PFE makes strategic sense, since they announced restructuring to focus on AD and oncology - instead of cardio.

As well as Celgene and Amgen. is that too far of a stretch?

personally wouldn't surprise me if nobody showed up at the table. i still think BMS will get them in the end.


http://www.ft.com/cms/s/2/d0258062-8e37-11dd-8089-0000779fd18c,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html

ImClone: USD 70 per share proposal submitted by US-based large pharma; Takeda not ‘mystery bidder’
by Sasha Damouni, Nadia Damouni and Kimberly Ha

Published: September 29 2008 16:12 | Last updated: September 29 2008 16:12


This article is provided to FT.com readers by dealReporter—a news service focused on providing insightful intelligence on event driven situations to investors. www.dealreporter.com

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Japan’s Takeda Pharmaceutical is not the so-called “mystery bidder” for ImClone Systems Incorporated (NASDAQ:IMCL) despite media reports, three industry sources familiar with the situation told dealReporter. Rather, it is understood that the company that submitted the USD 70 per share proposal for ImClone is a US-based large pharmaceutical company with strategic pipeline synergies, it was said.

ImClone disclosed on Monday that the unnamed large pharmaceutical company that submitted the proposal – initially subject to two-week due diligence – would either make a proposal, that is no longer subject to due diligence, or withdraw by 11:59 pm on 1 October. As mutually agreed, if the party withdraws and negotiations end, the name of the company will be disclosed.

Meanwhile, it is understood that ImClone is still not entertaining conversations with current bidder Bristol-Myers Squibb (NYSE:BMY) as it has not yet reached its offer criteria of USD 70 per share. ImClone’s Chairman, Carl Icahn called Bristol-Myers’ sweetened offer of USD 62 per share “absurd” on 24 September.

Although Takeda has been interested in US-based acquisitions in the areas of oncology and metabolic diseases, to get engaged in a hostile takeover, or competitive bidding situation would be “unusual,” to their corporate culture, a source close to Takeda said.

Instead, Takeda usually makes recommended, agreed deals, and are more under the radar when it comes to its M&A strategy, the source added.

Takeda acquired US-based oncology powerhouse, Millennium Pharmaceuticals at a 53% premium for USD 8.8bn earlier this year.

However, one industry oncology executive said Takeda was likely a party invited by Icahn to evaluate the company. “Keeping it quiet is in line with [Takeda’s] corporate culture,” the executive said.

He did note that Takeda is interested in developing its own pipeline, and any product with “the word prostate” would be an attractive add-on to the Japanese pharma company. ImClone recently initiated a Phase II trial in prostate cancer comparing its drug candidates IMC-A12 and IMC-1121B.

US companies that have been cited as possible bidders by sources and market investors include Celgene (NASDAQ:CELG), Amgen (NASDAQ:AMGN), Eli Lilly (NYSE:LLY) and Pfizer (NYSE:PFE).

It was said that Celgene, which is engaged in the development of treatment for cancer and immune-inflammatory-related diseases, could probably recognize the value of ImClone’s own products.

Although, it was said, that Celgene is not always described as a “large pharmaceutical company” but rather a biotech company, so it could be debatable if they are the unnamed bidder. Celgene’s CEO Sol Barer was in meetings throughout the day and could not return calls for comment.

But the industry oncology executive said ImClone may be less of a strategic fit for Celgene than for Amgen. The executive said it would not surprise him to see Amgen mull a bid as it has EGFR inhibitor, Vectibix, while ImClone’s lead drug Erbitux is also an EGFR-targeted agent. “There is certainly a lot of technical synergy with both Erbitux and its follow-on pipeline,” he said.

Similarly, ImClone’s products are also complimentary to Eli Lilly, which markets oncology drug Alimta indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) and Gemzar, which is indicated for the treatment of various cancers.

One market investor said Erbitux has shown a benefit in NSCLC patients with squamous cell carcinoma, one indication which Lilly’s Alimta is currently not approved for.

The source close to Takeda speculated that Celgene and Amgen could emerge as bidders for ImClone, however, said it was unclear whether it would make such synergistic sense from a product perspective.

As for valuation, the industry oncology executive said he “ran figures” on ImClone and noted paying over USD 70 per share does not make sense. “Up to USD 70 per share, over that, forget it,” he said.

But there is still the chance that a deal may not materialize, it was further offered. It was said that parties showing an interest now could wait and see if the unnamed bidder arises, and if not, would not need to pay more than USD 70 per share.

It was reported by this news service on Friday that it would not be a surprise if the due diligence period was extended past the Sunday deadline. It was further noted, however, that the mystery buyer was slightly taken aback by Icahn’s first public announcement of the USD 70 per share offer because the bidder’s approach was still at an early stage, but is serious.

The company opened trading for the week at around USD 63 per share.

Thanks. I agree. methylene blue as an AD cure is kind of a far stretch.. then again, PFE partnered with MDVN..so you never know.

it's an old report from 06

any thoughts on ACR data, savient's puricase doesn't look too hot. but i'm looking forward to AASLD next month. that should be interersting. a lot of action in the HCV space.

Question for the board - what is your favourite drug in development so far, in terms of blockbuster potential?

Personally, I'm going with the Alzheimer's drugs. In the next 5-10 yrs, hopefully we'll see the first disease modifying agent.

oral MS drugs in development are also pretty exciting.

hopefully M&A activiity will heat up even further in healthcare.

pharmawire on Takeda's alogliptin.

18-Sep-08 07:38 Takeda’s alogliptin US approval chances high, doctors say, although uncertainty remains over US regulatory climate
Story Key opinion leaders interviewed by this news service were largely optimistic about the US approval chances of Takeda’s alogliptin, seeing no obvious barrier to its approval – with a similar label to the others in the class – apart from a general uncertainty over the current US regulatory climate.
The Japanese company submitted its new drug application (NDA) to the FDA for its dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin for the treatment of diabetes at the end of December 2007 and under the normal approval timeframe a decision is expected by the agency at the end of October/November this year.
However, there is much confusion as to how it may be assessed by the FDA given the fact another drug in the same class, Novartis’ Galvus (vildagliptin), only received an approvable letter in 2007 after preclinical data showed the drug caused skin lesions in monkeys at high doses. The FDA were concerned that a metabolite of the drug may accumulate in patients in renal impairment and asked Novartis to conduct further Phase III studies in patients with renal impairment.
When asked to comment on this, a Takeda spokesperson said: “Based on pharmacokinetic data in patients with renal insufficiency we have not received a request for additional studies.”

Clean animal model

An abstract presented at this year’s American Diabetes Association (ADA) meeting showed that oral administration of alogliptin once daily for up to 13 weeks in patients with various degrees of renal impairment as well as end-stage renal disease (ESRD), was not associated with dermal toxicity in Cynomolgus monkeys – the same type as was used for vildagliptin [and BMS/Astrazeneca’s Onglyza (saxagliptin), also in the FDA approval process] where skin lesions were seen.
The spokesperson said this was “probably” submitted to the FDA as part of the NDA.
Speaking to this news service after presenting a poster of alogliptin at this year’s European Association for the Study of Diabetes (EASD) in Rome last week, Professor Richard Pratley, director of the Diabetes & Metabolism Translational Medicine Unit at the University of Vermont College of Medicine and a lead investigator on some of the research, said he was confident alogliptin would receive FDA approval.
He believes the FDA were “unreasonable” with their request for extra data from Novartis and said that given the fact that alogliptin induced no skin lesions in monkeys in preclinical studies, “I would not be at all surprised if alogliptin was the second DPP-IV on the US market.”
Pratley believes that Takeda has “enough” Phase III data in hundreds of patients with mild to moderate renal impairment and does not think that it will need to do any more studies in this patient population in order to gain regulatory approval.
Pratley also confirmed that the company is planning to do more studies in patients with severe renal impairment to assess whether dose adjustment is required.
“If alogliptin does have a problem with the FDA) then everybody (trying to get drugs in this class approved) has a problem,” he said.
He added that alogliptin is very potent and the 25mg dose is “well-tolerated” and in terms of the DPP-IV inhibitors, alogliptin is more similar to the already-approved Januvia (sitagliptin) and both are renally excreted unchanged, where as saxagliptin is more similar to vildagliptin.

Label warnings expected on all new DPP-IVs

When asked to comment, professor Anthony Barnett, head of diabetes and obesity group at the University of Birmingham in the UK, said he believes the FDA will scrutinise alogliptin “just as much” as the other gliptins but are “less likely to have a problem if the animal data is clean.”
He agreed with Pratley that “alogliptin looks more like sitagliptin and probably less problematic than vildagliptin and saxagliptin. Time will tell,” he added.
It was his feeling that after seeing what happened with vildagliptin, Takeda will have made sure they had all the necessary renal data to provide to the FDA.
It was also Barnett’s belief that all drugs approved in the DDP-IV class from now on, including alogliptin, will carry the same warnings on their labels.
Pratley agreed that alogliptin is likely to have the same labelling caution as the other drugs in class, even though he does not believe that any skin reactions in humans are due to a class effect – sitagliptin has had post marketing reports of serious allergic and hypersensitivity reactions in patients, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome occurring within three months of taking Januvia, sometimes after the first dose. The label has been updated to caution patients to discontinue using the drug if such a reaction is suspected.
Pratley said that the alogliptin development programme was different to that of other DPP-IV inhibitors in that all the patients studied in the Phase III trial were systematically assessed for any skin lesions/reactions. This trial design led to an increase of skin adverse events seen across the board but there were no significant drop outs related to this, he said.
When questioned as to his viewpoint, Professor Bo Ahren, dean of the Faculty of Medicine at Lund University, and an investigator on several of the vildagliptin trials, said that his opinion, based on information from meetings such as EASD, is that alogliptin is “very clean from a safety and tolerability point of view. Therefore, I anticipate no problem in the approval procedure.”
Meanwhile, on the sidelines of the EASD, professor Michael Nauck, head of the Diabeteszentrum Bad Lauterberg, Germany, who has also been involved in alogliptin research, said “as far as I know regarding the specificity, alogliptin is clean.”
“If you assume that cross reactivity with DPP-8 and -9 plays a role in possibly causing a reaction in the body then this may make a difference.”
In the literature, some non-selective DPP-4 inhibitors have been reportedly associated with dose- and duration-dependent skin lesions in monkeys, which may be related to off-target pharmacologic activity in the body. Novartis thinks there is no association, where as Merck thinks there is, he explained.
In terms of the FDA’s potential request for more renal data, Nauck said that it will depend on whether the company has submitted [adequate] pharmacokinetics data showing that the drug had no change in patients with renal impairment.
“Takeda seems quite confident. I don’t see a problem apart from a general change of policy towards diabetes drugs at the FDA.”
Ralph DeFronzo, professor of medicine and chief of the Diabetes Division at the University of Texas Health Science Center, who has also been involved in alogliptin research, echoed this sentiment, stating that in general he agrees with the statements of professor Pratley, in regard to alogliptin’s approval chances, but that “nothing can be established with certainty when dealing with the FDA and today’s environment.”
Steve Nissen notes expected changes in diabetes regulatory approval

Indeed, Professor Steven Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, Ohio, said that changes are underway at the FDA to “raise the bar” for the approval of diabetes drugs.
He said that an Advisory Committee in July had voted in favour of various proposals for change that he put forth, centred around a new two-step process for approval; the first being a requirement that the drug has enough data to demonstrate that it doesn’t increase the risk of cardiovascular events; and the second being a requirement to have a Phase IIIb study already enrolled and running prior to any approval is granted, in order to ensure that the drug will be monitored over a long period of time in a large real-world patient population.
It is now up to the FDA to implement the recommended changes and it is “quite likely” that they will do so and issue a guidance document on the changes by the end of the year or early next year, said Nissen – which is after the expected approval date for alogliptin. He was not sure what this would mean for the drugs that are already in the regulatory process.
He did point out however, that even when there is no problem with an approval package per se, the FDA has been “constantly missing” approval dates of late as the agency is becoming increasingly dysfunctional.
Takeda has a market cap of YEN 4198.035tn (USD 40bn).
By Kirsty Barnes in London

pharmawire - this is interesting.. any thoughts on TauRx? also rumoured that large pharma currently have partnership interst with them.

thoughts on mdvn? i thought that partnership kind of came out of the blue. might be a risky bet - but may pay off. who knows..


18-Sep-08 11:45 TauRx's Rember looks promising, but data still has to be replicated in larger studies, CEO says
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

pharmawire article - javelin trying to shop itself?

18-Sep-08 15:55 Javelin Pharma in the process of trying to sell itself; UBS retained as investment bank, sources say
Story Javelin Pharmaceuticals (JAV), the listed Cambridge, Massachusetts-based specialty pharmaceutical company, is in the process of trying to sell itself, sources said, despite company assertions of “robust” partnership strategy.
Late last month CEO Martin Driscoll told this news service that it hopes to have a partner in place for its injectable pain drug, Dyloject (diclofenac sodium) in the near future. Talks are currently ongoing Driscoll had said at the time, and it is unclear whether a single partner will emerge with worldwide rights or whether the company will choose to work with a different company in each region.
A first source familiar with the situation said that Javelin had retained UBS as its investment bank to run an auction process, which entails a sale. First round bids were due the final week of August, and at the time around seven bidders, of different types, including private equity, private companies, and smaller specialty pharma, were interested, the source added.
UBS declined to comment. In an email response, Javelin’s Driscoll said the company’s product partnership discussions are robust. Regarding M&A activity, he said it is Javelin’s policy not to comment.
A second source said it was to his understanding that the company has had a number of discussions to either partner their product or sell the business.
The company has three Phase III products – Dyloject for post operative pain, Rylomine (intranasal morphine) indicated for acute moderate-to-severe pain, and Ereska (intranasal ketamine), indicated for acute moderate-to-severe pain – of which firms have looked at over the past couple of years, the second source said. There has historically been some skepticism regarding these products, he noted, as the company has not been able to partner them or sell “them for a while.”
Still, the second source emphasized the company needs to consider either strategy as it is burning through a great deal of cash and would not have enough money to get the products on the market. Javelin's six month cash burn as of August 2008, was approximately USD 19m. The company has USD 41m in cash and cash equivalents.
The second source was more conservative on a private equity bid. He said private equity firms will look at a lot of things, and are "desperate" to make investments, but cautioned that taking Javelin private is risky due to high costs. He noted that he has communicated with Javelin in recent weeks, and the company has made it known it is still trying to partner some of their products.
UCB, the Belgian pharma group, which specializes in key therapeutic areas such as inflammation, oncology and the central nervous system, would be a logical suitor, the second source said. Yet due to UCB's current restructuring initiative, and plans to re-establish itself as specialty drug firm, the source said he remained unsure about its current viability as a bidder for Javelin.
The Belgian-based company plans to cut 17% of its worldwide staff, an approximate reduction of 2000 employees, as part of its restructuring plans, due to key drugs going off-patent.
Cephalon is another M&A suitor possibility, the second source added.
Endo Pharmaceuticals has also been flagged by an analyst as a potential partner for Javelin in a previous report published by this news service. The first source said he did not believe these would be the types of companies that would be potential partners.
Javelin has a USD 148m market cap.
by Sasha Damouni

Avastin -brain cancer bleeding risk??

http://www.ft.com/cms/s/2/f4bf6a1a-857b-11dd-a1ac-0000779fd18c,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html


Avastin may increase risk of neural bleeding and stroke in patients with glioblastoma multiforme, physicians say CORRECTION
By Klara Czobor

Published: September 18 2008 13:24 | Last updated: September 18 2008 13:24


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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(This report replaces the story published 18 September which had mistakenly cited Dr William Leenders in paragraph seven as saying the likelihood of experiencing a neural hemorrhage after receiving Avastin is approximately 70%. He had, in fact, said 17% (the actual figure was 15.4% based on two events in 13 patients according to one publication). Dr. Leenders was also incorrectly referred to as a physician when he is a researcher.

The article also contains further comment from Genentech in paragraphs in paragraph eight and in the penultimate paragraph)



Avastin (bevacizumab) may increase the risk of neural bleeding and stroke in a small population of patients with glioblastoma multiforme, according to several physicians interviewed by Pharmawire. The gravity of this side-effect should be carefully studied, they added.

The drug acts by targeting vascular endothelial growth factor (VEGF) and is thought to act by blocking the formation of new blood vessels (angiogenesis). The drug is approved by the FDA for the treatment of patients with non-small cell lung cancer, colorectal cancer and metastatic breast cancer. Avastin is currently undergoing Phase II clinical studies in patients with glioblastoma multiforme.

A significant side-effect of Avastin is that the drug’s administration may cause bleeding complications in the brain, according to Dr Steven Wong, a brain cancer expert at Harvard University. Genentech did not want to initiate clinical studies of Avastin in glioblastoma because the neural bleeding risk was so heavily feared, Wong said.

Serious bleeding complications occur in a little less than 5% of the patients who receive Avastin, Wong explained. Also, administering the drug in the time frame of four to six weeks before and after surgery could increase the risk of bleeding in the brain, he added.

A Genentech spokesperson said safety concerns did not emerge in the Phase II study of Avastin in patients with glioblastoma.

However, due to lack of data from randomized controlled clinical studies, physicians estimated that anywhere from 2% to approximately 15% of patients given the drug may experience the side-effect of bleeding. Treatment with Avastin has also caused stroke and hemorrhage in patients with colon and non-small cell lung cancers who have brain metastases, according to oncologists that treat patients with those diseases.

Dr William Leenders, who is currently studying Avastin in this indication, and an expert in the department of pathology at the Raboud University Nijmen Medical Centre, said the likelihood of experiencing a neural hemorrhage after receiving Avastin is approximately 15% (2 events in 13 patients according to one publication). Leenders said that according to another publication, 1 patient out of 35 (3%) experienced bleeding. Physicians cannot do anything to minimize patients’ potential risk of bleeding after receiving Avastin and many physicians are wary of administering the drug for glioblastoma due to this risk, Leenders said. Genentech has not seen such a high number of reported adverse events associated with Avastin in a clinical trial for any tumor type, a Genentech spokesperson noted. If this number is based on anecdotal reports from physicians, then it could be very misleading, the spokesperson said. In a Phase II trial for relapsed glioblastoma multiforme, Avastin was well tolerated and associated with low rates of bleeding, she added. Still, Dr Maria Juarez, a specialist at the Cancer Institute of Dallas noted that the rate of neural bleeding in past clinical studies of Avastin was so low, because they excluded patients with brain metastases. Avastin can increase the risk of hemorrhagic stroke, systemic stroke and blood pressure, Juarez said.

Yet Dr Henry Friedman, an investigator who has in the past received research support from Genentech, and who is also the deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University, where Avastin is currently being studied, disagreed and said that the bleeding caused by Avastin is “very rare”. It also does not appear that patients who are on anti-coagulants are at a higher risk for bleeding than those who are not, he added.

The rates of serious bleeding were in the 1-2% range in a clinical study that tested the effects of Avastin and Pfizer’s Campostar (irinotecan) compared to Avastin alone in patients with recurrent glioblastoma multiforme, said Dr Robert Mass, senior group medical director of BioOncology at Genentech. Campostar is a topoisomerase 1 inhibitor that is often administered in combination therapy with Avastin for a variety of indications. This rate of bleeding is acceptable since patients with glioblastoma are prone to experience bleeding as a result of their disease, Mass said.

“We knew that based on the way the drug works, we knew that bleeding is a complication, and there could be an increase in the risk of bleeding,” Mass said.

Patients with colon cancer who have brain metastases are at an increased risk of developing bleeding in the brain when given Avastin, added Dr Alfred Neugut, an oncologist who treats patients with colorectal cancer at Columbia University Medical Center. Physicians are especially concerned that patients given the drug may have a hemorrhagic stroke, Neugut added.

Treatment with Avastin has led to bleeding, and even death as a complication of the hemorrhage according to Dr Rakesh Jain, a brain cancer expert at Harvard University. The side-effects of the drug in this patient population have been published by the Duke University Study Group, Jain said. The drug’s adverse event profile and efficacy needs further study in Phase III clinical trials, he said. Genetech is planning on initiating a Phase III study evaluating Avastin in this patient population, a spokesperson noted. The Phase III trial will evaluate the standard of care of chemotherapy and radiation plus or minus Avastin in newly diagnosed patients with GBM.

Yet due to the lack of available treatments for patients with metastatic glioblastoma, if Avastin is shown to be an efficacious, it would be a major advantage for this patient population, said Dr Chin Wang, an oncologist at the Cancer Institute of Dallas.

Wang agreed that Avastin has been shown to be associated with an increased risk of stroke. It is not known if having glioblastoma and receiving Avastin increases your risk of a stroke even more so than receiving Avastin for other cancer indications, he added.

In addition, patients administered Avastin are at an increased risk for developing an ischemic stroke, which occurs after the formation of a blood clot in a vessel, explained Dr Leia Phioanh Nghiemphu, a specialist studying Avastin at UCLA. Higher rates of ischemic strokes have not occurred in the glioblastoma population to date, Nghiemphu said.

Still, ischemic strokes caused by Avastin could occur at a higher rate in the glioblastoma population which is comprised of older patients, she noted. Older patients receiving Avastin in the colon cancer trials were at an increased risk for developing ischemic strokes, Nghemphu added.

Several cases of cerebral hemorrhage in patients with brain metastases emerged in the studies used to gain FDA approval for Avastin for the non-small cell lung cancer indication. Future studies should investigate if Avastin increases the risk of bleeding in the brain after administering Avastin, Wang said.

The trials used to gain FDA approval for patients with non-small cell lung cancer did not enroll patients with brain metastases, Mass said. Currently Avastin is being studied in clinical trials enrolling patients with non-small cell lung cancer who have brain metastases, he said. The preliminary data that was presented of Avastin in this patient population at ASCO suggests that it is safe to give the drug in this manner, Mass said.

It is important for physicians treating patients with brain metastases to disclose the drug’s potential risk for causing bleeding and stroke, Wang advised. Physicians should also treat patients with chemotherapy or radiotherapy prior to administering Avastin, Wang said. Those treatments would potentially destroy some of the blood vessels feeding the tumor and thereby reduce circulation, Wang added. It is hoped that when the tumor is not actively growing as before, the chance for bleeding and stroke is lower, Wang said.

Nghiemphu, who has studied the drug in small clinical trial enrolling 20 patients, said that Avastin only increases the risk of bleeding by 1-3% in glioblastoma patients. Avastin’s benefits for glioblastoma patients outweigh its risks as glioblastoma is a very deadly cancer with a high risk of recurrence, she said.

Genentech is planning on conducting a randomized clinical trial of Avastin in patients with glioblastoma multiforme, based on the high tumor response rate and tumor free progression that was seen in studies to date, Mass said. “Genentech recognizes the importance of further evaluating Avastin in a randomized Phase III clinical trial in glioblastoma,” the spokesperson said. “The Phase II findings have with Avastin have exceeded our expectations, which is why we plan to submit an sBLA to the FDA for accelerated approval of Avastin,” she added.

Based on data from a Phase II clinical trial that was presented at ASCO this year, 0 out of 84 patients receiving Avastin alone and 3 out of 79 patients receiving Avastin and chemotherapy experienced a grade 3 or higher hemorrhage. A tumor response was seen in 28% of patients treated with Avastin and 38% of patients treated with Avastin in combination with chemotherapy.

amylin's byetta - does anyone know what is going on here? has this stock reached the floor yet??

also, does anyone know the mechanism of action for byetta - and exactly what causes pancreatitis??

thanks. pls advise.

CARDIOME CALL TMR AT 9 AM ET

Cardiome Pharma Corp. (NASDAQ: CRME / TSX: COM) today announced that a conference call and webcast will be held on Monday, July 14, 2008 at 9:00am Eastern (6:00am Pacific) to discuss final results from the Phase 2b study for vernakalant (oral). A press release will be issued prior to the call.
To access the conference call, please dial 416-641-6117 or 866-299-6655. There will be a separate dial-in line for analysts on which we will respond to questions at the end of the call. The webcast can be accessed through Cardiome's website at www.cardiome.com.
Webcast and telephone replays of the conference call will be available approximately two hours after the completion of the call through August 14, 2008. Please dial 416-695-5800 or 800-408-3053 and enter code 3266465 followed by the number sign to access the replay.

thanks jbog. i'm still waiting on word on the biogenerics legislation to clear up before getting into the biotechs...but DNA still has Avastin...which seems to be unaffected by erby or any competition right now for that matter. stock took a hit from that NY times article, but avastin is still the leading cancer blockbuster in the market. nothing else really comes close.

didn't the market price in the copaxone litigation already on Friday? down 8% you think there's more downside?


Long-term

DNA – Genentech

PFE – Pfizer

BDX – Becton Dickenson

ABT – Abbott Laboratories

ZHM – Zimmer Holdings

TEVA – Teva Pharmaceuticals

UNH – UnitedHealth

GILD – Gilead Sciences

CELG – Celgene

BAX – Baxter International


right now , the short term events i'm following are theravance, and cardiome.

and obviously the wyeth/elan Alzheimer's drug. did you see those two reports on the 20% potential downside from ICAD that came out on Fri?

thoughts on theravance? do you think they'll approve it this time? heard that they've cleaned up their manufacturing problems and that GSK is rumoured to be taking an M&A interest in them again..

top ten picks in pharma - which stocks do you see as top ten longs in the sector? heard that zimmer and strkyer are good buys due to the aging population.

also, any thoughts on if PFE is a good buy now? or will keep bleeding with the market?

Do you think DNA will still be the best long as we head into recession

Pharmawire article by Kimberly Ha in New York
12:41 Wyeth/Elan's Alzheimer's candidate bapineuzumab faces potential Phase III hurdles - analysis

thoughts? how likely is this drug going to get approved by FDA?
can we expect good or bad results at ICAD??

Story Wyeth/Elan's Alzheimer's candidate bapineuzumab faces potential Phase III hurdles, according to physicians and investigators.
Recently released data showed that bapineuzumab may improve cognitive functioning in patients who are non-carriers of the ApoE4 allele. Serious adverse events, such as vasogenic edema also occurred more frequently in bapineuzumab-treated APOE4 carriers.
Although the results for the subgroup were positive, the finding is inconclusive until it can be replicated and confirmed with larger follow-on studies, many of the physicians interviewed agreed.
“Many trials in the past reported findings that appeared highly promising, but were subsequently not confirmed in a duplicate trial,” said Dr. P. Murali Doraiswamy, chief of biological psychiatry at Duke University Medical.
APOE4 is only a correlating risk factor for Alzheimer’s, not necessarily a cause, and some physicians suggested that Wyeth and Elan’s bapineuzumab trials are just a “proof of principle” trials at best.
Scientists discovered the APOE4 correlation with Alzheimer's 15 years ago in the Roses Lab at Duke University, but have not yet established a causal link yet. Although 40-65% of AD patients have at least one copy of the 4 allele, APOE4 is not a determinant of the disease: at least a third of Alzheimer's patients are APOE4 negative and some APOE4 homozygotes never develop the disease.
Dr. G. William Rebeck, associate professor in the Department of Neuroscience at Georgetown University Medical Center, who has been conducting research on APOE since the early 1990s, said the study still needs to be duplicated as the higher frequency of vasogenic edema in patients carrying APOE4 was a post hoc analysis and there was no obvious underlying biological cause that would lead to such a reaction.
Dr Marwan Sabbagh, an investigator on Wyeth’s bapineuzumab trials and author of The Alzheimer’s Answer, said that so far the side-effects of vascular edema did not correlate with efficacy and are not predictive of a better response.
As APOE4 carriers (APOE4+) reported a higher incidence of adverse events, it is possible that bapineuzumab could be approved for non-APOE4 carriers. APOE4 status can be determined with a simple blood test.
Pfizer’s mild cognitive impairment (MCI) studies of Aricept (donepizil), a leading Alzheimer’s treatment, had a better effect in APOE4+ patients, while Wyeth’s bapineuzumab trial showed better effect in non-APOE4+ patients, according to Dr. Greg Jicha, an investigator on the Phase III trials, and professor of neurology at the University of Kentucky College of Medicine. Previous studies have found that the effect of the Aricept treatment lasted longer in those patients carrying the gene.
Studies have also shown that patients with the APOE4 gene have a higher propensity to develop Alzheimer's than the general population. "I query over this differential effect. I always took the Pfizer data to suggest that we can be a bit more definitive that patients with APOE4+ status had a higher likelihood of AD rather than an AD-mimicking disease," he added.
“The Phase IIb studies were clearly enough to make us understand we have to stratify dosing by genotype. It’s a first step in an area that will emerge as very common,” said Sabbagh.
When asked why Wyeth/Elan included APOE4+ patients on their Phase III trials, Rebeck said the companies were probably not "entirely convinced" from Phase II and would like to see it in a larger study.
Sabbagh said it is too late to change the trial design, even in light of the recent results. "My impression is that they were trying to just push ahead. It boils down to the first company to get an FDA-approved disease modifying agent, so there was this big push," added an anonymous investigator.
Another investigator speculated that a problem with Elan's Phase II trial was sample size calculation. "At least they got a signal in the non-APOE4 carriers which was enough for them to move forward," another investigator added.
Dr Neil Kurtz, CEO of Torreypines Therapeutics said Wyeth probably did not know about the APOE4 results, and that is why they recruited these patients into their larger Phase III trials.
An investigator who wished to remain anonymous explained that antibodies are specific for oligomers. Wyeth has said this drug is soluble for oligomers, he said, yet the drug was not designed to be specific. "I’m not sure whether they’re specific enough. If they could find any degree of activity, they can argue specificity. There are some antibodies that only recognize soluble oligomers, if you have a monoclonal cell line that produces a monoclonal antibody, you can humanize that and make it specific to a soluble amyloid."
He speculated that both companies are so invested in this antibody, "you don’t want to throw that out. But maybe we need to move to another approach."
In addition, the anonymous investigator said, "We had seen and heard there’s a great deal of skepticism about the agents that are pulling into Phase III trials. None of these agents have stellar early reports either. If I had Alzheimer's, I would enroll in Phase I and II studies rather than Phase III at this point."
Wyeth and Elan would not provide comment.
When asked whether Elan/Wyeth have the right Phase III trial design, such as patient characteristics and doses, the investigator said the companies were on target. Sabbagh added that protocol amendments can be done, but fundamental changes in trial design are usually not seen.
"APOE4 is definitely a risk factor and is found in roughly one-third of the US population. It seems to play an important role in the outcomes of clinical trials," said Dr Scott Turner, associate professor in the Department of Neurology at the University of Michigan Health System and incoming director of the Memory Disorders Program at Georgetown University Medical Center.
Only a subset of subjects will respond to certain medication, such as patients who are APOE4+. Myriad Genetics has data on the APOE4 status of patients on their recently failed Flurizan trial – but they haven’t released this specific data yet, said Turner.
"With the Flurizan trial, maybe some patients did tremendously on the drug, and some patients dragged down the overall results," said Jicha.
Myriad failed to meet its primary endpoint in a Phase III trial for a potential disease modifying agent named Flurizan earlier this week. "Flurizan tanked, just like Alzhemed. The site to site variation is plaguing the industry,” said Sabbagh.
The amount of resources needed for such large trials has become a problem, Rebeck noted. “When you’re analyzing data, sites ended up with statistically different results from each other. The assumption was that we could control for all the site to site variation,” he said.
Genotyping patients before deciding which therapy to give in the future may become a reality – and certain laws regarding APOE4 status to prevent genetic discrimination are currently underway, the physicians noted.
There is a clear need within the industry to develop and use a more objective quantifiable measure, such as the Pittsburgh Compound B (PIB), which binds to and can track levels of amyloid plaque in the brain.
“If we can quantify a reduction in amyloid load in the brain, that’s hard data that we as an industry have been sorely lacking. Many researchers in the field think it’s not good enough anymore, as we have surrogate markers now," said Sabbagh.
This is the first real step at looking at an objective measure in amyloid burden. Establishing a correlation with PIB would probably be the biggest finding of the year, and those works are underway, Sabbagh added. However, although the PIB principle is desirable, many physicians cautioned that proof is needed to show that PIB changes with disease progression. “I’ve heard some rumors that they have some studies that it changes with intervention,” said Sabbagh.
When asked whether PIB is at a stage where companies can start using that in trials, Sabbagh said, "theoretically, yes." One source close to Wyeth’s trials said PIB as an imaging agent was also proposed in the Phase III bapineuzumab trial, as well as many other studies. “Is PIB ready? No. Are we exploring it, yes,” he added.
If the correlation between amyloid plaque reduction and clinical improvement was shown by using the PIB imaging agent, it would be a significant move forward to Alzheimer's trials. PIB would be analogous to CD4 counts in HIV, said Turner.
"I think PIB will only give us a bit more biological data. We still need to find that surrogate marker," said Jicha.
There is currently no concrete correlation between amyloid plaque reduction and clinical benefit. "We don’t know that for a fact with human studies, but know that with mice. Plaques correlate with memory loss, and all of these are unanswered questions when it comes to human studies," said Turner.
"A lot of money is going into this. You can’t see individual plaques in living humans, but can see that on brain sections after death. You can see PIB binding in a nuclear medicine study, and this is one of the biomarkers being developed," said Turner.
The current industry goal is to stabilize the amount of plaque by the investigational drug, or even decrease the amount of plaque, and then conduct repeated PIB imaging scans as well as cognitive outcome measures to test for correlation, said Doraiswamy.
Some physicians also speculated that the recent failures may not have anything to do with the agent's efficacy, but a fundamental flaw in trial design, as there is no current standard set forth from the FDA on disease modifying agents for the treatment of Alzheimer's disease.
"On a practical level, as long as the patient is not worsening or improving, we might not care whether its disease modifying or not. In order to test that, we have to be able to determine disease burden while the patient is still alive. That’s why there is a lot of interest in this PIB scanning to determine this effect," said Turner.
But this would have to be validated by eventual autopsy studies and would take several years whether a drug is actually a disease modifying agent, physicians said.
"I think that we’re evolving into a field where we test for amyloid levels before giving a drug, and then test after for levels of PIB to show plaque reduction," said Turner.
However, most of the patient's on Wyeth's trials were also on Aricept - a drug which may also show a potential disease modifying effect. "Nowadays everyone is on Aricept and Namenda. Aricept might also have a disease modifying effect, and there is some evidence that it changes even some of the biological markers, and rate of brain atrophy," said Jicha.
Another potential reason behind both Neurochem’s Alzhemed and Myriad’s recent failure is the current gold standard endpoint used in Alzheimer’s trials – the ADAScog- may not be sensitive enough to pick up slight improvements in executive functioning in patients on trials, physicians noted.
"There is an interest in moving ADAScog out from being the primary outcome measure, and that the Flurizan data shows we don’t want to keep using ADAScog," said Sabbagh.
The ADAScog is not a perfect test, added Turner, but it’s a test that the FDA accepts as proof of efficacy. This is partially guided by what will convince the FDA and public that a drug has a positive outcome, he added.
"We’re certainly looking for better tests than the ADAScog. Other outcomes are used as well. It's certainly not a perfect test, but a standardized one," said Turner.
Jicha said the industry changed the entire treatment from symptomatic to disease modifying, but the FDA still depends on the symptomatic endpoints.
"There is some concern that we may have too many eggs in one basket, which is the amyloid basket. We still don’t understand the amyloid theory at a molecular level as much as we’d like to," added Doraiswamy.
Three different classes of drugs - the estrogens, statins, and anti-inflammatory class - were all promising in transgenic mice models, but physicians said have not shown success in human studies.
"This raises some questions about whether we’re approaching the amyloid pathway as precisely as we need to, or whether this is completely an epiphenomenon," added Doraiswamy.
“We know amyloid accumulates but we don’t know why. Is it the cause or effect? We also don’t understand the types of amyloid,” said Doraiswamy.
There are a lot of different subtypes of amyloid such as soluble and non-soluble types of amyloid. Amyloid plaques found in Alzheimer's patients can be in fibrillar form - long, insoluble fibers bound together in deposits called senile plaques. However, there are also soluble forms of amyloid beta, or oligomers, that may decisively contribute to neural degeneration.
Many physicians suggested that amyloid plaques may be analogous to cholesterol, where some types of amyloid are more protective - and some are harmful when removed.
Current agents such as Wyeth/Elan’s bapineuzumab are not selective enough to target a specific form of amyloid, said one trial investigator. “We’re targeting [amyloid] somewhat crudely, similar in the old days when we thought all cholesterol were bad,” supported Doraiswamy.
But at the end of the day, it will come down to risk-benefit, he added. The issue is not the side-effect, but the frequency of these events and whether they are dose dependent and predictable, he explained.
Elan found in their initial studies that there was a slightly higher frequency of vascular edema in APOE4+ subjects. The original theory was that APOE4 patients had more deposition in the brain, but there is still no hard evidence that these events are APOE4 status dependent.
“Nobody knows for sure what the right dose is still,” said Doraiswamy.
The company is being cautious, said Doraiswamy, noting that in the APOE4 non-carriers, the frequency was very low, so the company possibly felt a bit more confident with studying a broader dose range.
The next step in Alzheimer’s will be to develop a baseline PET scan that maps the level of amyloid load in the brain. The drug will then be combined to tailor the right dosing. Hopefully that will be the next step from companies 6-12 months from now, said Doraiswamy.
Doraiswamy noted that Wyeth currently needs two trials for approval, unless it’s expedited approval. "They would have to see very clear results, and minimal side effects. If the drug reported marginal side effects and continued to have the same risk of edema, I don’t think the field would be that excited," he added.
Rebeck said they are starting to incorporate the PET scan in trials, but this work is still preliminary.
Current Alzheimer's trials which are usually 18-months in length are too long, and are exposed to too many external variables and confounding effects. In order to get rid of that variation, there has to be a relatively quantifiable measure, some physicians said.
"The search for a biomarker where you can quantitatively measure something in a relatively short period of time is absolutely essential for the field to move forward," said Rebeck.
Ideally, a biomarker, or a ‘Factor X’ is identified in the mild cognitive impairment population. Therapies could then be developed to bring down Factor X. “We don’t know what Factor X is right now. We don’t know whether if we modify a-beta in the short term, whether it’ll even help,” said Rebeck.
Dr Ralph A. Nixon, associate professor of psychiatry and an amyloid expert at Harvard Medical School and McLean Hospital in Boston, said biomarkers in the cerebrospinal fluid (CSF) are an area that is urgently in need of more research because it is holding up some of the clinical trials.
The issue with measuring amyloid levels in the CSF as a surrogate endpoint is that actual progression of the disease causes amyloid levels to decrease over time, said Jicha. "They are reduced with the disease progression, so how do we know whether it’s the disease or the drug? You’ll never have any definitive proof for it. That’s a big problem."
"The fact that they may be doing the study may not necessarily be indicative of using it as an outcome measure. It may be a parallel analysis," added Nixon.
"The bottom line is this is the time where we have to do a lot more work. There are studies being designed to include PIB assessment before treatment and after treatment is part of the design. That is going to be a very important element in testing the efficacy of amyloid lowering as a viable therapy," Nixon said.
Nixon added that the current investigation is underway on patients from Wyeth's very first immunization trial that have now come to autopsy. "They have the clinical information after that trial as well as some pathologic information," he said.
"It's not that the current approaches are bad, but we need to take a fresh look at targeting the specific pathology of the disease," said Jicha.
Wyeth has a current market cap of USD 61.92bn. Elan has a current market cap of USD 16.58bn.

i guess my major concern with auxilium is that - is their drug already available in generic form OTC?

that is a good point. haha.

anyone still following auxilium? does anyone know a market size for their lead drug xiaflex?

pharmawire article:

15:03 Auxilium's Xiaflex unlikely to be used off-label for cellulite; faces safety, efficacy questions in cosmetic use - physicians
Story BioSpecific's collagenase injection, which is in Phase I studies for cellulite, already faces skepticism about its efficacy and potential to cause off-target effects, physicians say.
Even if the drug - known as Xiaflex - reaches the market next year as a treatment for Dupuytren's Contracture, a debilitating hand condition, it is unlikely to be widely used off-label for cosmetic purposes, they add.
The collagenase enzyme has been available for years through compounding pharmacies, and is already used in a controversial cellulite treatment known as mesotherapy, in which patients receive injections ranging from caffeine to artichoke extract to help dissolve fat.
Nevertheless, it's nearly impossible to find studies of the agent in cellulite - something that would be easy enough for physicians to conduct, noted Dr Adam Rotunda, a clinical instructor of dermatology at UCLA's David Geffen School of Medicine. "I would imagine that this would have big buzz," he said. "I'm very skeptical about injectable treatments for cellulite."
Collagenase breaks down the collagen bands that run through fat and are believed to cause dimples under the skin. "Collagen is only one of several reasons for cellulite," Rotunda said, adding that there's no proof that breaking down these fiber bands will improve the look of cellulite. "That's the jump of faith."
He added that the thick bands are very difficult to isolate and destroy; even liposuction doesn't always work for cellulite. In addition, "collagenase does not melt fat," he said. "That's not true."
Collagenase is also being tested for lipomas, benign tumors made of fatty tissue, but Rotunda noted that the enzyme only breaks down fibrous tissue, not fat.
But Dr Sam Assassa, president of the American Association of Aesthetic Medicine and Surgery and founder of Beverly Hills Aesthetics, disagreed that the enzyme doesn't impact fat - and counts himself among the agent's fans. "I love collagenase," said. "It's a very effective enzyme to help with cellulite."
Assassa compared fat distribution to a tent with ropes attached; breaking down the ropes could help create a smoother appearance, he noted.
Dr Alastair Carruthers, a dermatological surgeon in Vancouver, described collagenase as an "interesting" concept, perhaps for patients with a small area of cellulite. But he noted that there could be off-target effects. "Our bodies are full of collagen," he said. "If you're putting enough collagenase in, you could cause problems. How are you going to deliver this stuff over a wide area?"
Cellulite is one of those conditions for which everything seems to work a little bit, he suggested, pointing to therapies - like massage - that are side effect-free. "It's not my cup of tea," he said about collagenase.
Assassa noted that side effects can occur when the product is injected too shallowly, causing skin necrosis and ulcers of the skin. "It is safe as long as you know what you're doing," Assassa said. "It all has to do with the knowledge of the physician."
Collagenase is currently available from compounding pharmacies for about USD 50 per syringe, according to Assassa - a steep discount over the thousands of dollars BioSpecifics and co-partner Auxilium plan to charge for Xiaflex in Dupuytren's.
Yet James Fickenscher, Auxilium's CFO, noted that the companies' collagenase product is purer and has more activity than the compounded version. Asked about off-label use, he said that "there's always a risk," but suggested that physicians will wait for data from the FDA.
Rotunda noted that collagenase could find a place as part of tumescent liposuction, in which a mixture of anesthetics and other medications are injected under the skin prior to fat removal. While he said that physicians would rather use an FDA approved product than a compounded version, Xiaflex's price tag could limit its use.
Phase II trials, scheduled to start in the second half of this year, are now on hold indefinitely while the companies focus on the Dupuytren's indication, this news service previously reported. Auxilium has not yet exercised its option to commercialize the cellulite indication with BioSpecifics.
BioSpecifics has a market cap of USD 69.5m.
by Beth Herskovits

what is the likelihood of erbitux replacing avastin in wild-type KRAS patients in NSCLC? when will the survey results be released? thanks. i took the survey, btw.

ASCO JOURNAL EDITORIAL

Molecular Selection of Patients for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time
Frances A. Shepherd

Princess Margaret Hospital, Toronto, Ontario, Canada

Blockade of the epidermal growth factor (EGF) pathway through inhibition of EGF receptor (EGFR) is now well established in the treatment of non–small-cell lung cancer (NSCLC).1 However, considerable debate remains regarding when to initiate EGFR inhibitor therapy, how best to select patients for treatment, and how EGFR markers should be incorporated into clinical decision making. With respect to this last issue, EGFR protein expression determined by immunohistochemistry (IHC), EGFR gene copy number determined by fluorescent in situ hybridization (FISH), and EGFR mutation status determined by gene sequencing or other more sensitive techniques may each contribute important information regarding which patients are likely to benefit from treatment.

In NSCLC, small molecule inhibition of the EGFR tyrosine kinase pathway has been the most successful strategy to date, and two oral tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, have received approval for treatment in the second- and third-line setting.2,3 In contrast, the addition of these agents to systemic chemotherapy in the first-line setting does not result in improved response or survival rates.1

Barely 4 years have passed since Lynch et al4 and Pao et al5 first reported an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR TKI therapy. Lynch et al4 also showed that mutations were associated with in vitro enhanced TK activity in response to EGF, and increased sensitivity to gefitinib. Based on these early clinical and laboratory observations, the investigators hypothesized that EGFR mutations would be predictive of response to EGFR TKI therapy and that screening for these mutations might be useful to select patients for treatment. Subsequently, numerous studies confirmed the association between mutation status and response6; in addition, many authors reported that the presence of mutation was associated with longer survival in patients receiving EGFR TKI therapy.6

The early trials that led to the approval of EGFR TKIs for the second- and third-line treatment of advanced NSCLC did not select patients on the basis of any EGFR marker. After identification of the activating mutations on exons 19 and 21, some investigators speculated that the survival benefit seen in the placebo-controlled trials was due entirely to a small percentage of patients who had mutations, and some even went as far as to suggest that EGFR TKI therapy should be limited to patients with mutations. Subsequent studies clearly showed that patients with wild-type EGFR could also derive significant survival benefit from treatment even though they had lower response rates compared with patients with mutations.7,8 Furthermore, other EGFR markers including protein expression and high EGFR copy number have now been shown to be predictive of response,7,8 and in at least one trial, both of these markers were associated with a differentially greater survival benefit.8

In view of the unexpectedly high response rates seen in patients with mutations, several investigators postulated that it might be appropriate to treat these patients with first-line EGFR TKI therapy rather than chemotherapy. In this issue of the Journal of Clinical Oncology, Sequist et al9 report their experience in the first-line treatment of 34 patients with mutations (79% exon 19 deletions or exon 21 L858R point mutations) with gefitinib. As has been reported in almost all series, mutations were seen more frequently in females, lifetime nonsmokers, and patients with adenocarcinoma. Their overall response rate of 55% is in keeping with reports from other investigators, although no patient with atypical mutations achieved response. The authors reported a median progression-free survival of 9.2 months and overall survival of 17.5 months. As discussed by the authors, their results are similar to those of the other single arm phase II trials of either erlotinib or gefitinib in patients with mutations.

Sequist et al also evaluated EGFR gene copy number by FISH, and concluded "FISH appeared to provide no additional clinical information." Undoubtedly this is because most patients who harbor EGFR mutations on exons 19 and 21 also have high gene copy number. However, patients with wild-type EGFR may have high copy number, and as shown by many authors now, these patients have a significantly higher chance of response than those with low copy number. This raises the question not addressed by Sequist et al as to whether other EGFR markers, particularly gene copy number, have the potential to guide patient selection for first-line EGFR targeted therapy. The Denver group has completed a 140 patient, randomized, phase II trial that compares first-line single-agent erlotinib to chemotherapy alternating with erlotinib in patients who are EGFR IHC or FISH positive. This trial, although not powered for definitive results, may provide an important signal that may guide the design of subsequent phase III trials.

In their discussion, Sequist et al comment that their patients had "significant clinical benefit" and that their results were "two-fold greater than typical results with cytotoxic regimens in unselected NSCLC populations." The unselected NSCLC population is definitely not the appropriate comparator on which to judge their results. There have now been several publications in which the survival rates of patients with EGFR mutations treated with chemotherapy have been reported.1 Invariably, their survival has been significantly longer than that of patients with wild-type EGFR, and in several publications, the median survival has not been reached at 2 years. The first thing that this tells us is that the studies of first-line EGFR TKI therapy in mutation-positive patients likely have all been published prematurely, with median follow-up times less than half the expected survival time of patients treated with chemotherapy. With this in mind, does the 17.5-month median survival in the Sequist et al study really compare favorably to historical controls? The study, while demonstrating the feasibility of selecting patients based on their molecular profile, does not tell us that first-line treatment of patients with EGFR mutations should be with an EGFR TKI. Before this conclusion can be reached, we must await the survival results from randomized studies comparing chemotherapy to EGFR TKI therapy. Such a study in prospectively identified patients with EGFR mutations is ongoing now in Spain. In addition, although the analyses of mutation status will be retrospective, a 1,200-patient trial comparing gefitinib to chemotherapy in nonsmoking Asian patients with adenocarcinoma recently has completed accrual. It is expected that 30% to 50% of patients in this study will harbor EGFR mutations, and so the results are awaited with interest. Until the randomized studies confirm that first-line treatment of patients with EGFR mutations does not result in inferior survival (and this is possible in view of historical data), such treatment should be considered experimental. However, even if EGFR TKI therapy does not result in superior survival, equivalent or noninferior survival rates would make this an attractive treatment option, or even the treatment of choice in view of its extremely favorable toxicity profile.

To date, the focus of EGFR profiling has been to select patients who should be treated with EGFR inhibitors. It may, however, be equally important to select patients for whom EGFR inhibitor therapy is not appropriate, and to date, some of the studies of negative predictors seem to be providing us with even stronger signals than the positive predictors. KRAS is a downstream effector of the EGFR pathway, and mutations occur in approximately 20% to 30% of NSCLC cases.10 Several studies have now reported that KRAS mutations are associated with lack of sensitivity to EGFR inhibitors, and in some studies, the survival of patients with KRAS mutations was shown to be significantly worse when treated with EGFR TKIs.1,10 Lack of response to the EGFR monoclonal antibodies cetuximab11 and panitumumab12 also have been reported in patients with colorectal cancer whose tumors harbor RAS mutations. KRAS and EGFR mutations seldom occur simultaneously in the same tumors, and undoubtedly, that is why Sequist et al have not reported on RAS mutation status in their study.

A second EGFR point mutation in exon 20 (T790M), in patients who have developed resistance to treatment with erlotinib or gefitinib, has now been identified.13 Finally, MET, the protein product of the c-met proto-oncogene, is commonly overexpressed in NSCLC, and recently, resistance to gefitinib has been described as a result of amplification of MET.14 The identification of the T790M mutation and MET amplification in Sequist et al's patients with EGFR exon 19 and 21 mutations who did not respond to gefitinib supports the early observations, but larger studies of these potentially negative selection markers are needed.

In summary, both clinical patient characteristics and molecular tumor markers may be used to predict the likelihood of response to EGFR TKI therapy. It is likely—indeed probably inevitable—that a panel of tests will be used in the not too distant future to determine which patients are likely to respond, and of almost equal importance, to determine which patients are unlikely to derive benefit from EGFR inhibitor therapy. At this time, molecular selection of patients for first-line therapy with EGFR TKIs is not quite ready for prime time and we eagerly await the results of the prospectively designed randomized trials.

PHARMAWIRE ARTICLE ON MOLECULAR PROFILING IN NSCLC
by Kimberly Ha

09-Apr-08 18:27 Molecular profiling in lung cancer faces an uphill battle, NSCLC remains a difficult indication - analysis
Story Molecular profiling for the KRAS mutation in lung cancer currently faces an uphill battle due to a lack of a standardized approach and could take up to five years for clinical adoption, according to physicians.

Companies targeting the EGFR pathway include Imclone's Erbitux, Amgen's Vectibix, OSI Pharmaceuticals' Tarceva and AstraZeneca's Iressa.

“At this point, this is no clear role for molecular profiling with regards to selecting targeted therapies in lung cancer,” said Dr Jack West, a medical oncologist and director of medical therapeutics for Thoracic Oncology at the Swedish Cancer Institute in Seattle, Washington.

Although the theory of molecular profiling is interesting, as it would select patients who will better respond to certain treatment, in clinical practice, “right now, we’re not,” said West. Physicians are still using these drugs in the way they were applied in clinical trials, he added.

Although Amgen’s data on Vectibix and KRAS were convincing, more trials need to be conducted, physicians agreed.
“I don’t routinely use these markers in my clinical practice, and the vast majority of physicians don’t as well,” said West. It remains premature on whether to use KRAS mutations to negatively select patients. It is not currently standard practice and is not written in any guidelines, added West.
Dr Ivan Horak, chief scientific officer at Enzon Pharmaceuticals, said one would have to conduct a confirmation study under certain rigor to validate the KRAS biomarker. So far the data with EGFR and activating mutations suggests that patients who have the KRAS mutation could likely have a strong response to EGFR inhibitors.

Although controversial, KRAS mutations seem to be associated with smokers, said West. However, patients who develop NSCLC and who have never smoked seem to have dramatic and striking benefit with Tarceva or Iressa.

A lot of drugs for the treatment of NSCLC have failed, which has partly been due to trial design, said West. Nexavar's ESCAPE trials in NSCLC were halted as it did not show an increase in overall survival. The trial treated a large patient population with squamous-cell cancers, based on the presumption it would not be toxic. “It’s potentially quite dangerous to treat NSCLC squamous with Avastin,” said West.

“You could make a good drug look bad by treating the wrong population" said West. “With Erbitux, if we don't find the right population for this drug, it’s going to look a lot less impressive,” he added.

Mike Morrissey, head of R&D at Exelixis, said there have been a number of high profile setbacks in this setting, with recent failures by Nexavar and Recentin. Exelixis is developing compound XL647 for the treatment of NSCLC, which has potent activity against 16 out of 17 resistant mutations.

The recent failures are basically more or less focused on the VEGF axis, which underscores the opinion that the VEGF pathway may not play a major role in lung cancer. "These as a single agent, or on top of standard chemotherapy do not seem to work," said Morrissey.

Horak added that lung cancer patients have more underlying medical problems. “Sixty percent of the patients might be heavy smokers. The protoplasm of these patients is not in good shape,” he said. Secondly, lung cancer tumors are exposed to carcinogens, which creates a multiple oncogenic event.
Dr Ramaswamy Govindan, chief of the lung cancer program in the division of medical oncology at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, said very few drugs get approved for cancer and the majority of cancer trials end up being failures.
In the past, most cancer drugs failed in trials due to toxicity, as the older drugs were cytotoxic chemotherapy drugs. "As we move into the new era therapy, failures are increasingly due to lack of efficacy," said Govindan.

Lung cancer will eventually be seen as not one or two diseases, but 20 different diseases on the molecular level, believed Govindan. The majority of cancers are caused by disruption of several genes. Govindan said that the treatment of cancer gets to be very challenging as cancer cells turn on certain genes and their pathways when a drug blocks off other genes and their pathways in order to survive. "Eventually, we have to be smart about turning off more than one or two pathways at a time without harming normal tissues," said Govindan.
Lung cancer is a multi-gene process, Govindan explained, and "it’s naïve to think you can turn off one pathway, and benefit all patients."

"The previous model in lung cancer doesn't work very well, because all patients with lung cancer were categorized in one or two groups," said Govindan. Eventually, cancer therapy will be personalized based on the tumor genetic make-up.
However, the physicians did not seem too excited about Avastin's recent approval in this setting, as it did not provide much in terms of clinical outcome improvement, said Horak.

Dr Louis Matis, president and CEO of Immune Tolerance Institute (ITI), a non-profit organization developing high-value biomarkers to guide new drug development, said although there are a good number of surrogate markers in oncology, there has not been a successful history through to market.
Stephen Hurst, chief business officer at ITI, said there has to be a certain level of diligence with biomarkers. "This is a huge struggle for the industry, and something the FDA is struggling with," he said.

The crucial standard is that the biomarker data has to be repeatable. Poorly qualified assays will produce different results. “In five years, we’ll be awash in a sea of biomarkers,” he added.

“The FDA is demanding that if you’re using a biomarker or diagnostic test to inform a clinical decision, the clinical data needs to be as rigorous as the drug,” said Matis.
Another issue that may hinder the development of biomarkers is the financial incentive for large pharma to develop tailored therapies. “That would include a price premium for higher efficacy drugs. Overall, you’re reducing needless administration costs and eliminating side-effects to people who don’t benefit from treatment,” said Matis.

by Kimberly Ha in New York

PHARMAWIRE ARTICLE ON ERBITUX -
BY KIMBERLY HA

07:17 Imclone's Erbitux unlikely to displace Avastin in wild-type KRAS patients in first-line metastatic colorectal cancer - analysis

Story Imclone's Erbitux is unlikely to displace Avastin in wild-type KRAS patients in first-line metastatic colorectal cancer (mCRC), according to physicians and industry sources.
Although preliminary data unveiled in ASCO abstracts show a significant correlation between Erbitux's efficacy in mCRC patients with wild type KRAS, many physicians believe that it is premature to change the current treatment paradigm in mCRC based on these recent results.

The wild-type or non-mutant KRAS gene is found in up to 65% of colorectal cancer patients. Although this may become an important biomarker to predict response to targeted treatments such as Erbitux that inhibit the epidermal growth factor receptor (EGFR) pathway, physicians believe more data is needed.

Dr Eric Rowinsky, chief medical officer at Imclone, said since Erbitux's approval in 2004, the company is now learning which patients are likely to better respond to this therapy. This has great ramifications, as we could avoid treating certain patients and avoid needless toxicities, he said.

If physicians can start treating patients who have KRAS wild-type earlier on, this could really channel a greater benefit, said Rowinsky. "That is the spirit of personalized medicine. The challenge now remains identifying those specific patients."
Amgen will also be presenting data with its EGFR drug Vectibix, but it will present data in the third-line setting, but first-line is where most benefit can be done, said Rowinsky. Imclone will be presenting data on the KRAS mutation in the first-line setting, said Rowinsky. Around 30-35% of mCRC patients currently have this mutation, so if patients can be selected for better response, that would be phenomenal, he added.

Dr Yun Yen, an oncologist who co-leads the Developmental Cancer Therapeutics Program of the City of Hope Comprehensive Cancer Center, said more data needs to be gathered before physicians start changing current treatment. "Based on these results, should we change our treatment? Probably not yet," said Yen.
In certain ethnic populations, like in Asians, there is a higher portion of KRAS mutations, he added. "We still need to do a lot of work, such as using mathematical models with systems biology and computerized bioinformatics to analyze these mutations," said Yen. It could be the case that three to four other biomarkers in combination show better predictive value than KRAS itself, he added.

A KRAS diagnostic is not even approved in the US yet. Some patients that have the mutation may still show some effect with EGFR inhibitors, physicians said. "That’s the reason why the FDA is trying not to approve these diagnostic tests so easily, until we completely understand this mutation," said Yen.
Three years seem to be the magic number physicians agreed on before a meaningful diagnostic is developed and used in the clinic. One single biomarker to answer all questions is not possible, and KRAS is just one issue in the whole pathway, Yen explained. Clinical trials limit age, and certain patient groups, which could be misleading and lead to a misinterpretation of the mutation.

Dr Stephen Cohen, a colorectal surgeon at Atlanta Colon & Rectal Surgery, said both Erbitux and Avastin have bad side-effects. "We don’t have a choice in politics, but with drugs, we have a choice," he said in response to whether Erbitux should be used in place of Avastin based on recent results.
A better strategy may be a better focus on preventative medicine, and adequate screening via routine colonoscopies - as colorectal cancer has a high cure rate if detected early. Everyone at age 50 should get a colonoscopy, but only 40% of the population is doing it. Three curable cases can be found out of every 100 patients that are screened. "I’m going to find 17 pre-cancerous polyps out of 100 patients," said Cohen.

One competing industry executive said the whole mutation issue was "irrelevant," in response to whether Erbitux would displace Avastin in this subset of patients. In Europe, where Amgen's Vectibix has an approved diagnostic, many physicians choose not to use it. Physicians have not reached a level of sophistication to start selecting which patients should use Erbitux first, instead of Avastin. "Right now, they don’t have the tools. They will inject everything, and try everything," he said.

An industry observer added that Genentech's Herceptin has a very different developmental story , although both drugs use biomarkers. "There were prospective studies done in HER2 patients, but the KRAS subset is very different. Most oncologists would recognize this difference," he said.
"Nationwide, we’re not in a position where people are doing genetic testing with this drug, but I think that we’re in a developmental area," said Dr John Cromwell, associate professor of surgery and chief of colon & rectal surgery, at the University of Tennessee Health Science Center in Memphis.
As the data matures, and if Erbitux does show more efficacy in that group, we have to start testing for it, said Cromwell. "As we have more widespread testing available commercially, that will help us decide if it’s worthwhile."

Dr Monica Mita, principal investigator at the CTRC Institute for Drug Development on another drug affecting the KRAS pathway called Reolysin by Oncolytics Biotech, said although the results are promising, more studies needed to be conducted to determine whether physicians need to test everyone for KRAS.
Especially with advanced metastatic disease, she remained skeptical that one biomarker or one mutation has driven the malignant transformation. "I think it's difficult to say that KRAS will change the face of what we’re doing now," said Mita. The Oncotype DX breast cancer assay takes into consideration several pathways, and looks at 21 different genes. In Europe, they use 70 genes to identify patients that will respond to chemotherapy in breast cancer, she added.

Until the National Comprehensive Cancer Network (NCCN), an alliance of 21 of the world's leading cancer centers, or ASCO guidelines suggest the use of KRAS testing, only then will this test will be implemented, said Mita. "Otherwise, I don’t believe so."

"We can’t make the decision for all patients based on data from approximately 50 patients. It’s too premature. We need confirmatory studies, and larger studies to confirm this. I’m not ready to order it for my patients until very strong data confirms this is what we really need to do," said Mita.

by Kimberly Ha in New York

this was a story back last year:

02-Nov-07 18:45 Altus Pharmaceutical unlikely to appeal FDA decision to revoke Orphan Drug designation from TheraCLEC, CFO says

Story Altus Pharmaceutical will most likely not appeal the Food and Drug Administration’s (FDA) decision to revoke its Orphan Drug designation on its TheraCLEC (ALTU 135) compound, said CFO Jonathan Lieber.

The FDA granted TheraCLEC Orphan Drug designation in 2003, however, the agency revoked this STATUS late last year because it said the number of patients exceeded the statutory limit of 200,000 patients. The FDA included HIV/AIDS patients, who may also suffer from pancreatic insufficiencies, but do not necessarily take this class of drugs. Altus can appeal the decision up to its New Drug Application (NDA) date.
Altus plans to file an NDA for TheraCLEC by the first half of 2009, Lieber said. The company started Phase III studies in 2Q this year, he said. It is holding two trials: one for efficacy and one for safety. The efficacy trial will last eight weeks and Altus plans to release top line data for the study by 2Q 2008, Lieber said. The safety trial will be complete towards the end of 2008. The company plans to enroll 150 evaluable patients for its efficacy trial and 100 for its safety trial. Patients enrolling in the safety trial can op to stay on and enroll in the efficacy trial as well.
TheraCLEC is an orally delivered enzyme replacement therapy for the treatment of malabsorption as a result of pancreatic insufficiencies, a condition that affects most patients with cystic fibrosis (CF), chronic pancreatisis and pancreatic cancer. The current standard of care uses porcine enzymes.
Lieber said the current porcine-derived drugs have been widely used for over 50 years, yet still have their limitations. The pill burden is very high, with patients having to take four or five capsules with every meal or snack. With TheraCLEC patients can take as little as one capsule with every meal or snack. Also TheraCLEC is more stable, he said.
TheraCLEC has received interest from companies who would like to partner the drug, the CFO said, and discussions have taken place. He declined to go into more detail. Altus is seeking to partner the drug in the rest of the world but prefers to keep all the North American rights, he said.
Lieber said he is not aware of another company with a compound as far along in the clinical trial process as Altus. France-based Meristem Therapeutics and Swedish-based Biovitrum have similar compounds, he said, but to his knowledge both companies have held only small Phase II trials.
The enzyme replacement market place is very well established said Matthew Casbon, Director of Marketing for competing Belgian pharmaceutical company, Solvay, whose drug CREON has a 25% market share. Generics also have a 55% market share, he added. If and when TheraCLEC is approved, Casbon said, it will have a place in the market but is unlikely to make a huge impact. Still, he added that TheraCLEC’s microbially-derived mechanism seems to be the way forward and Solvay has also considered developing a similar drug.

Altus has another compound that has also completed Phase II trials, ALTU 238, which is partnered with Genentech in North America and the latter has the option to extend this for rights for the rest of the world, he said. ALTU 238 is a crystallized formation of the Human Growth Hormone (hGH) that is designed to be administered once a week for the treatment of hGH disorders in pediatric and adult populations.

Altus Pharmaceutical has a market capitalization of USD 428m.

by Gayatri Iyer

pharmawire article

12:07 Altus Pharmaceuticals retains Morgan Stanley to review strategic options - sources
Story Altus Pharmaceuticals has retained Morgan Stanley to review strategic options, it is understood. The listed biopharmaceutical, based in Cambridge, Massachusetts, is said to have only just appointed the US investment bank.
A spokesperson for the company declined to comment.
One source familiar situation said that Morgan Stanley was working with the drug developer but did not divulge any further information. A second source said that they had seen an information memorandum on the company.
Other sources said that were not surprised by the news, with one US business development consultant noting that Altus had been "shopping its products at the same time". The company had a setback last December when Genentech sold back the development and commercial rights to ALTU-238, a growth hormone drug that the two companies had partnered on. At the time, the company believed it could find another partner for the drug.
In February, chief executive Sheldon Berkle resigned and was replaced by chairman Dr David Pendergast, who is still assuming executive duties until a replacement is found. Pendergast was part of the management team at Transkaryotic Therapies when it was sold to Shire in 2005, and subsequently headed up the UK-listed company's genetic therapies unit. Altus has been previously reported as a possible target for Shire.
Altus is developing a series of products to treat gastrointestinal and metabolic disorders. Its lead compound is Trizytek, a porcine-free enzyme in Phase III development for pancreatic insufficiency.

Altus has a market cap of USD 123m.

pharmawire article...what do you think about this?

i thought altus' drug failed..

12:07 Altus Pharmaceuticals retains Morgan Stanley to review strategic options - sources
Story Altus Pharmaceuticals has retained Morgan Stanley to review strategic options, it is understood. The listed biopharmaceutical, based in Cambridge, Massachusetts, is said to have only just appointed the US investment bank.
A spokesperson for the company declined to comment.
One source familiar situation said that Morgan Stanley was working with the drug developer but did not divulge any further information. A second source said that they had seen an information memorandum on the company.
Other sources said that were not surprised by the news, with one US business development consultant noting that Altus had been "shopping its products at the same time". The company had a setback last December when Genentech sold back the development and commercial rights to ALTU-238, a growth hormone drug that the two companies had partnered on. At the time, the company believed it could find another partner for the drug.
In February, chief executive Sheldon Berkle resigned and was replaced by chairman Dr David Pendergast, who is still assuming executive duties until a replacement is found. Pendergast was part of the management team at Transkaryotic Therapies when it was sold to Shire in 2005, and subsequently headed up the UK-listed company's genetic therapies unit. Altus has been previously reported as a possible target for Shire.
Altus is developing a series of products to treat gastrointestinal and metabolic disorders. Its lead compound is Trizytek, a porcine-free enzyme in Phase III development for pancreatic insufficiency.

Altus has a market cap of USD 123m.

the FDA hasn't even gotten a KRAS diagnostic on the market yet. isn't Amgen still working on getting that DXS KRAS diagnostic approved for vectibix? does anyone have any timelines for that.

i agree. the bap trials seem a bit too high risk right now. esp with the whole brain inflammation - vascular edema thing going on.

get out while you still can! also, i wonder when the halt on Wyeth's AD vaccine trials will lift. i thought they asked for it to be lifted a couple weeks ago.

well, PFS is confounded by how good the second and third line drugs are.

also, for other secondary points like .. tumour size reduction - might be differences between the imaging tests you're using in trials to test for that (CT scan vs x-ray, etc)

i'm also being told that hazard ratio is more accurate predictor. any thoughts?

for example. if erbitux shows OS benefit in FLEX, but no secondary endpoint benefits in PFS, etc.

what will that mean for the outcome. but then again, I'm sure the FDA will basically accept the drug based on OS benefit. that's the whole point - survival.

you're right. Thanks Dew. not sure if you have a litigation thread already, but what would you consider as the top legal situations ongoing in pharma right now?

or the cases with upcoming decision dates. thanks. or high profile cases. i really want to look into this.

basically anything in the AD disease modification space is too early right now.

a) FDA has to decide on an endpoint - right now, still looks like ADAScog, which is not sensitive enough to test for executive function (milder AD patients)

b) side-effects from biologics , mABs like Wyeth's bap.

c)reimbursementproblems

d) Baxter IVIG seems to be good, but major supply issues.

e) Myriad's flurizan approval upcoming - likely to be neg. bad for sector.

f) Wyeth AD vaccine problems - side effects. spoke with investigator on trial, basically should be recruiting milder patients, or MCI patients, but .. cannot recruit 'healthy' patients at moment, as AD patients have to act like guinea pigs in trials to test for safety problems with these new meds.

g) correlation btn reduction in b-amyloid plaque and clinical improvement still premature.

i give it at least 4-5 years before the first one makes it to market.

28-Feb-08 13:31 Momenta's generic Lovenox product likely to be stalled because of cautious environment at FDA, attorneys note

Story The FDA is taking a conservative approach in evalutating follow-on protein products before a biogeneric regulatory pathway is in place, which could spell bad news for Momenta's M-Enoxaparin candidate, sources say.

M-Enoxaparin is a generic version of Sanofi-Aventis' Lovenox, a blood thinner made of complex sugar chains. Privately-held generic drug maker Amphastar also has an application for generic Lovenox pending in front of the FDA.

The agency late last year issued a non-approvable letter to Momenta and partner Sandoz, requesting more immunogenicity data.

Lovenox was approved under the Food, Drug and Cosmetic Act (FDCA), which means that the FDA does have the authority to approve generic versions. Most biologics, in contrast, were approved under the Public Health Services Act, which is the focus of the current legislative push to create a generic approval process.

However, some attorneys are skeptical about whether the FDA is willing to approve a biogeneric even under the FDCA.
"We're in an election year - they're just shutting everything down," said Jill Deal, a partner at law firm Venable, who specializes in litigation and lobbying for the food and drug industry. "They're going to be very careful about what they do, and how they use 505(b)(2)."

Under the FDCA, a 505(b)(2) application relies on a reference product's previous safety and efficacy studies. Sandoz's Omnitrope, sometimes called the first biogeneric, was approved under this process.

Deal noted that the agency is also concerned about major drug companies threatening lawsuits over the scope of 505(b)(2) - something Pfizer did when Sandoz first submitted its application for Omnitrope. (Pfizer manufactures reference product Genotropin, a human growth hormone.)

"Periodically, there have been threats to take the agency to court over the scope of 505(b)(2)," she said, adding that the FDA would prefer not to get involved in a lawsuit.
Momenta's product, in contrast, was submitted under a standard ANDA, not a 505(b)(2). Even still, the FDA has been under heavy scrutiny over drug safety issues and likely wants some clarification on the science needed to approve follow-on proteins before issuing an opinion, according to David Rosen, a former FDA official and partner at law firm Foley & Lardner.

"Right now the issue is science … as opposed to not having a pathway," he said. "The FDA is still raising significant issues [on] how best to approach the concerns regarding immunogenecity."

Yet he acknowledged that many of those scientific concerns will be resolved once a pathway is in place under the PHSA.
Executives at Momenta and Sandoz did not respond to requests for comment. A former industry executive who said he recently spoke with Momenta noted that the company remains "optimistic" about its application. "But who knows," he said.

There are also questions about whether such a pathway will be in place this year, as people in the generics industry have previously told this news service.
"I don't think we're going to see a lot of stuff happening until there's an election," Rosen said.
"People have been trying to read the tea leafs - and it's just so hard in an election year," said Deborah Shelton, a partner at law firm Sheppard, Mullin, Richter & Hampton. "This is a really complex task."

Shelton wouldn't rule out the possibility that the FDA could approve other generic protein products under the FDCA, but that clinical trials for immunogenicity would be a key issue.
"The FDA has been under fire for pushing products through," she said. "I think the FDA has been pretty clear - and rightfully so - [that the Omnitrope approval] doesn't really tell us much."

Momenta has a market cap of USD 281.63m.

by Beth Herskovits

Source Pharmawire

would be amazing if kuvan could also treat enlarged heart disorder..takeover speculation continues. what are the changes of them being acquired by Novartis i wonder. are they currently partnered with them? i think so.

OS endpoint in avastin adjuvant trial??

http://www.ft.com/cms/s/2/6dbeadd2-21b7-11dd-a50a-000077b07658,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html


Genentech’s Avastin study should evaluate drug’s effect on overall survival as primary endpoint, physicians say
By Klara Czobor

Published: May 14 2008 14:29 | Last updated: May 14 2008 14:29


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
--------------------------------------------------------------------------------------------------------


Genentech’s study of Avastin in patients with colorectal cancer in the adjuvant setting should examine the drug’s effect on a primary endpoint of overall survival, physicians told Pharmawire.

Avastin has been approved by the FDA for the treatment of metastatic colorectal cancer, non-small cell lung cancer and metastatic breast cancer.

Genentech, in an attempt to broaden the drug’s label to the adjuvant colorectal cancer setting, is studying Avastin in the ongoing C-08 study. The Phase III trial is comparing the addition of Avastin to infusional 5-Fluorouracil (5-FU), Leucovorin and Oxaliplatin (mFOLFOX6) to the same therapeutic regimen without Avastin. The primary endpoint of the study is the combination therapy’s impact on prolonging disease-free survival (DFS) while the secondary endpoint is prolonging survival.

The standard endpoint to evaluate in cancer trials is overall survival, according to Dr Brian Czito, an associate professor at Duke University. Avastin was initially approved because it demonstrated an impact on overall survival in the metastatic setting and no less should be expected of the drug in the adjuvant cancer setting, Czito added.

“Overall survival is the gold standard, especially in adjuvant studies,” noted Dr Steven Sorscher, an assistant professor of medicine at the Washington University School of Medicine. Physicians do not want to administer a drug that could potentially keep the cancer at bay but killing patients at the same time because it is so toxic. Still, if the drug makes a statistically significant impact on disease free survival for a long time, then it’s a good way to analyze studies, Sorscher said.

For example, if statisticians analyze the results of the C-08 trial and 10% of patients receiving the Avastin and mFOLFOX6 regimen are disease free at three years, it does not mean that the drug will prolong survival. However, if they are disease free at five years, then the drug definitely has a survival advantage.

Progression free survival was a recognized endpoint by the FDA, according to Dr Carmen Allegra, the chief of hematology at the University of Florida and an investigator on the study. Allegra further explained that the trial will be analyzed using survival analysis, after a certain number of events have occurred.

“I am not sure that there is a date or a time for the completion of the study since it is event driven,” said Allegra. “3 year disease free survival was shown and accepted by the FDA in this particular setting.”

Even if Avastin therapy does not make a dent in overall survival, patients may ask to be given the drug, said Dr Rakesh Jain a professor of tumor biology, at Harvard-MIT Health Sciences and Technology Program. If a drug does not impact overall survival, the drug’s administration depends on the opinions of the physician and insurance companies. These therapies are expensive, so it’s important for patients to receive insurance coverage, Jain added.

A major problem associated with measuring overall survival in adjuvant studies is that patients may have to wait for many years until the results are available, Sorcsher explained. If a drug could potentially improve disease outcomes, patients want to know about it as soon as possible and have access to the therapy, Sorcsher added.

Avastin has a peak sales forecast of 9,319 bn USD in 2012.

Avastin - adjuvant CRC

okay, the question is .. why would ppl take avastin in the adjuvant CRC setting - when you can just get screened and remove the polyps? or get a colonoscopy, or virtual colonoscopy...am i missing the market opportunity here.

another article courtesy of Pharmawire. basically the investigator said... side-effects seem to be a concern. that may be a major hurdle for approval. regardless, the final results .. are due a couple of years away.

what do you think the major Avastin data will be? the AVADO trial and the glioblastoma P2 results maybe?


Genentech’s Avastin associated with gastrointestinal side-effects in the adjuvant colorectal setting, physicians say


Story Genentech's Avastin (bevacizumab) in the adjuvant colorectal cancer setting is associated with an increased risk for gastrointestinal side-effects, according to physicians. Patients in the adjuvant setting are healthier than in the metastatic setting, where the drug is currently approved, so the adverse event profile needs careful evaluation, they said.
Avastin works by inhibiting angiogenesis and prevents new blood vessels from developing around the tumor. The drug is currently an FDA approved treatment for metastatic colorectal cancer, non-small cell lung cancer and metastatic breast cancer.

To determine whether Avastin benefits a wider patient population in colorectal cancer, the drug is currently being studied in the ongoing C-08 trial. The purpose of the trial is to determine if a combination of Avastin and infusional 5-fluorouracil (5-FU), leucovorin and oxaliplatin (mFOLFOX6) has a greater impact on prolonging disease-free survival (DFS) than the same regimen minus Avastin.

According to a spokesperson for Genentech, safety is a significant concern in the adjuvant setting, but the company is pleased regarding the interim results of the ongoing study, as the data currently appears to be safe. The company will be presenting safety data at the upcoming American Society of Clinical Oncology at the end of the month in Chicago, she added.

Dr Carmen Allegra, an investigator on the study and chief of hematology at the University of Florida, said patients in the C-08 study who were administered Avastin experienced an increase in wound complications. Also, most of them were not related to abdominal surgery, but rather to the port used to deliver infusional therapy in patients, he explained. At times, it may have necessitated surgical intervention, but despite the increase, the side effects were easy to manage, he said.

It is a "very proven policy" that Avastin impairs wound healing, noted Dr Brian Czito, an assistant professor at Duke University. The drug, however, is a concern to physicians as it can impede the body's ability to heal wounds, Czito added. In a Phase II study where he is investigating Avastin in the pre-operative adjuvant setting, the drug is administered 8-10 weeks before surgery due to these concerns, Czito said.

The addition of Avastin to any chemotherapeutic regimen increases toxicity, concurred Dr Rakesh Jain, a professor of tumor biology at Harvard-MIT Health Sciences and Technology Program. "I don’t think that [physicians] are going to argue that toxicity is increased," Jain added.
The bar is set much higher for drugs being tested in the adjuvant setting for toxicity and efficacy, according to Dr Steven Sorscher, an assistant professor of medicine at Washington University School of Medicine. If Avastin was associated with terrible adverse effects in this therapeutic environment, then physicians would not want to administer the drug, Sorscher said.

For example, the administration of anthracycline therapy to patients with metastatic breast cancer is associated with the risk of causing acute leukemia, Sorscher said. Approximately 1 in 700 patients administered the drug are at risk for developing the disease, but physicians still administer the drug anyway, because patients are more likely to die in that setting from breast cancer. Physicians will have to measure the risk/benefit profile of the drug, Sorscher explained.

Side-effects of Avastin that have emerged in previous trials are nosebleeds, proteinuria, hypertension and neutropenia. In rare cases, the drug’s administration resulted in congestive heart failure, especially in patients who have received an anthracycline chemotherapeutic regimen. Patients who take Avastin with chemotherapy are at an increased risk for developing a stroke and heart problems.

Still, even though interim data is being presented at ASCO, it will take a few years for physicians and scientists to understand the drug’s real benefit in this setting, noted Dr Yubao Wang, an oncologist at the University of Texas Science Center. The adjuvant field of drug development is extremely challenging and it is likely that this trial will be negative, Wang added.

Avastin has a peak sales forecast of 9bn USD in 2012.

by Klara Czobor and Kimberly Ha

genitope bombed a while ago. i feel sorry for the ceo, he was a nice guy.

what do you think the chances of their alzheimer's drug hitting all the endpoints? didn't wyeth/elan create a completely new endpoint instead of the ADAS-cog. wonder how the fda will view that.

alzheimer's in general, esp the disease modifying agents have all failed. not one has made it through the FDA. be it errors in statistical trial design, or simply not recruiting the right patients.

i believe all these companies are not recruiting the right patients. they should all be targetting the pre-AD patient population. but then again, screening and diagnostics costs money. trials are large, you're dealing with dropout, site2site variation, the works.

should be interesting to see how that turns out.

Pfizer aims to reformulate HIV prevention drug: report
Wed Jan 30, 2008 5:19am EST Email | Print | Share| Reprints | Single Page | Recommend (0) [-] Text [+]
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Learn to Trade with a FREE Guide.NEW YORK (Reuters) - Pfizer Inc is seeking to reformulate its HIV drug to prevent the transmission of the virus through a partnership with a nonprofit group, The Wall Street Journal reported on Wednesday.

The report said Pfizer will license Selzentry, its oral HIV medicine, to the International Partnership for Microbicides, which will try to turn it into a vaginal gel, ring, or film that prevents transmission of the virus.

Pfizer officials were not immediately available for comment.

Selzentry was the first drug designed to keep the HIV virus that causes AIDS from entering healthy immune cells. Older AIDS drugs attack the virus itself.

(Reporting by Ritsuko Ando)

15:41 Pfizer's new HIV drug Selzentry sees physician concern over lack of long-term safety data; similar GSK drug previously terminated due to liver toxicity
Story Pfizer's Selzentry (maraviroc) will have to be monitored for potential long-term health effects from blocking the CCR5-receptor, HIV specialists have said. Selzentry is the first drug approved in a new class of drugs called CCR5 antagonists. It was approved on 6 August 2007 for use in treatment-experienced patients.
Drugs in this class work via a unique mechanism of action by blocking the CCR5 co-receptor, a predominant viral entry route into T-cells.
The drug basically prevents HIV from binding to the CCR5 co-receptor and prevents the virus from entering the cell and reproducing itself.
Last week, the FDA approved another new HIV drug in a different class, Johnson & Johnson subsidiary Tibotec Pharmaceuticals' antiretroviral drug Intelence (etravirine) for treatment-experienced patients.
Dr Tony Mills, an investigator on the Intelence trials, said the long-term effects of blocking the CCR5 receptor remain unknown. "A lot of people have concerns about that," he said. Mills is currently conducting research on five different CCR5-inhibitors.
Pfizer's Selzentry only works in a certain group of HIV patients, and a diagnostic test has to be given to confirm whether a patient is infected with the CCR5-tropic HIV-1 (R5 virus). It is also indicated only for use in treatment-experienced patients infected with that specific virus.
However, Mills said from his research, 70% of patients who were screened initially were dual/mixed-(D/M) or X4-tropic HIV patients. Regarding Selzentry, Mills said the drug's efficacy in treatment of this group of HIV patients is unknown.
According to a Pfizer company press release, "If Selzentry is selected as an active drug for patients infected with D/M or X4-tropic HIV, it may not contribute to virologic suppression and could result in emergence of resistance to other drugs in the treatment regimen."
Alfred Merriweather, CFO of Monogram Biosciences, the California-based company that develops the Trofile tropism assay, a diagnostic test that determines whether a patient will respond to Selzentry, said Schering also has a similar drug in Phase III trials, which Monogram is currently working with.
As an example of drugs with side effects that emerged in the long term, Mills pointed to Merck's Crixavan (indinavir), a protease inhibitor, which is known to cause side-effects such as kidney stones, metabolic abnormalities such as hyperlipidemia, and alterations in body shape known as lipodystrophy. "These are powerful drugs, as we learned early in HIV. There were some drugs like Crixavan, but then the long-term side effects ended up outweighing the benefits," said Mills.
Dr Gervais Frechette, an HIV specialist in New York, said his only concern with this newly approved CCR5 drug is that studies have only been conducted on a small number of patients.
Pfizer conducted two randomized, placebo-controlled clinical trials, known as MOTIVATE I & II, which compared 209 patients receiving optimized therapy plus placebo to 426 patients receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily.
Frechette, who was an investigator on GSK's clinical trials on a CCR5 drug that was terminated, said Selzentry was only approved on a small patient study. "That's not a big number, when we compare studies we have done with other diseases," he added.
Pfizer did not return calls seeking comment.
"We don't have long-term data on potential side-effects," said Frechette, adding that there is also no information on whether the long-term use of drugs in these new classes will lead to side effects such as lipodystrophy.
"The FDA does require the reporting of side-effects," said Frechette, adding that he hopes there will be none reported with Selzentry.
In 2005, GlaxoSmithKline announced termination of its investigational CCR5 entry inhibitor, aplaviroc (GW873140), due to safety data observed in Phase IIb studies.
"GSK has received reports of severe hepatotoxicity with elevated liver enzymes and total bilirubin in clinical trials involving treatment-naïve patients. GSK has taken immediate steps to protect the welfare of patients in clinical studies of aplaviroc," according to a company statement released in 2005.
"After review of these liver toxicity findings with the US Food and Drug Administration, GSK has terminated the aplaviroc clinical trials in treatment-naïve patients," the statement added.
Frechette, who was an investigator involved in GSK's CCR5 trial, was "surprised that Pfizer has a similar drug" that has not reported elevated liver enzymes.
On the aplaviroc trial, he said, "1% of people who were on that drug were dying of liver failure, or developed liver failure."
GSK then decided to shut down the trial because the company's president at the time did not want to "have another Vioxx" situation.
As well as potential safety concerns, Pfizer also faces looming competition from Schering-Plough, currently developing vicriviroc, a Phase III investigational CCR5 antagonist. Schering's drug, if approved, will have a dosing advantage over Pfizer's drug which currently has to be dosed twice-daily.
Schering will present results at the upcoming Conference on Retroviruses and Opportunistic Infections (CROI) on 3-6 February in Boston.
Bob Consalvo, a spokesperson for Schering, said the currently marketed CCR5 drug has to be dose adjusted in terms of drug background, and also has to be taken twice daily. Schering's drug vicriviroc will have significant advantages over the currently marketed CCR5 drug as it will not require dose adjusting and has a dosing advantage of being a once-daily pill.
He added that, as a class, the main advantage of CCR5 drugs is that they work extracellular. "So by their very nature, you would not expect cross resistance to current drugs. This will be especially important for the treatment-experienced line of patients, you need a totally new class," said Consalvo.
When asked about the long-term side effects of CCR5 drugs, Consalvo said that current nucleoside drugs that work internally also carry certain metabolic side-effects that may translate into long-term effects.
However, whether or not this new class of CCR5 drugs have a better risk-benefit ratio remains to be seen, the specialists added.
Pfizer has a current market cap of USD 157bn.

by Kimberly Ha in New York

Also, i wonder what is going on with cardiome. should be making an announcement anytime now. what do you th ink? do you think the drug may have a chance because the FDA is stalling?

otherwise, chances are they might have already announced the bad news already.

What do you guys think about THeratechnologies sale process? do you think their drug will get approved. i highly doubt they will get approval due to FDA scrutiny on safety. potential elevation of glucose levels. similar drug by genzyme got rejected last year.

also, new anti-retrovirals - lipodystrophy not seen as much.
company probably tried to shop themselves below the radar starting 2H07, but no partners, no buyers.

i think high risk, drug likely not approved.


UPDATE 1-Theratechnologies mulls options, could sell, merge
Tue Jan 29, 2008 8:45am ESTPost Your Comments | All Comments


TORONTO, Jan 29 (Reuters) - Theratechnologies Inc (TH.TO: Quote, Profile, Research) said on Tuesday it is considering strategic options, including a sale or merger of the company, as well as the licensing of its lead compound tesamorelin.

As part of the review of its options, the company has filed for a preliminary base shelf prospectus that would allow it to issue up to C$35 million of common shares.

The Montreal-based firm said a committee of independent directors would oversee the review, and that it has hired Lazard and BMO Capital Markets as advisors.

It said the strategy to develop and commercialize tesamorelin -- which treats HIV-associated lipodystrophy, a disease that increases central fat accumulation in the bodies of HIV-infected patients -- was on schedule.

CANACCORD ANALYST REPORT

PHASE 3 GREEN LIGHT, BUT LONG
ROAD AHEAD AND FINANCING
COMING; REITERATE HOLD
EVENT: Telaprevir Phase 3 to start in March; data expected by mid-
2010. As a reminder, telaprevir is Vertex’s oral hepatitis C protease
inhibitor in development for the treatment of hepatitis C. The first Phase
3 trial will study two 24-week telaprevir-based regimens (one including
eight weeks of telaprevir, the other including twelve weeks of telaprevir).
The second trial will study one 48-week telaprevir-based regimen. Both
studies will include a 48-week standard of care control arm.
IMPACT: Mixed. We note that today’s news eliminates the uncertainty
around the timing and design of the Phase 3 program for telaprevir. A
successful result in Phase 3 could allow telaprevir to be approved for use
in a 24-week treatment regimen (half that of standard of care). However,
many investors were hoping that the Phase 3 program would not also
look at telaprevir treatment as part of a 48-week treatment arm. In
addition, we believe that many investors were expecting a potential
telaprevir approval in 2010 (we now expect approval in 2011).
ACTION: Reiterate HOLD rating. We continue to believe that telaprevir
will generate positive Phase 3 data that will justify FDA approval for the
treatment of hepatitis C. However, with a financing likely coming in
H1/08 and data coming this year from potential competitors, we
recommend staying on the sidelines.
VALUATION: Lowering price target from $28 to $25. Our price target is
based on a probability adjusted pipeline NPV analysis. We have changed
our estimate for telaprevir approval from 2010 to 2011 and removed
VX-702 (development on hold pending partnership) and VX-680
(development on hold due to safety signal). We would note that our NPV
analysis does not reflect prospective dilution from future financings.