And where is Betty Dragon? or the scientist behind this test. i have to admit, i was basing most of my confidence back then on her reputation, and credibility in terms of her research, etc.

rkrw, i think you also raised some good points. only time will tell...

i always thought that SQNM would make a comeback. i mean, afterall, they are sequenom. despite everything's that happened, they were still one of the hottest names in Dx.

will be intersting to see if investors can get over the bad reputation..and regain some trust in the company management.

Interesting.

Hmm. that is quite sketchy. does anyone know his overall track record in healthcare. he's made some good calls - some bad calls too. so i guess you could say "mixed results." pun intended.

a philantropic czar. that part was hilarious. that cracked me up. :)

aurora kinase class in general doesn't work. there was the VRTX failure a couple of years ago, or last year. supergen i think also has this class, but has never worked..

i would be surprised if any compound from this class works..

anyone have any thoughts on whether the MM015 trial will show significant separation in curves? so far most ppl i've spoken with have said no..

thanks.


Celgene's Revlimid and Takeda's Velcade gaining traction in four-drug combination regimen in NDMM - oncologists




2009-11-23 Pharmawire


Intelligence Details


Celgene's (NASDAQ:CELG) Revlimid and Takeda/Millennium Pharmaceuticals' Velcade are gaining traction in combination with dexamethasone and cyclophosphamide in previously untreated multiple myeloma patients, according to oncologists.

Positive data from the EVOLUTION trial, which tested this combination, was presented last year at the American Society of Hematology (ASH) Annual Meeting, but left some oncologists questioning whether patients should be treated with these agents upfront in combination or sequentially. Updates from this trial will be provided on 6 December 2009.

Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms, although there also appeared to be higher rates of serious adverse events including possible treatment-related mortality in the VDCR arm.

Using the most active agent upfront, can provide the highest degree of sustained complete remission, said
Dr Nancy Simonian, chief medical officer at Millennium Pharmaceuticals. The data at ASH looking at three and four drug combinations will be an increasingly important area, she said. The question is whether an upfront regimen can provide high enough remission rates to delay stem cell transplant. The idea is similar to the CHOP regimen in lymphoma, in which transplant can be delayed, she explained. Multiple myeloma has reached a point where clinicians can consider early or delayed transplant. Velcade can produce high remission rates in the front-line setting, she said.

Dr Paul Richardson, an investigator for the EVOLUTION trial, associate professor of medicine at Harvard Medical School and medical oncologist at Dana Farber Cancer Institute, said the challenge of using all these agents upfront is the tolerability of the regimen, but when it is manageable, early use is the best treatment option. There were concerns as to whether patients would be salvageable upon relapse, but this does not appear to be an issue, he said.

This is definitely a positive trial and this regimen has been confirmed by providers and academics, noted Dr Jacob Laubach, a medical oncologist at Dana Farber. But a heated debate is still ongoing about whether sequential or upfront treatment is best, said Dr Joseph McGuirk, an oncologist at the University of Kansas Hospital. McGuirk said he believes that inducing the deepest remission is optimal for patients before transplant. Data suggests that patients have better outcomes with upfront therapy in terms of progression free survival (PFS).

There is the idea that with upfront treatment, transplant might not be an option, but the aim is to offer upfront therapy to get the best and most durable response, said McGuirk. Clinicians are looking for the depth and durability of response with an upfront combination, he said. This regimen could evolve as the "CHOP equivalent" in multiple myeloma if combination without toxicity is possible, he said.

There is no strong consensus at this point on whether upfront or sequential therapy is best, agreed Dr Guido Tricot, the director of the Utah Blood and Marrow Transplant and Myeloma Program. There are some academics who believe it is best to focus on extending survival as long as possible, and there is another camp that believes it is best to treat multiple myeloma as a chronic disease, he explained. Yet, with other malignant diseases, attempts to make them chronic have not worked in the past, and are unlikely to work in multiple myeloma, he added. When the disease relapses, the cells become smarter and more difficult to control, rendering a patient without options, he said.

Dr Kenneth Anderson, an oncologist at Dana Farber, said that the results together are so extraordinary and that data with Revlimid, Velcade and dexamethasone has demonstrated a 100% response rate.

Sequential therapy will not stand the test of time, said Dr Keith Stewart, a hematologist/oncologist at the Mayo Clinic, who also noted that transplant eligible patients should use all agents upfront.

Still other physicians such as Dr Brian Durie, chairman of the board and co-founder of the International Myeloma Foundation and multiple myeloma specialist at Cedars-Sinai Outpatient Cancer Center, were more in favor of using these agents sequentially, when the need arises. "We're not curing myeloma with these combinations, but achieving chronic disease control. With RD and MPR, you’re saving the other drugs for later," he said. By using the Revlimid and Velcade combinations sequentially, there is an additional period of disease control that seems more attractive and more cost effective, he added.

Dr William Matsui, associate professor of oncology in the division of hematologic malignancies at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, agreed that it is best not to use all agents upfront, noting that there is no evidence that doing so can provide longer remission or better quality of life. This combination exposes patients to more toxicity and there is nothing left for salvage if they relapse, he said. If the combination could possibly cure patients, then it might be worth the risk, but there is no long-term evidence with this combination, he said.

Anne Quinn Young, program director of the Multiple Myeloma Research Foundation, said the trend is to use newer agents upfront, rather than save them for later. She added that with regards to using the four-drug combination upfront, changing the regimen seems to resensitize patients. There is not as much data with Revlimid, but some patients who failed Velcade, but then went on Vel/dox, responded. There is also evidence from clinical trials looking at Velcade in combination with other proteosome inhibitors, she added.


Dr Robert Rifkin, an oncologist at the Rocky Mountain Cancer Center, US Oncology, said the long-term question in MM is whether this disease will be similar to lymphoma, where patients are treated with the R-CHOP regimen. "Our expectations for therapy in multiple myeloma have really changed, since the response rate bar now is much higher," he added.

by Elizabeth Krutoholow and Kimberly Ha

source: Pharmawire

Celgene's Revlimid: MP comparator arm sufficient for approval in first-line multiple myeloma; already substantial off-label use, experts say


PHARMAWIRE

September 29, 2009

By Elizabeth Krutoholow and Kimberly Ha

Story Celgene's (NASDAQ:CELG) Revlimid is expected to received approval in first-line multiple myeloma, based on the results of the Phase III MM-015 trial, which tested the agent against melphalan and prednisone (MP), experts said.

The chosen comparator and the endpoint of progression-free survival (PFS) are both sufficient from a regulatory perspective, they noted.

MM-015 is a 459 patient, randomized, double-blind, placebo controlled, Phase III trial comparing melphalan, prednisone and Revlimid (MPR) followed by continuous Revlimid (MPR+R) against MPR followed by placebo as well as melphalan and prednisone followed by placebo (MP+Pl) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for stem cell transplantation..

An independent Data Monitoring Committee (DMC) notified Celgene that the pre-specified efficacy analysis comparing MPR+R to MP+Pl demonstrated a highly statistically significant improvement in the primary efficacy endpoint of PFS. This difference crossed the O'Brien-Fleming boundary for superiority. In addition, no safety concerns were reported by the DMC. Full data is expected at the upcoming American Society of Hematology meeting in December.

Revlimid is currently approved for use in patients who have failed other therapies, but is used off-label in the front-line setting. According to Dr Kenneth Anderson, Kraft Family Professor of Medicine at Harvard Medical School and an oncologist at the Dana-Farber Cancer Institute, Revlimid is commonly used front-line together with dexamethasone or with Takeda (PINK:TKPHY)/Millennium's Velcade and dexamethsone in NDMM transplant candidates.

Assuming the data holds, Anderson said he believed Revlimid should receive approval in this setting with MM-015 as the pivotal trial and the ECOG studies as supporting trials. PFS is sufficient for approval in this setting since it has been shown to be predictive of a survival benefit, he said. "In upfront and in relapsed multiple myeloma, we are blessed because new drugs have shown that PFS is predicting for OS," he said, explaining that this was true for trials testing Revlimid with dexamethasone and Velcade with Doxil.

Celgene declined to comment.

The FDA and EMEA are looking for PFS, said Dr Antonio Palumbo, the primary investigator of the MM-015 trial and a medical oncologist at the University of Torino. Complete response rates have limited clinical importance, he said. Regimens VMP and MPT - which combined MP with Velcade and Celgene's Thalomid, respectively - gained regulatory approval in EU by demonstrating statistically significant overall survival (OS), he said.

Earlier this month, the FDA accepted for review an sNDA based on long-term OS data from the VISTA trial testing the use of Velcade-based therapy in patients with previously untreated multiple myeloma.

Dr Paul Richardson, lead investigator of the VISTA study and an oncologist in hematological malignancies at Dana Farber Cancer Institute, also noted that the results of the MM-015 trial will provide a platform for FDA approval. The implication is that the Revlimid-based arms have demonstrated improvements over MPT and that the Revlimid measured improvement surpassed what is required for approval, he said.

Richardson agreed that Revlimid is already used substantially in the front-line setting, based on the results of the ECOG studies, which also demonstrated the tolerability of the agent. He deemed the comparison of Revlimid to MP in MM-015 as "fine," since this was the approved regimen when the trial was launched. Moving forward, MPT is no longer viable, he said.

The new control arm in this setting will likely be MP with one of the newer agents, such as Revlimid or Velcade, Anderson agreed, saying that he doubted that MP will be the control arm for randomized trials for approval any longer.

Dr Amrita Krishnan, the director of City of Hope's Clinical Multiple Myeloma Program and an investigator on Velcade's EVOLUTION trial, said the company will probably be able to get Revlimid approved with a PFS endpoint. Achieving OS in multiple myeloma is very difficult and PFS alone is sufficient, she said. The VISTA trial did show OS at some point, but that took much longer, she added.

The front-line Revlimid-Velcade-dexamethasone combination showed an extremely high 100% response rate. "I haven't routinely used the three drugs upfront.. I've used two, and then added a third agent," Krishnan said, adding that patients have done quite well on the RVD combination.

The results of the MM-015 trial are likely to increase the use of Revlimid in the front-line setting in older non-transplant patients with MP, Anderson noted.

Myelosuppression is a concern, since both Revlimid and melphalan are known to lower blood counts, said Anderson. Yet while this combination is myelosuppressive, it is not myelotoxic - an important distinction, noted Richardson. Patients can take a break from therapy with growth factors, he explained.

The combination of RVD is "very exciting," as it has shown a 100% response rate with complete response rates approaching 50%, according to Richardson, who called this the most active combination to date. The challenge is using these agents all at once but when tolerability is good, early use is the best approach. The concern had been the risk of resistance when combining all agents upfront, but thus far this does not appear to be an issue, he said.

The early trials, even 10 years ago, with regimen VAD, showed a 5% complete remission rate, so expectations for therapy have really changed and the response rate bar now is much higher, said Dr Robert Rifkin, medical director of cellular therapeutics at the Rocky Mountain Blood and Marrow Transplant Program in Denver. In the EMEA, if Revlimid is approved based on the results of the MM-015 trial, its use will be a matter of order of administration, Palumbo said. Velcade works faster, making it better for aggressive disease. In patients eligible for autologous transplant, Velcade is used and then eventually Revlimid. In those patients without the option of transplant, which is approximately 70 percent of patients, about 20-30 percent are treated with Velcade induction and the other 70 percent with Thalomid (thalidomide). According to Palumbo, if Revlimid is approved without a budget issue, oncologists will move from thalidomide to Revlimid.

Dr Nancy Simonian, chief medical officer/regulatory affairs at Millennium Pharmaceuticals, said the new question on the table now is whether or not an upfront regimen gets high enough complete remission rates on its own to delay transplant in patients.

Rifkin said although Revlimid is not approved first-line for MM, it is very commonly used in that setting. It is not usually given as a single agent, but in combination with dexamethasone, or one other agent. "We're trying to create the R-CHOP equivalent for lymphoma. I think they're trying to develop a regimen that will really take care of MM."

"We're not there in myeloma yet, but the future will be combination with both Velcade and Revlimid used up front," Rifkin said.

Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma. The estimated frequency of multiple myeloma is five to seven new cases per 100,000 persons per year. The five-year relative survival rate for multiple myeloma is approximately 33%, one of the lowest of all cancers.

Celgene has a market cap of USD 24.98 bn.
by Elizabeth Krutoholow in Washington, DC and Kimberly Ha in New York

Pharmawire, FT on Acorda's approval chances:

http://www.ft.com/cms/s/2/b7b50454-af64-11de-ba1c-00144feabdc0,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html

cervarix really sucks. one of my friend's nieces in the UK, who received the vaccine had to stop school for 2 yrs or something, because she developed severe allergic reactions. her knee was swollen, it was just bad.

that's encouraging to hear how your wife is doing on 4-AP. hopefully once the formulated sustained release version from Acorda Pharmaceuticals is marketed, it will be even better. no risk of compounding error, and it will get reimbursed.

the drug should be approved on Oct 22..so finger's crossed!

i heard a rumour last year around ICAD that elan's managemnet locked their key shareholders in a room, had some potential bidders, they wanted to get someone to buy the company before the bap data came out at ICAD last year.

i don't know if that's true though. but if it is, then the mangement is def shady.

well, at least Serono finally issued a press release today on the sNDA filing for clad!

does anyone here on this board still think bap will see approval? i'm going to vote no...

Pharmawire reported back in 2008, that the next-generation protease inhibitors would likely see ritonavir boosting:

now, it's finally begun. well, it was first the SGP '518 compound.

11-Sep-08 16:10 Next generation HCV protease inhibitors could theoretically benefit from ritonavir boosting, despite first generation failures - analysis

Story Next generation hepatitis C (HCV) protease inhibitors could still theoretically benefit from ritonavir boosting, despite past failures with first generation inhibitors, physicians said.

The current standard of care for the treatment of HCV is combination therapy with pegylated interferon-alfa, which is an injectable, and ribavirin. If left untreated, HCV can cause serious liver disease, including liver failure.
Vertex and Schering explored drug-drug interactions between ritonavir and their respective compounds telaprevir and boceprevir in earlier clinical studies. Vertex worked with experts in the HCV community in 2006 and 2007, and the conclusion from those studies was that ritonavir does not boost telaprevir, according to a company spokesperson.
Yet some physicians and an investigator still said that HCV protease inhibitors could theoretically benefit through pharmacokinetic enhancement by ritonavir, similar to what is currently done in the treatment of HIV. Ritonavir, trade name Norvir (Abbott Laboratories), is an antiretroviral drug from the protease inhibitor class used to boost HIV drugs.
Previous studies by Abbott showed that there was a benefit to ritonavir boosting with both boceprevir and teleprevirin in mouse studies. These studies suggested that ritonavir boosting may significantly increase levels of these two protease inhibitors, and promote better dosing regimens. Abbott declined to comment for this article.
A leading investigator on numerous ongoing HCV trials in the US said that although first-generation protease inhibitors by Vertex and Schering did not benefit from ritonavir boosting, a next-generation protease inhibitor eventually will be boosted. "When you boost, it means you have a longer half-life and a more robust effect. I'm telling you, we’re going to see it," he said.
Second-generation protease inhibitors which act on a different pathway or metabolize differently may benefit from ritonavir boosting, the physicians said. Ritonavir boosting of protease inhibitors currently happens in HIV treatment, but can lead to liver toxicity at high doses, the leading investigator said.

One researcher working at a company developing an HCV compound agreed that ritonavir boosting is possible. Evidence from the Abbott study suggested it may be possible, he said, but there may be complications due to drug-drug interactions, as well as difficulties with HIV co-infected patients.
Depending on the individual compound and how it is eventually metabolized, a spokesperson for Schering said ritonavir boosting could improve dosing regimens for newer, second generation agents in development. "In theory, it could work. But I don’t know if anyone has reported anything on this issue."

Dr Christopher O'Brien, chief of clinical hepatology at the Divisions of Liver and GI Transplantation at the University of Miami, School of Medicine, said that Vertex and Schering's protease inhibitors did not benefit from ritonavir boosting as these compounds inhibit CYP450 in humans.
Ritonavir undergoes cytochrome P450-mediated biotransformation in human liver microsomes to three major metabolites, explained O'Brien.

Dr Andrew Talal, associate professor of medicine at Weill Medical College, said the main safety issue concerning potential interactions between antiretroviral therapy and HCV drugs is the efficacy of ritonavir boosting, and whether they are tolerable in patients, who may already be receiving an additional HIV protease inhibitor in addition to HCV therapy.
The physicians also predicted that future treatment would evolve into an all oral regimen of direct antivirals, but there is a potential for drug resistance with teleprevir, and protease inhibitor monotherapy will produce a lot of resistant mutations, the investigator said.
Dr Eugene Schiff, professor of medicine and director of the Center for Liver Disease at the University of Miami, said boceprevir and teleprevir are both robust drugs. "What is lagging, is the development of polymerase inhibitors that are safe and effective. Many of the polymerase inhibitors have had side effect issues," said Schiff.
Idenix is one company developing a polymerase inhibitor, despite the failure last year of its valopicitabine compound, which was found to cause liver toxicity. The company has since reformulated its compound to prevent liver toxicity in current trials. "What you want is a drug that you can give once a day rather than three times a day," said Schiff.
There are currently 300,000 people with HCV who have been treated, and approximately 700,000 who have been diagnosed and not treated, said Schiff. "As HCV treatment gets closer to combinations of small molecules, with a low side-effect profile, more people will get treated because of the attractiveness of a higher cure rate," he said.

Schiff said that, despite the current debate regarding the possibility of a non-interferon based regimen, future treatment would be a combination therapy utilizing a potent protease inhibitor paired with a less robust polymerase inhibitor, which effects another part of the virus to reduce the chances of "escape resistant" mutations.

Merck tried combination therapy using a polymerase and protease inhibitor to treat an infected chimpanzee with HCV. It was ultimately cured without using interferon or ribavirin.
Although combination therapy with a protease and polymerase inhibitor is possible, it may encounter challenges from the FDA, said O'Brien.

The FDA is against prolonged treatment with small molecule agents alone, as there is evidence to suggest the emergence of resistance within one or two weeks when interferon is eliminated from therapy, said O'Brien. "Some companies have both a polymerase and protease inhibitor in development, but they are reluctant to combine them," he added.
Patients likely have three potential resistant mutations present before treatment, said Schiff, and when they are treated with one protease inhibitor, their viral levels drop significantly, which allows resistant mutations to take over and replicate at a much higher level, leading to drug resistance.

The FDA has advised that both ribavirin and interferon should be given with protease inhibitors to clear out resistant mutations. "That's why you don’t use Vertex’s protease inhibitor alone," said Schiff.

Telaprevir is a robust drug, but can cause a minority of patients to develop a rash, Schiff said. "But when it develops, it’s pretty significant. And the longer you’re on it, the greater the likelihood," said Schiff. The four week lead in group seems to show a higher SVR, or cure rate. "They’re getting four weeks of the peg-intron and ribavirin first, to prime the immune system before adding the protease inhibitor," Schiff said.
Many patients are currently reluctant to receive HCV treatment due to the current requirement for interferon therapy, and the mild to moderate flu-like symptoms, such as fever, muscle and joint aches, and chills, according to Schiff. In the US, only 150,000 people are currently receiving HCV treatment out of the 4 million sufferers, estimated the Schering spokesperson. But once the treatment paradigm shifts into all oral therapy, it really should increase and open up the market.

Vertex has a current market cap of USD 3.72bn.

by Kimberly Ha and Elizabeth Krutoholow

Source Pharmawire
Drug Norvir
R1626
boceprevir
telaprevir

Originator Abbott Laboratories
Originator Roche Holding Ltd
Originator Schering Plough Corporation
Originator Vertex Pharmaceuticals Incorporated
OTHER Abbott Laboratories
OTHER Roche Holding Ltd
OTHER Schering Plough Corporation
OTHER Vertex Pharmaceuticals Incorporated

Intel. Type Product Development
Other

Countries USA

Intel. Grade Strong evidence
Intel. ID 696600

any thoughts on denosumab??

Source: Pharmawire


21-Sep-09 10:49 Amgen’s lack of symptomatic endpoints in denosumab trials treating bone metastases in breast cancer raises questions about place in patient management - oncologists

Story * Time to first skeletal related event (SRE) is probably a more meaningful endpoint than percentage of patients with a reduction in SRE
* FDA prefers time to first SRE, as percentage of patients with a reduction in SRE is not a very sensitive measure

* Although a majority of trials include symptomatic endpoints, such as looking at the rate of bone fractures - they are not necessary for FDA approval



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Amgen’s (NASDAQ:AMGN) omission of symptomatic endpoints in the Phase III head-to-head trial comparing denosumab to Zometa for the treatment of bone metastases in breast cancer, makes it unclear where denosumab will fit into patient management, oncologists said.

Novartis’ (NYSE:NVS) Zometa is a 15-minute infusion given every 3 to 4 weeks in a doctor’s office or at a clinic. It is currently approved to reduce or delay bone fractures or pressure on the spinal cord that can result from bone damage from advanced breast cancer. In advanced breast cancer‚ metastasis to the bone occurs in 65%-75% of patients.

The Phase III trial showed that denosumab significantly delayed the time to the first skeletal related event (SRE) and significantly reduced first and subsequent SREs compared to Zometa. Complete Phase III data will be presented at the European Society for Medical Oncology (ESMO) meeting in Berlin on 22 September.

Time to first SRE is probably a more meaningful endpoint than percentage of patients with a reduction in SRE, because with percentage, an arbitrary time is chosen, said Dr Matthew Raymond Smith, an oncologist in the Clair and John Bertucci Center for Genitourinary Cancers at Massachusetts General Hospital.

Percentage of patients with a reduction in SRE is not a very sensitive measure, and the FDA prefers time to first SRE, Smith said. Multiple event analysis and time to first SRE will be examined for denosumab, which will provide a more robust statistical analysis, he explained.

In response for company comment, Dr Roger Dansey, the executive medical director of global development for Amgen's oncology and hematology department, clarified that the primary endpoint of time to first SRE also included symptomatic endpoints. The primary endpoint is actually a composite endpoint, which also looks at fractures, radiation given to the bone, surgery performed on the bone, and spinal cord compression, explained Perlmutter. All four of these components are highly symptomatic, he added.

Karen Swenson, a research scientist at the Park Nicollet Institute, said although a majority of trials include symptomatic endpoints, such as looking at the rate of bone fractures, they are not necessary for FDA approval. These endpoints are important since they are considered to be more objective, but will not influence whether physicians will use denosumab, she added.

The FDA generally only wants to see the time to SRE, and majority of physicians are accepting of this endpoint since it is highly correlated to the rates of symptoms, Swenson explained.

Dr Allan Lipton, professor of Medicine at Penn State Milton S Hershey Medical Center said denosumab has potential since there were fewer events and the time is delayed. Statistically, this trial design has a better chance, he agreed.

Dr Mark Clemons, a medical oncologist at the Princess Margaret Hospital in Toronto, said the denosumab study is “very exciting,” since it was tested against Zometa, the best commercially available agent. It will be important to look at the data to determine if the benefit manifested through asymptomatic SREs - which can be picked up by x-ray but don’t affect the patient - or through symptomatic events like fracture, where pain requires management, he said.

Symptomatic changes include painful fractures as opposed to loss like vertebral height, explained Dr Jeffrey Holzbeierlein, associate professor of urology at the University of Kansas Medical Center. If there is a fracture, the patient would know. If the benefits are asymptomatic like hip fracture, patients and oncologists are normally aware of it, but it does not alter patient management, Clemons explained. This effect is less important, he added.

There is an association of mortality and morbidity with pain and fracture, agreed Dr Edward Schwarz, professor of Orthopaedics and associate director of the center for musculoskeletal research at the University of Rochester. Pain should be included as an endpoint, he noted. In breast cancer, Schwarz said he would look to use denosumab after seeing the data.

Pranela Rameshwar, Ph.D, professor of medicine in Hematology/Oncology at New Jersey Medical School, said the clinical benefit of denosumab based on this trial is questionable, since the focus is on bone metastases. Amgen should be focused on prevention, she said.

The prevention of recurrence is most exciting, since this treats early stage metastases, Clemons agreed. Oncologists need to see where the benefit for denosumab was manifested to determine if it will be important in patient management. SREs are not all the same, and delay in time to first and subsequent SREs is just delaying time for the inevitable, Rameshwar said. The disease is very painful and pain should be an endpoint, she added.

Pain was never an endpoint in Novartis’ Zometa trials, or for Amgen, because the companies do not want this to be considered a pain drug, Lipton said.

When considering asymptomatic SREs, one should determine whether they are osteoporotic or not since a patient can have painful osteoporotic fractures, explained Dr Joel Nelson, chairman of the Department of Urology, University of Pittsburgh School of Medicine. Denosumab’s place in patient management is more related to symptomatic versus asymptomatic change, he said.

Amgen is not doing a head-to-head study against Zometa with OS as an endpoint and is only looking at OS in prostate cancer, Clemons said. Several oncologists referenced the AZURE trial, an open-label trial comparing Zometa plus standard therapy to denosumab and Zometa alone. Standard therapy for bone metastases in breast cancer patients comprises of chemotherapy and/or hormonal therapy.

The inclusion of overall survival is a “big deal,” said Smith. Data from the trial will be available this year or early next year and will have a “major impact,” according to Clemons.

Amgen has a market cap of USD 60.72bn.

by Elizabeth Krutoholow in Maryland and Jacqueline Kwong in New York

merck got cladribine submitted today. but erbitux still blows: does anyone think it will ultimately get approved in the EU for lung cancer?

Erbitux’s marginal clinical benefit in lung cancer could prompt second look from regulators
By Kimberly Ha and Elizabeth Krutoholow

Published: August 13 2009 22:40 | Last updated: August 13 2009 22:40


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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Eli Lilly’s (NYSE:LLY) cancer drug Erbitux (cetuximab) has demonstrated such a marginal clinical benefit in non-small cell lung cancer (NSCLC) that neither FDA rejection nor approval is likely to change current prescription habits in the US market, physicians told Pharmawire. Further patient stratification based upon genetic analysis is required to increase the survival benefit of the agent, they noted.

The European Union rejected the drug’s prospects to expand into lung cancer last month. Merck KGaA, which markets Erbitux in Europe, has stated that it plans to appeal the decision. The drug is also facing delays in the US, as partners Bristol-Myers Squibb (NYSE: BMY) and Eli Lilly (NYSE: LLY) withdrew their supplemental biologics license applications earlier this year, after FDA concerns with manufacturing and controls concerns, but they will eventually it.

Only the Phase III FLEX study showed a statistically significant benefit in overall survival (OS), whereas the BMS099 and LUCAS trials did not. Patients given chemotherapy plus Erbitux in the FLEX trial survived longer than those in the chemotherapy-alone group, with a median survival rate of 11.3 months vs 10.1 months. There was no statistical difference in progression-free survival (PFS).

Conclusive evidence has demonstrated that patients harboring an activating EGFR gene mutation have a better response to EGFR-tyrosine kinase inhibitors such as Genentech’s Tarceva and AstraZeneca’s Iressa.

Erbitux could be useful if a patient’s mutational status were known, said Dr Manlio Mencoboni, head of the medical oncology unit at Villa Scassi Hospital in Italy. Recently published studies have demonstrated that Erbitux can be a good agent for patients who are deemed responders based on the characteristic rash associated with Erbitux and other EGFR inhibitors.

Mencoboni said it is likely that the FDA will view the data submission package in the same light as the EMEA. Additional mutational status analysis is needed to be scientifically considered and this is an economic consideration too, he said. Appropriate selection of patients for Erbitux should increase the survival benefit. Knowing only the EGFR mutational status without further genetic determinants is not the best strategy, he said.

A spokesperson for Eli Lilly said she was not aware of any additional trials involving Erbitux in NSCLC, when asked whether the company will be conducting further trials for subgroup analysis based on EGFR expression. However, she noted that the company’s ownership of the drug is still fairly new.

Regulators, doctors take ‘hard look’ at data

The EMEA’s rejection of Erbitux was a surprise because the trial was positive from a regulatory point of view, as the FLEX trial met its primary endpoint, said Dr Federico Cappuzzo, a medical oncologist at the Istituto Clinico Humanitas IRCCS in Italy. There is a global strategy to restrict the use of an expensive drug unless there is a clear benefit and there is no evidence of such a benefit in any subgroup with Erbitux, he said. For the FDA, demonstrating a survival benefit is important and there is a benefit with Erbitux, he said. However, the benefit is so marginal that even if it is approved it will not have significant adoption.

Despite the EU rejection, Cappuzzo said that his treatment strategy will not change as he was never confident in the drug and will not miss its use.

”I am not surprised that the regulatory agencies are taking a hard look at the magnitude of the FLEX trial and the absence of a benefit in the BMS trial,” said Dr Nathan Pennell, an oncologist who specializes in the treatment of thoracic malignancies with a focus on lung cancer at the Taussig Cancer Center, Cleveland Clinic.

Until physicians have a consistent subgroup of patients who are clearly going to benefit from using Erbitux, this drug will face limited clinical uptake, Pennell said. ”Not many people are using Erbitux right now. It’s part of the NCCN [National Comprehensive Cancer Network] guidelines, so physicians can consider using it. But I haven’t used it myself.”

Dr Harry Raftopoulos, a lung cancer specialist at the Monter Cancer Center, North Shore-LIJ Health System, also voiced a similar opinion, and said even if Erbitux receives approval in lung cancer, he does not intend to use it.

”If approved, the main difference is that it allows for marketing. There will be some physicians who will prescribe it, but the benefits seem to be very low,” said Raftopoulos.

Dr Karen Reckamp, assistant professor in the Medical Oncology & Therapeutics Research unit at City of Hope in Duarte, California, said the drug’s initial perception by the medical community was not positive, so its recent rejection by the European regulatory agency does not change her views on this drug. ”The drug’s use never really increased. I think its use is still incredibly low,” she said.

”Nobody believes in that result for the FLEX trial,” said Dr Silvia Novello, an oncologist from the University of Torino.

She added that ”in our minds, there is no Erbitux for our patients.” The drug has to be combined with a chemotherapy backbone that is not the standard of care, and coupled with the drug’s toxicity profile, it is impossible for the drug to be used in a large group of patients, Novello said. She agreed that it will probably take the company a long time before resubmitting a new application in the US.

In addition to the problem of the chemotherapy combination, Novello noted that the percentage of patients on Erbitux in the FLEX trial who reported febrile neutropenia – or an abnormally low white blood cell count – is also a concern. ”You can’t do a first-line therapy that [has such a high rate of] febrile neutropenia, when 50% of patients will request and undergo a second-line therapy,” Novello said.

Additionally, it is not possible to administer cisplatin at the doses used in the FLEX trial, said Mencoboni. For most patients, there would be too many toxicities, he explained.

Vinorelbine plus cisplatin is not the standard of care in the EU nor in the US, Novello said, adding that the drug’s toxicity profile is important.

Asked whether treatment with Erbitux is worthwhile, in light of the mediocre one-month survival benefit, Dr Pasi Janne, assistant professor of medicine at Harvard Medical School, said unfortunately none of the current therapies cure lung cancer. Physicians just have to make sure that the chosen course of therapy is actually associated with a reasonable quality of life, he said.

If the toxicities are terrible, even though there is an incremental increase in life, these are questions that will have to be discussed with patients individually, Janne said.

Dr Chandra Belani, deputy director of the Penn State Hershey Cancer Institute and the lead investigator of Lilly’s Alimta maintenance study, said Erbitux also has issues with its pharmacological formulation. The FDA wanted to see if the drug manufactured in the US was comparable with the formulation used in the EU. The company will have to show the equivalent pharmacokinetics between the EU and US formulations.

”I think that the data is modest,” Belani said, adding that the drug would probably beneficial if clinicians can target a specific group of patients. Data presented at ASCO, for instance, suggested that KRAS mutations matter, he said.

Genetic mutations yield few clues

Neither EGFR nor KRAS mutations are a predictor to response to Erbitux. KRAS mutations are a lot less prevalent in lung cancer, so there is only a limited subset of patients to pull data from. ”This marker hasn’t been shown to be predictive,” said Reckamp.

Dr Chao Huang, an oncologist specializing in lung cancer and head and neck cancer at the University of Kansas Medical Center, said although the approximate one month median survival is not really exciting, the study requires a look into particular patient subsets.

There does not seem to be a correlation between KRAS mutation and response, Huang said. ”So that’s very different from the results seen in colorectal cancer [CRC]. In lung cancer, KRAS doesn’t seem to tell us which patients respond better,” he said.

KRAS is not panning out as a predictive marker for Erbitux like it is in CRC, and there is also limited data, agreed Dr Shirish Gadgeel, associate professor at the Karmanos Cancer Institute at Wayne State University.

Oncology groups such as the Southwest Oncology Group are now looking at EGFR expression and response to Erbitux. Its study looks at gene amplificiation with FISH to detect EGFR over-expression to see if patients respond better to Erbitux based on these markers.

For EGFR expression analysis, IHC and FISH are standard tests. The EGFR mutational analysis is a more specialized test. While any hospital should be able to perform those tests, EGFR testing is not routine. ”Those tests cost money, and sometimes insurance may not cover that,” Huang said.

The problem with tests is the availability of tissue. ”We usually just do a fine needle aspiration test to collect a tissue sample from the patient,” said Huang. Sometimes, there is not enough cells or tissue left to conduct a FISH or IHC test. Clinicians may not have enough tissue sample available to do additional testing to see if EGFR or RAS mutation is present before making treatment decisions. There is also the question of whether oncologists need to re-biopsy some patients.

In the future, more routine testing, such as FISH and EGFR expression, should be conducted, Huang said.

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Date: September 2, 2009
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conference call ongoing right now.
Q&A starting now.

any updates on the ALTH decision?

thanks genisi. A key concern for me is what the actual market opportunity is, for this drug.

apparently, 2/3 of patients don't respond. there are around 10,000 pts on 4-AP right now.

plus the drug will get heavily blackboxed, also likely with a strict REMS.

what do you guys think about this article?

Why I Doubt the FDA Will Approve Acorda's Fampridine 12 comments
by: Dr. Anthony April 24, 2009 | about: ACOR
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Font Size: PrintEmail TweetThis Yesterday there was an announcement that Acorda (NASDAQ: ACOR) has amended their NDA application for fampridine. After after taking a closer look at their Phase III study (MS-F203), here is a reason why come February 23, 2010 the FDA will provide a verdict of NOT APPROVED or at best APPROVABLE. Either case, it will have a detrimental effect on the stock's price.

Here is my analysis of the pivotal study (MS-F203):

The primary endpoint of this study was to measure the percent of patients who improve their walking ability from baseline. Again, the primary endpoint does not quantify the significance of improvement from baseline and how that relates to clinical benefit. So, to use an analogy, say I have a miracle drug that will lower ALL patients' blood pressure, but I don't say by how many mmHg. Is this clinically meaningful? Suppose I say that it was by 1mmHg, but that ALL patients' blood pressure will be lowered. Would you approve this drug? The same goes for this endpoint. Furthermore, the the results from this study showed that only 35% of patients taking fampridine demonstrated a response compared to 8% placebo. And what exactly is this response? A.51ft/sec (6 inches/sec) improvement in walking speed.

So what about the 65% of patients who didn't respond? A 16ft/sec (2 in/sec) improvement in walking speed, no better than a sugar pill (placebo) .10ft/sec improvement.

The FDA will not approve a drug that only helps 35% of the patients walk 4 inches/sec faster than the placebo while having a side effect profile causing seizures, anxieties, and loss of balance. The benefits are just not there over the risks the drug pose.

Interestingly, also look at the patient characteristics in the study. It is skewed in favor of the Fampiridine group.

Look at the male/female ratio:

Placebo 40%/60%
Fampridine 29%/71%
Non-responders 31%/69%
Responders 24%/76%
As you can clearly see, it looks like males have poorer outcome with this endpoint than females, as demonstrated by more males not responding to the drug vs. responders. Furthermore, there is a skew towards more males in the placebo group who are more less likely to have positive outcome.

In conclusion, I question the validity of the primary endpoint. Simply stating that a higher percent were able to walk faster is not a valid endpoint.

Finally a telltale sign is the insiders' transactions.

Disclosure: None

12:56 Auxilium: Xiaflex's presence in the blood system could lead to systemic toxicities; immunogenicity concerns remain - experts
Story * FDA advisory panel meeting scheduled for 16 September 2009
* Detecting Xiaflex in the urine indicates that it traveled through the blood system and could affect other organs

* Xiaflex specific for Types I and III collagen, but liver and lungs abundant with these types of collagen

* Even a slight elevation in IgE levels could elicit severe allergic reaction, said an expert



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


Auxilium’s (NASDAQ:AUXL) Xiaflex for Dupuytren’s contracture could potentially harm organs in the body, since 7-28% of the collagenase was found in patients’ urine - indicating that the drug enters the blood system, physicians said. The experts interviewed also questioned whether the immune response observed in early clinical trials is negligible.

In a paper titled "Collagen as a Clinical Target: Nonoperative Treatment of Dupuytren’s Disease," which published the data from one of Xiaflex’s Phase II trials, the authors stated that 7-28% of the drug was recovered in patients' urine after 30 to 60 minutes, and claimed that this finding may indicate the kidney’s ability to concentrate collagenase. The paper - which was published in the Journal of Hand Surgery in 2002 - further noted that no collagenase was detected in any of the serum samples collected from one minute to 19.5 hours after the injection was given.

Will Sargent, Auxilium’s vice president of investor relations and corporate communications, also noted that the signal for IgE (immunoglobulin E) – an antibody that plays an important role in allergy – was initially seen in the early development stages of Xiaflex. However, the Phase III results reported that no systemic allergic reactions were noted, despite the fact that the most common adverse events were pain, swelling, bruising and pruritis at the injection site and transient lymph node swelling.

A BLA was recently submitted for Xiaflex and an FDA advisory committee meeting will be held on 16 September 2009.

If 7-28% of collagenase is found in the urine, it means the enzyme must have circulated in the blood plasma and subsequently filtered in the kidney and in the urine, said Dr Erik Ilso Christensen, a professor of anatomy at Aarhus University. Consequently, the collagenase could enter a variety of organs from the blood, notably the liver, he added.

Various PKA studies were done to monitor for systemic exposure but it was very difficult to find evidence, according to Dr Larry Hurst, chief of hand surgery and chair of the department of orthopedics of the Health Science Center at the State University of New York at Stony Brook, and primary investigator of the Phase III CORD trials. The drug "seems to go away," he said.

“How the collagenase got from the Dupuytren’s cord in the hand all the way to the kidney is a mystery if it did not pass through the blood compartment,” said Robert G. Hamilton, PhD, a professor of medicine and pathology at the Johns Hopkins University School of Medicine and the investigator who conducted the pharmacokinetic studies for Xiaflex.

Dr Vijay Vanguri, an instructor in the department of pathology at the University of Massachusetts Medical School, agreed that if collagenase is injected locally into the body, but is detected in the urine, the only way for the drug to appear in the urine is to travel through the bloodstream and filter through the kidneys.

Furthermore, Vanguri noted that the fact the collagenase is circulating through the bloodstream opens the possibility that the drug could affect other organs as well. Collagenase has to be in the blood for some time in order to reach the kidney, added Dr Helmut Rennke, a professor of pathology at Brigham and Women’s Hospital. The time it takes collagenase to travel from the hand to the kidneys provides ample time for the drug to reach other organs in the body, added Rennke.

Sargent noted that Xiaflex is specific for Types I and III collagen, which is not present in nerve bundles. However, Rennke noted that other Types I and III collagen were abundant in other parts of the body.

The liver and lungs could be significantly affected by the type of collagenase that makes up Xiaflex, as both these organs have Types I and III collagen, said Rennke. He also noted that bones have Type I collagen, which could also be "damaged" by the drug.

The company should really test the collagen content in the body, especially in the liver and lungs, to determine whether Xiaflex dramatically decreases the amount of collagen in these organs, Rennke said. A major decrease in collagen content could destruct the structure of these organs, he added.

A couple of sources also questioned whether the lack of collagenase in the tested blood actually indicated that the drug did not circulate through the body. “I suggest that the best analytical assays we had available to measure collagenase were most likely too insensitive to detect the administered level of collagenase that was diluted by the total blood volume of five liters,” said Hamilton. He added that it was possible that the time when the blood was collected was not ideal to catch the bolus of collagenase in the blood.

If the level of collagenase found in the blood is low, but is found in the urine, this indicates that tissues must have absorbed the drug as it flowed through the blood system, added Rennke. “To me, this is evidence that organs take up the collagenase,” he said.

Physicians also questioned whether the immunogenicity response seen in the clinical trials could be considered a negligible response. “Truth be told, even though Xiaflex is injected into the cord in the hand, there is sufficient inflammation at the site to allow effective antibody responses to be detected,” said Hamilton.

He also mentioned that although Auxilium stated that low levels of IgE were detected among patients, the conclusion that there would be no allergic response could not be drawn. As an example, Hamilton noted that very low levels of IgE anti-venom in combination with a honeybee sting could elicit a severe allergic reaction in a predisposed individual.

Because the collagenase used for Xiaflex comes from a bacterial source, there will always be a concern that patients would form an immune complex, said Rennke. A serious immune response, such as serum sickness, could cause serious complications, he added.

Serum sickness is an allergic reaction to proteins derived from a foreign source, such as an animal. A patient with serum sickness will experience hypocomplementemia, which is the condition where proteins cease to function or perform poorly.

Dr Bo Yu, a former researcher at Advance Biofactures, a subsidiary of Biospecifics Therapeutics (NASDAQ:BSTC) - the innovators of collagenase for Dupuytren's contracture – who is familiar with the pharmacokinetic studies of Xiaflex, also agreed that immunogenicity is a potential problem with collagenase.

Rennke further noted that the fact that Xiaflex is given intermittently could greatly decrease the drug's efficacy. The amount of time in between each injection allows patients to form antibodies against the drug, which would make them immune to the collagenase, he said.

Dr Roy Meals, a clinical professor of orthopedic surgery at the University of California, Los Angeles and an investigator for Xiaflex, noted that Xiaflex is a foreign protein so patients can develop an allergic reaction, but such reactions have not been observed. Some patients in the Phase II and III trials had as many as eight injections over a year, and there were no allergic responses. The expression of antibodies was not an issue, he added.

Dr F. Thomas Kaplan, a surgeon at the Indiana Hand Center, noted that blood work was performed throughout the trial for immunogenicity testing, but the results were not provided to the investigators. Investigators were initially concerned about the immunogenicity of Xiaflex because it is a large protein, but the immune response has been studied and it is not an issue, according to Hurst, who has personally done over 300 injections and only seen one episode of hives that was treated with a shot of Benadryl. Lymph node swelling decreased rapidly, he said.

When asked if an immune response would be mechanistically linked to collagenase or if it were specific to Xiaflex itself, Dr Roy Kulick, associate professor of orthopedic surgery at Albert Einstein School of Medicine and director of orthopedic hand surgery at Montefiore Medical Center in New York, noted that mast cells are not activated by collagen breakdown. Mast cells are involved in allergic and anaphylactic response.

With regards to the upcoming advisory panel, the FDA has only requested total antibody data, according to Sargent. He also noted that Savient Pharmaceutical's (NASDAQ:SVNT) advisory panel for its gout drug Krystexxa demonstrates the fact that the FDA Arthritis Advisory Committee does not focus on IgE and only looks for clinical events.

Xiaflex treats Dupuytren’s Contracture – a condition where the hand is constantly in a contracted position - by dissolving the collagen in the contracted cord in the hand. The collagenase that makes up Xiaflex is purified from the bacteria clostridia.

Auxilium has a market cap of USD 1.25bn.

by Jacqueline Kwong and Elizabeth Krutoholow

Source Pharmawire

who thinks Erbitux's chances at FDA approval in NSCLC are screwed bc of the recent EU decision.

any chance that merck will win the appeal in EU?

i've been following this company for awhile, spoke to their CEO a couple of times at investor conferences.

maybe some ppl have slight hope..since the FDA approved Vanda's drug when nobody had any faith left..

we've been thrown a lot of surprises lately. DNDN, VNDA..MDRX was acquired. should have seen the last one coming though.

anyone like Zymo's lupus drug on this board??


23-Jul-09 14:34 ZymoGenetics' atacicept may benefit from Benlysta's headway, yet mechanism of action potentially different enough to see varied results, physicians say
Story ZymoGenetics (NASDAQ: ZGEN) and partner Merck Serono's atacicept has the road ahead of it partially paved by trailblazer Benlysta, however the drugs' mechanisms of action are different enough to produce disparate results, physicians said.

Atacicept, currently in Phase II/III trials, is a recombinant fusion protein that binds and neutralizes BLyS and APRIL, two molecules important to the survival of B-cells. This unique approach differs from anti-CD20 targeted monoclonal antibodies as its effect extends over the entire lineage of B lymphocytes as well as plasma cells.

Human Genome Sciences (NASDAQ: HGSI) and GlaxoSmithKline (NYSE: GSK) announced earlier this week that Benlysta, another developmental lupus agent, met the primary endpoint in BLISS-52, the first of two pivotal Phase III trials in patients with serologically active systemic lupus erythematosus.

Benlysta is a human monoclonal antibody that specifically recognizes and inhibits activity of B-lymphocyte stimulators (BLyS). BLyS are believed to contribute to the production of autoantibodies that attack and destroy the body’s own healthy tissues, according to the company's website.

Atacicept is promising but the drug seems to be almost “too powerful” in lupus because the drug hits multiple targets, said Dr David Jayne, in the renal medicine department at Addenbrooke's Hospital, Cambridge, United Kingdom. The side effect concerns seen in the Phase II study could be reduced by giving the drug with lower doses of steroids or using lower doses of the agent, Jayne speculated. The success of Benlysta is likely to make development easier for atacicept, Jayne added.

Dr Bevra Hahn, chief of rheumatology at UCLA Medical Center, explained that atacicept’s mechanism of action inhibits the bindings of ligands and more receptors than an anti-BLyS such as Benlysta does. She noted that while in theory this sounds better, there was a possibility that perhaps only one receptor should be blocked. Hahn added that if others are blocked, it could blunt the effect of inhibiting just one receptor.

The primary abstracts available on atacicept demonstrate that the drug has potential, but there were some concerns with trial design, according to Dr Daniel Wallace, a lupus expert. The drug may have a broader future compared to Benlysta, due to its effects on multiple pathways, Wallace said, but also cautioned that the data available on Benlysta is very preliminary. He added that the companies developing the drug should have an “easier time” because Human Genome Sciences Benlysta is paving the pathway in lupus development.

Treating lupus patients with co-stimulatory blockers is likely to be fruitful, said Dr Mary Dooley, a lupus expert at the University of North Carolina who is also a Benlysta investigator. Atacicept is one of the agents that is currently showing the most promise in development, and the drug affects multiple targets, so it could have broader ranging effects, Dooley said.

Dr Susan Manzi, associate professor of medicine in the division of rheumatology and clinical immunology at the University of Pittsburgh, said while any b-cell targeted therapy in theory makes sense in a lupus trial, she did not necessarily believe that Benlysta and atacicept should be linked. "You could say that because it [atacicept] is similar to Benlysta it will have a better chance, but I’m not so sure of that," Manzi said.

Manzi added that ultimately atacicept’s current trial’s level of success will come down to trial design issues, such as who was enrolled and what background therapy the patient population is using. She noted that these factors go a long way in determining later phase lupus trials.

Atacicept interferes with many signaling molecules that are implicated in lupus pathology, according to Dr Joan Merrill, a Benlysta investigator. However, since the drug has many targets – BAF, BLyS and April – side effects could be a concern with the agent, Merrill said. Also, the drug is self-administered, which may not be a significant advantage in lupus, Merrill said.

by Klara Czobor and James Avallone
Source Pharmawire

23-Jul-09 09:09 Targacept open to approaches by CRO companies with Phase I CNS trial experience, in active partnership discussions over antidepressant TC-5214, CEO says
Story Targacept (NASDAQ: TRGT) is open to hearing from clinical research organizations with prior experience in conducting Phase I studies in central nervous system (CNS) disorders, according to President and CEO Donald deBethizy.

The company is also in active partnership discussions over compound TC-5214, an augmentation therapy for major depressive disorder. The drug recently reported positive results showing an improvement in symptoms of depression in patients who did not respond to Forest Lab's (NYSE:FRX) Celexa, a currently marketed antidepressant.

Presentation of the full data set for TC-5214 will occur at the Society for Neuroscience meeting in October.

"The magnitude of its effect is superior compared to the old drug. We haven’t reported that yet [at a scientific conference]," deBethizy said. TC-5214 is wholly owned by Targacept, and the FDA allowed the company to conduct one Phase I trial before going directly into Phase IIb trials, he said.

Potential partners for antidepressant drug

Wedbush Morgan analyst Kimberly Lee said she anticipates a potentially large partnership for TC-5214, which could occur by year-end. "Management has proven that they can execute on obtaining large pharma partnerships as evidenced by the AstraZeneca collaboration for AZD3480," she noted.

A second industry analyst named Eli Lilly (NYSE:LLY), Novartis (NYSE:NVS), and potentially Pfizer (NYSE:PFE) as potential interested parties in this compound. "I do not think Merck (NYSE:MRK) [would be interested], but Bristol-Myers (NYSE:BMY) has the ability so you never know," he said.

Current partners GlaxoSmithKline (NYSE:GSK) and Astrazeneca (NYSE:AZN) do not have first rights to these drugs, deBethizy said. An ideal partner would be a large pharmaceutical firm with global reach and experience in this area.

Targacept is currently debating whether to partner its compound with a company that has a competing product. Bristol's Abilify and AstraZeneca's Seroquel are other drugs in the antidepressant market, deBethizy noted, adding that both drugs share movement disorder, obesity and diabetes risks.

"We’re very excited about sharing this data with them. We’re just not promising a partnership at this point," he said. The company would prefer a co-development, co-commercialization deal, as this approach preserves more control in terms of future direction of the drug's development, he explained.

In terms of Japanese pharma interest, deBethizy said Targacept has not focused on Japanese pharmaceutical companies at this point. "Finding Japanese partners is just a challenge, unless they find us first," he said, adding that the company would be willing to entertain offers from Japanese suitors. "It's a competitive bidding process."

As far as timing, deBethizy noted that the company believes that it would be best to have a partner sooner than later. It also aims to initiate a clinical trial in 2Q10. "We are actively looking at partnerships, and we’ve been doing that for a year now," deBethizy said, adding that most of the parties wanted to wait until they saw the recent data.

Clinical research out-sourcing strategy

Targacept has a "blended" outsourcing model. "We do the core things ourselves, then outsource the context," he said.

The Phase IIb trial of TC-5214 as an augmentation treatment for major depressive disorder was a two-phase study conducted at 20 sites in India and three sites in the United States.

The Indian trial was conducted in partnership with an Indian CRO. "We have a lot of familiarity with that group, since the founder of that company used to work for us," said deBethizy.

Targacept hired a new senior medical director from GSK, and transferred the executive to India to make sure things got pulled together. "We also use site management organizations. We use CROs in a variety of areas," he said.

Targacept does all the preclinical work, and GMP is outsourced through CMOs. "We just had a strategic meeting on Sunday, because we hadn’t really planned for this good of an outcome. One of the things we agreed to is we’re going to use this semi-virtual model," he noted.

"We’re not going to build out infrastructure because we’re blessed with two very good molecules, so we will be careful," deBethizy said, adding that the quality of services from CROs is much higher today and the company's continued strategy will be to outsource those functions.

Targacept has good clinical development capabilities, but if it chooses to do a portion of the Phase III trial, it would do that with a CRO, he said. "Whenever we have success like this, we get a lot of emails from various vendors. We know most of the CROs; we have a lot of relationships," he said.

Yet he said the company would most likely welcome contact from CROs that have done Phase I work in CNS trials.

"We’ve done a lot of work in France, because they were very good at CNS work. Work has also been done in India; we’ve got a CRO there now. We are now conducting preclinical safety work in China," he said.

"Everyone is preparing their balance sheet for the patent cliff, and the advantages for a US market are not as advantageous with the managed care and the US government likely to take over more of healthcare," he said.

Companies are preparing and realizing there is growth in China, India, and South America. Everyone is watching the development of new intellectual property laws in those regions, he said.

Targacept ended last year with USD 88m, with guidance of USD 54m ended 2009. The company has enough cash until 1H11.

Targacept has a current market cap of USD 217m.

by Kimberly Ha in New York

Pharmawire Article on Auxilium:


by Elizabeth Krutoholow and Jacqueline Kwong

09:27 Auxilium’s Xiaflex Advisory Panel to focus on surgeon education program to limit tendon rupture, nerve damage, surgeons say

Story Auxilium’s (NASDAQ:AUXL) Xiaflex FDA Advisory Panel will likely be focused on a surgeon education and training program that will be in place to limit side effects from improper use, such as tendon rupture and digital nerve damage, hand surgeons said.

The FDA’s Arthritis Advisory Committee will tentatively review Xiaflex on 16 September 2009. The FDA advisory committee is looking at including hand and/or orthopedic surgeons on the panel, but the breakdown has not been revealed, according to Will Sargent, vice president of investor relations and corporate communications at Auxilium.

Regardless of the FDA pathway, Auxilium believes that educating the surgeon base about the proper technique for injecting Xiaflex is important, Sargent said. The company is planning a “robust” education program that it plans to share with the FDA, and is in a dialogue now, he said. The education program would ensure that surgeons are aware of the risk/benefit profile and are aware of what worked best in clinical testing, he added.

Dr Srinath Kamineni, a consultant orthopedic surgeon and elbow, shoulder, hand and wrist specialist in London, said that extensive training is needed - citing the potential risks of tendon rupture and nerve damage with injections. Tendon rupture is a huge concern because if Xiaflex is injected in the wrong place, it could lead to tendon breakdown, he said.

In the CORD I and II studies, the open-label JOINT I and II studies and the pharmacokinetics study, there were a total of three confirmed tendon ruptures (rate per injection = 0.14%); one reported tendon rupture remains unconfirmed (rate per injection = 0.05%).

The rate of tendon rupture is probably acceptable, according to Dr Roy Kulick, associate professor of orthopedic surgery at Albert Einstein School of Medicine and director of orthopedic hand surgery at Montefiore Medical Center in New York. If the cord is on top of a tendon, ruptures could occur if the injections are deep but they do not happen often, he said.

Tendon rupture is a major concern, said Dr Robert Szabo, professor of orthopedic and plastic surgery at the UC Davis School of Medicine. The clinical trials have been performed by surgeons who are more familiar with the disease so the results are better than they will be once Xiaflex is available to the public. The concern is that Xiaflex will have to be limited to surgeons, he said. If it is marketed to everyone, there will be a lot of problems, he added.

It is really a question of training, said Dr Larry Hurst, chief of hand surgery and chair of the department of orthopedics of the Health Science Center at the State University of New York at Stony Brook, and primary investigator of the CORD trials, noting that certain trials in Australia were done by rheumatologists.

The rate of tendon rupture was reasonable, said Dr Roy Meals, a clinical professor of orthopedic surgery at the University of California, Los Angeles, and an investigator for Xiaflex. Tendon rupture is partly technique dependent, he said. Education will probably start in hand surgery, where surgeons will be taught the potential risks and benefits of Xiaflex so they can use it safely, he said.

Xiaflex should be approved but with some reservation about widespread use, noted Dr William Townley, a plastic surgeon at Salsbury District Hospital in the UK. The agent will probably have the best safety if given by qualified hand/plastic surgeons with the appropriate anatomical knowledge, experience and ability to deal with complications, as well as awareness of surgical alternatives, he said.

The technique should be relatively easy to pick up, but the company will need to tell doctors to learn it well or else might Xiaflex may cause tendon rupture, said Dr F. Thomas Kaplan, a surgeon at the Indiana Hand Center.

Meals said many physicians hope that Auxilium will restrict the distribution of Xiaflex to prevent rheumatologists and dermatologists from using it because there would probably be more tendon ruptures if they did. These specialties have not seen the cord of tissue that causes the contracture and do not have a good spatial understanding of the hand, he said. “It is a scary thought,” he added.

However, the severity of the rupture depends on which tendon is affected since some patients would not even know that a tendon ruptured if it did not disrupt motion, Meals said, noting that these patients already have limited motion from the contracture and that if Xiaflex brings the contracture towards normal a tendon rupture is much less of a consequence.

Yet a surgeon who spoke on the condition of anonymity said that since some authors are reporting tendon ruptures, he believed that “the nails are in its coffin.” Fasciectomy or fasciotomy seem much safer, he added. The surgeon was not aware of any cases of neurolysis, but said that the occurrence is feasible.

Dr Bing Siang Gan, a surgeon at the Hand and Upper Limb Centre at the University of Western Ontario, agreed that any tendon rupture is one too many.

With nerve damage, the risk becomes higher as one injects distally, similar to traditional surgery, Kamineni explained. In over 1000 patients and over 700 injections, there was no nerve damage, Hurst said. Kaplan also described nerve injury as surprisingly low and added that no one reported temporary numbness.

However, in Dupuytren's, nothing is standard and predictable and while the cord can be palpated, it is not possible to feel the nerves so a physician would know where to inject but would not know where not to inject, Szabo cautioned.

There are different forms of collagen and some are resistant to collagenase, Meals said when asked about the potential for neurolysis. Some patients have experienced skin lacerations with Xiaflex, he noted.

One plastic surgeon noted that improper injection could result in serious consequences. If improperly injected into a digital artery, patients can lose a finger since Xiaflex works through dissolution, he said. He also noted that accidents may result in skin loss.

Vessel rupture is also a concern since many vessels are covered in collagen, said Kamineni, who explained that this could result in hematomas. There is a potential complication of hitting normal tissue with Xiaflex that is depends on on how and how often it is given, said Dr Scott Zashin, a rheumatologist and clinical associate professor of medicine at the University of Texas, Southwestern Medical School.

According to Sargent, while nerve damage appeared to be an issue in vitro, Xiaflex does not appear to affect the nerve, large arteries, or veins.

Kamineni said that lack of proper training is the “quickest way to go wrong” for the company but believed that Xiaflex genuinely has a place in treating Dupuytren's contracture.

Physicians are optimistic about approval, but there is a concern that problems may emerge if patients who do not need Xiaflex get treated with it due to the convenience of administration, Szabo said.

Meals agreed that hand surgeons were enthusiastic over the potential for Xiaflex, but noted that many adverse effects are often identified after an agent comes to market. However, he said that Xiaflex seems remarkably safe.

Auxilium has a market cap of USD 1.33bn.

this is a pretty interesting article:

http://www.solaltech.com/doctors/3/HOT%20OFF%20THE%20PRESS%20Premarin-The_Intriguing_History_of_a_Controversial_Drug.pdf

bap is never going to get approved. i sat in on the bap presentation at AAN around a month ago. there were over 10 cases of vasogenic edema reported in their Phase II trial, and the worst part is that its not dose dependent.

it's basically triggered by the difference in dose. you can go down in terms of dosing, and trigger VE. something to do with crossing blood brain barrier. i'm sure of the exact mechanism of action, but basically, bottom line is bap is a really risky drug.

most analysts have dropped this drug from the valuation.

who knows, maybe pfizer will drop partnership after the wyeth acquisition closes. why does pfe need bap when its got their own AD pipeline, and they've got dimebon in combination with everything right now.

just my 2 cents. :)

allos - next takeover target in the sector. Who on this board thinks that Allos with PDX is the next to go? they seem like a prime takeover candidate for CELG, or anyone really.

also, any news on BIIB and when someone will finally take them out???

you think its getting close? end of this year?

Elan in talks to sell minority stake: report
Sat May 30, 2009 6:34pm EDT Email | Print | Share| Reprints | Single Page[-] Text [+]

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More Business & Investing News... CHICAGO (Reuters) - Irish biotech firm Elan Corp (ELN.I) is in late-stage talks to sell a minority stake to Bristol-Myers Squibb Co (BMY.N), a deal that could be a precursor to a full takeover of Elan, the Wall Street Journal reported on Saturday.

Bristol-Myers is one of two serious contenders for an Elan stake that could also include board representation and an ability to take control of the company later, the Journal said, citing a person familiar with the matter.

Spokespersons for Bristol-Myers and Elan declined to comment.

The Journal said a deal could be reached as early as next week, though the talks could still break down. It did not identify the other contender.

Elan hired Citigroup in January to conduct a strategic review of its business, which it said at the time could lead to a sale or merger of the company.

Elan was under pressure at the time from investors critical of Chief Executive Kelly Martin's leadership and the state of the biotech company, which was burning through cash at a rapid rate. In its most recent quarterly earnings report it posted a net loss of almost $103 million.

Biotechnology company Biogen Idec Inc (BIIB.O) and Elan jointly market the multiple sclerosis drug Tysabri. Drugmaker Wyeth (WYE.N), being acquired by Pfizer (PFE.N), and Elan are jointly developing the experimental Alzheimer's drug bapineuzumab. These are currently Elan's two most important products.

(Reporting by Ben Klayman in Chicago and Ransdell Pierson and Lewis Krauskopf in New York, editing by Jackie Frank)

there was also a really high placebo arm dropout rate in Celldex's trial: ACT II, but i believe the company amended that protocol in their Phase IIb/III ACT III trial.

14:20 Pfizer/Celldex: CDX-110 immunotherapeutic vaccine study data may be difficult to interpret due to high drop-out rate and patient selection bias - physicians
Story * Conclusions cannot be drawn from current data when half of patients on placebo dropped out of trial, one investigator said
* Company amends ACT III trial design based on recommendation of the Independent Data Monitoring Committee, so patients in control arm have option to receive CDX-110

* FDA will likely require overall survival for approval, two physicians said



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


Pfizer (NYSE:PFE) and Celldex Therapeutics' (NASDAQ:CLDX) immunotherapeutic vaccine CDX-110 has a high drop-out rate and lack of randomization in its current trial, which may cause difficulties with data interpretation, physicians said.

At the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), the companies announced the presentation of updated data from two clinical trials of CDX-110 in newly-diagnosed glioblastoma multiforme (GBM).

CDX-110, an investigational immunotherapeutic vaccine that targets the tumor-specific molecule, epidermal growth factor receptor variant III (EGFRvIII), was developed by Celldex Therapeutics and is now partnered with Pfizer.

Data from the 40 evaluable patients in ACTIVATE and ACT II trials continues to suggest that vaccination with CDX-110 may be able to improve time to tumor recurrence and overall survival when used in patients with newly-diagnosed GBM. These results also continue to suggest that tolerability and side effects associated with CDX-110 are minimal.

Thomas Davis, chief medical officer at Celldex, said there was a high drop-out rate in one of the CDX-110's trials. Patients in the placebo arm knew that they were not being administered the vaccine, since there was no injection, so they discontinued treatment, he explained.

Dr Martin J Van Den Bent, head of the neuro-oncology unit of the Daniel den Hoed Cancer Center, Erasmus University Hospital in Rotterdam, Netherlands, said patient selection in the Phase II trials could have been biased. Patients were only enrolled in this trial if they had no signs of disease progression at the end of radiation therapy, after surgery and after standard care. Celldex conducted another controlled trial, but this study reportedly failed due to a high drop-out rate in the control arm of the trial, he explained.

“At this moment, we cannot draw definite conclusions on the data that is available,” van den Bent said.

A company spokesperson said data in ACT II showed an approximate doubling of overall survival. In the ACT III trial - a randomized open-label, two-arm, Phase IIb/III trial comparing CDX-110 combined with temozolomide to temozolomide alone in patients with newly diagnosed GBM - there will be an amendment in study design to minimize placebo dropout.

The amendment of the ACT III clinical trial follows the recommendation of the Independent Data Monitoring Committee, as a majority of patients randomized to the control (standard of care) arm withdrew from this open-label study after being randomized to the control arm. Patients currently participating on the control arm of the study will be offered the option to receive treatment with CDX-110.

Dr Morris Groves, who focuses on cancers metastatic to the lining of the brain and spine at The University of Texas MD Anderson Cancer Center, said the current data available from CDX-110's trial appear better, as the study is testing the agent in a newly diagnosed, healthier patient population.

Dr Herbert B. Newton, a professor and director in the division of neuro-oncology at Ohio State University Hospitals and School of Medicine, agreed that there is a patient selection bias in studies such as the one testing CDX-110. Patients are enrolled in a trial right after surgery, and younger patients with tumors that are more amenable to treatment with surgery are enrolled, Newton said. These patients have a better clinical prognosis, he added.

A problem with another study that was conducted is that patients who were randomized to receive the placebo, which was Schering-Plough's Temodar (temozolomide, the standard of care), dropped out of the trial, Groves explained. Patients dropped out of the trial because they did not want to receive the standard of care, Groves said.

Dr Amy Heimberger, an investigator on the trial and associate professor of neurosurgery at The University of Texas MD Anderson Cancer Center, said it is necessary to study CDX-110 in patients with earlier stage disease. Patients with GBM have very immunosuppressive tumors, and patients do not have a hope of responding if they are treated later in the disease progression, she noted. Most companies developing drugs for the treatment of this patient population appreciate that they need to treat patients with earlier stage disease, she added.

“I think that it is very important to administer the vaccine early on in clinical trials,” Heimberger said.

Another investigator on the trial said that it is not possible to draw conclusions about CDX-110 when half the patients in the placebo arm left the trial. It would be interesting to know more information about the patient groups receiving the vaccine and those receiving placebo to draw solid conclusions about the data, the investigator said.

All current Phase II trials have demonstrated a statistically significant increase in time to progression and a significant increase in median survival, Heimberger noted. The company will likely have to use an overall survival (OS) endpoint for agency approval. “I suspect that the FDA will require OS for approval,” Heimberger said. Davis similarly noted that the company will likely have to demonstrate OS for FDA approval.

CellDex has a market capitalization of USD 142.70m.

by Klara Czobor in Orlando and Mintoi Chessa-Florea in London

didn't see this one coming!

why would anyone still get into anti-psychotics, or whatever that pim drug is used for...i can't remember, was it for Sz. haha, thanks McBio. it's true. sometimes i just scan the headlines - you caught me.

how come all the news services, bloomberg, reuters, others were all positive on cladribine data after AAN? all the headlines said first oral MS drug to market?

is there a disconnect there?

I think NVS FTY720 will probably make it to market first.

Campath also reported excellent efficacy data at AAN. company is running a risk management program. I think they all should run REMS programs.

didn't ACADIA just sign a partnership??

i think they even halted Invega for that reason. has the FDA finally approved Invega? is it that much different to risperidone?

the me-too days are over in pharma, i agree.

did you guys just see the CNBC huckman on Byetta, potential black box warning on Byetta?

who thinks the monotherapy version will get approved? i doubt it. .. .

also doubt LAR's chances at approval. how do you get that drug out of your system? so it keeps giving you pancreatitis over and over again. doh!

thanks Dew, thanks woofer! this makes life easier.

i totally agree. i doubt the FDA will approve cladribine without an additional study. also, does anyone know how many patients went on Rebif from placebo? i don't think the presenter answered that question at the CLARITY presentation.

all these new oral agents seem to carry a lot of risk, but if ppl are willing to prescribe Tysabri, then maybe they'll be comfortable with these new oral agents.

FTY720, more long term safety data than cladribine.

one thing i'm trying to figure out is ACOR. street seems mixed on the drug's chances at approval. has anyone seen that Leerink report? highlighted some good issues re: RTF.