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First win for ZGEN - all KG's motions for preliminary injunctions were denied:
http://www.reuters.com/article/idCNBNG41041820091210?rpc=44
If you're looking for another possible "good sign of things to come", I bought back some of my trading shares yesterday at TASE
Gilead moves closer to US approval of CF treatment
http://finance.yahoo.com/news/Gilead-moves-closer-to-US-apf-2781888632.html?x=0&.v=2
Gilead Sciences says panel recommends approval of cystic fibrosis treatment aztreonam
FOSTER CITY, Calif. (AP) -- Gilead Sciences Inc. said Thursday an advisory committee has recommended U.S. approval of the biotechnology company's inhalable cystic fibrosis treatment candidate.
The company said the Anti-Infective Drugs Advisory Committee of the Food and Drug Administration recommended that aztreonam be approved. The drug is aimed at treating chronic lung infections caused by the bacterium Pseudomonas aeruginosa. Gilead has said those lung infections are the biggest killer of people with cystic fibrosis.
The FDA is not required to follow the recommendation of its advisory committees, though it normally does. The FDA set a target review date of Feb. 13 for the drug candidate.
The drug is already conditionally approved in Canada and the European Union under the trade name Cayston.
A tiny buy in an ocean of selling...
Other events: (source: http://www.protalix.com/press_release.html)
NDA submission with the FDA for prGCD - completed, as expected.
Proposed pediatric investigation plan to the EMEA - filed (triggers a milestone payment of $5M by Pfizer).
Full phase III data will probably be presented at the 6th Annual Lysosomal Disease Network: WORLD Symposium on Feb. 10-12, 2010.
Complete results presented at ASH.
Novartis Tasigna(R) Trial Shows Superior Results to Gleevec(R) in Patients With Early-Stage
http://www.forbes.com/feeds/prnewswire/2009/12/08/prnewswire200912080915PR_NEWS_USPR_____NY22511.html
EAST HANOVER, N.J., Dec. 8 /PRNewswire/ -- In a large Phase III clinical trial, Tasigna® (nilotinib) 200 mg capsules demonstrated greater efficacy over Gleevec® (imatinib mesylate) tablets* in the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase(1).
To view the multimedia assets associated with this release, please click: http://multivu.prnewswire.com/mnr/novartis/41444/
In the first head-to-head comparison of these two oral therapies as initial treatment for this life-threatening blood cancer, Tasigna results showed statistically significant improvement over Gleevec in every measure of efficacy, including major molecular response (MMR), complete cytogenetic response (CCyR) and prevention of progression to accelerated or blastic phase(1). The new data were presented as a late breaker abstract at the 51st annual meeting of the American Society of Hematology (ASH), held in December, in New Orleans, USA.
At 12 months, significantly fewer patients progressed to accelerated or blastic phase on Tasigna 300 mg twice daily than on Gleevec 400 mg once daily (2 patients vs. 11 patients)(1), demonstrating a statistically significant improvement in disease control(1). In the study, Tasigna was well tolerated. Fewer patients discontinued due to adverse events from the Tasigna 300 mg twice daily arm of the study compared to the Gleevec 400 mg once daily arm. No patients in the study had prolongation of QT interval >500 milliseconds(1). No sudden deaths occurred with either treatment(2).
"The outstanding rates of response observed with Tasigna, combined with the very low rate of disease progression, strongly indicate that patients who begin their treatment with Tasigna may have long-term improvement of progression-free survival," said Giuseppe Saglio, University of Turin, San Luigi Hospital, Orbassano-Torino, Italy, a member of the study management committee. "The efficacy results and tolerability of Tasigna should support its use in newly diagnosed Ph+ CML patients."
With Tasigna 300 mg twice daily, the rate of MMR at 12 months was twice that of patients receiving Gleevec 400 mg once daily (44% vs. 22%, p < 0.0001)(1). In addition, 80% of patients achieved CCyR with Tasigna versus 65% with Gleevec 400 mg once daily (p < 0.0001)(1). Responses were achieved faster in the Tasigna group than in the Gleevec group(1).
MMR was defined in the study as reduction in the level of the abnormal Bcr-Abl protein to less than or equal to 0.1% of the pre-treatment level based on an internationally agreed standard(1). This can be interpreted to mean that for every 1,000 cells containing Bcr-Abl that were present in the blood at the start of therapy, only one cell was present at the 12-month follow-up. CCyR indicates that no CML cells containing the diagnostic Ph chromosome can be seen in a sample of bone marrow taken from the patient.
"Novartis is pioneering research targeting the molecular origin of Ph+ CML, which has led to treatments of unprecedented effectiveness and safety," said David Epstein, President and CEO of Novartis Oncology and Novartis Molecular Diagnostics. "Considering the already low rates of progression to advanced disease and the excellent long-term survival of patients on Gleevec, the efficacy and safety profile of Tasigna at 12 months is fantastic news and brings promise for further improving the outcomes of patients with Ph+ CML."
Tasigna is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML(2,3). Upon initial reports of resistance in the Gleevec registration trials, Novartis scientists created a new molecule, Tasigna, just a year after the launch of Gleevec. The first clinical trials began just 21 months after discovery. The drug received its first regulatory approval in the second-line indication in 2007.
Novartis plans to file worldwide applications for approval of Tasigna as a treatment for adult patients with newly diagnosed Ph+ CML. Tasigna is currently approved in more than 80 countries including the European Union, United States and other countries for the treatment of adult patients with Ph+ CML in chronic phase or accelerated phase who are resistant or intolerant to prior treatment including Gleevec.
Study details
The clinical trial, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients (ENESTnd), is a Phase III randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase(1). It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients. Designed to detect a difference in MMR between Tasigna and Gleevec after 12 months of treatment, it is also the first registration study in which molecular traces of a key biomarker specific to Ph+ CML have been used as a primary endpoint for regulatory review. The trial's secondary endpoints included CCyR, as well as progression to accelerated or blastic phase, and overall survival.
ENESTnd is being conducted at 220 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 400 mg twice daily (n = 281), Tasigna 300 mg twice daily (n = 282) or Gleevec 400 mg once daily (n = 283). The primary endpoint was MMR at 12 months; a secondary endpoint was CCyR by 12 months(1). Planned follow-up is for five years(2). Patients on the Gleevec treatment arm who had suboptimal response or treatment failure will be able to escalate dose and/or switch to Tasigna via a protocol extension.
Samples for molecular response were evaluated by a single reference laboratory. The blood test used to determine molecular response can detect a single cell containing traces of Bcr-Abl in up to one million normal blood cells(4). In addition to being simpler and less invasive for patients, the test has a much greater sensitivity than standard cytogenetic tests, which require a sample of bone marrow to be drawn for visual detection of cells containing the Ph chromosome(5).
All patients had a minimum of 12 months of treatment or discontinued early; the median follow-up was 14 months. Overall, 84%, 82% and 79% of patients remained in the study on Tasigna 300 mg twice daily, Tasigna 400 mg twice daily and Gleevec 400 mg once daily, respectively.
Rates of MMR at 12 months were statistically higher for patients in the Tasigna 300 mg twice daily group compared with Gleevec 400 mg once daily (44% vs. 22%, p < 0.0001) and also for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (43% vs. 22%, p < 0.0001). Among patients who achieved MMR, median time to MMR was faster for Tasigna 300 mg twice daily (5.7 months) and Tasigna 400 mg twice daily (5.8 months) compared with Gleevec 400 mg once daily (8.3 months). Molecular response was assessed by polymerase chain reaction (PCR) at baseline, monthly for three months, and every three months thereafter.
Rates of CCyR by 12 months were significantly higher for Tasigna at 300 mg twice daily compared with Gleevec 400 mg once daily (80% vs. 65%, p < 0.0001) and for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (78% vs. 65%, p = 0.0005). Overall, progression to advanced disease was lower for Tasigna 300 mg twice daily (2 patients) and Tasigna 400 mg twice daily (1 patient) compared with Gleevec 400 mg once daily (11 patients).
Both Tasigna and Gleevec were well tolerated overall. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for Tasigna 300 mg twice daily, 11% for Tasigna 400 mg twice daily, and 9% for Gleevec 400 mg once daily.
About Ph+ CML ...snip
ITMN-191 presentation at the HepDart conference:
http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9MjIzNjF8Q2hpbGRJRD0tMXxUeXBlPTM=&t=1
(in the ritonavir + 191 trial, boosted doses are 100 and 200mg, slides 18-19)
Topline data on 534 reported in July looked good.
Celgene's MM-015 trial
Study hits its primary endpoint of improvement of PFS in patients who received MPR-R (R maintenance until progression) versus patients who received MP.
Also, stat-sig separation was seen in curves between MPR-R and MPR (R for 9 cycles without maintenance). However, there was no difference between MPR and MP.
http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1363079&highlight=
Agree that the approval path remains murky, I think that removing the peripheral neuropathy isn't enough, carfilzomib needs to show at least 25% ORR in Velcade refractory patients in order to get accelerated approval with this open label single arm phase IIb trial, so far it's 18%.
Onyx drug shows promise in multiple myeloma study
http://www.reuters.com/article/idUSN0614012520091207
* Overall response rate 46 pct at 20mg among Velcade naive
* Time to disease progression with carfilzomib 7.6 months
* ORR 53 pct with dose escalation to 27 mg
* ORR 18 pct in those previously treated with Velcade
* Onyx says could file for FDA approval in late 2010
By Bill Berkrot
NEW YORK, Dec 7 (Reuters) - An experimental cancer drug recently acquired by Onyx Pharmaceuticals Inc <ONXX.O> showed promising response rates in patients with relapsed and/or refractory multiple myeloma, according to interim data from a pair of small mid-stage trials.
The studies, presented on Monday at the American Society of Hematology (ASH) meeting in New Orleans, tested carfilzomib given intravenously every 28 days in 73 patients who had not previously been treated with Takeda Pharmaceuticals' <4502.T> Velcade, and in 33 others following treatment with Velcade.
"These interim results suggest that carfilzomib could benefit patients with multiple myeloma who are no longer responding to current therapies," Dr. David Siegel, co-investigator of the studies, said in a statement.
Onyx acquired carfilzomib with its purchase last month of Proteolix Inc, saying the drug for multiple myeloma, a blood cancer, has the potential for accelerated U.S. approval in 2011.
Among those who had not received prior Velcade treatment, or Velcade naive patients, carfilzomib led to an overall response rate (ORR) of 46 percent among 54 patients at a 20 milligram dose, and a 53 percent overall response among 19 patients with dose escalation to 27 mg, researchers said.
Patients who were previously treated with Velcade, known chemically as bortezomib, achieved an overall response rate of 18 percent when administered carfilzomib, they said.
The Velcade naive patients had relapsed or worsened following other prior therapies.
Multiple myeloma results from abnormal plasma cells, usually in the bone marrow. More than 180,000 people are living with the disease worldwide and about 86,000 new cases are diagnosed annually, Onyx said.
Median survival from relapsed and refractory multiple myeloma -- when the disease returns and progresses following a response to therapy -- can be as short as six to nine months.
In addition to overall response, the Proteolix-sponsored trials looked at secondary goals of time-to-progression and duration of response.
In the Velcade naive group time-to-progression, or the amount of time before the disease worsens, was 7.6 months, and duration of response was 8.4 months.
In the group previously treated with Velcade, interim results showed a time-to-progression of 5.3 months and duration of response of more than 9 months.
"These findings are truly an advance for patients with multiple myeloma," Dr. Michael Wang, of the MD Anderson Cancer Center in Houston and one of the lead investigators, said.
Noting that other life-extending drugs often have adverse side effects, including severe nerve pain, Wang said "carfilzomib is showing good response rates with an improved side effects profile."
Treatment with carfilzomib was well tolerated with no unexpected side effects, researchers said.
More than 20 percent of patients were able to complete the full 12 cycles (48 weeks) of therapy in both studies without cumulative side effects, and with low incidence of neuropathy, researchers said.
"These data support our ongoing carfilzomib program in multiple myeloma, a disease that has poor long-term survival," Michael Kauffman, Onyx's interim chief medical officer, said in a statement, adding that the company could file its application seeking U.S. approval by the end of 2010.
Celgene to Acquire Gloucester Pharmaceuticals
For $340M in cash, plus up to $300M in future milestones
http://www.gloucesterpharma.com/press/releases/pr120709.html
Very good results, still it will take more time and data before Bendamustine plus rituximab will take significant share from CHOP plus rituximab (or R+CVP) in 1st line NHL.
This program looks dead:
Cubist Pharma halts enrollment in trials on safety concerns
http://www.reuters.com/article/marketsNews/idCNBNG41302320091203?rpc=44
Dec 3 (Reuters) - Cubist Pharmaceuticals Inc said it suspended enrollment in two mid-stage trials of its experimental treatment to reduce bleeding in on-pump cardiac surgery, after certain data from one trial showed a higher rate of death.
The Data Safety Monitoring Board recommended a temporary suspension in enrollment after it observed a statistical difference in mortality between the arms of the CONSERV-2 trial, the biopharmaceutical company said in a statement.
The drug, ecallantide, which Cubist licensed from Dyax Corp, is also being tested in another mid-stage trial, named CONSERV-1, where no such imbalance was detected.
Cubist said an initial review showed mortality observed in the trial was due to a variety of causes typically expected in a high-risk-for-bleed population undergoing cardiac surgery.
Indeed our local market is already some 500 patients and there are a couple hundreds untreated more.
I wasn't thinking of a direct monetary inducement to settle, rather on no AG.
...the begging of a wonderful friendship
First Human Embryonic Stem Cell Lines Approved under New NIH Guidelines
http://www.genengnews.com/news/bnitem.aspx?name=69955197&source=genwire
NIH director, Francis S. Collins, M.D., Ph.D., today announced the approval of the first 13 human embryonic stem cell (hESC) lines for use in NIH-funded research under the recently adopted NIH Guidelines for Human Stem Cell Research.
“In accordance with the guidelines, these stem cell lines were derived from embryos that were donated under ethically sound, informed-consent processes,” points out Dr. Collins. “More lines are under review now, and we anticipate continuing to expand this list of responsibly derived lines eligible for NIH funding."
Children's Hospital Boston developed 11 of the approved lines, and The Rockefeller University in New York City developed the other two. An additional 96 lines have been submitted to NIH for either internal administrative review or consideration by the external Working Group for Human Embryonic Stem Cell Eligibility Review and the NIH Advisory Committee to the Director (ACD). The working group provides findings to the ACD, which makes recommendations to the NIH director, who decides whether the hESCs may be used in NIH-funded research and lists those deemed eligible on the NIH Human Embryonic Stem Cell Registry.
Over 30 NIH grants funded in the 2009 fiscal year, totaling more than $20 million, proposed to use hESCs; these grants have been restricted until approved lines became available on the NIH registry.
With today's announcement, these principal investigators may obtain registry-listed hESCs from the owners of the lines and proceed with their research. This group of grants includes research using hESCs for the therapeutic regeneration of diseased or damaged heart muscle cells, developing systems for the production of neural stem cells and different types of neurons from hESCs in culture, and developing a cell culture system for the large-scale production and self-renewal of hESCs.
In addition, a number of Challenge Grant applications, which could be funded through the American Recovery and Reinvestment Act in the 2010 fiscal year, proposed to use hESCs.
On March 9, President Obama issued Executive Order 13505: Removing Barriers to Responsible Scientific Research Involving Human Stem Cells. The executive order stated that the secretary of the HHS, through the director of NIH, may support and conduct responsible, scientifically worthy human stem cell research including human embryonic stem cell research to the extent permitted by law.
The NIH Guidelines for Human Stem Cell Research, published on July 7, implement the executive order as it pertains to extramural NIH-funded stem cell research, establish policy and procedures under which the NIH will fund such research, and help ensure that NIH-funded research in this area is ethically responsible, scientifically worthy, and conducted in accordance with applicable law.
I don't have a better explanation to the slide back in share price. I have listened to the webcast of the analyst meeting (http://www.wsw.com/webcast/plx/), especially to the PFE's guy - David Simmons. He sounded quite excited about PLX's platform using terms like "groundbreaking technology " and "dynamite combination" when referring to PFE/PLX collaboration. Gave the feeling that this is the begging of a wonderful friendship :) All in all, I think PLX is indeed on the right track and expect it to do well.
A few more Neupogen knockoffs were approved in the EU and several next generation long-acting reformulation of G-CSFs including Teva/CoGenesys Neugranin are in clinical trials.
I thought Teva would launch at-risk on July 2010. Either the market looks too small for the risk or ABT gave them something in return to the 8 months delay.
The United States Department of Health and Human Services (DHHS) updated its HIV treatment guidelines as well. Key updates on page 2:
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
Pharma CPR
http://www.the-scientist.com/article/display/56179/
Meet the stalled drugs that pharmacogenomics (aka personalized medicine) might bring back to life—or kill for good.
By Ken Orvidas
Michael Bristow has been in biotech long enough to see more than a few promising drugs flounder in clinical trials, but he’s not ready to give up on bucindolol. Back in the 1990s, the University of Colorado cardiologist and molecular pharmacologist helped guide the Phase III Beta-Blocker Evaluation of Survival Trial (BEST) for the heart failure drug, which was first developed by Bristol Myers and then under license to Intercardia in North Carolina.
The trial ran for 5 years with nearly 3,000 patients—what the team called “a demographically diverse group”—but it was halted early after failing to show significant gains in all-cause mortality, the primary study endpoint. “When the plug was pulled, all we knew was the primary endpoint hadn’t been met,” says Bristow. “The company was running low on funds and needed to conserve cash. Later on, as more information came in, it was clear that the plug probably should not have been pulled.”
When the team published their disappointing results in the New England Journal of Medicine in 2001, they noted that there was a significant survival benefit for non-black patients, an observation that they attributed to genetic differences in either the renin-angiotensin system that regulates blood pressure and water balance or the beta-adrenergic pathway targeted by the beta blocker. The human genome project had just been completed and the promise of personalized medicine was still just that—a promise. As it turned out, however, the BEST trial was the first ever heart failure trial that had taken DNA samples of all the enrolled patients.
Even so, it wasn’t until August 2003 that the data-coordinating center in Palo Alto faxed Bristow the pharmacogenomic results, revealing that a polymorphism in the beta-adrenergic receptor played a role in the response to the drug. “I don’t know if it was that night or the next day,” Bristow says, but it didn’t take him long to launch Arca Biopharma with the hope of licensing bucindolol and getting it approved as a personalized therapeutic.
With a longtime champion of personalized medicine, Francis Collins, now at the helm of the National Institutes of Health, many expect the approach to finally take center stage in the quest for new, targeted therapeutics with greater efficacy and fewer side effects. “If Merck could have known in advance who would have cardiovascular problems from Vioxx,” explains Edward Abrahams, executive director of the Personalized Medicine Coalition in Washington, D.C., “they may not have had to withdraw it from the market.” For Abrahams, there is no such thing as a failed drug. “‘Failed’ just means it failed in a percent of the population.”
Encore, Encore
Several drug candidates in areas ranging from cancer to schizophrenia that fell short of becoming blockbuster therapeutics are now finding niche applications with the development of novel genetic tests. Take the case of methotrexate, a chemotherapy drug developed in the 1940s that is now limited to treating leukemia, as newer drugs have proven more effective against solid tumors. A recent laboratory study in EMBO Molecular Medicine (1:323–37, 2009) found that the drug can destroy cells that contain a mutant MSH2 gene, which is responsible for about 5% of bowel cancer cases, triggering targeted clinical trials for this novel application.
Some companion genetic tests are also having unexpected impacts on the way currently approved drugs are used. Iloperidone (Fanapt), from Vanda Pharmaceuticals, was approved by the Food and Drug Administration in May to treat schizophrenia after Novartis shelved it for nearly a decade. Although the drug was ultimately okayed for all schizophrenics when a clinical trial proved it was superior to another currently approved therapeutic, Vanda had been pursuing a companion diagnostic from the beginning to identify patients with the genetic profile that responded best, along with those who may experience a potentially fatal side effect, which causes the heart to beat too fast. The company says it plans to release that companion diagnostic in the future.
Of course, bringing drugs back from the dead is not necessarily easier than starting over again. First, there’s the expense: According to Rina Wolf, a consultant whose clients include Axial Biotech and Zeissen, developing companion diagnostics can cost between $15 million and $100 million, depending on the complexity of the test. Second, companies must contend with the stigma associated with a drug that has a bad track record, particularly when it has been pulled from the market for safety reasons. For instance, Novartis’s painkiller lumiracoxib (Prexige), which is a cox-2 inhibitor like Vioxx, has never been approved in the United States and was pulled from foreign markets in 2007 after causing liver damage. While some outlets reported in August that Novartis had developed a diagnostic test to go along with the drug, which would use undisclosed biomarkers to identify patients at risk for liver side effects, the company is keeping mum on any definitive plans to revive the drug.
Ellson Chen, a former Celera scientist who founded Vita Genomics in Taiwan, once referred to his company’s work as a drug-rescue program, but today he prefers to call it “repositioning.” “When we first contacted pharmaceutical companies,” Chen says, “they didn’t like the name ‘rescue’ because it means something went wrong and that gets investors nervous.”
Rescuing drugs through personalized medicine is fraught with scientific challenges as well. In the late 1990s, Ruth March, director of personalized medicine at AstraZeneca, was working on ximelagatran (Exanta), the first drug in a new class of blood thinners. During Phase 3 clinical trials, the team discovered that over the long term, Exanta could raise liver enzymes in a small number of patients, a red flag for causing liver damage. In 2000, the company decided to try to develop a test to screen those patients, but it had to collect genetic samples retrospectively because they had not been obtained during the original clinical trials. Over the next 5 years, March’s team was successful in developing and publishing a biomarker, but it only predicted 50% of patients with the adverse events. That wasn’t good enough. AstraZeneca finally abandoned the drug in 2006 after discovering further safety issues, but March says the biomarker, called HLA-DRB1*07, has proven useful in predicting similar adverse events with other drugs (Pharmacogenomics J, 8:186–95, 2008).
Today, the company has procedures in place to identify personalized medicine candidates early on in development to avoid running inappropriate—and costly—clinical trials. “We spent 5 years trying to get these things into the early pipeline,” March says, “Now, we’re trying to not have too many surprises.”
For March, the last big “surprise” will probably be Iressa. When the lung cancer drug was first in clinical trials 10 years ago, the drug only proved effective in 10 to 15 percent of patients in 2004, a borderline case for FDA approval at the time. It would probably not have been approved today. Iressa is now restricted to patients already using it, however, diagnostic tests are available to identify patients in the general population with an EGFR mutation making them responsive to the drug. AstraZeneca would not confirm whether it will seek reapproval of the drug.
Curtain Calls
Although such diagnostics hold promise for patients, some companies may still be quivering at the possibility that new tests could eat into their profits. Over the summer, the FDA announced a labeling change for the colorectal cancer drugs cetuximab (Erbitux) and panitumumab (Vectibix) to reflect the fact that they do not work for people with mutations in the KRAS gene. The diagnostic firm DxS currently sells a KRAS mutation test in Europe and is now seeking approval from the FDA.
For Edward Abrahams, there is no such thing as a failed drug. “’Failed’ just means it failed in a percent of the population.”
And earlier this year, a study indicated that the bestselling antiplatelet therapy clopidogrel (Plavix) is ineffective in preventing heart attack in 30 percent of patients (NEJM 360: 354–62, 2009). This deficiency was linked to a single gene variant, and following publication the FDA initially requested a labeling change that would recommend patients get tested prior to using the medication. However, after discussions with the drug’s maker, Sanofi-Aventis, the FDA has apparently softened on that stance. Even so, with Plavix nearing the end of its exclusivity period and a new Eli Lilly drug prasugrel (Effient) now on the market as a more effective alternative, a diagnostic test that pinpoints people who thrive on Plavix may be just what the company needs to keep the drug alive.
In the case of bucindolol, Bristow was able to get seed funding and Series A that amounted to $16 million, launching his third biotech company. In 2006, Bristow and his collaborators published a reanalysis of the BEST trial using genetic data in the Proceedings of the National Academy of Sciences (103:11288–93, 2006). “For 50% of the population, this seems to be the drug of choice,” he says. Unfortunately, the FDA does not agree: Arca’s first submission was not accepted in June, owing to questions over the statistical analysis and the fact that some original records no longer exist at study sites used in 1999.
Bristow, for his part, seems unfazed, and says that the agency had not reviewed supplementary data submitted in May and the company is now in discussions about whether additional clinical trials are necessary. “You have to line up a lot of dominoes to make this thing work,” he says.
Thanks, Roy.
PLX/PFE
Nice deal with a strong partner that can play against GENZ and Shire but the stock is down 5% now at TASE after a 9% surge on the news.
Looked up the patent and it seems to be running until 2013 only.
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5506214.PN.&OS=PN/5506214&RS=PN/5506214
Merck didn't say what the FDA wrote in the RTF Letter but if it is another phase III trial, I doubt Merck are going to do it.
Celgene Cancer Pill to Triple Sales on Data Threatening J&J
http://www.bloomberg.com/apps/news?pid=20601087&sid=aQWaVfVDmVN8&pos=7
By Elizabeth Lopatto
Nov. 30 (Bloomberg) -- Celgene Corp. can more than triple sales for its best-selling cancer pill Revlimid on new data that may convince doctors to choose the drug as a first option over Johnson & Johnson’s intravenous medicine, Velcade.
Revlimid generated $1.3 billion in sales last year as a back-up therapy for patients with the blood cancer multiple myeloma who don’t respond to other options. Findings from research to be reported next week will show how well the pill works as a first-choice treatment, in long-term use and against other tumors. A preliminary report on one study, released in July, suggested Revlimid helped patients live longer.
About 20,000 Americans are diagnosed yearly with multiple myeloma, which kills two-thirds of patients within five years, said Kenneth Anderson, a professor at Harvard Medical School in Boston. Broadened use of Revlimid may push annual sales to $4.4 billion by 2016, said Mike King, a Merriman Curhan Ford & Co. analyst in New York, in a telephone interview.
Positive results “change the standard of care,” said Anderson, who is an oncologist at Boston’s Dana-Farber Cancer Institute, in a telephone interview. “We treated the very first patients with Revlimid here many years ago. I have patients who have now spent 10 years on Revlimid therapy who are doing quite well. People will be very willing to go onto maintenance therapy” with this drug, he said.
Celgene, of Summit, New Jersey, fell 78 cents, or 1.4 percent, to $54.97 in Nasdaq Stock Market composite trading on Nov. 27. The stock had increased 5.5 percent in the 12 months before today. J&J, based in New Brunswick, New Jersey, declined 41 cents to $62.89 in New York Stock Exchange composite trading.
Bone Marrow Tumors
Multiple myeloma causes malignant plasma cells to form tumors, and hinders the body’s ability to fight infections. Revlimid, derived from the drug thalidomide, works by programming cancer cells to commit suicide, and by creating an environment that stalls tumor reproduction.
Celgene reported early results in July on the so-called MM- 015 study, designed to show whether using Revlimid and two older cancer therapies helped patients live longer than taking only the other drugs. That report suggested patients may benefit, and that the therapeutic effect was superior to Velcade’s in a similar trial, said Mark Schoenebaum, a Deutsche Bank analyst in New York, in a telephone interview.
The MM-015 trial is one of more than 200 involving Celgene to be reported at the American Society of Hematology meeting starting Dec. 5 in New Orleans. Given that Revlimid generated 59 percent of Celgene’s revenue last year, the MM-015 data will be “the first, second, and third act” of the meeting for Celgene, Schoenebaum said.
Market Share
“The better the data” on that study, Schoenebaum said, “the more market share Revlimid gains.”
Convenience will drive increased Revlimid use, because patients will prefer a once-a-day pill to infusions done in a medical office, said Ivan Borrello, an associate professor of oncology at Johns Hopkins University in Baltimore.
“Does someone who’s actively working want to go into a doctor’s office twice a week to get Velcade?” Borrello said in a telephone interview.
Revlimid was approved in the U.S. in December 2005 for patients with myelodysplastic syndromes, disorders of the blood cells that can lead to leukemia. It was cleared six months later for use as a secondary multiple myeloma therapy.
Celgene already has gained about 30 percent of the first- line multiple myeloma market, even though it doesn’t yet have U.S. approval for that use, said Yaron Werber, an analyst with Citigroup Global Markets, in a note to clients this month. Velcade’s share is about 40 percent, Werber said.
Velcade Sales
Velcade sales surged in 2008 after it won U.S. clearance as a primary treatment for multiple myeloma.
J&J, the world’s biggest maker of health products, markets Velcade outside the U.S. and last year reported a 47 percent increase in revenue to $787 million. Japanese drugmaker Takeda Pharmaceutical Co., of Osaka, sells the medicine in the U.S., where it generated $413.7 million last year, a 43 percent jump, said Lauren Musto, a spokeswoman.
The study that helped Velcade win clearance for first-line use in 2008 was a test similar to Celgene’s MM-015 research. Each trial examined whether patients lived longer without their tumors worsening after adding the new drug to a standard regimen of two older therapies, the steroid prednisone and Celgene’s Alkeran, sold generically as melphalan.
In the Velcade trial, patients kept cancer at bay an average of eight months longer when the drug was added to the regimen. For that trial, patients were treated for 39 weeks.
‘Big Win’
The Revlimid trial included 30 weeks of therapy or placebo, said King, of Merriman Curhan Ford.
“So you tie Velcade? That’s a big win,” King said. “You’re treating for a shorter duration, plus it’s a once-a-day pill rather than a twice-weekly infusion.”
J&J declined to comment, referring calls to Takeda.
Manisha Pai, a U.S. spokeswoman for Takeda, said in an e- mailed statement that she was “looking forward to interesting data at ASH that examine both the cost and convenience of Velcade compared with oral multiple myeloma therapy options, such as lenalidomide and thalidomide.”
Revlimid is designed to be a more potent derivative of thalidomide, first approved in the U.S. in 1998 for leprosy, a progressive skin disease. This family of medicines can also trigger the immune system to fight tumors and hinder growth of blood vessels that nourish them.
Thalidomide was linked to severe birth defects, including malformed limbs, in the 1960s and temporarily withdrawn from the market. The drug returned as a potent tumor-fighter, with a warning against use in women who are pregnant.
Thalidomide Risks
Because multiple myeloma is a difficult-to-diagnose form of cancer, it is often found late, when the benefits of treatment outweigh the risks associated with thalidomide, Harvard’s Anderson said.
“Revlimid has made a remarkable difference in terms of the response you can achieve,” Anderson said. “The characteristics that make it attractive are that it’s oral, low dosage, and has few side-effects.”
Celgene will also present preliminary results from its test of Revlimid as maintenance therapy at the hematology meeting, with more detailed results to follow in 2010 at the American Society of Clinical Oncology conference.
That trial, called IFM-05-02, “has the potential to establish Revlimid as long-term maintenance therapy,” said Geoffrey Porges, an analyst for Sanford C. Berstein & Co. in New York, in a Nov. 11 note to investors.
Other Cancers
Additional data at the hematology meeting will show how Revlimid works when combined with Velcade and Swiss drugmaker Roche Holding AG’s tumor-fighter Rituxan, approved in non- Hodgkin’s lymphoma and rheumatoid arthritis.
Revlimid is also being tested in chronic lymphocytic leukemia, a cancer of the white blood cells, and in so-called smoldering, or aysmptomatic, multiple myeloma.
Another study at the hematology meeting will offer the first large human study results for Celgene’s experimental drug pomalidomide, a next-generation product in the same family of medicines as Revlimid.
Pomalidomide “is expected to have significantly greater potency,” and “may genuinely have a role in late line multiple myeloma, even in patients who have progressed on prior Revlimid,” Porges said in his note.
sibutramine increases pulse rate, and for some obscure reason also tends to increase blood pressure in patients with normal (or low) blood pressure, while reducing BP in hypertensive patients.
CEO Morris Laster is leaving for personal reasons.
http://www.globes.co.il/serveen/globes/docview.asp?did=1000517074&fid=1725
It's also worth noting that in 2005, the FDA rejected a Public Citizen petition to ban Meridia saying the overall risk-benefit profile of the drug supports keeping it on the market.
Sorry, not following Celldex in particularly.
Given unveils next-generation Colon Pillcam
http://www.globes.co.il/serveen/globes/docview.asp?did=1000516276&fid=942
Given Imaging has already obtained the EU CE Mark for the Pillcam Colon2.
Globes' correspondent23 Nov 09 14:50
Endoscopic capsule developer Given Imaging Ltd. (Nasdaq: GIVN; TASE: GIVN) today unveiled its next-generation Pillcam Colon at the Gastro 2009 Conference in London. The Pillcam Colon2 is a development of the Pillcam Colon1, and is aimed at being more patient friendly, as well as providing better visualization of the colon.
The Pillcam Colon2 includes proprietary, innovative technologies, including intelligent functionality and superior imaging, designed to provide physicians with clear and precise views of the colon and polyps of interest.
Article continues after advertisements
Given Imaging has already obtained EU CE Mark certification for the Pillcam Colon2 and has begun marketing in select European countries, with continent wide availability planned by mid-2010.
The Pillcam Colon2 has two-way communications to improve the capsule's motion and imaging. The number of images has been increased to 35 frames per second from four frames per second. Advanced optics provides a 172-degree field of view offering a near 360-degree view of the colon.
A comparative study of which PillCam Colon2 to colonoscopy at five hospitals in Israel showed a sensitivity of 89% and a specificity of 76% in detecting polyps six mm or larger, and a sensitivity of 88% and a specificity of 89% in detecting polyps ten mm or larger. The study included 98 patients who had risks or warning symptoms of colon disease.
Given Imaging president and CEO Homi Shamir said, "PillCam Colon2 incorporates the cumulative expertise gained from the first PillCam Colon as well as more than one million PillCam capsule ingestions worldwide. Despite the small size of this initial study and the relatively low prevalence of polyps, we are very encouraged by this data and look forward to working with leading gastroenterologists in Europe, the United States and other markets to initiate additional clinical trials."
Given Imaging also has Pillcams for the small bowel and esophagus.
Pradaxa vs Warfarin in VTE
Boehringer’s Pradaxa Matches Warfarin as Clot Therapy in Study
http://www.bloomberg.com/apps/news?pid=20601202&sid=aikUAPjkYf6A
By Naomi Kresge
Nov. 23 (Bloomberg) -- Boehringer Ingelheim GmbH’s blood- thinning pill Pradaxa was as effective and safe as the standard therapy for potentially deadly clots, according to the results of a head-to-head study.
Just 2.4 percent of patients given Pradaxa for six months after their initial treatment developed clots in the legs and lungs, similar to the 2.2 percent rate for those given the generic drug warfarin, according to an abstract of the so-called Recover study posted on the American Society of Hematology Web site last week. There was no increased risk of major bleeding, a complication of blood-thinning treatments.
Unlike newer medicines like Pradaxa and Bayer AG’s Xarelto, warfarin requires regular checks to ensure patients are getting the right dose. Doctors are divided over whether to keep using warfarin for longer than six to 12 months because of the monitoring required and because it can increase the risk of fatal bleeding. Some 1.6 percent of patients who took Pradaxa in the Recover study experienced major bleeding, compared with 1.9 percent of those on the older drug.
The pill “is as effective and safe as warfarin,” researchers led by Sam Schulman, a professor in the department of medicine at McMaster University in Hamilton, Ontario, wrote in the abstract.
Researchers will present full results of the trial in which none of the 2,539 patients or their doctors knew which medicine was being given on Dec. 6 at the American Society of Hematology medical conference in New Orleans.
The Boehringer drug and Bayer’s Xarelto, co-developed by Johnson & Johnson, are approved in some European countries.
About that option to buy Ception Therapeutics for its humanized IL-5 Mab - reslizumab:
Cephalon stock drops after mixed drug trial data
http://www.reuters.com/article/marketsNews/idCNN2320024420091123?rpc=44
* Cephalon delays decision on Ception acquisition
* Delay follows mixed results of esophagus drug
* Cephalon shares drop 8.3 pct in premarket trading
By Toni Clarke
BOSTON, Nov 23 (Reuters) - Shares of Cephalon Inc (CEPH.O: Quote, Profile, Research, Stock Buzz) fell more than 8 percent in premarket trading on Monday after a drug for a rare type of inflammation of the esophagus showed mixed results in a clinical trial.
The drug, Cinquil, was developed by privately held Ception Therapeutics Inc, to treat pediatric eosinophilic esophagitis, or EoE. Cephalon paid $100 million to Ception in January for an option to acquire the company and Cinquil, its lead product.
Cephalon had been waiting to see what the results of the mid-to-late stage trial of the drug in EoE showed before deciding whether to exercise its option to acquire all the outstanding stock of Ception for $250 million.
The companies have agreed to extend Cephalon's option exercise period until after results of a mid-stage trial of the drug, which is known generically as reslizumab, in a different condition -- eosinophilic asthma.
Cephalon's shares fell 8.3 percent to $54.66 in premarket trading from a close on Friday of $59.61.
The companies said the study for patients with EoE was designed to evaluate improvement in two co-primary endpoints. The first measured changes in the blood level of a type of white blood cell associated with the disease. The second measured changes in symptoms of the disease.
While there was a statistically significant reduction in white blood cells known as eosinophils in patients taking Cinquil compared to those taking a placebo, there was not a significant improvement in clinical symptoms.
Cephalon said the lack of statistical significance in clinical symptoms was due to the fact that there was also an strong improvement in symptoms in patients taking the placebo.
The study evaluated the drug in 226 children between the age of five and 18. About 80,000 children in the United States have EoE, according to the Journal of Clinical Investigation.
EoE decreases the ability of the esophagus to stretch, making it harder to swallow and absorb solid food.
Symptoms of the disease in children include abdominal pain, nausea, vomiting and a failure to thrive.
Glaxo temporarily withdraws Avodart cancer filing
http://www.reuters.com/article/governmentFilingsNews/idUSGEE5AM1SM20091123
* Says needs to update data, unrelated to safety or efficacy
* Glaxo had filed for prostate cancer risk reduction Oct. 1
LONDON, Nov 23 (Reuters) - GlaxoSmithKline (GSK.L: Quote, Profile, Research, Stock Buzz) temporarily withdrew its application to U.S. regulators for a new use of its Avodart drug in preventing prostate cancer because of a technical problem with the file, it said on Monday.
"We identified data that needed updating -- and it's not in relation to safety or efficacy -- so we have withdrawn the file and will change it and then resubmit it," a company spokesman said.
Glaxo expects to resubmit the file shortly. A review of the European filings will begin once the same update has been provided to EU regulatory agencies.
The Britain-based drugmaker filed its supplemental new drug application for Avodart with the U.S. Food and Administration on Oct. 1, following positive results from a clinical trial in cancer prevention. [ID:nLR589373]
Avodart, which had sales of 399 million pounds ($663 million) in 2008, is currently approved to treat benign prostate enlargement.
Preventing prostate cancer, the second leading cause of male cancer death, could open up a substantial new market for Avodart, as well as reinforcing its position in benign disease.
Weekend read, nothing new:
Refocusing on Therapeutic Protein Production in Plants
http://www.genengnews.com/specialreports/sritem.aspx?oid=68943994
Patricia F. Dimond, Ph.D. Nov 20 2009, 12:01 AM EST
In July FDA asked Shire and Protalix BioTherapeutics to submit treatment protocols for their Gaucher disease therapies in the wake of Genzyme’s Allston Landing plant closing. The company halted production after it detected a virus that impaired growth of producer cells in one of the site’s six bioreactors. Genzyme’s Gaucher drug, Cerezyme, was affected by the plant shutdown with third quarter sales dropping by 69.7% to $93.6 million.
The closing thus gave Shire and Protalix an opening to accelerate clinical testing and commercialization of their recombinant protein drug candidates, velaglucerase alfa and taliglucerase alfa (Uplyso), respectively. Both Shire and Protalix have reported positive results from Phase III trials in the last couple of months.
Protalix’ shares rose nearly 9% on the Phase III data news; the company said it expects to complete its NDA at the end of this year and could have the drug on the market by mid-2010. FDA has granted priority review to Shire’s drug, and the PDUFA date has been set as February 28, 2010.
Analysts expect serious competition for Genzyme, should both new drugs win marketing approval. “We see Shire and Protalix as real competitors in the space and remain skeptical that Genzyme will be able to win back all of its patients once its manufacturing issues are resolved,” notes JP Morgan analyst Geoffrey Meacham.
These recent events bring into focus the problems with systems used for recombinant therapeutic protein production. Perhaps as a result, there seems to be a renewed interest in plant-based methods.
More than 370 therapeutic proteins are currently in development, according to BIO. Current mammalian cell production capacity is thus experiencing serious stress.
Traditional cell culture methods require significant capital and labor investment; cell culture facilities cost about $250 million to $450 million to build, take from three to five years to build, and must be individually approved and certified by the FDA prior to full-scale operation. Additionally, animal cells generally require costly and complex media to sustain the cells and the addition of growth factors and animal-based products that may themselves introduce contaminants into culture systems.
Genzyme’s Cerezyme is produced by recombinant CHO cells, and Shire’s drug is produced in an undisclosed human cell line. Cerezyme requires postproduction chemical modification to humanize the glycosylation pattern. Shire's technology, on the other hand, activates expression of glucocerebrosidase in a cell line in which it is not normally expressed.
This produces a protein with the same human amino acid sequence as the native human enzyme and with the human glycosylation pattern, according to the company. Glycosylation patterns affect the biological properties of therapeutic proteins including their activity. They are thus closely monitored during therapeutic protein production, as a change in pattern may provide an early indication of a problem.
Plant-Based Production
Scientists have long noted the benefits of plant cell culture in achieving human-like protein production. Like bacteria, plant cells can be grown in relatively simple synthetic media. Additionally, since they are eukaryotes like mammalian cells, they can execute post-translational modifications that occur in human cells. They don’t harbor human pathogens, and they don’t produce endotoxins. The use of plant cells and plant tissue culture, however, has historically been held back by certain limitations, chief among them getting expression levels that make plant-production commercially viable.
Protalix claims that its plant cell-based manufacturing for therapeutic proteins produces potentially less expensive products that are therapeutically equivalent or superior to the existing mammalian cell-produced treatments. Instead of using stainless steel tanks, Protalix grows recombinant carrot cells expressing the human protein in disposable 800-L bags. This cuts down on cleaning costs as well as expensive plumbing.
In particular, the company notes that its proteins don’t require post-translational modification because plant cells produce glycosylation patterns more closely resembling human proteins. The plant cell-produced proteins do not, thus far, show increased immunogenicity. The company says that data from its clinical trials showed that the half-life of Uplyso is significantly longer than that of Cerezyme when measured and compared to publicly available data on Cerezyme.
Uplyso is Protalix’ lead product, and the plant-produced replacement enzyme was well tolerated, with 6% of patients in the trial developing antibodies to the protein during the study. The nine-month, double-blind, parallel-group study randomized patients to receive either 60 units/kg or 30 units/kg of Uplyso administered intravenously once every two weeks, with a total of 31 patients enrolling in the trial. The trial met its primary endpoint, a mean reduction in spleen volume among treated patients after nine months compared with baseline, at both doses.
Protalix has three other plant cell-produced enzymes in its preclinical pipeline: PRX-12, a galactosidase enzyme-replacement therapy for Fabry disease; pr-antiTNF, a biosimilar version of Enbrel; and acetylcholinesterase to treat nerve-gas and pesticide poisoning.
Restricted Competition Among Plant-Based Manufacturers
Biolex Therapeutics develops therapeutic proteins in its LEX system in Lemna, a small aquatic plant about 0.5 cm in diameter. Lemna is especially suited to recombinant protein expression because it is clonal, and the original transformant can be converted to a stable production line within six months, according to COO, David Spencer, Ph.D.
Tiny but powerful, Lemna doubles its biomass in 36 hours, allowing rapid scale-up to a multiton format. Grown in disposable plastic bags in medium consisting of water and inorganic salts, the plant does not require any animal-derived products to support growth.
Biolex’ lead product, Locteron, combines BLX-883, a recombinant interferon alpha produced in the LEX system, with controlled-release drug-delivery technology developed by OctoPlus. Lemna secretes BLX-883 into the plant-culture medium, greatly facilitating its purification.
Dr. Spencer says that unlike mammalian cell culture or with products produced in transgenic animals, “We don’t have to deal with pre- and postviral inactivation zones in our production facilities, nor do we require a viral inactivation process since the plants don’t contain animal viruses.”
Biolex completed enrollment for a Phase IIb study of Locteron in chronic hepatitis C patients in June and will meet with the FDA early in 2010. The company is also working on BLX-155, a full-length recombinant human plasmin being developed as a clotting agent, and BLX-301, a humanized anti-CD20 mAb in development. Both are produced on the LEX system.
While neither Protalix nor Biolex have much competition right now, Dr. Spencer says, “I think we need more entrants into the plant field.” Both Biolex’ and Protalix’ plant-cell culture technology circumvent the issue of foreign genes in food crops and the patent disputes around bacterial and mammalian protein-expression systems. At the moment, however, neither company has much competition in the plant-cell production business.
Protein-expression economics and investor enthusiasm, though, might change all that. Signs of this are already popping up with Biolex closing a $60 million Series D financing in October 2008. Additionally, Cannacord Adams reiterated its Buy rating on Protalix on November 10, saying “We think Uplyso data gives good proof of concept to Protalix’ plant-based protein-expression platform, which could be the basis of additional clinical programs and partnerships.”
Protalix located in Karmiel, Israel, has also garnered several pharma suitors like current partner Teva Pharmaceutical and Pfizer. Protalix CEO, David Aviezer, said that he has no plans to sell the company unless an exceptional offer is tendered.
Medco is running a comparative effectiveness study of Plavix vs Effient trial, in which patients in the Plavix arm are genotyped for their CYP2C19 status. (http://clinicaltrials.gov/ct2/show/NCT00995514). Medco is trying to prove non-inferiority of Plavix in normal CYP2C19 metabolizers. If it works out for Medco, by the time Plavix goes of patent, simple genotyping test can distinguish those who can take cheap generics from those who cannot. Now, can you see a link to Medco's Plavix/heartburn trial that made you suspicious?
The term "Complete Response Letter" sounds very final to my non-English-programed brain, when it actually means there's more to be done... And yes we definitely see more of them and I thought this is since CDER stopped using Approvable Letters and Not Approvable Letters in Aug. 2008, but we also see less approvals, so I suspect it has got to do with "safety first era" at the FDA.
AstraZeneca Files Brilinta New Drug Application With FDA:
http://online.wsj.com/article/BT-CO-20091119-701542.html
LONDON (Dow Jones)--AstraZeneca PLC, the International healthcare business, said Thursday it has submitted a new drug application, or NDA, to the U.S. Food and Drug Administration for ticagrelor, an investigational oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndrome.
MAIN FACTS:
-The proposed trade name for ticagrelor is Brilinta, pending approval from the FDA.
-Submission is based on the results of a comprehensive programme, including data from PLATO--a study of platelet inhibition and patient outcomes--, the Phase III head-to-head trial comparing ticagrelor plus aspirin with clopidogrel, or Plavix, plus aspirin.
If the date for that clinical trial slipped, Merck didn't update on that since its 2008 form 10-k, as filed with the SEC on February 27, 2009, where it states:
(“HPS2-THRIVE”) cardiovascular outcomes study, which is expected to be completed in January 2012. Merck anticipates filing an NDA with the FDA for MK-0524A in 2012.