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sorry, jetlagged. i misread and posted on DYAX!
on dynavax.. i spoke with some ppl, and they said its over. HBV vaccines. merck has given up on HIV vaccine dev. didn't dynavax's partner pull out already? company seems strapped for cash...
Hi Dew, i've been MIA for awhile - but now i'm back on the board. how is everything? i noticed that the board isn't available on the Biotech NASDAQ list anymore. did you guys move?
i've been doing a manual search for 'biotech values' in the search box. but now i've added it to favorites and bookmarked it.
didn't have a chance to go to EASL this year. but went to AAN for the CLARITY results trial. the speaker seemed to really downplay cladribine's risks for malignancies. i don't know how i felt about that. most of the sell-side analysts that i met up with at the event were also talking about both cancer risk with FTY and Clad.
i'm more worried about the fact that they are 4 diff types of cancer with clad. one in a pregnant women. but you can argue that if the drug is going to be used in treatment experienced patients, these women are likely to be older and have passed the childbearing age already.
it will be interesting to see how the FDA views the first oral MS drug approval and how strict they are in terms of REMS, patient monitoring, and labelling.
i've also been following ACOR. street seems mixed on that. recent .. i think lazard or piper report cautioned on fampridine's regulatory risk. what are your thoughts on the seizure risk with that drug? also, heard from neurologists at AAN that Sanofi's nespiridine?? is a much safer drug, and now in Phase II, moving into P3 enrollment. earlier than expected. don't know what that's going to mean for ACOR's drug once this Sanofi drug hits the market - if it indeed has no seizure risk, since it targets both Na and K channels, unlike Famp.
Nexavar failed in melanoma, but that was hardly surprising. i guess the next biggest thing will be ASCO. tarceva ATLAS/SATURN trials. wonder if OSI shares will take off.
we'll have to wait and see!
hope everyone on this board is enjoying the nice weather!
20-Apr-09 13:13 Viropharmas's Cinryze and CSL Behring's Berinert P for acute HAE bolstered by long-term safety data; competitors leverage subcutaneous delivery – analysis
Story Viropharma's (NASDAQ:VPHM) Cinryze and CSL Behring's Berenert P have long-term safety data to make their case for approval in acute attacks of hereditary angioedema, physicians said. However, acute attacks can have a rapid onset, making subcutaneous delivery with the potential for self-administration attractive, they said.
Hereditary angioedema (HAE) is a rare disorder caused by deficient or improper function of the plasma protein C1 inhibitor (C1-INH) causing swelling in various parts of the body. The disease can be fatal when swelling occurs in the larynx. In the US, five agents are currently in testing or jockeying for approval.
Cinryze and Berenert P are both C1 esterase inhibitors. C1 esterase inhibitors have been used in Europe for many years for both acute attacks and prophylaxis, according to Dr Albert Sheffer, clinical professor of medicine at Harvard Medical School. In the US, for acute attacks, the only current treatment is fresh frozen plasma, he said.
Cinryze is currently approved in the US for prophylaxis in HAE and has a PDUFA date set for 3 June 2009 for its BLA submission for acute treatment. Berenert P is approved in Europe, and has filed a BLA with the FDA on 6 March 2008. Both treatments must be delivered intravenously in a physician's office or medical facility. CSL Behring is currently running a comparative trial of IV vs. subcutaneous delivery of Berenert P, according to clinicaltrials.gov.
Cinryze and Berenet P are purified proteins taken from donors and are then administered as replacement for the C1 inhibitor that is lacking in patients with HAE, said Dr Michael Frank, professor of pediatrics at Duke University Medical Center.
Having been used in Europe extensively, Dr Andreas Lehmann at the Clinic for Anesthesiology and Operative Intensive Medicine in Germany said C1 inhibitors are a good treatment for acute attacks as well as prophylaxis. "Short-term prophylactics are needed for surgery, and long-term prophylactics are needed for severe HAE," he said. C1 inhibitors have a long history of use, though all the therapies in testing will be efficacious, he said.
Dyax's DX-88, a kallikrein inhibitor, received a REMS notice from the FDA on 26 March 2009. The advantage of DX-88 is that, in addition to clear efficacy, it can be delivered subcutaneously, with the potential for self-administration, physicians said.
"The ultimate goal is to put it in the hands of patients, but the fact that we are worried about serious side effects [such as anaphylaxis], this is hard to reach," said Dr Marc Riedl at the David Geffen School of Medicine at UCLA. However, the subcutaneous delivery method, even if given in a physician's office, is advantageous, he added.
"The difficulty with HAE is that intermittent swellings can happen anytime," said Dr Hilary Longhurst a consultant immunologist at Barts and the London NHS Trust. "There is always a risk of asphyxiation," she said. Longhurst added that due to the rapid presentation of acute symptoms, a subcutaneous delivery would offer a real advantage, especially if it could be self-administered or given by family practitioners who are less inclined to use IV delivery for acute care.
A fourth compound, Jerini's icatibant, will begin a confirmatory Phase III trial in 3Q09 after receiving a "Not Approvable" letter from the FDA in April 2008, according to a company press release. Icatibant is currently approved in Europe for acute treatment of HAE and marketed as Firazyr by Germany-based Jerini. Firazyr is a first-in-class compound that works on the B2 receptor as an antagonist to bradykinin, working further downstream than C1 inhibitors. Firazyr is delivered subcutaneously, but not self-administered.
Dutch biotechnology company Pharming (AMS:PHARM) is also testing rhucin, a recombinant protein made in rabbits. The company will submit application for approval to the European Medicines Agency in September 2009 and will request a pre-BLA meeting at the FDA in the second half of 2009.
by Janan Cargile
Source Pharmawire
17-Mar-09 11:29 Viropharma's Cinryze regarded as reliable and safe, but IV delivery does not meet acute treatment challenges, physicians say
Story Viropharma's (NASDAQ:VPHM) Cinryze, currently approved for prophylaxis of hereditary angioedema (HAE), is effective and safe, but treatment through IV administration will be a challenge for acute attacks, physicians said.
Cinryze has a PDUFA date set for 3 June 2009.
Hereditary angioedema (HAE) is a rare disorder caused by deficient or improper function of the plasma protein C1 inhibitor (C1-INH). It causes swelling in various parts of the body, and can be fatal when swelling occurs in the larynx. The disease presentation varies widely; attacks may be weekly in severe cases while other individuals experience only one or two attacks a year.
Cinryze is a human-derived C1 esterase inhibitor that targets the underlying cause of HAE. C1 inhibitors are the standard of care in Europe, but are not currently approved in the US for acute attacks. There are no marketed treatments available for acute attacks of HAE in the US. Cinryze was approved for routine prophylaxis against angioedema in adolescent and adult patients with HAE in October 2008, with a December 2008 launch.
Dr Marc Riedl, an immunologist at the David Geffen School of Medicine at UCLA, said he believes that the efficacy data for all acute HAE agents is fairly compelling, but the positive factors are "somewhat offset by the logistics and complexity of arranging for quick and efficient IV administration." Two therapies in the pipeline for acute attacks of HAE, ecallantide (Dyax's DX-88) and icatibant (Shire's Firazyr), could be administered subcutaneously, and there is a clear advantage to those agents from their delivery, he added.
Viropharma CEO Van Milano said he believes that Cinryze is uniquely positioned for acute treatment as it represents one solution for all HAE patients, should the drug receive approval for acute treatment of HAE.
Dyax's (NASDAQ:DYAX) DX-88 has a PDUFA date set for 23 March 2009. Although an FDA advisory committee voted last month to recommend DX-88 for approval, members raised safety concerns, including anaphylaxis. Although the DX-88 decision remains to be seen, the history of safe use for Cinryze is a competitive advantage, Milano said.
C1 inhibitors have been widely used in Europe and work well for both prophylaxis and acute attacks, according to Dr Andreas Lehmann, an immunologist at the clinic for Anesthesiology and Operative Intensive Medicine, Germany. But all of the drugs currently being tested will be effective, he added.
Dr Hilary Longhurst, a consultant immunologist at Barts and the London NHS Trust, said C1 inhibitors are the gold standard in Europe for HAE. But the difficulty in treating acute episodes is that intermittent swellings can happen anytime and can be triggered by other health conditions, she said. And not everyone is set up for continuous treatment, especially those who get infrequent attacks and seek treatment only for acute care, she added. Even in a healthcare setting, the subcutaneous form would be easier to administer, especially for the family practitioner who may not be as inclined to administer IV therapy, she said.
Viropharma has a market cap of 323.56m.
by Janan Cargile
06-Mar-09 17:00 Dyax's DX-88 subcutaneous delivery would be an advantage, despite safety concerns, physicians say
Story Dyax's (NASDAQ:DYAX) DX-88 (ecallantide) subcutaneous delivery would be an advantage in treating acute attacks of hereditary angioedema (HAE), physicians said.
Hereditary angioedema (HAE) is a rare disorder caused by deficient or improper function of the plasma protein C1 inhibitor (C1-INH), which causes swelling in various parts of the body. Disease severity is wide ranging; some patients experience weekly attacks while others can go years between attacks. The disease can be fatal when swelling occurs in the larynx. In the US, there are no marketed treatments available for acute attacks of HAE.
DX-88 is a small protein that has shown to inhibit plasma kallikrein, an enzyme in the inflammatory cascade, in laboratory experiments. C1 inhibitors, which are the standard of care in Europe, are not approved in the US for acute attacks. DX-88 was granted orphan drug designation for HAE in the US and Europe, and a Fast Track designation in the US.
Dr Hilary Longhurst, an immunologist at Barts and the London NHS Trust, London, said she believes that the subcutaneous aspect of ecallantide would be advantageous because the drug could potentially be self administered. Even if it's not self administered, it is simply much easier to administer a subcutaneous form rather than an IV form, she added.
Dr Marc Riedl, an immunologist at the David Geffen School of Medicine at UCLA, cautioned that while a subcutaneous form is preferable in any setting, self-administration may be too risky since there is a risk of anaphylaxis. The safety risk does reduce the attractiveness, particularly in regard to self-administration of the subcutaneous form, he added. Despite the potential for adverse events, "I am very much in support of it, but it should be managed and monitored carefully," he said.
A source familiar with the FDA regulatory process agreed, asserting that the risk of anaphylaxis challenges whether DX-88 is sufficiently safe. However, the unmet need for acute treatments is pressing and must be weighed into the equation, he said. The drug works and patients are in great need of treatment for this disease, he added.
C1 inhibitors have been widely used in Europe with good effect, according to Dr Andreas Lehmann, of the Clinic for Anesthesiology and Operative Intensive Medicine, Germany. The subcutaneous aspect of ecallantide will be an advantage, particularly if there is the possibility of self administration, he noted.
Although no current treatments are approved for acute attacks of HAE in the US, fresh frozen plasma has been used in the US with some benefit, according to Dr Albert Sheffer, clinical professor of medicine at Harvard Medical School. Given limited options, fresh frozen plasma may be used but in some cases has led to worsening the condition, Riedl noted.
Historically, anabolic steroids have been administered as a preventative in severe HAE. When taken daily, androgens are effective at suppressing 80 to 90% of attacks in patients, but there are many side effects, Reidl said. Viropharma's Cinryze (NASDAQ:VPHM) was the first C1 inhibitor to be approved in the US in 2008, but is limited to prophylactic treatment of HAE. The data showed that about half of patients are breaking through, and though it is a useful strategy, "it is no magic bullet," according to Reidl.
Dyax has set a PDUFA date for 23 March 2009 after an FDA advisory committee voted six to five in favor of approval. Viropharma is seeking approval for Cinryze as an acute therapy in HAE, with a PDUFA set for 3 June 2009.
by Janan Cargile
source: Pharmawire
01-May-09 13:11 Merck Serono's cladribine should be tested against active comparator in Phase III trials, neurologists say
Story Merck Serono's cladribine should be compared to an active comparator in Phase III trials for multiple sclerosis (MS) as opposed to placebo, neurologists at the American Academy of Neurology said.
According to Phase III data from the pivotal CLARITY study, patients in the cladribine treatment groups had a statistically significant reduction in the annualized rate of relapses compared to placebo. Patients treated with low-dose cladribine experienced a 58% relative reduction in annualized relapse rates with respect to placebo. Patients in the high-dose regimen group experienced a 55% relative reduction in annualized relapse rates with respect to placebo.
Novartis'(NYSE:NVS) FTY-720 was compared to Biogen Idec's (NASDAQ:BIIB) Avonex in the Phase III TRANSFORMS study. Genzyme's (NASDAQ:GENZ) Campath was also compared to high dose interferon in a Phase II study.
The FDA will look for registrational trials that go head-to-head with an active comparator rather than placebo controlled trials in MS, said Dr Michael Racke, professor and chairman of neurology at the Ohio State University Medical Center. This sort of trial is necessary to show dramatic efficacy, and superiority trials will also be crucial for getting the trial done in a reasonable amount of time, he said.
There is a shift towards using an active comparator instead of placebo, said Dr Hans Peter Hartung, professor and chairman of University Hospital Dusseldorf. The shift is from both from a regulatory and ethical standpoint, he said. Regulatory agencies should be in line on this issue, Hartung said. Furthermore, there are many Phase II drugs that are tested against a placebo when an active agent is available as a comparator, he added.
Despite the fact that cladribine has been tested against placebo, the biggest issue is that Merck-Serono is filing for approval based on one trial, Hartung said. The FDA and EMEA may suggest a second trial against an active comparator and give conditional approval, he speculated.
Dr AM Rostami, chair of the department of neurology at Thomas Jefferson University, said the ethical factor is a major impetus for active comparator trials, because the rationale is that there are already effective medications available that show a 30-50% reduction in attacks. It is not ethical to deny patients an effective treatment and an active comparator is require to effectively compare the tested agents, he said.
Dr Clyde Markowitz, the local principal investigator for several national and international clinical trials of new and combination MS therapies and assistant professor in the department of neurology at the University of Pennsylvania, was hesitant to say whether or not cladribine could receive approval based on one study.
Still other neurologists, such as Rostami, said if there is significant preclinical, Phase I and Phase II data, then a multicenter trial, if done adequately with good outcome measures could be enough for approval.
Merck-Serono could not be reached for comment.
Dr Mark Tullman, director of the Multiple Sclerosis Clinical Care and Research Center at Columbia University, said there are several ongoing trials that have active comparator arms. "We have head-to-head FTY720 versus Avonex. Cladribine was a placebo controlled trial," he added.
Biogen's BG-12 has a placebo arm, but also a Copaxone arm. Teva's (NASDAQ:TEVA) laquinimod has a placebo as well as an active arm. Campath is going head-to-head versus Rebif, Tullman said. "One needs to know how much better any given new therapy is, compared to the currently available therapies," he added.
"It's an FDA issue. Placebo controlled trials are still being done and can be done. It's the ethics of placebo controlled trials," he said.
Dr John Richert, executive vice president of research and clinical programs at the National Multiple Sclerosis Society in New York, said the current measures used in trials tend to fall short of what is needed to evaluate therapies effectively.
One of the dilemmas these days are clinical trial designs and outcome measures are not as useful as they were 10-15 years ago, Richert said. Back when companies could conduct reasonably large long-term studies of a drug versus placebo alone, clinical trial design was much easier, he said. "Now that it's not ethical in most locations to conduct a trial against placebo only, we're challenged a lot more in terms of head-to-head trials," he added.
"We already have drugs that are very beneficial. Don't give up on the current drugs yet, and look at the new drug's safety profile before making a decision," said Dr Jack Burks, clinical professor of neurology at the University of Nevada.
by Elizabeth Krutoholow and Kimberly Ha in Seattle
29-Apr-09 12:13 Dendreon's Provenge may show greater benefit in patients with earlier stage prostate cancer, sources say
Story Dendreon's Provenge may show greater benefit in patients with earlier stage prostate cancer, according to sources interviewed by this news service.
Provenge (sipuleucel-T) is a first agent in a novel class of active cellular immunotherapies. The drug is manufactured by using human cells which stimulate a patient's immune system with the hope of garnering an immune response to attack the cancer.
Dendreon recently announced that patients treated with Provenge experienced a median survival prolonged by 4.1 months compared to those treated with placebo. Those treated with Provenge lived for 25.8 months whereas those treated with placebo lived for 21.7 months.
The company did not respond to calls for comment.
All of the experts seem to agree that there could be an increased response observed in patients with earlier stage disease, noted an industry executive. The tumor mutates in ways that create an immunosuppressive effect, and it stifles a patient's ability to respond to therapy, the executive said. Also, patients with metastatic disease have received previous courses of radiation and chemotherapies, which prevent them from responding, he added.
"We think that if we progress to earlier stage patients, patients who do not have a high tumor recurrence, we believe that these types of patients are more likely to be responsive," the executive said. "I think that this phenomenon is true across the class of cancer therapeutics."
Provenge's Phase III IMPACT trial enrolled patients with metastatic, asymptomatic, androgen-independent prostate cancer.
The consensus in the cancer vaccine community is to try to treat earlier stage patients, because it is not always possible to generate a sufficient immune response, another industry executive said. The American Association of Cancer Research has suggested that "it's hard to go after bulky disease," the executive added.
Still, Edward John Allera, chairman of law firm Buchanan Ingersoll & Rooney's FDA and biotechnology section, noted that the agency is going to have to take precautions to make sure that Provenge is used in the appropriate patient population. The agency has to be really confident that the vaccine works, because if the efficacy is marginal then it will be very expensive, Allera added.
The average cost to treat a newly-diagnosed patient with Provenge is close to USD 80,000 compared to the average cost of USD 18,261 to treat this group of patients with current therapies, according to data published in the Journal of the National Cancer Institute.
It would be feasible to use the vaccine in an earlier setting, but it would be very expensive, agreed Dr Patrick Schoffski, the head of the department of general medical oncology at the Leuven Cancer Institute in Belgium. Treating earlier stage patients would open the door to a much larger market, Schoffski said.
A spokesperson for a company developing a cancer vaccine noted that overall survival is much easier to monitor in late-stage patients, who are near death, because companies only have to follow patients for a few months to determine whether there's an effect. In the metastatic setting companies will have to monitor patients for two years whereas in the earlier setting companies may need to follow patients for ten years, the spokesperson said.
by Klara Czobor and Kimberly Ha
Source Pharmawire
27-Apr-09 08:05 Dendreon Provenge’s complicated manufacturing could stain positive efficacy data, sources say
Story * Even though IMPACT was a positive study full data-set is needed to validate early stage results
* Making Provenge will entail several steps and voluminous amounts of paperwork
* The FDA may reject Provenge due to lack of evidence regarding consistent dosing, an FDA expert said
--------------------------------------------------------------------------------
Dendreon Provenge’s complicated manufacturing could stain positive efficacy data, according to several sources interviewed by this news service.
Provenge (sipuleucel-T) is in late-stage development for the treatment of patients with metastatic, androgen-independent form of prostate cancer where the cancer no longer responds to hormone therapy.
To manufacture Provenge, antigen presenting cells (APC’s) are extracted from a patient using a procedure called standard leukapheresis, a blood collection procedure which isolates a patient’s white blood cells. The patient’s APC’s are then transported to a facility where they are co-cultured alongside a recombinant fusion protein. Then the antigen-loaded, activated APC’s are delivered to a physicians office for administration.
Producing a cellular based vaccine such as Provenge is fraught with several significant hurdles, said the executive of a biotechnology company developing an anticancer vaccine. To manufacture an immunotherapeutic like Provenge, antigen presenting tumor cells need to be withdrawn from patients, and then sent to a lab to produce the vaccine before the final product is injected into the patient, the CEO explained. Dendreon and other companies developing cancer vaccines will encounter issues because the manufacturing process is so complicated, he speculated.
The process will need to be accompanied by a paper trail of safety and legal documents, and the cost will be quite high – not prohibitive - but may place Provenge at a competitive disadvantage, the executive noted. He further cautioned that although the trial was positive, and met its survival endpoint, physicians would like to see the complete dataset before drawing a definitive conclusion about the vaccine.
More data will be unveiled at the American Urological Association Annual Meeting on 28 April.
The agency wants to be really confident that the product can be manufactured and the data is robust, said Edward John Allera, chairman of law firm Buchanan Ingersoll & Rooney's FDA and biotechnology section. Obtaining consistent doses for vaccines is very difficult, and if the FDA wanted to reject Provenge, they can just say there is no evidence that the product used in patients was consistently the same, he speculated.
But the beauty of these vaccines is that they seem to be very safe, Allera noted.
A second cancer vaccine expert agreed that manufacturing biological agents, in general, is littered with complications, and producing a personalized cancer vaccine is likely to be challenging. The overall production process is long, with many complicated steps along the way, he said. “The agent has to be pushed to a site and you have to gain patient consent prior to surgery,” explained the source, who admitted that he is a traditional non-believer in cancer vaccines.
Furthermore, the efficacy of these vaccines is dubious, and many have stalled in development, he said. Cancer vaccines which are currently approved by regulatory agencies around the world, the HPV vaccines Cervarix and Gardasil, have been heavily criticized for their lack of efficacy, he added.
Smaller biotechnology companies which are currently in the process of manufacturing cancer vaccines lack sufficient quality control when making these vaccines, noted a clinical trialist for oncology agents in development. Companies such as Argos Therapeutics were scrutinized for the quality of measures used to asses their cancer vaccine, he said. While Argos was capable of evaluating the appropriate tumor antigen load, there are still questions whether or not the right amount of protein was extracted, regarding the assays used to measure their quantity, he noted.
Argos Arcelis is an immunotherapy in development for cancer which takes dendritic cells from a patient which are later matured for an immunotherapy, according to the company’s website.
“There are many, many issues manufacturing cancer vaccines and this is something that has emerged time and again,” noted a spokesperson for a company with a cancer vaccine in development. The manufacturing problem is inconceivable and there are large problems with product characterization, the spokesperson said.
When cancer vaccines are personalized, such as Provenge, it needs to express the tumor epitope which the vaccine is being directed at and this may vary from person to person, according to an executive at a cancer vaccine company. Also, another problem in the recent past with cancer vaccines has been that they were lacking an appropriate linker molecule and they were degraded before they actually made it to the endoplasmic reticulum and the golgi apparatus, where they need to be metabolized, the president said. The vaccines were not cleaved appropriately, so they did not show the same type of response, he said. However, this problem was observed mainly in vaccines using a viral based vector for delivery.
“So this aspect of taking things out and personalizing it to each and every individual, this is a real challenge in the field,” the source said. “This is a specific drug, and this is relevant to only a certain percentage of patients,” he added.
An investigator involved in cancer vaccine trials said there has not been a single setting in therapeutic oncology where vaccines have been shown to be efficacious. “The vaccines don’t work and the tumors are too aggressive,” he said.
Dendreon could not be reached for comment.
However, a second industry executive at a cancer vaccine company noted that although vaccine studies are generating greater success, these agents are not yet approvable by the FDA. “It is similar to where monoclonal antibodies were 15 years ago, and there is a strong belief that the various cell mediated immune technologies can work, and we are learning more with every trial,” he noted.
Cancer vaccines are on the threshold of becoming significant additions to the therapeutic armamentarium, and Provenge may be the first one to be approved, the same industry executive said. “While Dendreon’s technology may require the FDA to amend their rules, or perhaps create new ones, this is the natural evolution of regulatory science.”
By Kimberly Ha and Klara Czobor
Source Pharmawire
i don't think FDA will trade safety for convinience. both fty and cladribine both have such bad AEs.
i don't. sat in the CLARITY presentation today. I saw four cases of cancer. where was the 5th? i think the FDA will not lower their standard safety bar, esp if it is going to set the bar for approval criteria for these new orals.
NVS has tons of pt data.
http://www.ft.com/cms/s/2/363484d8-332a-11de-9316-00144feabdc0,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html
this article seems to be the only negative one on cladribine right now.
pharmawire on ACOR:
29-Apr-09 14:13 Acorda Therapeutics: Fampridine-SR approval uncertain, seizure risk likely scrutinized by FDA; REMS likely if approved - analysis
Story * Sanofi's Phase II nerispirdine could be competitor drug
* MS patients with Uhthoff's Phenomenon, the worsening of function with an increase in body temperature that occurs in 10-15% of patients, could see potential benefit
--------------------------------------------------------------------------------
Acorda Therapeutics' (NASDAQ:ACOR) Fampridine-SR (4-aminopyridine) is likely to be scrutinized by the FDA to assess its seizure risk, and the drug's approval remains uncertain, investigators and physicians said. A risk management program will likely be instated by the FDA, if the agent is approved, some MS experts speculated.
Fampridine-SR is a sustained-release formula of 4-aminopyridine (4-AP), which temporarily enhances nerve signaling by blocking tiny pores, or potassium channels, on the surface of nerve fibers, according to the National MS Society.
In a Phase III trial, 35% of patients on active therapy, compared to 8% on placebo, experienced significant improvements in walking speed. The walking speed for those who responded to therapy improved an average of 25.2% (in the timed 25-foot walk), compared to only 4.7% in the placebo group, over 14 weeks of therapy.
Last month, the FDA refused to accept the company's filing of the drug due to certain format issues and requested additional supporting information. The news on 31 March sent shares down 23% on the delay. Shares have since rebounded, as the company resubmitted its application earlier than expected last week.
Two serious adverse events that were potentially related to treatment with Fampridine-SR and led to discontinuation were anxiety in one patient and a focal seizure in another patient that was observed during an occurrence of sepsis associated with pneumonia.
A spokesperson for Acorda would not comment on whether the company is currently developing a risk management program for use with this agent.
Dr Denise Campagnolo, a neurologist at the Barrow Neurological Institute at St. Joseph's Hospital in Phoenix, Arizona, who has worked with this agent, said there have been attempts to market the active ingredient in Fampridine-SR, 4-AP, since 1993. "It was tried in spinal cord injury; I was involved with that study. The drug has a less than half effective rate, and the bottom line is, half the patients who take the medication are not helped at all," she said.
"If the FDA approves it, I would be shocked," Campagnolo said.
A second investigator said Fampridine-SR definitely works - but the only caveat is it only works in 30-35% of patients, since patients need intact axons to respond to the drug. "But I could tell who was on the drug, and who wasn't, even when the trial was blinded," he said.
"I know this drug works, because I was one of the examiners in the study and did the EDSS examinations," he said. The EDSS is a method of quantifying disability in multiple sclerosis, and quantifies disability across eight Functional Systems.
Yet Campagnolo stressed drug-to-drug interactions have been so far overlooked with Fampridine-SR, and noted that half of the MS patients may also be on the antidepressant Wellbutrin, which also carries a seizure risk. Half of these MS patients will also be on seizure medications, and there should be a major education program making sure patients understand the potent layering effect with respect to seizures she said, adding that this effect has not examined with due accordance from Acorda.
"I don't see it being a viable option for most folks in the future," Campagnolo said. The layering effects have not been fully considered, and she noted that she stood unconvinced that she would consider Fampridine-SR in the grand scheme of symptom management in MS. Since 4-AP is readily available, most physicians will probably get it compounded by a pharmacy, she added.
Depending on what other drugs MS patients are on, taking Fampridine-SR may increase their risks for seizure, Campagnolo said. The drug works in less than half of patients, and causes an approximate 25% improvement in walking speed.
The number of seizures that have been seen so far could be concerning to the FDA, agreed Dr Clyde Markowitz, the local principal investigator for several national and international clinical trials of new and combination MS therapies and assistant professor in the department of neurology at the University of Pennsylvania.
There is room for the agent in a sense, because its gives patients more energy in the day, but this is just symptomatic, said Dr AM Rostami, chair of the department of neurology at Thomas Jefferson University. He added that while Fampridine-SR is a slow release formulation of 4-AP, the risk for seizures is still present - and neurologists are concerned and should watch for seizure risk, he said. The FDA will look carefully at the risk and will probably require post-marketing studies, he added.
Dr Samuel Hunter, an investigator for numerous MS drugs in development and a neurologist at the Advanced Neurosciences Institute in Franklin, Tennessee, said drawing from experience in his practice, the compounded version of the agent also causes an increase in neuropathic pain, which limits use in some patients.
The drug definitely helps improve motor endurance and fatigue, but it only helps a minority of patients, Hunter said. "It will be used and tried in many MS patients, but I think its long-term use will be limited to a fraction of patients," he said.
Yet patients with Uhthoff's Phenomenon, the worsening of function with an increase in body temperature that occurs in 10-15% of patients, could benefit from Fampridine-SR, noted Dr Hans Peter Hartung professor and chairman of neurology at the University Hospital Dusseldorf.
The risk for seizues is pretty low and should not be an issue, but there will likely be a stipulation from regulatory authorities that Acorda must monitor for seizures in the post-marketing studies, Hartung said. The FDA has not been favorable on this agent, he added.
Dr Bhupendra Khatri, an investigator and director of the Center for Neurological Disorders at Aurora St. Luke's Medical Center, said like every drug in MS, Fampridine-SR is not going to work in every patient. But he also noted that the active ingredient is a potassium channel blocker that has been used for many years. "It's a good drug that works in patients, and can have a lasting effect," Khatri said. The compounded agent, 4-AP, has never been studied in an organized way, he added.
Dr John Richert, executive vice president of research and clinical programs with the National Multiple Sclerosis Society, said the clinical trial looked at walking speed as the primary outcome measure, but there are probably a lot of symptoms that are much more difficult to quantify in the study. He speculated that the drug may improve a patient's vision and fatigue as well.
The best thing about the drug is its effects on fatigue, but that outcome wasn't positive and didn't show a statistical difference, said Dr Jack Burks, an investigator on a number of MS trials, and president and CEO of Burks & Associates Health Care consultancy.
Dr Michael Racke, an investigator on a number of MS trials and the Helen C. Kurtz chair of neurology at Ohio State University Medical Center, said the seizure risk is always a concern. The drug blocks the potassium channel, and makes the neurons more excitable.
An additional question is whether MS patients are willing to assume the seizure risk for an improvement in walking speed, said Racke. While MS is disabling, it is not a fatal disease so physicians are uncomfortable with agents that increase of the risk of mortality, he added.
Dr David Brandes, medical director of the Northridge Multiple Sclerosis Center and assistant clinical professor of neurology at UCLA, said the incidence of seizures with Fampridine-SR is about five to six patients out of 430 patients. The agent has at least 15-20 years of use from the compounded version, he noted. In his experience, Brandes has observed several seizures in one group of patients who were on antiepileptics. Neurologists are not using the agent in patients who are at risk for seizures, he noted.
Currently, the maximum dose of the compounded formulation is 20mg twice daily, said Brandes. There are three to four patients who had seizures out of 500-600 people. "It is a rare but real concern," he said. One patient overdosed and had continuous seizures that lead to brain damage so it can be dangerous, Brandes said.
Yet Acorda is using a much lower dose of same preparation, he said, adding that the seizure issue is real but with the dose that will be used, it is very unlikely to occur.
Safety is becoming an issue in MS with new agents, Racke said. There is an increase in efficacy with an increase in safety risk, he said. Eventually, neurologists will have to have a conversation with patients to determine who is willing to accept the safety risk and monitoring, he said.
There is significant interest in a competing drug by Sanofi-Aventis, nerispirdine, though the drug is in ealier stages of development, said Campagnolo. She added that not not only is Sanofi's drug a potassium-channel blocker, but a sodium-channel blocker as well, with no risks of seizure seen so far.
A spokesperson for Sanofi-Aventis said the company is not presenting at this week's American Academy of Neurology meeting.
Nerispirdine (HP184) is currently in Phase II development, with an estimated enrollment of 368 patients. The study was started in December 2008, with a primary outcome measure of consistency of improved response in walking speed on the Timed 25-Foot Walk Test.
"That's coming through pipeline in Phase II right now. That's what I'll be waiting for to prescribe to my patients," Campagnolo said, adding that she believed the agent would be the safer compound.
Acorda has a market cap of USD 780m.
by Kimberly Ha and Elizabeth Krutoholow in Seattle
saw that one coming. melanoma is a tough nut to crack.
what do you guys think about this article?? is it legit?
Also, has anyone figured out which would be the preferred stat model? log rank analysis or cox regression rank? does that matter? Do they have to show both as positive for approval?
There was another recent article on BNET on other factors that may affect approval, like manufacturing that i thought was interesting.
http://industry.bnet.com/pharma/10001699/dendreon-still-faces-hurdles-for-provenge-despite-positive-phase-2-data/
I think the keys is whether the company shows the log rank data. If they don’t, there will be an issue. A cox proportional hazard model can violate itself.
Also, what do you guys think about the HR of 1.8. That is is really far from the median survival of the arm. I think the key questions are how should the Kaplan curve will be presented at AUA.
Could it still be a statitistical fluke?
21-Apr-09 11:59 Dendreon's initial Provenge Phase III trials unlikely to contribute much to FDA submission package, biostatisticians say
Story Overall survival (OS) data from Dendreon's previous Phase III trials, D9901 and D9902A, will add little, if anything, to the company's Provenge submission, a survey of biostatisticians said.
The data will be part of the package submitted to the FDA, along with data from the now-pivotal IMPACT trial, which was granted a special protocol assessment (SPA). Biostatisticians described the data from the previous, once-pivotal Phase III trials as exploratory, suggesting that it either not be used to influence the FDA's decision on Provenge, or that it be down-weighted.
The BLA for Provenge is expected to be resubmitted to the FDA in 4Q09, said CEO Mitchell Gold during a recent conference call held to announce that Provenge had achieved statistical significance in OS, with full data to be presented on 28 April. Shares of Dendreon have increased significantly in anticipation of positive OS numbers from IMPACT.
Initiated in 1999, the first Phase III studies for Provenge both failed to meet their primary endpoint, time to disease progression, and also failed to demonstrate statistical significance on other pre-specified endpoints. When the data from the two trials was pooled and analyzed retrospectively, Dendreon found that there was a difference in OS between the active and placebo arms. The current IMPACT trial, which has enrolled 512 patients, is designed with OS as the primary endpoint in accordance with the positive OS data generated from the original Phase III trials. The previous trials enrolled 225 patients.
Jeremy Taylor, a professor in biostatistics and radiation oncology at the University of Michigan School of Public Health, said that he doubted the FDA would like the pooled data because there are so many ways to pool or combine the data and different ways to analyze the pooled data. He said that it was then possible that the best of the data could be presented to the FDA, which would not be so good, unless the method of analysis was pre-specified.
A professor of biostatistics at a major university, who has more than 10 years of experience working with big pharma to get drugs approved, said that from a statistical point of view, using previous studies to provide information on effect size and endpoints was reasonable as a method to gain information on how to move forward.
"But you can never use a retrospective analysis with the agencies, changing the endpoint after the fact to get approval," she said. "Data generated from previous studies can't be used for regulatory approval, only the stuff that has the right endpoint can. If you deviate, you're doing a lot of tap dancing before the regulatory authorities."
When asked about the validity of OS results obtained through post-hoc analysis to support a drug's approval package, Daniel Scharfstein, a professor of biostatistics at Johns Hopkins University's Bloomberg School of Public Health, said that the company is free to submit OS as part of its package. "The FDA knows that this is post-hoc and will down-weigh its influence on their decision accordingly." He added that in his opinion the agency does not consider data-mining acceptable, and that it would give much more weight to analyses that have been pre-specified.
Dendreon did not respond to requests for comment.
Ruth Etzioni, a full member in biostatistics at the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center, who focuses on the development and implementation of statistical methods for prostate cancer studies, said that it was not a problem for the company to go back and look at data, but that there was a problem with choosing an endpoint retrospectively. "he problem comes when they pick the endpoint later because you know it was the one that showed the result, and you could have looked at variety of results, so it's not valid," she said.
Etzioni explained that the more endpoints a company looks at, the more likely that any single finding will be spurious. "With each citing of a finding from a different endpoint, there is a small chance that it will be spurious, and if multiple attempts are made to find an endpoint that works, those spurious possibilities can add up to something significant. The chance that any one of them will be spurious is considerably higher than if only one of them is spurious," she said.
Nicolas Jewell, a professor of biostatistics at the University of California, Berkeley, described the results from the initial Provenge Phase III trials as exploratory, likening them to being "ahead by a goal at halftime but purely by chance." Jewell ascribed little value to the fact that the post-hoc examination found OS benefit, saying that although it was great that such a benefit was identified, it would have to be properly confirmed. He added that unless an endpoint was pre-specified, it was possible to be fooled by error rates. "You need to make a technical adjustment to down-weigh the evidence from the first trials, anything otherwise is artificial. It's hard for people to accept that when there's a story behind it, like with overall survival."
This view was seconded by Brenda Gillespie, a professor of biostatistics and associate director for the University of Michigan's Center for Statistical Consultation and Research, who described the results from trials with outcomes not defined in a study protocol as exploratory and not definitive, saying that "exploring many outcomes is likely to yield significant outcomes by chance."
Dendreon is using a cox multivariate regression model for the analysis of OS data from the IMPACT trial.
When asked whether this type of model is appropriate for OS analysis, Jeffrey Albert, associate professor of biostatistics at Case Western Reserve University School of Medicine, said a cox regression model is a common method for assessing survival and has the advantage of controlling for important prognostic variables. That would be an appropriate method to assess the survival difference between randomized treatment groups, he said.
Cox models allow adjustment for risk factors, so they would be preferred, said Albert. This approach is similar to a log rank analysis, which corresponds to using the Cox model without prognostic variables, but either approach could be justified, added Albert.
When asked if the higher alpha lowers the bar for achieving success, Albert said so long as an overall 0.05 alpha level is maintained, the statistical integrity of the trial would generally not be undermined. It is common practice to spread the alpha over the interim and final analyses, he added.
The less standard feature here was the apparent change in the alpha-spending function in the midst of the trial. Also, the substantial decrease in the targeted number of events seems somewhat unusual. However, so long as these changes were not in response to early estimates of the treatment effect, the study validity should not be affected, Albert said.
"I think it's not that uncommon to modify the sample size or targeted number of events in mid-course. The key is what led to the change," said Albert. If it's based on interim data, particularly an estimate of the treatment effect, that might be more questionable. Yet Albert noted that, to his understanding in this case, the company made the modification before the interim analysis. "And it might have been due to external information, I'm not sure what their reason was."
He added, "I thought that was somewhat unusual, but that may be because I have incomplete information. I understand they are going to give more a complete report which should help reveal the design and decisions regarding the modifications."
Commenting on the crossover study design, Albert said the crossover rate and the choice of the crossover treatment (which was not Provenge) could be relevant. If it is an effective treatment, that could somewhat attenuate the results. So the company could argue that this approach is conservative. "I think that the study will be looked at carefully in regard to how much crossover there was as well as the issue of what they're crossing over to," he said.
The crossover would be done, or at least offered to patients, upon progression of disease, for ethical reasons. This is because they might want to take action upon progression. Albert said he thought that the main reason why the company didn't use survival as an endpoint initially is that the crossover might water down the treatment effect on survival, if the salvage therapy was effective.
"The way they pick and choose data for meta-analysis, you would be ridiculed," said Edward John Allera, chairman of law firm Buchanan Ingersoll & Rooney's FDA/biotechnology section, who previously served as associate chief counsel at the FDA.
Getting an SPA is not a big deal, said Allera. "The real issue is how robust the data is, and how that fits within the treatment armentarium," he said. The reported data looks very good data, but "whether the FDA agrees that's the real number is the issue," Allera said.
"It all depends on how robust that 22% [reduced risk of death] is, and whether its reproducible. That's the dilemma," said Allera. There is still a possibility the FDA could ask the company to run another follow on study, or even a post-marketing study, he added.
Dendreon has a market cap of USD 1.96bn.
by Eddie Smiley and Kimberly Ha
http://www.ft.com/cms/s/2/047da548-29b9-11de-9e56-00144feabdc0,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html
Dendreon: FDA may request additional confirmatory trial before Provenge approval due to first-in-class status
by Kimberly Ha
Published: April 15 2009 13:35 | Last updated: April 15 2009 13:35
This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
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Dendreon (NASDAQ:DNDN) may have to conduct an additional trial before FDA approval of Provenge, despite recent results showing that the company met its primary endpoint of overall survival (OS) based on one study, physicians and industry sources speculated.
A Phase III clinical study named IMPACT showed that Provenge improved overall survival in patients suffering from advanced prostate cancer, pushing Dendreon’s shares up 136%, reports Pharmawire.
The first Phase III studies for Provenge, named D9901 and D9902A, both failed to meet their primary endpoint and also failed to demonstrate statistical significance on other pre-specified endpoints. When the data from the two trials was pooled and analyzed retrospectively, Dendreon found that there was a difference in OS between the active and placebo arms. The current IMPACT trial is designed with OS as the primary endpoint in accordance with positive OS data generated from the original Phase III trials.
Dr CK Wang, an oncologist at the Cancer Institute of Dallas, said Provenge will receive scrutiny from the FDA, based on the failure rate of previous cancer vaccines. This is the first vaccine immunotherapy up for FDA approval. Cell Genesys’ (NASDAQ:CEGE) GVAX vaccine failed in late-stage clinical trials last year.
When asked whether the company would be asked to conduct a confirmatory trial, Wang said that is always ideal. A lot of times when drugs are approved, there are usually two concurrent trials published at around the same time to confirm the data.
Asked if it would be clinically significant if Provenge showed a four-month survival benefit, Wang said it would be, but the cost-benefit of treatment will be the next area of debate. ”More of these vaccines are getting approved with a much higher cost, compared to the older chemotherapies,” he said.
An industry executive agreed that the initial Phase III studies that pooled data from two studies together to form a larger trial is a point of concern, and would not be considered a second Phase III trial. The only Phase III trial that has OS as an endpoint is the IMPACT trial, and nothing will settle the question of whether the results can be reproduced, unless another well controlled Phase III trial is conducted, he said.
”If you combine two different studies, or studies with different patient criteria, you run into statistical problems and more scrutiny,” Wang said.
A second executive, who is familiar with Dendreon’s management, said it is quite unusual for a company to change the trial design in the middle of the game. ”In my experience, the FDA scorns such attempts as manipulative since these are agreed upon prospectively,” he said. On the other hand, if the results are dramatic enough, the FDA might show some flexibility, but that’s a real gamble, he added.
The standard that the FDA has always set is two well controlled large-scale studies, the first industry executive said. ”We have to be very careful interpreting results from a single study, particularly with immunotherapy since we don’t have any other data on this type of therapy,” he noted.
”My guess is it will get back to ODAC [the Oncology Drugs Advisory Committee], and at that point, depending on who is on the ODAC committee, the reproducibility of the study will be called into question,” the first industry executive said. At this point, it remains uncertain whether the FDA will ask Dendreon to conduct another trial, he agreed.
Dendreon did not respond to repeated requests for comment.
A biotech investor said that FDA almost always requires multiple Phase III trials, making rare exceptions for drugs that are already on the market for different indications. The investor identified health outcomes of high unmet need as an area where the agency might be more flexible as well. He added that as a bureaucracy, the agency would choose caution over risk, following rules and regulations as closely as possible with very few exceptions, and that in the case of a new chemical entity, it is expected that extra care would be taken to ensure that the proper decision is made.
Dendreon would not have been granted a Special Protocol Assessment (SPA) for IMPACT unless the agency found logic with pooling the trial data, but as this is a contesting BLA, the company will likely have to go back to ODAC, the first industry executive said. Although the main factor preventing the drug’s use in the market may be cost considerations, the FDA can only consider safety and efficacy in their approval decision regarding Provenge, he added.
A third industry executive, at another immunotherapy company, said the FDA will be in a quandary because in one sense, Dendreon has complied with the agency’s requests outlined in the letter for approval. But on the other hand, the FDA is now forced in a position where they will have to ”bend a couple of rules” if they approve Provenge.
One issue will be the quality control regarding the manufacture of Provenge, the third industry executive said. The FDA is now in a position where they may have to approve a vaccine, where the quality control is ambiguous, since every dose is a different drug, he explained.
The FDA manufacturing hurdles to produce Provenge will be high, added another industry investor. Since Provenge is a tailored immunotherapy, isolating an individual’s dendritic cells is not an easy procedure. Taxotere’s results showed a two month survival benefit, and if Provenge shows a four-month survival benefit, it is still ”not going to knock people’s socks off,” he said.
Dr Mark Scholz, of Prostate Oncology Specialists in California, said he would use Provenge in his clinic, if approved, although only some patients respond to the treatment. The measured overall survival in clinical trials is only an average of all the patients - where some men get no benefit - but since the toxicity is low, there is no reason not to use it, he said.
In many cases, immunotherapies are drugs that do not have specific dose response relationships, the third industry executive said. ”We don’t know why some immunotherapies work in some patients and not in others,” he said. It remains unknown what the correlates of response are, and maybe the response is based on the patient’s unique genetics.
If the FDA requires another confirmatory trial before approval, there is no way to align the two patient populations from the two different trials, since it still remains unknown why the patients in the IMPACT trial responded to Provenge, the third industry executive noted. In another cohort of patients, even with the same exclusion/inclusion criteria, there is no way to ensure that the patient population in a second, confirmatory trial will respond to Provenge in the same way, he stated. ”It’s an unfair burden from the FDA, to insist that the manufacturer has to show how the drug works,” he added. The current FDA structure and model used to evaluate drugs may not fit with immunotherapies, so something has to change, he added.
The first industry executive said whether the positive results released today will result in FDA approval is a whole different story, since the company just has one positive prospective trial.
But the FDA may be facing a lot of political pressure from prostate cancer groups to approve Provenge, the second biotech investor said. ”Prostate cancer groups are very politically active, and now that Dendreon has met their SPA endpoint, it’s going to place a lot more pressure on the agency [to approve this drug],” he said. But whether Provenge will be a commercial success, if approved, remains the key question, the industry executives added.
Dendreon has a current market cap of USD 1.68bn.
no i don't think so.
do you guys agree with this?
DIABETES FDA PANELS THIS WEEK!!
31-Mar-09 21:31 Novo Nordisk's liraglutide potential thyroid cancer risk sees physician concern on chances of approval; Amylin's Byetta LAR could experience knock-on effect
Story Novo Nordisk’s (NYSE:NVO) diabetes candidate, liraglutide, has diabetes specialists concerned that its luster has been diminished as potential thyroid cancer risks could see the FDA request additional information. In addition, potential regulatory delays could be a knock-on effect on Amylin's (NASDAQ:AMLN) Byetta LAR, physicians speculated.
An upcoming FDA advisory panel meeting is expected this Thursday.
An FDA document released 31 March showed a prevalence of thyroid tumors when rats and mice were administered liraglutide. Liraglutide and Byetta (exenatide) both belong to the GLP-1 class of injectable drugs. Liraglutide is dosed once-daily, while exenatide is dosed twice- daily. The long-acting release version of Byetta is in Phase III trials, and expects an FDA decision in 4Q2009.
The FDA discussions should not solely be about cardiovascular (CV) risk, but also as to whether calcitonin level testing will be needed, which would be an overhang, said Dr Sonal Singh, assistant professor at Wake-Forest University School of Medicine. The calcitonin test is primarily used to help diagnose C-cell hyperplasia and medullary thyroid cancer.
The agency has to consider that if liraglutide is approved, there could be a requirement for routine thyroid ultrasounds, and other tests, he pointed out. "The thyroid cancer risk makes me very worried," Singh emphasized.
Dr Zachary Bloomgarden, clinical professor at the Department of Medicine at Mount Sinai School of Medicine, said although there is a likelihood that thyroid cancer is a chance finding, this side-effect "could knock them out of the running."
If liraglutide was approved with a recommendation that every patient has a thyroid sonogram every six months, “that would be a drag," he further noted.
Similar to the demise of inhalable insulin devices, notably - Pfizer's (NYSE:PFE) Exubera - which was marketed, and subsequently removed from the market, inhalable insulin devices required routine 6-month pulmonary function testing, which made use of these drugs very cumbersome, Singh noted.
Singh said the FDA will probably enforce a risk management program if liraglutide is approved. He said today’s news on the potential for thyroid cancer is much more worrisome than any CV events.
Regarding liraglutide's chances at approval, Singh said it would ultimately depend on who is on the FDA panel. However, he cautioned that the agency has been increasingly critical on new diabetes candidates, in lieu of safer alternatives on the market. "We don’t know how liraglutide works, but the drug's benefit is sugar control - and we have enough agents that do that already," said Singh.
The FDA has been far more vigilant after serious CV events cropped up with GlaxoSmithKline’s (NYSE:GSK) marketed candidate, Avandia. In December 2008, the FDA issued guidelines that new therapies in Type-2 diabetes should not cause an increase in CV risks. Out of the 6000 patients on the liraglutide Phase III trials, very few suffered CV-related events.
Singh noted that an observational study of thyroid cancer and GLP1 analogs needs to be conducted, but other physicians noted that this study would require thousands of patients, and would likely be an arduous undertaking. Another alternative would be to conduct data mining studies for thyroid cancer.
Dr Dean Lim, a clinical assistant professor in the department of medical oncology & therapeutics research at City of Hope in Duarte, said thyroid cancer in general is not that common, and to his knowledge, diabetes should not lead to an increased risk for thyroid cancer.
Lim agreed that the recent news gives off warning bells, and there has to be long term follow up with liraglutide, to see whether it causes thyroid cancer in patients.
"Thyroid cancer is one of the rarest cancers, and on top of that, it's a rare type called papillary thyroid cancer," Singh said.
Dr Guenther Boden, section chief of endocrinology, diabetes and metabolism at Temple University School of Medicine, said he was not aware that GLP-1 agonists caused heart risks.
Still, he voiced his worry about the chances that Byetta LAR would be approved. "They talked about this for the last three years, and they always said next year but its still not on the horizon. Something bad is happening there," said Boden, who used to be on the FDA advisory panel committee for Byetta.
Bloomgarden added the FDA will require a whole separate testing program with Byetta LAR and will not really accept the Byetta data as Byetta LAR data. Byetta is active in the patient about half of the day, and Byetta LAR is active 24/7, he said, and as a result would lead to potential side–effect differences between the two.
Dr John Buse, president of the American Diabetes Association, and an investigator for Amylin, said he did not believe the thyroid cancer risk is a class effect of GLP-1 drugs, or would affect Byetta. Bloomgarden also said he was unsure whether the risk for thyroid cancer was a potential class effect.
Amylin reported to the FDA that there have been nine spontaneous postmarketing reports of thyroid cancer - three papillary and six unspecified type - out of an approximately seven million prescriptions filled. As of 30 September 2008, there were no cases of thyroid cancer in clinical trials of Byetta, according to the FDA document.
With liraglutide, there were four cases of papillary thyroid cancer among patients and one case among comparator-treated patients, at the time of submission of the NDA. In completed trials, this corresponded to rates of 1.8 and 0.9 events per 1000 patient-years of exposure, respectively. With the 120-day safety update, an additional case of papillary thyroid cancer was reported for a liraglutide-treated patient.
To conduct a trial to see if GLP-1 agonists causes thyroid cancer would require an immense number of patients, said Bloomgarden. He noted that 40,000 patients would probably have to be monitored over 10 years. There are very clear ways of conducting power calculations but in order to do them, the expected incidence rate has to be figured out, he said.
Amylin and Eli Lilly (NYSE: LLY) could not return comment as of press time.
Novo Nordisk could not be reached for comment.
by Kimberly Ha and Sasha Damouni
I agree 110% with Dew. Especially with the whole push for comparative effectiveness. The NY Times ran a pretty good article on that recently.
yeah, they definately could be a fit. for BIIB, NVS. but isn't BIIB also pushing for a sale this year?
maybe NVS?
here is a good brainstorming exercise. which kinds or types of drugs would be hit the hardest by the push for comparative effectiveness?
this is a segment from a NY Times article last month:
Dr. Elliott S. Fisher of Dartmouth Medical School said the federal effort would help researchers try to answer questions like these:
Is it better to treat severe neck pain with surgery or a combination of physical therapy, exercise and medications? What is the best combination of “talk therapy” and prescription drugs to treat mild depression?
How do drugs and “watchful waiting” compare with surgery as a treatment for leg pain that results from blockage of the arteries in the lower legs? Is it better to treat chronic heart failure by medications alone or by drugs and home monitoring of a patient’s blood pressure and weight?
For nearly a decade, economists and health policy experts have been debating the merits of research that directly tackles such questions. Britain, France and other countries have bodies that assess health technologies and compare the effectiveness, and sometimes the cost, of different treatments.
-----------------------
my thoughts are .. basically anything that the govt could deem a lifestyle drug, or could be helped with lifestyle changes such as obesity drugs - could potentially face reimbursement problems.
also, Pfizer's Chantix is another one. that drug is already having a hard time in the markets already. there are so many cheaper alternatives.
thoughts? appreciated.
also, the ADA is already making a push to ask docs to use insulin after failure on the cheaper sulfyneureas and insulin.
Merck's Januvia wasn't even on the guidelines list, Byetta was a Tier 2 agent.
it seems like the govt may start working with all these guidelines , like ASH, or ASCO and start phasing expensive branded drugs out.
i hope that doesn't happen. that would be a major blow to the public.
for example, Revlimid is a much better drug than thalomid. but will the govt say, we're not going to pay for Rev? who knows.
that really sucks. not a good time to get diabetes right now. or cancer, hopefully they'll finally put that personalized tissue sampling to use soon, on a wider scale.
i don't see any hope for albuferon at this point. NVS might even drop the partnership.
OUCH! also, when will GSK drop Synta like a hot potato?
haha.
16:43 Human Genome Sciences' Albuferon fails to impress investors despite meeting endpoint in Phase III trial - report
Story Human Genome Sciences' (Nasdaq: HGSI) Albuferon failed to impress investors even after meeting its primary endpoint in a Phase III hepatitis C trial, according to a report in the Washington Business Journal.
Shares took a 55% dive to hit an all-time low, the report stated.
Citing results from the second of two Phase III trials, the report noted that 48% of patients on Albuferon experienced a successful response to treatment compared to 51% on Roche's Pegasys.
It quoted Barry Labinger, executive vice president and chief commercial officer, who told analysts in a conference call that Albuferon's biweekly dosing schedule would offer a "very big benefit."
But it also stated that Albuferon was not able to best Pegasys on quality of life measures and also had a much higher discontinuation rate (10% to Pegasys' 4%.) Side effects, however, were comparable in both groups, the report noted.
The company has USD 400m in debt coming due in 2011 and 2012; at the end of last year, it had USD 373m in cash and equivalents, according to the item.
The report valued the hepatitis C market at USD 2.5bn.
Source Washington Business Journal
don't know if this will be true or not - kind of seems up in the air.
13:20 Merck-Serono's chances with oral MS drug cladribine face physician scrutiny over single trial design
Story Merck-Serono's oral drug cladribine for first-line treatment of relapsing forms of multiple sclerosis has received expedited FDA review based on one single trial, with some physicians questioning the drug's chances at approval.
Recent top-line CLARITY Phase III data released earlier in January showed that cladribine met its primary endpoint, with a 58% reduction in annualized relapse rates with the low dose and a 55% reduction with the high dose at two years.
Based on the successful completion of the CLARITY study, Merck-Serono plans to submit cladribine tablets for registration to the EMEA and to the FDA in mid-2009.
More data from the CLARITY study will be presented at this year's American Academy of Neurology conference, which runs from 25 April to 2 May.
Dr Neil Lava, professor of neurology at Emory University, said cladribine's side effects need to be discussed further to have a better understanding of this drug. He did not rule out a possibility that the FDA could request that the company run another trial before approval.
Lymphopenia, an expected event based on the presumed mechanism of action of cladribine, occurred more frequently in the cladribine treatment groups. Apart from lymphopenia, the most frequently reported adverse events in the study were headaches and nasopharyngitis.
Lava said his concerns regarding cladribine's side effect profile were not limited to this agent, but to other aggressive MS drugs in development as well.
"I am not so optimistic about that drug and do not follow new updates closely. I think fingolimod is more interesting," said Dr Konstantin Balashov, a specialist in general neurology and multiple sclerosis at the Robert Wood Johnson University Hospital. Fingolimod, or FTY720, is a competing oral MS agent in development by Novartis (NYSE:NVS).
Novartis is conducting three Phase III studies of FTY720 in MS patients. The FREEDOMS study is a randomized, double-blind, placebo-controlled trial that will assess the efficacy and safety of fingolimod in 2,000 patients over a 24-month period.
Yet Dr Mark Cascione, medical director at the South Tampa MS Center, said the FDA would be satisfied with one large study, since it was a well-designed two-year Phase III trial with little, if any red flags, and a large patient enrollment. He noted that additional add-on trials with cladribine and interferons were already enrolling, so by the time Merck-Serono submits its application to the FDA, there will be more data.
Another trial, the ONWARD study, tests cladribine with Rebif (interferon beta-1a) in MS patients who have active disease despite treatment with Rebif. In the United States, Rebif is co-marketed by EMD Serono (the US affiliate of Merck-Serono) and Pfizer (NYSE:PFE).
Merck-Serono could not be reached for comment.
Dr John Richert, executive vice president for research and clinical programs at the National Multiple Sclerosis Society, noted that the FDA told the company that it will fast-track cladribine based on one trial. Richert addressed the issue on a recent panel in response to a question on whether the single trial design is sufficient for FDA approval.
Yet expediting treatments in a disease where a patient's life expectancy is similar to normal individuals is a tough justification, said Mike Namaka, a neuroscientist at the University of Manitoba's MS Clinic. "You're balancing patient safety against expedited trials," he said.
Dr Jeffrey Bennett, associate professor of neurology at the University of Colorado Health Sciences Center, who was also on the panel, noted that the single trial may temper quick adoption. "But if the topline data holds up, it will be something to add to the list," he said.
The Phase III CLARITY study was a randomized, double-blind, placebo-controlled trial. A total of 1,326 patients were enrolled.
When asked whether Merck's cladribine patient population is small compared to other oral MS agents in development, Namaka said that depends on the statistical analysis of endpoints, and one cannot draw a comparison between different trials.
"We don't know enough about the product yet, until it gets distributed to the population at large," said Namaka, who pointed to the safety issues physicians learned about Tysabri after its approval. Although the Tysabri trials recruited a large number of patients, the drug still wound up causing an adverse reaction in the larger population - which was fatal in some cases, Namaka said.
Tysabri, by Biogen and Elan, was pulled off the market in February 2005 after three patients in clinical trials developed a rare, serious brain infection called progressive multifocal leukoencephalopathy (PML). Two of those patients died. The drug was subsequently reintroduced back to the market in 2006, under a strict risk management program.
Dr Mark Tullman, director of the Multiple Sclerosis Clinical Care and Research Center at Columbia University, said clardibine's use in the marketplace will come down to safety as well as clinical data. "Assuming it's approved, neurologists are generally a pretty conservative bunch," he said.
by Kimberly Ha and James Avallone
Source Pharmawire
i agree. i think Byetta LAR , liraglutide, all T2D drugs, given the FDA's strict stance on patient safety, and the overall reimbursement climate..its going to be a tough call.
look what happened with HGSI's albuferon today. that drug is basically dead. good luck with trying to get it reimbursed.
11-Dec-08 13:01 FDA sends letter alerting all companies with diabetes INDs to its new cardiovascular risk assessment approach; drugs with NDAs not addressed
Story The FDA has issued letters to all companies that have open investigational new drug applications (IND) for diabetes agents, outlining its new approach to assess cardiovascular risk prior to granting approval, although diabetes drugs that have already been filed for a new drug application (NDA) have not been addressed.
A source close to the situation confirmed that “virtually all companies developing diabetes drugs” have received a letter from the FDA that contained a new requirement for companies to conduct a combined analysis of their entire Phase II and III data as part of their NDA submission.
The source said that companies have been informed that they will be required to demonstrate that the upper 95% confidence interval (CI) for the hazard of cardiovascular (CV) risk outcomes is not worse than 1.8.
“This means that any new diabetes drugs have to show that they do not increase CV risk by more than 1.8 fold,” the source said. “Depending on this analysis, the company may or may not be then required to initiate an extensive Phase IV clinical programme before approval is granted.”
A number of major pharmaceutical players in the diabetes space have confirmed with this news service that they received the letters, including AstraZeneca/Bristol-Myers Squibb, Takeda, Boehringer Ingelheim, Amylin/Eli Lilly, Novo Nordisk, Sanofi-Aventis and Roche.
Other big pharma firms believed to have received the letter include Merck, Pfizer, GlaxoSmithKline (GSK) and Novartis, although they did not respond to a request for comment prior to the time of publishing.
Roche said that it “is aware of the FDA guidance and our development plans for taspoglutide [which is now in Phase III] will be in line with this.”
Meanwhile, a spokesperson on behalf of AstraZeneca/BMS said they only received the letter specific to dapagliflozin, which is also in Phase III. “We plan to incorporate the FDA guidance into our dapagliflozin development program.”
He also confirmed: “We have not yet received a letter from the FDA regarding Onglyza (saxagliptin)” [which is in the midst of regulatory review].
Takeda also confirmed that the letter it received was only in relation to its compounds that have not already been submitted for approval, i.e. it did not receive a letter regarding alogliptin, which is also undergoing regulatory consideration by the FDA.
“Takeda will continue to examine the safety and effectiveness of diabetes drugs and work with the FDA for the appropriate running of clinical trials of compounds that are in early stage of development,” the firm said.
Similarly, Novo Nordisk confirmed that it has not received any such letter regarding its once-daily version of liraglutide, which is currently under regulatory review.
However, the company said that “a couple of days ago” it did receive a letter from the FDA regarding the once-weekly version of liraglutide, which is in Phase II development.
“The letter specifies the agency's general requirements to a future Phase III programme. There's nothing surprising, it is a very common sense requirement, which we will take into account when at some point we start the planning for the Phase III programme for once-weekly liraglutide.”
What the FDA’s intentions are for the three diabetes products that are already going through the approval process [saxagliptin, alogliptin and liraglutide] remains uncertain.
AstraZeneca said it expects the issue to be addressed during the ongoing regulatory discussions that are ensuing, but did add that in more than 4,000 patients who were given saxagliptin in clinical trials, “we have not seen a cardiovascular safety signal.”
Novo Nordisk said: “We are in the midst of the regulatory process for once-daily liraglutide, so we can't say anything with certainty, but some kind of post-approval commitment is not unlikely.”
Takeda did not return a request for further comment prior to the time of publishing.
Commenting on the developments, Professor Steven Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, Ohio, told this news service that he was “very pleased” that the FDA had” essentially accepted” his suggestions.
In July Nissen proposed that the FDA implement a two-step process in order to “raise the bar” for the approval of diabetes drugs; 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.
Nissen said that this action by the FDA means that companies will have to adjudicate their trials and assess them individually as to their cardiovascular risk and it also means that they will have to include more patients in their studies that are at higher risk of cardiovascular events, which is more reflective of the real world situation.
He explained that this is because in order to demonstrate that a drug does not increase the CV hazard by more than 1.8 times, the data analysed will need to contain the occurrence of a minimum 122 CV events, so to ensure that there are enough events occurring, more higher risk patients will need to be used.
Regarding the companies that have already started or completed their Phase III trials, Nissen said that “all is not lost, they could go back and more carefully collect/analyse their existing data and if they do not have 122 cardiovascular events they may have to extend their trial and enroll more patients to gain the required data for submission.” The possibility also exists for those drugs that have already filed an NDA, although he did not know of the FDA’s intentions for these drugs.
Amylin/Lilly, who have already had their pre-NDA meeting for Byetta LAR, its once-weekly version of Byetta (exenatide), said that it was aware of the FDA’s new approach but added that the exenatide once weekly development program builds upon the existing data set from the approved exenatide product and in an analysis of 2,800 patients who had completed long-term clinical studies in the exenatide programme, treatment-emergent coronary artery disease and related events occurred at similar rates for all exenatide-treated and comparator placebo-treated groups.
Diabetes expert Keith Campbell, professor of pharmacy at Washington State University, said that since the FDA has been "embarrassed" with the issue surrounding rosiglitazone, it has declared that all new drugs to treat diabetes – which are not meant to negatively impact the cardiovascular system – will be more closely evaluated and be required to do additional studies to prove their safety in this regard.
“This will increase the cost of the drugs and delay their approval.”
by Kirsty Barnes in London.
13:41 Isis and Genzyme's cholesterol-lowering agent mipomersen faces limited physician enthusiasm as it enters Phase III trials
Story * 26 week trial duration not being sufficient to evaluate safety
* Requirement for patients to be on low-fat diets could avoid the potential problem of fatty liver
* Patient exclusion criteria could cause mipomersen to have label restriction
* Excluding LDL-apheresis patients could severely limit the use of mipomersen in homozygous familial hypercholesterolemia patients, one physician noted
____________________________________________________________________________
Isis Pharmaceuticals (NASDAQ:ISIS) and Genzyme's (NASDAQ:GENZ) hypercholesterolemia drug mipomersen faces limited enthusiasm from physicians as it enters Phase III trials.
Mipomersen is a first-in-class apo-B synthesis inhibitor, intended to reduce LDL-cholesterol, or LDL-C, by preventing the formation of atherogenic lipoproteins. The drug is currently being developed for patients who cannot adequately control their cholesterol levels with current therapies and who need new treatment options.
One of the current therapies - LDL apheresis - is a treatment for patients with uncontrolled LDL levels. Like dialysis, a patient's blood is cleared of LDL by infusion. Patients are treated with LDL apheresis once every two weeks.
Isis' Phase III trials test mipomersen on LDL-apheresis eligible patients, hypercholesterolemic patients at high risk for coronary heart disease, and patients with uncontrolled lipid levels while on the maximal dose of statins. Each trial will run for 26 weeks, and participants are given the option to participate in an open-label follow-up study.
Dr Cy Stein, a professor of medicine at the Albert Einstein School of Medicine, said a trial duration of 26 weeks in Phase III trials is not a sufficient amount of time to assess mipomersen's long-term safety.
"This is actually a really crucial issue," said Dr Gilbert Thompson, professor of medicine at the Imperial College School of Medicine, who agreed with Stein that a 26 week duration is not sufficient to evaluate mipomersen's safety.
Dr Robert Hegele, a professor of medicine and biochemistry at the University of Western Ontario and an investigator for the mipomersen trials, said data on mipomersen that is longer than 26 weeks is definitely needed. But long-term safety concerns can be answered by the optional open-label follow-up study, he added.
"My sense is, based on experience, most patients will exercise this option, and we should be able to see the long-term effects of mipomersen from this optional study," he said.
Dr John Millar, a senior researcher at the University of Pennsylvania, also voiced his concerns about the potential side effect of fatty liver. Fatty liver is a major problem for lipid lowering drugs, and the current study duration is sufficient to determine whether this side-effect will be a problem for mipomersen, according to Millar.
Yet he was not convinced that the trial design would adequately address whether fatty liver would be a problem. The enrollment criteria of the Phase III trials could avoid instances of fatty livers, and Type I diabetics and patients with uncontrolled Type II diabetes were also excluded from the trial, he added.
Participants were required to be on a low-fat diet, and diabetics with high blood sugar levels and people on high fat diets are the people who are most prone to fatty livers, Millar explained. By avoiding these types of patients, the Phase III trials could potentially avoid the issue of fatty liver, but this does not mean that fatty liver is not a problem with mipomersen, he warned.
Physicians may actually want to see additional studies of mipomersen in diabetics and patients on high fat diets, agreed Dr Bruce Sachias, an assistant professor in the department of pathology and laboratory medicine at the University of Pennsylvania. Fatty liver remains a theoretical concern with these patients, especially if physicians do not know how mipomersen affects these patients, he added.
Dr Harold Bays, the president and medical director of the Louisville Metabolic and Atheroscelorsis Research Center, said the exclusion criteria of the Phase III trials are common for drugs that treat lipid disorders.
Thompson also commented that it was confusing that the Phase III trials excluded patients who undergo LDL apheresis. This is puzzling, because mipomersen is targeted for homozygous familial hypercholesterolemia patients, but the majority of these patients undergo LDL apheresis, he explained.
Excluding LDL apheresis patients could very well lead to a labeling restriction against use in the majority homozygous familial hypercholesterolemia patients, Thompson further suggested.
Sachias agreed that this exclusion could lead to a restriction against LDL apheresis patients, but argued that not all homozygous familial hypercholesterolemia patients are treated with apheresis. Mipomersen would still be available for homozygous familiar cholesterolemia patients and does not exclude this entire patient group, Sachais said.
A spokesperson from Isis noted that LDL apheresis patients were excluded from the trials due to the difficulties of measuring LDL levels in this group. LDL apheresis patients have dramatic changes in their LDL levels, and measuring LDL levels to assess the efficacy of mipomersen would be a problem, she added.
Familial hypercholesterolemia is a genetic disorder that causes patients to have very high LDL levels in their blood. People with homozygous familial hypercholesterolemia have two copies of the gene that causes the genetic disorder and are at high risk for cardiovascular disease at an early age.
The very high risk population in the United States is about 1.5 to 2m patients, who are either compliant on both statins and Schering-Plough's Zetia (ezetimibe) or who are highly statin intolerant.
Isis has a market cap of USD 1.18bn.
by Jacqueline Kwong
Source Pharmawire
Merck's Januvia not included in new ADA/EASD diabetes treatment guidelines; reimbursement concerns draw criticism from physicians
Main article Merck's (NYSE:MRK) Januvia and other branded type-II diabetes drugs may face a harder time with reimbursement due to a recent consensus statement on the medical management of hyperglycemia in type II diabetes, according to physicians.
Most physicians disagreed against the proposed "one size fits" all approach, and also raised caution against the new recommendation of giving a patient insulin earlier on in treatment, after failure on metformin and sulfonylureas.
The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) late last year released a joint consensus statement to suggest lifestyle changes and metformin as the initial treatment to help newly diagnosed type II diabetes patients achieve A1C goals.
"My feeling, which echoes that of most of my colleagues, is the recent guidelines are based on the current economic situation, and are trying to make physicians prescribe less expensive medications," said Dr Joel Zonszein, director of the clinical diabetes center at the University Hospital of the Albert Einstein College of Medicine, a division of Montefiore Medical Center.
The FDA has now asked for long-term trials with cardiovascular outcomes, and diabetes has become a disease for which it will become harder to develop new drugs, Zonszein noted. There will be more and more limitations placed on pharmaceutical companies developing new drugs in diabetes, due to political reasons, and many companies are going to be discouraged from developing new products, he said.
Suggested second-line treatment from the new recommendations included the addition of pioglitazone (Takeda's [TYO:4502] Actos) or a GLP-1 agonist as well as lifestyle changes and metformin. If these measures do not maintain A1C goals, under the new revisions, initiation of basal insulin, and then transition to intensive insulin is recommended.
Several classes were not included in either the Tier I or Tier II categories. The consensus statement stated that these agents were not included owing to their lower or equivalent overall glucose-lowering effectiveness compared with the Tier I and Tier II agents and/or their limited clinical data or relative expense. These agents included acarbose (Precose), nateglinide (Novartis' Starlix), pramlintide (Amylin's Symlin), repaglinide (Novo Nordisk's Prandin) and sitagliptin (Januvia).
The consensus statement did include one of the newer medications, Amylin's (NASDAQ:AMLN) Byetta, a GLP-1 agonist, as a Tier II agent. But it also indicated that there is insufficient clinical use to be confident regarding long-term product safety.
A spokesperson for Amylin said a majority of managed care providers have added Byetta to their formularies, with about 85% of covered lives able to obtain Byetta for the lowest branded co-pay amount. "With education and updated guidelines, attitudes are shifting towards an increased understanding of the importance of managing both A1C and weight," she said.
The revised treatment guidelines introduced Byetta as the only new addition, placing it in a much more prominent position and suggesting it as the treatment of choice in patients for whom both weight management and hypoglycemia are a concern. About 80% to 90% of the 25m people living with Type II diabetes in the United States fall into this category, according to the spokesperson.
Dr Carol Wysham, a member on Amylin's North American Advisory Board and an endocrinologist at Washington State University, Rockwood Clinic, said the physicians who wrote the consensus statement are more conservative in their approach and treatment of diabetes. Insulin and the sulfonylureas have the best outcomes evidence, she noted, adding, "Byetta and Januvia haven't been subjected to the same randomized trials."
But since Byetta was part of the statement - albeit a Tier II drug - the associations lend very strong support to using a GLP-1 agonist, Wysham said. "We just didn't have enough long term safety and outcomes data to put Byetta into a Tier I category yet," she said.
A spokesperson for Merck said the company is in ongoing conversations with managed care companies. "We look forward to working with ADA and EASD to work on the inclusion of additional classes, which include DPP-4 inhibitors," she said.
Dr Gerald Bernstein, former president of the American Diabetes Association and vice president for medical affairs at biotech company Generex, said the recommendation to use insulin after failure on metformin and sulfonylureas has a lot to do with cost issues. "The push to use insulin earlier has been emerging. But now it's a shift, when organizations have made these statements," he said.
Dr Narinder Duggal, a clinical pharmacy specialist, internist and medical director of Liberty Bay Internal Medicine, who specializes in diabetes care, said under this new statement, physicians may have a harder time with reimbursement for more expensive branded drugs. "With these hard economic times, patients will have a pretty expensive co-pay. With the cost of these drugs, people are very sensitive to that," Duggal said.
Unfortunately, these guidelines are not based on hard clinical data, Zonszein said. There are no clinical studies to show that one medication is better over another, and the problem with the push to ask physicians to use insulin earlier on in treatment, after failure on metformin and sulfonylureas, will be patient monitoring. "Insulin also causes a greater risk for hypoglycaemia and hospitalization, especially in elderly patients," he added.
Reimbursement concerns were cited by a number of physicians, as under the new treatment guidelines, branded drugs may face a higher uphill battle for coverage. "Unfortunately, the people who ultimately look at these guidelines are the HMOs. The result is more hardship for physicians," Zonszein said.
One of his patients, who was denied Januvia, ended up getting hypoglycaemia from using insulin. "They want to save the hundred dollars for Januvia, but don't think about hospitalization costs," Zonszein said, adding that he did not agree with the decision to place DPP-4 inhibitors out of mainstream therapy when they may be very effective in elderly patients.
This new treatment algorithm certainly continues to push for metformin's use, as its safety margin is unprecedented, said Duggal. But insulin may come in as a third-line agent now, he explained, even though it may not be the most appropriate agent to use in some patients. "But it's the easy way for physicians. Doctors will take the path of least resistance to bring the HbA1c levels down to normal," said Duggal.
Dr Sonal Singh, an assistant professor of internal medicine at Wake Forest University Baptist Medical Center, said this is why physicians need a center for comparative effectiveness that can decide if newer therapies are cost-effective. "Pushing insulin use quicker in the treatment doesn't mean Lantus, it just means insulin," he said, referring to Sanofi-Aventis' branded drug.
Actos will likely benefit from this statement, and is going to be there as a third-line drug, under the guidelines, Duggal added. Panel members unanimously advised against GSK's (NYSE:GSK) Avandia based on the potential associated cardiovascular risks.
Sulfonylureas are basically are out of the picture, or should be, said Bernstein. Clinicians and researchers believe this class either causes too much hypoglycaemia, or increases cardiovascular risks, he said, adding that the use of this class probably only has one advantage - it's cheap.
The spokesperson for Merck said the company is not surprised or concerned that the DPP-4 class was not included, as it typically takes more time for newer drugs to be included in the treatment algorithm. Other guidelines that include DPP-4s include those from the American Association of Clinical Endocrinologists, the Canadian Diabetes Association, and the recently updated NICE guidelines.
Two-year safety data on Januvia was published in October 2008, and showed a favorable risk-benefit profile, the spokesperson said. Januvia offers a strong efficacy profile with no associated weight gain or increased risk of hypoglycemia, she added. "Januvia works. The side-effect profile is actually pretty good," Bernstein said.
"Many patients will respond better to some medications than others. To use a one size fits all approach is not a very smart thing to propose," said Zonszein.
Merck has a market cap of USD 55bn.
by Kimberly Ha and Sasha Damouni
13:10 Onyx's Nexavar likely to join graveyard of failures in melanoma, physicians say
Story Onyx Pharmaceuticals' (NASDAQ:ONXX) Nexavar (sorafenib) will likely fail in melanoma, physicians said.
There has been a graveyard of failures in melanoma, from CTLA-4 inhibitors like Pfizer's (NYSE:PFE) tremelimumab and Medarex's (NASDAQ:MEDX) ipilimumab, to Genta's (OTC:GNTA) Genasense. More recently, Synta suspended development of elesclomol due to serious safety concerns.
Dr Salvatore Del Prete, director of clinical research at the Bennett Cancer Center, Hematology Oncology Associates, said it would be a "leap of faith" to say that Nexavar can be used in melanoma, even though it works in kidney cancer. But he acknowledged, "Other drugs that have worked in renal cell carcinoma, like IL-2 and interferons, happened to work in melanoma."
"It doesn't seem like a big step forward any way we look at it," said Dr Antoni Ribas, an associate professor of hematology and oncology and a researcher at UCLA's Jonsson Cancer Center.
Ribas explained that Nexavar was first developed as a c-Raf inhibitor. In 2002, a discovery was made that melanoma patients have a mutation in BRAF - but later studies found that Nexavar does not block mutated BRAF in melanoma. "Most of its effect is not through the c-Raf pathway in patients, but through blocking VEGF kinases for blood vessel formation," he added.
BRAF mutations occur in 60-70% of melanoma patients, according to Ribas. "It's a high percentage of melanoma patients, and more frequent in younger patients," he added.
The mutation renders the BRAF protein constantly active, which implies that this pathway could be a viable target for drug development.
New drugs in development by Novartis (NYSE:NVS), Roche (OTC:RHHBY) and Plexxikon block BRAF specifically, said Ribas. Novartis is developing RAF265, which targets the BRAF protein kinase, and Roche and Plexxikon have PLX5568 in the pipeline.
"Those drugs will tell us whether blocking BRAF is what we anticipated, and is a way of treating melanoma," Ribas said. The preclinical data suggests BRAF is important, but whether it's a viable target will depend on the data unveiled at ASCO, he said.
Dr Anna Pavlick, director of New York University's Langone Medical Center's melanoma program, said the current first-line treatment in metastatic melanoma is to enroll patients in a clinical trial, since nothing else works better. She explained that a lot of patients make it to second-line therapy and there is supportive care. "Most patients are diagnosed when they are asymptomatic and are not losing weight," she said.
The Phase III Eastern Cooperative Oncology Group (ECOG) trial is testing Nexavar in combination with carboplatin and paclitaxel in patients with unresectable stage III or stage IV melanoma. Data from this trial is likely expected in 2Q09, according to analyst reports.
"There is a tremendous unmet need for new therapies in melanoma, a historically difficult tumor to treat," an Onyx spokesperson said. "We are looking forward to data from the Phase III melanoma study sponsored by a cooperative group in the U.S. to understand if Nexavar can provide a new option to help these patients and their families."
Pavlick questioned the trial design, explaining that paclitaxel is not the standard of care in melanoma. "What if we are using all of these patients' lives to find that the carbo-taxol design is a bust?" she said in an interview. The best cytotoxics for use when designing a trial for melanoma have yet to be determined, and the company is trying combination this based on a single Phase I/II study, she added.
Pavlick had previously expressed doubts about Nexavar's success in melanoma on a recent panel. "I don't think the randomized Phase III trial will be positive," she said at the time.
Synta's SYMMETRY trial, which tested elesclomol in combination with paclitaxel in chemo-naive patients with stage IV metastatic melanoma, was recently suspended due to an imbalance in overall survival, with a greater number of deaths occurring in the combination arm (elesclomol with paclitaxel) compared to the control arm (paclitaxel alone).
Dr Gary Schwartz, chief of the melanoma and sarcoma service at Memorial Sloan Kettering Cancer Center, said Nexavar and carboplatin are poor inhibitors of MAP kinase, which is part of the same pathway as BRAF. But in combination with the right drug, there may be some hope there, he said.
Yet Schwartz added that he has reservations at this point regarding Nexavar's success in melanoma. He added that KIT mutations may be another tumor type to target in the future.
Onyx has a market cap of USD 1.85bn.
by Kimberly Ha and Elizabeth Krutoholow
this is a msg from investorvillage:
Re: The Surprise.............Bio
.
Yes that wait for the Interim Results for TT223/EGF was about 9 1/2 months. But it is my understanding that it was the Patent Protection that was the hold up. They had to apply for the Patents before releasing the Data. Protection of the IP is paramount and at that time was very much a part of Transitions Corporate Presentation and was the subject of Seminars held at the MaRS Discovery District and presented by representatives from Transition.........
......If you look at the current Patents it becomes quite clear that TT223 now has pretty much got the i's dotted and the t's crossed. The current Patents very well may even cover the "Longer Acting Gastrin that Transition is developing right now with Lilly" (as per Dr. Cruz last CC) because it goes on about the possible Modified Gastrin Versions and "Pegylation" and "polymeric microspheres"and "Bifunctional crosslinking agents" etc. etc. and other methods of Formulating Modified Gastrin to be Longer Acting.
We could get the Interim Results quickly if the current Patents are up to date, which they certainly do look like they are (Gastrin is even in the COMBINATION TREATMENTS WITH GASTRIN Patent as being an option to use Gastrin alone for the same effects) ......But a good question to ask Transition nevertheless. Just the way that Dr. Cruz answered the Analysts question about the TT223-SA Data timelines leads me to believe it will be sooner than later. You know me I'll be on the phone pushing for the results come late May/June....LOL!
=======================================================================================
I'm glad you brought up the Byetta-LAR subject. Although the Byetta Pancreatitis news is Old News it still warrants consideration. The pancreatitis associated with Byetta-BID has led the FDA to take a real good look at Byetta-LAR and (guily by association) Liraglutide. At this point it looks like the pancreatitis cases are specific to exenatide and even then the cases seen with Byetta-BID seems to be no worse than the cases found in the Diabetes population. Byetta may have First In Class status but First In Class doesn't necessarily equate to Best In Class. Any Regulatory changes would apply to all but at this point it looks like no sweeping changes. In my opinion Byetta-LAR will get an approvable letter.
My own personal opinion on Byetta-LAR is that even if it gets approved the Uptake will be a miserable dissapointment. Byetta-LAR may have a weekly dosing regimen BUT it is simply Not Patient Friendly by any means. Byetta-LAR will have the advantage of once weekly administration. Thats the only advantage. This once weekly has generated some great Glucose Control and is very efficacious and side effects came down a bit.. ......BUT there are some very interesting draw-backs to the LAR formulation.
..........Firstly the drug can't be combined and stored in a single needle. It must first be stored separately by the patient and then Reconstituted by the patient before it is injected. Secondly because Alkermes technology makes it into a very large molecule the Needle Gauge they have to use is a Gauge 23 which when compared to the Gauge 31 Needles all the other GLP1's use including Byetta BID (except Roches Taspoglutide which uses a Gauge 29 needle) ..........is almost 3 times longer and 3 times wider. There is Bruising, Pain and Irritation at the injection site. These draw backs alone could very well could limit it's use. Dr. Cruz has stated that TT223/LYGLP will be in a single needle and the GLP that Lilly brings to the table is according to Lilly promo material a "Small Gauge" needle........so Gauge 29 -31.
Novo Nordisk and Eli lilly.......now theres two Co,'s you'll not soon see collaborating........I am of the opinion that Novo is going to win Round-1......Byetta-BID is stuck at around 50,000 scrips.....no growth....Liraglutide approval will take a lot of that as well. Even if Byetta-BID gets approval as a Monotherapy I don't think the scrips will improve much. If Byetta-BID Adjunct gets hit with a Black box warning Byetta-BID Monotherapy (if approved) will get hit with a Black box warning as well.
Round2 will be won by Lilly/Transition.................Yup. I have a crystal ball that sees a Lilly-Amylin Divorce coming. Will Lilly run another Phaselll for Byetta-LAR if thats the conditions in the approvable letter?? I doubt it. If the conditions in the Approvable Letter are extensive will Lilly proceed?? I doubt it. A CitiGroup analyst figures Lilly is set to severe their ties with Amylin. Case in point being that Lilly hasn't Opted in to any of Amylins initiatives. Being that Amylin failed to Opt-in to Lilly's two other Weekly GLP1 programs it looks like Lilly has found another partner with better IP and potential. Transition Therapeutics. Thats my wag. ( I like that expression Bio)
.
i don't see them rebounding. GSK will probably terminate the partnership soon. everything just fails in melanoma. is it like .. in the last 50 years, nothing has come to market. reminds me of lupus.
i can't believe Takeda partnered with them. i think they will probably try to partner with either Cougar or Medivation. those 2 companies have the most adv prostate cancer drugs in development.
I'm pretty encouraged by Cougar's candidate, abiraterone acetate.
that is a hilarious flowchart. Acorda should be on there, and Biogen. I still think Biogen will probably try to repurchase Tysabri rights off Elan. and then try to shop themselves, if they haven't started to do so already.
Does anyone know what happened to CELG? they seemed to have dropped off to 45/share! reimbursement concerns?
Amylin again! i'm still on the sidelines with Byetta LAR. but both companies still say the pancreatitis is not caused by exenatide. will the FDA take that chance?
09:01 Amylin Pharmaceuticals: Physicians cautious about Byetta LAR approval
Story * NDA for Byetta LAR on track for submission to the FDA by the end of 1H09
* FDA still reviewing several prescribing information updates submitted by Amylin and Lilly, including revision of safety language related to pancreatitis
* Physicians still debating over potential cause of pancreatitis
_________________________________________________________________
Amylin Pharmaceuticals' (NASDAQ:AMLN) potential Byetta LAR (exenatide once weekly) approval this year has fallen under physician scrutiny, in light of the unresolved pancreatitis associated with the active ingredient exenatide.
A spokesperson for Eli Lilly said the NDA for exenatide once weekly is on track for submission to the FDA by the end of 1H09.
The company currently markets injectable Byetta to improve glucose control in adults with type II diabetes. It can be used with metformin, a sulfonylurea or a thiazolidinedione. The drug is currently partnered with Eli Lilly (NYSE:LLY), and was approved by the FDA in 2005. Byetta LAR is the long-acting release version of Byetta, and has not been approved yet.
Dr Gerald Bernstein, former president of the American Diabetes Association and vice president for medical affairs at biotech company Generex, said the only reason patients take Byetta is for the weight loss, and once they reach a plateau, they get bored with taking the injection.
"I hope it's not approved, but depending on who sits on the committee, it might be approved," said Dr Sonal Singh, an assistant professor of internal medicine at Wake Forest University Baptist Medical Center. "We don't need more agents. We need better use of available agents."
The FDA last August announced plans to strengthen warnings about the risk of pancreatitis linked to Byetta after two patient deaths and four other hospitalizations in Byetta users. Those patients had hemorrhagic pancreatitis or necrotizing pancreatitis. All six patients were hospitalized, and their Byetta treatment was stopped. Last October, the FDA noted 30 reports of acute pancreatitis, which is sudden inflammation of the pancreas, with the drug. None of those patients had hemorrhagic or necrotizing pancreatitis.
The Eli Lilly spokesperson said the FDA is reviewing several prescribing information updates submitted by Amylin and Lilly for Byetta, including revision of safety language related to pancreatitis. The FDA is also reviewing the submission for Byetta as monotherapy, she added.
In the event the long-acting version is approved, Byetta LAR will probably face strict labeling and patient monitoring guidelines, due to the pancreatitis concern, said Dr Narinder Duggal, a clinical pharmacy specialist, internist and medical director of Liberty Bay Internal Medicine, who specializes in diabetes care. The drug may face use limited to endocrinologists, if the monitoring requirement is too cumbersome, he suggested.
"If I was a betting man, I would say no, they're not going to approve it," Duggal said about Byetta LAR's shot at FDA approval.
A spokesperson for Eli Lilly said the company does not have an answer to whether Byetta LAR be required to have a patient monitoring system for pancreatitis since an NDA has not yet been submitted for the once weekly product.
One physician on background said recent FDA approval decisions have not been very kind, particularly for new diabetes drugs. It may not be a favorable outcome, and the agency may ask the companies for larger trials, he said. The FDA is asking for two-year clinical trials in larger populations. "They may ask for more data, but this is pure speculation," he said. "I've seen the results. The clinical outcomes are very nice compared to short-acting Byetta. It's more weight loss, more glycemic control."
Yet Dr Carol Wysham, a member on Amylin's North American Advisory Board and an endocrinologist at Washington State University, Rockwood Clinic, said based on her interpretation of the data, half the pancreatitis cases reported are not really true cases. Patients are being misdiagnosed based on blood tests and not the full clinical picture. "The statistics don't show any risk [above] what you would expect in the general diabetic population for Byetta. I'm leaning towards the innocent bystander effect," she said.
"I am still absolutely not convinced from my experience. I think we're seeing what happens in the general population. It just happens to be that patients develop pancreatitis after taking Byetta," Wysham said.
One question that remains unanswered is whether Byetta's mechanism of action directly causes pancreatitis, and whether it is a class effect of GLP-1 analogs.
Duggal said he believes the pancreatitis issue mars the entire GLP-1 class, adding that if long-acting exenatide is associated with pancreatitis and receives a black box warning, physicians will be concerned about how long it takes to get the drug out of a patient's system.
"I think if the company is hoping to maintain patent protection or try to get market share, it's going to be a hard sell," said Duggal. "If you ask 20 doctors what Byetta's mechanism of action is - what is the hypothetical mechanism? - I don't think they can tell you."
Bernstein, who has done significant research in this area, explained that all of the incretin mimetics work, in part, by slowing down the discharge of food from the stomach to the duodenum. This slows down the absorption rate of glucose, and slows down the digestion of carbohydrates. Gastric motility studies conducted 15 years ago on a large group of patients with clinical diabetes showed that gastric motility was altered, diminished or dysfunctional in 50% of the population.
"Now if you take a stomach that is already having trouble with gastric emptying, and you add a drug that enhances that, you could get a patient from a sub-clinical to clinical state. That's why a lot of patients [on Byetta] have ulcers and throw up," Bernstein said.
Physicians said the key question remains whether the whole process contributes to pancreatitis. "My own feeling is, if it's that direct, you would have seen more cases of pancreatitis [with Byetta]. We haven't seen a case at our clinic," Bernstein said.
Rajinder Dawra, an assistant professor who has conducted extensive research on the pathophysiology of acute and chronic pancreatitis at the division of basic and translational research at the University of Minnesota, explained that delayed gastric emptying should help prevent pancreatitis rather than cause pancreatitis.
Byetta, or exenatide is a synthetic version of exendin-4, a peptide that stimulates GLP-1.
The development of acute pancreatitis is likely due to pancreatic acinar cell injury, which leads to blockage of the secretion and intracellular activation of digestive enzymes, Dawra said. RyR (ryandine receptors) calcium signaling has been shown to be involved in pathological digestive enzyme activation in pancreatic acinar cells.
Dawra further hypothesized that exendin-4 induced cAMP causes aberrant calcium-receptor response through RyR in some individuals resulting in intracellular digestive enzyme activation and in the development of pancreatitis. Exendin-4 binding on acinar cells generate cAMP, which is known to modulate RyR in calcium signaling.
Acinar cells are an integral part of the exocrine system, which is involved in digestion. Therefore, exendin-4 potentiates secretion of factors involved in digestion such as cholecystokinin or carbamylcholine. Therefore, it is unlikely that Byetta contributes to secretory blocks, Dawra explained.
Duggal said his sense is that the pancreatitis cases are specific to exenatide. By blocking a receptor, you're causing more of a gap in the pathway, as opposed to shutting off the pathway. "It's irreversible, which is what we saw with COX-2 inhibitors like Merck's Vioxx. There were irreversible side effects," he said.
"You can look at a lot of drugs in the historical database. The one receptor, one pathway inhibitors, cause downstream effects," said Duggal.
Dr Daisy Merey, a specialist in bariatric medicine in Miami, and the author of Beyond Diet and Exercise, said in her clinic, she has never had any reports of pancreatitis or problems with her patients. "I still prefer to give Byetta versus insulin," she said.
But, she noted, "We're being constantly bombarded by new drugs, but we don't really know much about them. We know the mechanism of action, but is that enough? We don't know the long-term side effects."
Dr Joel Zonszein, director of the clinical diabetes center at the University Hospital of the Albert Einstein College of Medicine, a Division of Montefiore Medical Center, said the FDA language used to define pancreatitis is accurate, and many diabetic patients have other diseases.
Novo Nordisk's liraglutide, a competing GLP-1 analog, should be approved by April 2009, if everything goes well, said Zonszein. "I don't agree it is not a class effect [of GLP-1s]. There is no evidence. In early studies with liraglutide, they also saw some cases of pancreatitis. We don't know the true incidence of pancreatitis," he said.
Zonszein further suggested that some Type II diabetes patients are more susceptible to developing pancreatitis, and he explained that as exenatide slows down gastrointestinal motility in patients, that may cause some problems with the pancreatic duct, and some pancreatitis may be due to this mechanism of action.
"My feeling is, it may be a class effect, although it is rare. If Byetta LAR stays in the patient for a whole week, what is that going to do? We really don't know. We need very large studies," said Zonszein.
The success of these two drugs in the marketplace, given the similar efficacy, will ultimately come down to a marketing war between Eli Lilly and Novo Nordisk, physicians said.
Yet physicians did not believe Byetta LAR would ever replace Sanofi-Aventis' Lantus (insulin glargine). "I don't think it will replace Lantus. That's a pipedream. We're going to use safer therapies that have a known safety record," said Singh.
DURATION-3, the third trial in a planned program of superiority clinical studies, compares Byetta-LAR to Lantus in patients using oral diabetes medications. Results from this study are expected in the 3Q09.
"Byetta LAR replacing Lantus, not in a million years," said Bernstein.
Amylin has a market cap of USD 1.44bn.
by Kimberly Ha and Sasha Damouni
Source Pharmawire
what do you guys think about albuferon? their date is coming up. still, there is no combination data with albuferon and the new direct antivirals, so i don't see how they are going to compete with roche and schering.
thoughts appreciated.
19-Feb-09 13:39 Human Genome Sciences' albuferon may see physician hesitation in combination therapy with new direct antivirals due to lack of data - analysis
Story
* Interferon likely to be part of HCV therapy for some time, probably until 2015, one physician said
* One co-investigator speculated that albuferon is not going to achieve 50% SVR, which is seen with Pegasys
* Higher doses above 900 mcg unlikely to work, one co-investigator said
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Human Genome Science's next-generation interferon treatment albuferon may struggle to find a role alongside or in combination with soon-to-market direct antivirals, physicians said.
Vertex's telaprevir is currently positioned to be the first-to-market direct antiviral for the treatment of hepatitis C (HCV). As the treatment landscape changes, physicians cautioned that albuferon lacks the necessary clinical data for physicians to be comfortable in prescribing the drug in combination with future direct antivirals, which will change the treatment paradigm.
Some physicians have speculated that by the time albuferon reaches the market, the role of interferon therapy may be eliminated from the regimen, due to direct antiviral therapy. Albuferon's Phase III trial results are expected next month.
The drug is being tested as a standalone therapy against Roche's Pegasys and in combination with the current standard of care, ribavirin.
Dr Smruti Mohanty, a co-investigator on albuferon's trials and a gastroenterologist at the center for liver diseases at the University of Chicago, said there's a lack of data on combining the drug with direct antivirals in development, and physicians will hesitate to use it in combination due to fear of litigation. "Without FDA approval, patients can potentially sue you, and that's a concern for all of us," he said.
"Without clinical data showing results of combination therapy with direct antivirals, physicians will not use these drugs in combination," he said. Any time physicians use combination therapies, there is a worry about cumulative side effects and complications, he added.
Yet Dr Stephen Chris Pappas, director of clinical research at St. Luke's Texas Liver Institute, said on a recent conference panel that albuferon will reduce the burden of treatment. "[It] doesn't sound too scientifically sexy, but it will help with improving the dosing regimen," he said.
"If the side-effects are more tolerable, then more patients will finish treatment. Currently, less than 30% of patients finish the course of therapy," said Dr Douglas Dieterich, professor of medicine and director of outpatient hepatology in the division of liver diseases at Mount Sinai School of Medicine.
Pappas added that physicians will have to look at the intention-to-treat number. "If you don't meet standard of care efficacy, you're not in the game," he added. If albuferon is equivalent to current interferons, whether or not patients opt to switch over to albuferon will depend on the individual, he said.
"If it doesn't meet standard of care efficacy, [albuferon is] not going to be prescribed," said Mohanty.
Barry Labinger, executive vice president and chief commercial officer at Human Genome Sciences, who was also on the panel, said the company is shooting for comparable efficacy to Pegasys, the current standard of care.
A spokesperson for the company said interferon will likely be a part of the HCV regimen for at least for the next five to seven years. "It's a long way before they figure out combination therapy to eliminate interferon from the equation," he said.
Pappas added that the only downside to albuferon is if patients forget that they've already taken the drug, since its a once every two week injection. "If you take it every other week, maybe they will forget," he said. But Mohanty did not believe that would be the case.
Mohanty said when patients are given albuferon 1200 mcg every four weeks, the efficacy is a bit decreased compared to when the drug is given every two weeks. He added that he did not believe albuferon's efficacy would achieve 50% SVR - a measure of sustained virologic response to therapy - and would be slightly lower than Pegasys. "I think they're positioning it mainly as instead of a once a week injection, they are stretching [the duration] for longer," he said. "Perhaps it will replace Pegasys or Pegintron, if that looks good. We don't know yet. But preliminary data shows equal efficacy."
Mohanty said he did not believe the 1200mcg or 1800mcg dose of albuferon would be successful. "I think it's going to be 900 mcg because it's better efficacy. I would not prescribe 1200 mcg twice a month, unless it clearly shows [added benefit]," he said.
He further suggested that as long as albuferon shows equal efficacy and similar side effects, with a lower dosing frequency, the "FDA won't have any problem, unless they see serious adverse events compared to Pegasys."
"Ultimately, everyone wants to avoid interferon, but that's not going to happen anytime soon until 2015," Mohanty said, referring to a potential time when interferon will replaced by direct antiviral combinations.
Human Genome Sciences has a market cap of 323m.
by Kimberly Ha in New York
Source Pharmawire
there was also some recent WSJ article citing JNJ as a potential suitor for either Vertex or Schering. did you see that one? i think VRTX is more likely.
an industry source who is pretty networked in with the company.
here's another story:
29-Jan-09 15:42 Momenta to eye bolt-on buys with "complex" proprietary technologies, CFO says
Story Momenta Pharmaceuticals (NASDAQ:MNTA), the Cambridge, Massachusetts-based generic drug developer, could use the proceeds from its latest stock offering for bolt-on buys, CFO Richard Shea said.
Momenta, with a market cap of USD 412m, last month raised net proceeds of USD 24.1m in a registered direct stock offering to a group of selected investors.
Momenta will indeed continue to scout for potential acquisitions throughout 2009, said Shea. Momenta is particularly keen to look at acquisition and investment opportunities of companies with "very specific expertise" and "products that are complex in nature," he said. Momenta is paying particular attention to companies with focuses in analytical technology, protein manufacturing, peptide mixtures and polysaccharides technology, he said.
Momenta’s Shea would not provide a target price range for potential buys and investments, but stressed that while Momenta is open to M&A it intends to be very conservative with its cash in the coming months.
Framingham, Massachusetts-based GTC Biotherapeutics could be a logical collaborative partner for Momenta, according to VP of corporate communications Thomas Newberry. “We are not looking to make any divestitures, but we are definitely looking for partners for our programs in blood plasma protein and monoclonal antibodies,” he said.
GTC has a number of products in the area of recombinant forms of blood plasma protein that the company is very interested in discussing with potential partners, Newberry said. GTC has expertise in the production of monoclonal antibodies, and could benefit from pairing up with a company with the marketing and product expertise to aid in scaling up the program. GTC’s market cap is USD 70m.
As of its quarterly report for the period ended 30 September 2008, prior to its December stock offering, Momenta had USD 95m in cash and short-term investments and USD 8.7m in debt on its balance sheet.
by Colleen Taylor in San Francisco and Ilene Friedland in Boston
Source Pharmawire
You guys really think that JNJ will take VRTX out? but why now. shouldn't they have done that a while ago?
I've also been hearing that MNTA's generic Lovenox will probably be approved in April.
09-Feb-09 13:21 Eli Lilly: Erbitux as potential first-line agent in NSCLC may limit use of second-line EGFR-inhibitors like Tarceva if patient progresses - analysis
Story * Duke University's Institute for Genome Sciences & Policy is conducting research on identifying specific molecular signatures to tailor therapy
* Erbitux may also be restricted to patients who do not have KRAS mutation, similar to colorectal cancer
* After failure on Erbitux, which inhibits the EGFR pathway, one physician said he would probably use Alimta or Sutent, which target another pathway
____________________________________________________________________________
Eli Lilly's (NYSE:LLY) Erbitux, if approved for use as a first-line agent in non-small cell lung cancer, may limit the use of second-line EGFR-inhibitors like Tarceva and Iressa, physicians said.
Erbitux is a monoclonal antibody that targets a protein called the epidermal growth factor receptor (EGFR). It is currently approved to treat colorectal and head and neck cancers. Eli Lilly and US partner Bristol-Myers Squibb (NYSE:BMY) recently withdrew an FDA application to market Erbitux as a first-line treatment for non-small cell lung cancer (NSCLC). Both drug makers said they will eventually resubmit the application.
Current second-line EGFR targeting agents include OSI (NASDAQ:OSIP) and Genentech's (NYSE:DNA) Tarceva and AstraZeneca's (NYSE:AZN) Iressa.
Dr Chandra Belani, deputy director of the Penn State Cancer Institute, said if a patient is given Erbitux in the front-line setting, and becomes resistant, then other drugs that also inhibit the EGFR pathway cannot be used. "You can't use Tarceva or Iressa when Erbitux is used front-line," he said.
Eli Lilly, Genentech and AstraZeneca could not be reached for comment.
Dr Paul Michael, a medical oncologist with Comprehensive Cancer Centers of Nevada, noted that if his patient failed on Erbitux first-line, he would probably put a patient on a second-line agent that targets another pathway, like Eli Lilly's Alimta or Pfizer's (NYSE:PFE) Sutent. "I wouldn't use another EGFR drug, if I've used one that failed," he said.
Belani added that there are EGFR inhibitors in development targeted for resistance, such as Boehringer Ingelheim's BI992 and another drug by Pfizer. The targeted therapies for patients who failed on both Tarceva and Iressa could be better, he added.
Dr Joan Bull, director of the division of oncology at the University of Texas Medical School, said learning how to sequence these new biologics, and their dosing, will probably take some time before finding the optimal regimen. "Erbitux's greatest problem is the [side effect of] rash, which can be quite severe. But 99% of the time, it's not life threatening," she added.
Dr Jack West, a medical oncologist and medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington, said although there is no real clinical evidence that patients who fail on Erbitux will also fail on small molecule EGFR tyrosine kinase inhibitors (TKIs), such as Tarceva and Iressa, there is clear evidence from clinical trials that physicians are less likely to prescribe patients another EGFR inhibitor after failure on Erbitux.
"I don't think there's any reason to think class failure is going to be the case. But most oncologists believe that there is not going to be any value," he said.
However, Dr Nathan Pennell, a lung cancer specialist at the Cleveland Clinic, said he would not withhold Tarceva from patients if they progressed on Erbitux. He added that he would not recommend eliminating TKIs from 2L or 3L treatment, if and when Erbitux is available as a first-line agent in lung cancer.
So far, Erbitux has only seen modest off-label use in the treatment of lung cancer, said West, due to concerns about reimbursement. Some oncologists and community experts claim the drug's one month survival benefit could be considered mediocre, and have reported that the benefit with Genentech's Avastin is more clinically significant, he added.
"For several years now, we've been very aggressively studying the biology of patient tumors to understand how they will respond to chemotherapy and targeted therapies," said Dr Geoff Ginsberg, director of Duke University's Institute for Genome Sciences & Policy.
For instance, Erbitux may also be restricted to patients who have a normal KRAS gene, as colorectal cancer patients on the drug who are KRAS mutant do not appear to show any benefit. "It's only a matter of time before there is evidence that KRAS mutated patients may not respond to EGFR inhibitors in NSCLC. It will happen," Ginsberg said.
Ginsberg's lab at Duke Medical, in conjunction with the pharmaceutical industry, is helping lung cancer patients determine which drugs they are resistant to before deciding on a course of treatment, based on a simple surgical procedure. An upfront biopsy of the patient's tumor is conducted for a molecular analysis of the tissue. The turnaround time is five-to-seven days. "If you're going to make an important treatment decision, that's a pretty reasonable time to let the patient recover from their biopsy," said Ginsberg.
Pharmaceutical companies should define molecular subsets to identify the potential patient population who will most likely show benefit, said Ginsberg. With the help of microarrays and gene chips, Ginsberg's lab is developing molecular signatures that will be predictive of response to standard of care chemotherapy and other cytotoxic chemotherapy agents.
"Oncologists in the not too distant future will be using these signatures to make decisions on which drug combinations a patient should receive up front," said Ginsberg.
Eli Lilly has a market cap of USD 43.41bn.
by Kimberly Ha and Elizabeth Krutoholow
Source Pharmawire
Pharmawire on Erbitux NSCLC :
by Kimberly Ha and Elizabeth Krutoholow
06-Feb-09 13:34 Eli Lilly: Erbitux unlikely to be widely adopted in NSCLC despite potential approval as mixed-results from FLEX and BMS-099 trials still linger
Story * Clinical significance of marginal benefit in registrational FLEX trial questioned
* Lack of benefit in BMS-099, use of different chemotherapy backbone in Phase III trials complicates position in lung cancer market
* Identification of subgroups that may show increased benefit will be necessary for clinical adoption, one physician said
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Eli Lilly's Erbitux (cetuximab) is unlikely to be widely adopted for the treatment of non-small cell lung cancer (NSCLC), despite a potential label expansion into this setting, physicians said. They also questioned whether the drug would really be a significant addition to the current treatment armamentarium, given a marginal overall survival benefit with a chemotherapy regimen that is not widely adopted in the US.
Physicians from a number of cancer clinics in the US cited a host of factors - including a different chemotherapy backbone in the Phase III trials, the drug's marginal benefit in the pivotal registrational FLEX trial, and the confounding failure in the BMS-099 study - that may limit its use.
Eli Lilly was not immediately available for comment.
"Most of the physicians have not regularly adopted Erbitux in NSCLC," said Dr Nathan Pennell, an oncologist specializing in the treatment of lung cancer at Cleveland Clinic.
Eli Lilly and Bristol-Myers Squibb recently withdrew the sBLA for Erbitux in NSCLC, citing manufacturing issues.
Dr George Simon, director of thoracic oncology at Fox Chase Cancer Center in Philadelphia, said the FLEX study was marginal in its improvement. "The bottom line is, before Erbitux starts influencing practice in NSCLC, if it ever does, it's going to be a while," he said.
In the FLEX trial, patients receiving Erbitux in combination with chemotherapy had a median overall survival that was prolonged by 1.2 months when compared to chemotherapy alone (11.3 months vs 10.1 months, p=0.044.).
The BMS-099 study did not meet its primary endpoint of progression-free survival (PFS); however the median overall survival (OS) in patients receiving Erbitux in combination with a taxane and carboplatin was 9.7 months compared to 8.4 months with chemotherapy alone. The results from this overall survival analysis did not reach statistical significance because the trial was not powered to detect an improvement in OS.
The bigger question is what Erbitux is doing in the FLEX trial, Pennell said, as the BMS-099 trial also showed a marginal benefit in the overall population. Pennell explained that it is very abnormal to see an OS benefit in a trial that did not demonstrate a benefit in PFS.
Physicians are in a really in a difficult position here, he added, as there are a limited number of therapies to treat lung cancer, and they do not want to withhold a drug that has an overall survival benefit, however marginal it may be.
With a median improvement in overall survival of only 1.2 months, FLEX was statistically significant, but the question is if it is clinically meaningful, physicians said.
When asked whether the p-value of 0.044 is concerning, and whether it would bring the statistical significance under question, an oncologist on background said OS is the gold standard, and if you break a p-value of 0.05, it is a positive trial. "The problem is that Erbitux only showed a one-month survival improvement, which is much more modest than what physicians are used to."
"I think PFS is a great endpoint from a patient perspective, but from a payer's standpoint, OS is a more relevant target," said Dr Geoff Ginsberg, director of Duke University's Institute for Genome Sciences & Policy.
Dr Joan Bull, director of the division of oncology at the University of Texas Medical School, agreed that the FLEX study was marginal in its improvement. She added that with cisplatin, a physician can only give six to seven cycles of treatment.
Another significant factor that will limit the drug's use is the fact that the cisplatin/navelbine chemotherapy backbone used in the FLEX study differs from the standard the carboplatin and taxol backbone employed in the US, some physicians noted. "The FLEX chemotherapy backbone is very toxic, and the dosing can be difficult," said Pennell. The studies using the carbo-taxol combination did not show much of a benefit, he added.
While the FLEX trial's chemotherapy backbone is commonly used in the EU, no physician in the US would use this combination, said the oncologist on background.
US physicians are not going to drop using carboplatin and taxol for cisplatin, said Dr Jack West, a medical oncologist and medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington. "No one is even remotely considering swapping to cisplatin, and there is no way this regimen will be taken over as an appealing choice," he added.
However, a second oncologist on background said it will be difficult to switch from cetuximab/cisplatin/vinorelbine to the carboplatin/taxol chemotherapy backbone, citing the lack of benefit seen with the latter in the BMS-099 study.
The first oncologist on background added that the incidence of febrile neutropenia is a concern with adding Erbitux. "With cisplatin and vinorelbine alone, it occurred in 15% of patients, and with Erbitux it increased to 22%. This is too high of a rate," he said.
West said he believed the reasons why the drug has not really been adopted was two-fold. Physicians are not really adopting Erbitux because there is an equal concern about reimbursement, as the drug is not approved yet in this setting, and the benefit has been underwhelming. "Oncologists, and community experts have reported that they consider the benefit with Avastin to be more clinically significant," West added.
"It's going to come down to marketing. I see the options as Avastin followed by Erbitux," said the first oncologist on background.
Cost considerations will also be a significant factor in light of the current regulatory environment, the oncologist on background said. "Erbitux will probably be used in Avastin-ineligible or squamous cell patients," the oncologist on background said.
One industry executive, at a company that is also developing a NSCLC drug, said Erbitux will have a position in first-line treatment of squamous cell patients. "It's clear that Eli Lilly's strategy in lung cancer is driven by it's patent expiration for Gemzar in 2010. Erbitux fits in perfectly in their franchise, the Achilles' heel for Avastin is the squamous cell patients."
"Erbitux is not used presently; if the results were great, then physicians would use it already," said the second oncologist on background, who also questioned Erbitux's chances at approval in this indication. "It's a long shot, the chances are small," he said.
There are enough question marks surrounding the drug that will keep it from being widely adopted, unless the company can identify a clear patient subgroup to increase that marginal benefit, said Pennell. The FLEX study was diluted out by treating the entire population, he added.
The skin rash experienced by patients on the drug seems to be the best predictive marker for response so far, according to Pennell. Recent results showed that patients on the BMS-099 trial who had a rash tended to do better, and it was a very significant difference, he said.
Ginsberg said the industry will make a major step forward if reimbursement of these agents is limited to those patients that will most likely receive benefit, based on imaging and genomic technology.
Eli Lilly has a market cap of USD 43.32bn.
Source Pharmawire
Obesity...again, went to BIO conference in New York recently. i still don't see how the FDA will approve these obesity compounds.
I know there is talk that Arena 'might' strike a deal on locaserin, and the company has been in Japan..but i doubt it will be a deal with good terms.
Obesity drugs in development face challenging regulatory environment for FDA approval
By Elizabeth Krutoholow in New York
Published: February 9 2009 13:17 | Last updated: February 9 2009 13:17
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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Obesity compounds in late-stage development by Amylin Pharmaceuticals, Arena, Orexigen Therapeutics and Vivus, will likely face a challenging regulatory environment this year, physicians told Pharmawire.
As weight loss is only a surrogate measure of a patient’s quality of life, companies developing these compounds will face a high burden of proof to show that these drugs cause no psychological harm.
The FDA has long held a position that the actual way a patient loses the weight is important, since the means to an end may be adverse, said Dr David Orloff, ex-director of the division of the metabolism and endocrinology products at the FDA from 2000-2006, and executive director of regulatory affairs at Medpace.
There has been no demonstration in clinical trials on how weight loss treatment affects how a patient functions, feels or survives, as weight-loss is only a surrogate marker of benefit, Orloff explained. There is definitely a requirement from the FDA for a high assurance of safety, he added. The adverse psychological effects the failed CB-1 class had on mood, behavior and cognition provide a clear example of the level of tolerance that the regulatory agencies have for adverse events with obesity drugs, he added.
The problem with the CB-1 class was that everyone looked at the peripheral effects of the drugs, but the class mainly worked on the brain, according to Justin Halford, an expert in appetite and obesity at the University of Liverpool. The companies involved in the development were led by the regulatory agencies but if these drugs had been checked for specificity, the failure of the entire class could have been prevented, he speculated.
Regulatory agencies are not asking sufficient questions about the exact mechanism of action for drugs that act on behavior, said Halford. Ignoring the idea of how weight-loss is achieved, is storing up problems, he said. We still don’t know the effects of these drugs on behavior, mood and cognition, he said.
Timothy Morris, CFO of Vivus Pharmaceuticals, a firm developing a proprietary obesity therapeutic called Qnexa, said he agreed that safety will be very important. ”We will probably collect a variety of information, but [information on patient behavior] is not required for approval. The FDA will probably look at safety, efficacy and the drug’s mechanism of action,” he said.
Amylin, Arena and Orexigen declined to comment for this article.
The safety bar for approval is very high, said Dr Daniel Bessesen, an endocrinologist and professor at the UC Denver School of Medicine. While the market potential for obesity drugs is enormous, the hurdles are phenomenal, added Dr Nick Finer, an obesity clinician at the Wellcome Trust Clinical Research Facility, Addenbrooke’s Hospital.
It still remains unclear what a company needs to do to convince the regulatory agencies of the safety and efficacy of an obesity drug, Finer added. There is a high burden of evidence to show that patients on these drugs report no psychological harm, he said. This is of particular concern, as these drugs will be taken over the long term, which makes them subject to misuse, he said.
Dr Steven Smith, co-primary investigator on Arena Pharmaceutical’s obesity drug lorcaserin drug trials, said there are still concerns that the insistence on a perfectly clean drug profile does not address the real risk-benefit ratio for patients with a higher body mass index.
In terms of efficacy, the FDA looks for a minimum of one to two years of data that demonstrates at least a 5% placebo subtracted weight-loss, said Finer. In Europe, the regulatory board looks for at least a 10% weight-loss from baseline that is statistically greater than the loss with placebo. There is a definite need for direct measurements of health improvement like a decrease in cardiovascular risk, or improvements in glycemic control, but measuring these hard outcomes is difficult, Finer said.
If an obesity drug eventually reaches the market, it will need to clear a commercial viability bar, since a number of drugs that only showed a 5% weight-loss are not market blockbusters, Bessesen said.
This is the rationale behind Vivus’s Qnexa and Orexigen’s Contrave, two obesity therapies in development that combine two generic drugs, as patients want more weight-loss than the individual drugs can provide, Smith said. “The truth is, products live or die based on total weight-loss,” said Bessesen.
To receive approval for a combination drug, the FDA requires that the safety and efficacy of the fixed dose agent is more efficacious than either individual component, said Finer. “While there are theoretical reasons for combination, I wouldn’t want to use any of these agents alone,” Finer said, citing their side-effect profiles.
A fixed-dose combination that is associated with at least twice the weight-loss of either component will be viewed more favourably, but this is a tough thing to achieve, said Finer. ”We’re already struggling with evaluating single agents.”
The FDA does not have a clear approach to approval of combination drugs, but if the components are already marketed, there is more data on their safety profiles, said Finer. A fixed dose combination drug is still bound to the same standards of safety and efficacy as a novel agent. While it is reasonable to look at these combinations, it is interesting that only the smaller, newer pharmaceutical companies are developing them, he said. “There is a high risk, but it may pay off,” said Finer.
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