilly is poised to lose a number of products to generic competition over the next several years, so I think they're doing what they need to do," said David Moskowitz, an analyst for Caris & Co.
ImClone and Bristol-Myers declined to comment. Eli Lilly could not be immediately reached for comment. Continued...
just read a rodman analyt report today as well, saying how avastin trends, projected sales downgrades.
thoughts? will avastin still be the key oncology blockbuster in the next couple of years??
i've been hearing good and bad news about their C-08 trial (adjuvant CRC).
15:42 Genentech’s Avastin unlikely to show survival benefit in patients with metastatic melanoma, physicians said
Story Genentech Avastin's mechanism of action may not alter disease outcomes for patients with metastatic melanoma, physicians said. Avastin's target – vascular endothelial growth factor (VEGF) – may not play a significant role in the disease pathology, they said.
Yet the drugs being combined with Avastin (bevacizumab) in the ongoing clinical study – carboplatin and Taxol (paclitaxel) - will likely be approved as the next combination therapy for metastatic melanoma, they added.
Genentech could not be reached for comment.
Avastin is a monoclonal antibody against VEGF which inhibits tumor growth by preventing angiogenesis, or blood vessel formation, essentially starving tumors. The drug is approved for the treatment of metastatic colorectal cancer, non-small cell lung cancer and metastatic breast cancer.
Avastin is not the ideal drug to study in metastatic melanoma because the anti-angiogenic mechanism does not play a prominent role in the disease, according to Dr Antonio Ribas, an oncologist at the University of California at Los Angeles.
"Avastin seems to have done many things right in many cancers, but [VEGF] is not a key event that we are blocking in metastatic melanoma," Ribas said.
Although VEGF is an attractive target, there is a lack of evidence in metastatic melanoma that acting on it will have an impact, said Dr John Kirkwood, an oncologist and vice chairman for clinical research at the University of Pittsburgh School of Medicine. Although angiogenesis plays a role in melanoma, it is not as prominent as in other cancer types, Kirkwood added.
Drugs that target VEGF have not historically had positive results in treating patients with metastatic melanoma, noted Dr Theodore Logan, an oncologist at the Simon Cancer Center at Indiana University. Bayer AG's Nexavar – which also against VEGF – recently showed no activity in its phase III PRISM trial.
Dr David McDermott, an oncologist at Beth Israel Deaconess Medical Center in Boston, said that ongoing Avastin studies are currently excluding patients with elevated HDL levels, who have a poorer disease prognosis. Companies such as Medarex have also adopted this approach in their trials of ipilimumab, as stratifying patients in this manner might reveal a sub-group benefit, McDermott noted.
Physicians are not overly optimistic about Avastin's prospects to treat patients with metastatic disease, as every drug "with a glimmer of hope" has ended up failing during the past 15 years, Kirkwood said. Avastin is also undergoing clinical trials in the adjuvant setting, in a trial known as the CRUC study, he added.
Still, even if Avastin fails to benefit this patient population, the drug is being used as a part of a cocktail therapy that is likely to stick around, Ribas noted. Currently, Avastin is being studied in combination with carboplatin and paclitaxel, he explained. Approximately 17% of patients respond to carboplatin and paclitaxel, he added.
"The reality is that the carboplatin and paclitaxel works in a significant number of patients with melanoma," Ribas said.
Kirkwood agreed that the carboplatin and Taxol combination regimen is likely the next combination to be approved for metastatic melanoma.
Progression free survival is being measured as a primary endpoint in an ongoing phase II multicenter, randomized, double-blind, placebo-controlled trial. The study is examining the efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel chemotherapy for the first-line treatment of patients with metastatic melanoma.
by Klara Czobor and Beth Herskovits in New York
Source Pharmawire
14:17 Eli Lilly's prasugrel could face FDA advisory committee panel; slight chance for additional trial, cardiologists speculate
Story Eli Lilly's prasugrel may face an increased chance of review from an FDA advisory committee as the agency continues to delay approval, cardiologists said.
The blood thinner, which Eli Lilly is counting on to compete against Bristol-Myers Squibb and Sanofi-Aventis’ Plavix (clopidogrel), has been plagued by multiple delays since the original PDUFA date of 26 June. The most recent delay came following the 26 September PDUFA date, which came and went without any word from the agency as to how long it would need to make a decision.
The delays hold particular importance for Eli Lilly because Plavix may lose its patent protection as early as 2011, forcing prasugrel to compete against cheaper generic clopidogrel.
Somewhat unexpectedly, the drug never came up before an agency advisory committee before its PDUFA date, and no explanation was given. But cardiologists said the delay may signal some difficulties the agency was having as it examined the NDA, increasing the likelihood an advisory panel would deal with the drug this time around. It is also unclear whether the FDA believes prasugrel can effectively be managed by a Risk Evaluation and Mitigation Strategy (REMS).
Dr Antonio Gotto, who is an authority in the field of cardiovascular medicine and dean of Weill Cornell Medical College, said he believed the odds of an advisory committee have increased significantly since the latest delay. Gotto said it was possible the agency would ask for more data from the company, but given the amount of data on hand he believes the agency is likely grappling with how to deal with the increased bleeding risk.
In the pivotal Phase III TRITON-TIMI 38 study, patients who took prasugrel reduced the risk of cardiovascular death, non-fatal heart attacks, or non-fatal strokes by 19% when compared to Plavix. Cardiologists interviewed by this news service also cited the 50% reduction in stent thrombosis for prasugrel when compared to Plavix.
On 26 September, Eli Lilly released a statement concerning the delay. "We remain engaged in collaborative and productive discussions with the FDA regarding the details of our application. This is a very large, complex submission, and it should not be surprising that delays occur," Jennifer Stotka, MD and vice president for Global Regulatory Affairs said in the statement. "Daiichi Sankyo and Lilly will not speculate on the timing or what the outcome will be. However, the review is very far along, and we remain optimistic." A spokesperson for the company said there was no further update on the drug’s status.
Dr James Wilson, a cardiologist at St. Luke’s Hospital in Houston, Texas, said he felt there was plenty of data to warrant approval, but that an advisory committee would likely be asked to look at the data to help the agency deal with any label warnings. “That’s probably what’s going to happen, they’ll kick it back and say please give us some recommendations on what to do with this one,” Wilson said.
Dr Eric Bates, a site investigator for the drug and a cardiologist at the University of Michigan, said the agency could be looking at the groups in which the bleeding risk showed up: patients over the age of 74, weighing under 60 kg, or those with a previous neurologic event. He said it was possible the agency could ask for another trial, excluding the at-risk groups. But Bates still believed the drug had proved efficacy, and that the risk-benefit ratio merited approval.
Bates said prasugrel would get “approved in some capacity,” but remained uncertain over the drug’s bleeding risk, and whether it would be labeled with a black box or not.
While all cardiologists agreed there was a slight chance the agency would require another trial from the company, they agreed there was sufficient data to approve the drug with warning labels that highlighted the bleeding risk. They also pointed to the unusually large NDA for the drug, which could help explain at least some of the delay. All cardiologists interviewed by this news service said they believed prasugrel should be approved.
Dr Bonnie Weiner, past president of the Society for Cardiovascular Angiography and Interventions (SCAI), said that while it was possible another trial could be required, it is more likely the agency would simply approve the drug with the at-risk populations excluded. “Certainly looking at what’s been published, this would potentially be a drug that would be a valuable addition to the choices we have for patients. That’s the bottom line,” Weiner said.
Eli Lilly has a market cap of USD 50.46bn.
by Marc Longpre
Source Pharmawire
pharmawire article on TauRx's Rember.
also a ref to this article here:
http://www.memorycenternj.com/index.php/uncategorized/taurxrember-is-it-for-real/
18-Sep-08 11:45 TauRx's Rember looks promising, but data still has to be replicated in larger studies
Story * Rember, a potential first-in-class tau aggregator, is generating interest as an Alzheimer’s treatment though larger studies are called for
* Statistical analysis was designed to test the viability of treatment and lowest effective dose.
TauRx Therapeutics' recent Phase II 24-week primary efficacy data announcement has garnered considerable interest and controversy, CEO Claude Wischik said.
Addressing market misconceptions over its lead product Rember, a new formulation of methylene blue for the treatment of Alzheimer's, Wischik said the trial was not a post-hoc subgroup analysis and still needs to be replicated in a larger number of subjects.
Rember has also been used to treat urinary tract infections.
Recent market reports and some physicians have called into question the hype surrounding TauRx's Rember, and whether that can be replicated in larger studies. If successful, the drug could be a potential first-in-class tau aggregator for the treatment of Alzheimer's disease (AD).
The Alzheimer's space over the last year has been rife with failure, such as Neurochem's Alzhemed, Myriad's Flurizan, and more recently Wyeth and Elan's bapineuzumab, which failed to meet its primary endpoint.
"There is a lot of excitement about this agent, but I’m a bit more cautious," said Dr Gregory Jicha, assistant professor of neurology, University of Kentucky, Sanders-Brown Center on Aging.
The study was done in a very limited number of study sites, as opposed to an international study. "We’re on a rollercoaster ride with some of these agents, just like Alzhemed and Flurizan, which were very promising in the beginning," Jicha said.
Wischik said the primary efficacy end-point at 24-weeks was prespecified not just as a general intention to analyse ADAS-cog change from baseline at 24-weeks, but was very precisely defined in terms of a specific statistical model, with predefined methodology and covariance structure.
The prespecified analysis preserved multiplicity by using the Westfall correction, which increases p-values to take account of simultaneous testing of different dose groups, he said.
TRx-014-001 was an exploratory dose-range finding study whose purpose was to discover whether tau aggregation inhibitor therapy was viable and what was the lowest effective dose, said Wischik. "It was the largest disease modifying Phase II trial for the disease modifying AD indication conducted to date."
Dr Andrew Medhurst, GSK's programme leader for H3 antagonists, said the Rember data was certainly an interesting outcome. "It’s going to take several trials before we really understand the picture with different antibodies and approaches," he added.
"It is an intriguing finding, but follow up studies are required to either confirm or dismiss the claims," said Medhurst.
Wischik said the recent results now need to be confirmed in a larger study, but it is inevitable for a completely novel treatment approach which tests a range of doses, that the groups which prove in retrospect to be of greatest interest are necessarily small.
Even so, there were 321 subjects randomised, 227 entering the 50-week phase of the study, and 169 entering the 84-week phase of the study. The study showed that 60mg tid is the lowest dose needed to achieve control of disease progression in AD.
Another question is what Rember's lowest effective dose is. Having demonstrated efficacy against placebo at the 60mg dose as the lowest effective dose in the ITT analysis, testing of higher doses ceases in a formal sense, said Wischik, although the algorithm provides corrected p-values for all doses tested.
To take account of testing of multiple doses in both mild and moderate subjects, a Bonferoni correction was used, he explained, so that the significance threshold was lowered to p = 0.025. The demonstration of efficacy of the 60mg dose in moderate subjects met this criterion after imposing the Westfall correction for multiplicity at p = 0.021. The treatment effect therefore met all requirements for significance as prespecified, he said.
Wischik also countered market criticism that efficacy was demonstrated at 24 weeks only in a small number of subjects. Although it is true that only 28% of the subjects in the study were moderate at baseline, the numbers of moderate subjects available provided a power of 81% for demonstration of the effect size of -5.5 ADAS-cog units in moderate subjects that was observed. "The study was adequately powered to detect the treatment effect in moderate subjects even after allowing for the Westfall or Bonferoni corrections for multiplicity."
There were 181 mild subjects entering the 24-50 week phase of the study, of whom 41 received the 60mg dose, 28 received the 30mg dose, and 51 were in the control arm. This provided adequate numbers to confirm in mild subjects the efficacy first seen at 24 weeks in moderate subjects at the 60mg dose. Efficacy was also demonstrated after pooling mild and moderate subjects, and separately in the severity subgroups, he said.
The efficacy of the 60mg dose was again confirmed at 84 weeks, in that subjects treated with Rember at the 60mg dose had not declined significantly from their baseline scores.
The analysis at the 24 week interval did not invalidate subsequent analyses. Although senior TauRx management had access to this analysis, due to strategic planning, the conduct of the study remained entirely double-blind at the operational level, for the investigators, patients and study monitors in the trial over the duration of 84 weeks, said Wischik.
The company did not pool placebo and 100mg subjects after the 24-weeks analysis. Subjects originally randomised to placebo were switched to 100mg bd after 24 weeks, and then were re-randomised to either 60mg tid or 100mg tid after 50 weeks. The switch to a presumptively active dose after 24 weeks was required because of ethical objections raised at the trial design stage against keeping subjects on placebo for longer than 24 weeks.
It was only because the 100mg dose was found to lack clinical efficacy for reasons of formulation that permitted subjects randomised to the placebo/100mg arm to be used as the control arm at the 50-week time point. This analysis therefore respected the original randomisation, and did not include any post-hoc pooling of subjects, stressed Wischik.
It was not known prior to initiation of the study that the 100mg dose would lack clinical efficacy, he said. This only emerged after the 24 week analysis, and the study was allowed to continue as designed. This lack of efficacy first seen after 24 weeks was further confirmed in subjects transferred from placebo to the 100mg bd dose after 24 weeks.
Calculation of an inferred placebo decline over weeks 24 to 50, by subtracting the small effect observed for the 100mg dose over the first 24 weeks in a mixed effects repeated measures analysis, revealed that there was essentially no difference between the expected placebo decline over 50 weeks and that actually observed in the placebo/100mg arm used as control for the 50 week analysis.
Therefore, the fortuitous failure of the highest dose 100mg capsule provided a useful internal minimal efficacy comparator arm for the purpose of the 50 week analysis. This made the study much more powerful over 50 weeks than had originally been intended, said Wischik.
The original plan had been for the 50 week analysis to have been conducted with reference to historical controls, despite the well-known weaknesses of this approach. This was because there was at the time no ethically acceptable alternative to demonstrating a long term disease modifying effect in a monotherapy design.
Subjects originally randomised to the 100mg dose originally remained on this dose throughout the study and were not pooled with any other group. They remained a separate study arm, despite the fact that the formulation defect prevented the release of the active form of Rember. This study arm was not used for main analyses at either 50 weeks or 84 weeks.
The possibility of an apparent effect on disease progression by biased retention of non-declining subjects was also examined, he said.
There was no evidence of biased withdrawal to 24 weeks, but there was evidence of biased withdrawal occurring between weeks 24 and 50. This occurred selectively in the minimal efficacy treatment arms (placebo/100mg bd control arm and the 100mg tid treatment arm).
The effect of this biased retention was to reduce the apparent rate of decline in the control arm, leading to an underestimate of the effect size. Analyses conduced with and without correction for biased withdrawal both showed that the effect of treatment with 60mg tid remained significant. Therefore, the effect of treatment with Rember at the 60mg dose in retarding rate of disease progression over 50 weeks cannot be explained by biased retention. There was no evidence of biased retention in the 60mg tid treatment arm over 50 weeks.
The most striking outcome of the trial was demonstration of the treatment effect precisely in those brain regions known to be affected by tau pathology in prior clinico-pathological studies, said Wischik. In particular, the demonstration of treatment efficacy in the medial temporal lobe structures, the regions affected earliest and most severely by neurofibrillary pathology, supports the possibility of early intervention in disease progression from Braak stage 2 onwards, when these brain regions are first affected by the disease.
The trial was conducted in 17 trial centers, 16 of them in the UK, and one in Singapore. All of the trial planning, management and oversight was conducted from UK.
There is an extensive and distinguished publication record over 24 years from Wischik's research team, advocating the tau pathology of AD as the most appropriate therapeutic target for prevention and treatment of AD.
The company's recent clinical trial is the result of 24 years of research aiming to discover a therapeutic approach based on the neurofibrillary tangles originally discovered by Alois Alzheimer.
by Kimberly Ha in New York
is that that drug they're running for wet-AMD, and some niche cancer indication?
that's the company that took 3 years to recruit 25 patients or something right? I heard they got new management recently. finally.
why is roche buying DNA?
can someone offer a valid suggestion or reason why roche has to buy DNA?
if the partnership is going well - why change anything. is it because roche's pipeline is bleak. accounting reasons??
thanks.
and it's LLY! anyone have any thoughts on whether Bristol will sweeten its offer? i think anything over 70/share is too much. even at 70, they might be paying too much already.
also, do you guys like imclone's pipeline. sure, erbitux is no stellar drug, but it's revenue stream is still decent.
We'll have to wait and see how it plays out.
my own thoughts -
SVNT - I never liked Puricase. ACR data didn’t look to great either. The abstract from ACR that was just posted online a week ago for ACR. Safety reasons and 10% rate of IgE formation are keeping all the rumored acquirors away. recent share price reflects investor sentiment regarding partnership/M&A - as previously speculated. will prob never happen.
UTHR - don’t like that one either. The pricing on that stock is ridiculous. Can’t wait to see the Cialis data – should be an interesting day.
SQNM - dropped close to 10% today. some ppl like them, some ppl don't. i still think their down syndrome's test looks pretty solid. anticipating more pt data. some analysts still think this stock is way over value.
Orexigen's Contrave:
i never liked contrave, and i still think it's going to face a hard time at the FDA.
But nevertheless, here are the abstracts for the upcoming Obesity Meeting next week:
The Obesity Society Annual Scientific Meeting, Phoenix Convention Center
Saturday, October 4
Poster Presentation
Abstract: 317-P
Title: "The Naltrexone-Bupropion Combination Reduces the Prevalence of the
Metabolic Syndrome and Improves Cardiometabolic Markers in At-Risk
Subjects"
Time: 5:00-7:00 p.m. MT
Sunday, October 5
Symposium
Event Code: E1280
Title: "Reward and Obesity; Too Much of a Good Thing?"
Time: 6:15-7:45 a.m. MT
Location: Hyatt Regency Phoenix, Regency Ballroom A/B
Oral Presentation
Abstract: 61-OR
Presenter: Ronald Landbloom, M.D.
Title: "Long Term Weight Loss from a Dose Optimization Study with
Zonisamide SR and Bupropion SR"
Time: 11:00-11:15 a.m. MT
Poster Presentation
Abstract: 585-P
Title: "Relative Bioavailability of Sustained-release (SR) versus
Immediate-release (IR) Naltrexone (NAL) Formulations in Healthy Obese
Volunteers: Implications for Improved Tolerability?"
Time: 5:30-7:30 p.m. MT
Monday, October 6
Oral Presentation
Abstract: 104-OR
Presenter: Sonja K. Billes, Ph.D.
Title: "Leptin Regulates Food Intake Via Dopamine Receptor-Dependent
Mechanisms"
Time: 11:30-11:45 a.m. MT
Poster Presentation
Abstract: 847-P
Title: "Quality of Life Improvements from a Dose Optimization Study with
Zonisamide SR and Bupropion SR"
Time: 12:45-2:45 p.m. MT
Poster Presentation
Abstract: 848-P
Title: "Timing of Response from a Dose Optimization Study with Zonisamide
SR and Bupropion SR"
Time: 12:45-2:45 p.m. MT
Upcoming Corporate Presentations
JMP Securities Healthcare Sector Focus Conference
Le Parker Meridien, New York
October 6, 2008
10:00 a.m. ET
BIOCOM Investor Conference
Hyatt Regency La Jolla, San Diego
October 28, 2008
4:00 p.m. PT
agreed. dosing will be paramount in HCV. once a second/third generation PI comes out with once daily - it's game over.
any thoughts on potential for ritonovir boosting with 2nd/3rd generation PIs in development?
or did that theory die in 07 when they tested telaprevir / boce with ritonovir (Abbott)