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VVUS - on the IP issue: I have posted sometime ago at SI (perhaps Roy can find that exchange with Biotech Jim), that JNJ holds a method-of-use patent covering the use of topiramate (Topamax) in obesity and there are overlapping claims with Qnexa patent so I believe JNJ has a ground to sue.
Edit: I've tracked that post:
http://siliconinvestor.advfn.com/readmsg.aspx?msgid=25226111
VVUS - did they release anything about what happened to their subjects after discontinuation of the drug taking? I wonder if there are long-term effects.
I'm quite certain that in Qnexa, the topiramate dose is released in the evening in order to reduce discomfort of the parasthesias side effect (the phentermine is immediate-release).
VVUS - Safety certainly looks acceptable but why would docs use
onexa brand when they can use the two generic components? perhaps if onexa is priced low enough.
AGN/Botox for migraine
Patients enrolled in the two phase III studies were the worst cases (see inclusion criteria for the trials), and they got 150-200 units of Botox per patient. I don't know why he wrote 200 units or more. I think the drug is already being used off-label for migraine and since reimbursement is likely, use will probably grow.
Botox May Get $1 Billion Face Lift as Allergan Migraine Drug
http://www.bloomberg.com/apps/news?pid=20601202&sid=aKu3NR4er2ks#
By Elizabeth Lopatto
Sept. 9 (Bloomberg) -- Allergan Inc.’s Botox, sold as a wrinkle- smoothing beauty aid since 1991, may be rejuvenated as a drug that prevents migraine headaches and is worth a potential $1 billion in added sales yearly.
About $50 million of $1.3 billion in revenue generated last year by Botox came from its unapproved use as a migraine treatment, said Larry Biegelsen, an analyst at Wells Fargo Advisors LLC in New York. Study results being reported at a medical conference tomorrow will determine whether the drug is effective for that use, a finding that may boost sales by as much as 75 percent, said Peter Bye, a Jefferies & Co. analyst.
Allergan already has submitted the findings to a medical journal and expects to supply the data to U.S. regulators before Sept. 30, said Caroline Van Hove, a spokeswoman for the Irvine, California, company. The results may lead insurers to pay for the treatment even before its approved in the U.S., Bye said.
“Theoretically, it’s huge,” Bye said in a telephone interview from his New York office. “It could add as much as $1 billion or more a year, if the data’s good enough.”
Allergan rose 32 cents to $55.24 in New York Stock Exchange composite trading yesterday. The company has jumped 37 percent this year, in part on speculation by investors that the company may be acquired.
The drug, a purified form of the poison botulinum, is administered by doctors as an injection. It helps to smooth wrinkles in facial skin by paralyzing the muscles underneath. Scientists don’t know how Botox helps to prevent migraines.
Pain Messages
At first, doctors thought muscle spasms were being quelled by Botox, making the headaches less painful, said Alexander Mauskop, a neurologist at the New York Headache Center in Manhattan. Now, researchers say the drug may stop pain messages from reaching the brain, preventing a cycle of escalating communication that culminates in a migraine, according to Mauskop, who participated in the trials and said he has received speaker’s fees from Allergan.
The drugmaker began researching Botox for migraines after doctors such as Richard Glogau, a dermatologist at the University of California San Francisco, linked the drug to migraine relief in case studies. Glogau in November 2000 reported at the American Society of Dermatologic Surgery meeting that patients given Botox to remove frown lines also reported having fewer migraines.
Current treatments for migraines include painkillers and the generic drug ergotamine, which lessens the severity of headaches already under way. The best-selling treatment, with $1.3 billion in 2008 sales, is Imitrex, made by London-based GlaxoSmithKline Plc. That drug, available as a generic since last year, is used to prevent an attack when patients feel it is imminent.
No Approved Drugs
No drugs have been approved for so-called chronic migraine, when patients have headaches on 15 or more days a month. Unapproved generic drugs used for this purpose include beta blockers and Topamax, made by New Brunswick, New Jersey-based Johnson & Johnson. Not all patients respond to them, Bye, the Jeffries analyst, said.
The Allergan studies test Botox in patients with chronic migraines, said Morris Levin, the director of the Dartmouth Headache Center in Lebanon, New Hampshire. To prevent headaches, Botox is injected into areas where migraine sufferers feel the most pain every three months, he said.
If the findings to be presented this weekend at the International Headache Congress in Philadelphia are positive, the FDA may move quickly to approval since the drug would answer an unmet need, Biegelsen of Wells Fargo said.
Immediate Revenue
Bye said Allergan may also see added revenue immediately. Migraines can entail “hidden” costs to insurers such as visits to the emergency room and lost work days, increasing the pressure to cover any drug that may be helpful, he said. A positive finding would be if the drug can cut the days patients have migraines by three or more, Bye said.
Allergan’s Van Hove declined to comment on potential sales of Botox as a headache treatment, since it hasn’t yet been approved for that use by the U.S. Food and Drug Administration. While companies must limit marketing to uses allowed by the agency, doctors in the U.S. may prescribe any FDA-approved treatments as they see fit.
The two Botox trials are both 56 weeks long, Van Hove said. One enrolled 679 chronic-migraine patients and the other had 705.
Extreme Headaches
Migraines are extreme headaches that can cause nausea, vomiting and sensitivity to light. They can be triggered by anxiety, stress, exposure to light, caffeine, alcohol, hunger, or sleeplessness, according to the American Medical Association’s Web site. Scientists aren’t sure what causes them
About 1 in 4 women will experience a migraine during her life, and 2 in 25 men will have a migraine at least once, the Chicago-based AMA says.
Preliminary data from the studies were released on Sept. 11, 2008. In one trial, Botox injections were better than placebo shots at decreasing the number of days patients had headaches, though the frequency of headaches was similar. In the second, Botox led to more reduction in the number of headache episodes and the number of headache days.
Allergan changed its measure of what constitutes success in the second study, said Corey Davis, an analyst for Jefferies & Co. in New York, in a telephone interview.
“It’s taken Allergan over a year to put together the data to file the drug application, which strikes me as immediately suspicious,” Davis said.
Crystal Muilenburg, an Allergan spokeswoman, said it “takes time” to properly review and interpret results.
25 Percent Difference
To matter to patients, the fuller data will have to show Botox outperforming the placebo by at least 25 percent, Davis said. Most pain treatments have placebo effects, which is why it’s important that Botox outperform a dummy treatment.
Allergan stands to boost sales from the added use, partly because the doses used for treating migraines are much higher than for cosmetic use, Davis said. Smoothing a brow takes about 25 units of the drug; migraines require 200 or more. A vial of 100 units costs $609.98 on drugstore.com.
The American Academy of Neurology said in guidelines released in May 2008, before the preliminary results, that Botox shouldn’t be prescribed for headaches because research didn’t yet support its use.
David Simpson, the director of the clinical neurophysiology labs at Mount Sinai Medical Center in New York and the guidelines author, said if new data supporting Botox’s use are published in a peer-reviewed journal, “we can definitely amend the guidelines.”
15 Years of Use
Mauskop, at the New York Headache Center, said he started using Botox for migraines about 15 years ago.
“We find it to be very effective after other treatments fail, and it’s extremely safe,” he said by telephone.
“I use it in my practice and I’ve had mixed results,” Dartmouth’s Levin said in a telephone interview. The headache treatment lasts about three months, according to Levin, who said he participated in the Allergan trials. The injection then needs to be repeated, he said.
“I have lots of patients who see me every three months for their Botox treatments,” Levin said. “I ask them how they’re doing and they say, ‘I was good until last week.’”
Allergan is also exploring Botox for use in strokes. In May, the FDA declined to approve the drug for patients who have suffered a stroke until Allergan develops a safety plan.
In April, U.S. regulators said that Botox must carry the strictest U.S. warning about the risks of botulinum, which is potentially deadly. The warning applies to all botulinum toxins used to smooth forehead lines or treat neurological disorders. Botox is sometimes used by doctors to treat arm and leg spasms, uses not approved by the FDA.
After that kick in the butt, Procognia is pursuing an old direction - cancer related glycodiagnostics field:
http://www.procognia-il.com/,news,24
Shire has accelerated its manufacturing timeline by almost 18 months in order to provide velaglucerase. Shire estimates this could translate into a range of 300 to 600 patients for uninterrupted treatment starting in September 2009.
http://www.earthtimes.org/articles/show/update-on-velaglucerase-alfa,950337.shtml
UK body (NICE) backs limited use of Lilly anti-clot drug (Effient)
http://www.reuters.com/article/rbssHealthcareNews/idUSL434811820090904
I didn't see the full data but the TASE statement says that the 2mg dose group, which had the best efficacy, was better than the placebo, but with p=0.03.
Can-Fite psoriasis treatment succeeds in Phase II trial
http://www.globes.co.il/serveen/globes/docview.asp?did=1000496028&fid=942
Adi Ben-Israel7 Sep 09 12:03
Drug development company Can-Fite BioPharma Ltd. (TASE:CFBI) today announced success in a large [75 patients is large?]Phase II clinical trial of its drug, CF101, to treat patients with moderate to severe Psoriasis.
Psoriasis is a skin condition that affects 2-3% of the general population. The market for psoriasis drugs is estimated at $3.5 billion annually. General anti-inflammatory agents are only partially effective and are limited by safety problems. New biologics targeting the underlying immune pathogenesis of the disease have been introduced, which while effective, are expensive and cause side effects characteristic of these types of medications.
CF101 has already been tested on more than 650 patients in past studies, and shown to be both safe and effective.
The Phase II trial included 75 patients, who were randomly assigned either various dosages of CF101 or a placebo. The drug was administered as a stand-alone treatment over 12 weeks. It was conducted under US Food and Drug Administration (FDA) guidelines at medical centers in Israel and Europe. The trial results were statistically significant, and progressive over time, suggesting that longer treatment will result in further improvement, particularly for patients who received 2 mg dosages.
Can-Fite believes that the fact that the 2 mg dosage of CF101 was shown to be the most effective dose has far-reaching consequences for further development of the drug, and could shorten the development timetable.
The company says that it has several alternatives for further development of the drug, including a Phase IIb or a Phase III clinical trial. It will review the results of the present trial, and after studying them and consulting with the FDA, it will decide on the nature of the next trial and drug development stages.
Can-Fite has already reported successful trial results for CF101 as a stand-alone treatment for dry-eye disease, which is also an inflammatory disease. Successes in trials for both diseases suggest that CF101 has general applications for inflammatory diseases, and that the drug's potential markets could be worth billions of dollars altogether.
The trial's principal investigator, Dr. Michael David, Head of the Department of Dermatology at the Rabin Medical Center, said, “The study data is impressive and promising. CF101 is a unique small molecule orally bio-available drug with an impressive safety profile based on accumulated experience in more than 700 patients. There is a market need in psoriasis for small molecule drugs and I am confident that Can-Fite should progress with the clinical development of CF101 based on the study data."
Can-Fite CEO Pnina Fishman added, "We're very pleased by the trial results, which further confirms the effectiveness of CF101 for treating inflammatory diseases. The success of this trial, as well as the success in the previous trial, gives solid grounds for hoping that the drug will be a commercial success, as well as validating the technology platform that underpins Can-Fite's development. We hope that we can bring relief of sufferers of psoriasis, who currently have no similar treatment that is both effective and without side effects."
OT: Re: Nebido "18-gauge needle. Big ouch!"
That could be a benefit in some patients, the wannabe body builders with their phony prescriptions.
"Man that shit hurts, must be REAL good"
Scientific Meeting Calendar
NOTE: ANYONE MAY UPDATE THIS FILE
Edits: Added ACR; delete obsolete entries.
SEPTEMBER 2009
Interscience Conference on Antimicrobial Agents and Chemotherapy - ICAAC
September 12-15, 2009
San Francisco
http://www.icaac.org/
OCTOBER 2009
International Congress on Coronary Artery Disease - ICCAD
October 11 to 14, 2009
Prague, Czech Republic
http://www2.kenes.com/cad/pages/home.aspx
American College of Rheumatology - ACR
October 17-21, 2009
Philadelphia, USA
http://www.rheumatology.org/annual/index.asp
Society for Neuroscience - SFN
October 17-21, 2009
Chicago, USA
http://www.sfn.org/am2009/
World Diabetes Congress - IDF
October 18-22, 2009
Montreal, Canada
http://www.worlddiabetescongress.org/
American Society of Human Genetics - ASHG,
October 20-24, 2009
Honolulu, Hawaii
http://www.ashg.org/2009meeting/
Renal Week 2009
October 27 November 1, 2009
San Diego, CA
http://asn-online.org/education%5Fand%5Fmeetings/renal%5Fweek/
American Association for the Study of Liver Diseases (AASLD)
Oct 31-Nov3, 2009
Boston
http://www.aasld.org/thelivermeeting/Pages/default.aspx
American College of Chest Physicians - CHEST
October 31 - November 5, 2009
San Diego, California
http://www.chestnet.org/CHEST/program/about09.php
NOVEMBER 2009
American College of Allergy, Asthma & Immunology - ACAAI
November 5-11, 2009
Miami Beach, FL
http://www.acaai.org/Member/Annual_Meeting/Annual+Meeting.htm
American Heart Association - AHA
November 14-18, 2009
Orlando, Fl
http://scientificsessions.americanheart.org/portal/scientificsessions/ss/seeyounextyear2009
DECEMBER 2009
American Epilepsy Society - AES
December 4-8, 2009
Boston, MA
www.aesnet.org
American Society of Hematology - ASH
December 5-8, 2009
New Orleans, LA
http://www.hematology.org/meetings/2009/index.cfm
International Respiratory Congresses - AARC Convention
Dec. 5–8, 2009
San Antonio, Texas
http://www.aarc.org/education/meetings/#future_congress
American College of Neuropsychopharmacology - ACNP
Dec 6-10, 2009
Hollywood, Florida
www.acnp.org
--
Procedure for Updating Calendar
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Correct, Testim and Androgel are short-acting, daily topical gels, and the preferred testosterone replacement treatment by far. There's also a 3-month testosterone pellet implant - Testabel. Nebido is a 10-12 week depot testosterone injection. Its advantages over topical gels should to be steady testosterone levels and no transference risk.
Nebido is injected IM using an 18-gauge needle. Big ouch!
this acquisition gives ABT something to compete with Alcon’s Restor® product line
Reminds me of the story of Cre-Lox technology which was patented and did not become easily available even to the scientific community for a very long time. It drove scientists crazy and a black market of tools and reagents was developed. However, the company (DuPont) closely followed the literature and anyone publishing using Cre-Lox without licensing were sued. That led to the development of alternative technologies that became freely available to the scientific community (e.g., the TET systems) although they were also patented.
Thanks, the IP issue explains it.
Bayer/Algeta $800M licensing deal for a late stage cancer drug:
http://www.reuters.com/article/rbssHealthcareNews/idUSL358283220090903
There are various ways to target specific regions of the genome. The most exciting right now are the zinc finger nucleases that allow very efficient gene targeting in embryonic as well as somatic cells in mammals and non mammals. The French comp try to be original and work on a different kind of nucleases that can be manipulated to provide gene targeting. I have no idea why Monsanto decided to license this technology rather than the zinc finger nucleases. Maybe they are trying both to be on the safe side. Or perhaps there are no publications regarding zinc finger targeting in plants.
Roche is paying PTC Therapeutics $12M upfront, and potentially up to $239M in milestone payments, and double digit royalties, as part of an agreement to develop small molecule CNS disease drugs.
http://ptct.client.shareholder.com/releasedetail.cfm?ReleaseID=406547
Shire is ahead of PLX with its NDA but yet it was PLX that closed almost 6% up on a down day. Could be the troubles GENZ is having with EMEA inspectors:
http://www.boston.com/business/healthcare/articles/2009/09/01/inspectors_find_major_flaw_at_genzyme_plant/
Or gossip regarding the quality of Shire's data. Shire announced that Velaglucerase hit all primary and secondary endpoints in both studies (head to head with Cerezyme, and switch-over from Cerezyme), but did not disclose full data.
The accompanying editorial by Dr Mariell Jessup
http://content.nejm.org/cgi/content/full/NEJMe0907335?resourcetype=HWCIT
MADIT-CRT — Breathtaking or Time to Catch Our Breath?
Cardiac-resynchronization therapy (CRT) received Food and Drug Administration approval for use in selected patients with left ventricular systolic dysfunction in 2001. Since that time, CRT has been embraced as a recommended approach to achieve meaningful clinical improvement in patients who have heart failure with a reduced left ventricular ejection fraction (LVEF) and who continue to have symptoms despite optimal medical therapy.1 A number of pivotal randomized trials and scores of additional safety and effectiveness trials have consistently shown that CRT improves the LVEF, quality of life, and functional status in symptomatic patients with an LVEF of less than 35% and a prolonged QRS duration (mean range, 155 to 209 msec).2 In addition, a systematic 2007 review calculated that CRT decreased the rate of hospitalization by 37% and lowered the rate of death from any cause by 22% in such patients.3
Despite the consistent and salutary benefits of CRT, at least 30% of patients who were selected for therapy according to the aforementioned criteria did not benefit from CRT.4 Moreover, many patients had a clinical response (e.g., an increase in exercise capacity or in quality-of-life measures) in the absence of improved left ventricular systolic function. Likewise, some patients had major evidence of reverse ventricular remodeling on echocardiography but had no enhanced functional tolerance.
These observations have led to two related areas of investigation: alternative measures to detect mechanical dyssynchrony (disparity in the timing of regional ventricular contraction) apart from the electrical delay that is manifested by a wide QRS duration and the selection of patients who are likely to have more consistent benefit from CRT. Evidence of mechanical dyssynchrony has been shown to be an independent predictor of clinical events and worsened survival in patients with heart failure and has correlated better than the QRS duration with the long-term benefit of CRT.4 Accordingly, multiple noninvasive techniques have been used to identify mechanical dyssynchrony in patients with heart failure, and the results seem to suggest that dyssynchrony is extraordinarily common in all forms of heart failure.5 However, attempts to translate these observations into an expanded indication for CRT or a greater response rate after device implantation have not been forthcoming.
For example, the randomized, controlled Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS (RethinQ) trial (ClinicalTrials.gov number, NCT00132977 [ClinicalTrials.gov] ) investigated the role of CRT in patients with heart failure who had mechanical dyssynchrony but a narrow QRS duration.6 At 6 months, there was no benefit from CRT on the primary end point of peak oxygen capacity or on heart-failure events. Similarly, the observational Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) trial (NCT00253357 [ClinicalTrials.gov] ), which was designed to identify echocardiographic predictors of response to CRT, revealed a low predictive accuracy for various measures of mechanical dyssynchrony.7
An argument that CRT might delay disease progression in patients with less severe symptoms through left ventricular reverse remodeling has led to a number of trials enrolling patients with New York Heart Association (NYHA) functional class I or II heart failure, including the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial (NCT00271154 [ClinicalTrials.gov] )8 and the Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) (NCT00251251 [ClinicalTrials.gov] ).9 The results of the REVERSE trial and other smaller CRT trials involving patients with mild-to-moderate heart failure are strikingly consistent, although all the studies had a relatively short follow-up period (6 to 12 months). The trials did not show any significant improvement in functional capacity, as assessed by the 6-minute walk test or NYHA classification, and there was no improvement in quality of life.9 However, there was a concordant and significant reduction in the left ventricular volume and an increase in the LVEF across the trials. In addition, the REVERSE trial showed a significant reduction (53%) in the relative risk of first hospitalization for heart failure in patients receiving CRT, although there was no difference in mortality between patients who received CRT and those who received optimal medical therapy.8
In this issue of the Journal, the results of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) (NCT00180271 [ClinicalTrials.gov] )10 confirm the earlier findings. The investigators followed 1820 patients with NYHA class I or II heart failure for an average of 2.4 years. The primary end point, a composite of death from any cause or nonfatal heart failure (which was defined as the need for intravenous decongestant therapy in an outpatient regimen or an augmented heart-failure regimen during hospitalization), was significantly reduced when CRT was added to an implantable cardioverter–defibrillator (ICD), as compared with an ICD alone. Patients in the CRT-ICD group also had significant improvement in cardiac function at 1 year. The superiority of CRT was driven solely by a 41% reduction in the risk of a first heart-failure event, since mortality was not influenced by the choice of device, even with an increased trial duration. In CRT trials enrolling symptomatic patients, the reduction in mortality among those receiving CRT has been evident by 6 months but has been larger in trials with the longest follow-up. In their meta-analysis of CRT trials, McAlister et al.3 calculated that 29 patients would need to be treated for 6 months to prevent one death. In the longer follow-up in the Cardiac Resynchronization in Heart Failure (CARE-HF) trial (NCT00318357 [ClinicalTrials.gov] ), another CRT trial enrolling symptomatic patients with NYHA class III or IV heart failure, in order to prevent one death, 13 patients would need to be treated for 2 years and 9 patients for 3 years.11 It is unlikely that less symptomatic patients receiving CRT would have a significant reduction in mortality unless a large number of patients underwent prolonged follow-up.
Should the guideline indications for CRT change as a result of MADIT-CRT? It is not completely clear how the enrolled patients differ from those in earlier CRT trials, since no objective criteria were used to classify functional status at baseline and the treatment of patients and their subsequent functional status were determined by clinicians who were aware of study-group assignments. Moreover, at least 10% of patients had NYHA class IV symptoms at least 3 months before randomization. We know from several cohort studies that the transition from stage B heart failure (i.e., patients with substantial ventricular structural abnormalities in the absence of symptoms) to symptomatic stage C is associated with an increase in the risk of death by a factor of five.12,13 It appears that MADIT-CRT enrolled patients with stage C heart failure and not patients who had always been asymptomatic (e.g., stage B). This is a critical point and would argue against the use of CRT in patients solely on the basis of a wide QRS duration. In addition, both the REVERSE trial and MADIT-CRT showed that the observed clinical benefit with respect to nonfatal heart failure occurred primarily in the prespecified subgroup of patients with a QRS duration of 150 msec or more.8,10
In 2007, it was estimated that 1 to 3% of all patients who were discharged after the index hospitalization for heart failure and 15 to 20% of patients who were observed in specialized heart-failure clinics met current CRT eligibility criteria: an LVEF of less than 35%, a QRS duration of more than 120 msec, sinus rhythm, and NYHA class III or IV heart failure despite optimal medical management.3 An analysis that was based on data from the five longest CRT randomized trials revealed that the incremental cost per quality-adjusted life-year gained was $32,822. The incremental cost-effectiveness of combined CRT with ICD devices, as compared with CRT devices alone, has been markedly higher in most analyses.3
In MADIT-CRT, 12 patients would need to be treated to prevent a single heart-failure event, whereas in the REVERSE trial, 20 patients would need to be treated to delay a heart-failure hospitalization. Is this money that could be spent more wisely? If the indication for CRT is expanded to all stage C patients with a low LVEF and a QRS duration of more than 120 msec, regardless of current symptoms or the duration of medical therapy, the potential "indication creep" in patients who are unlikely to derive a mortality benefit will alter the benefit-to-safety ratio and tip the score on cost-effectiveness even further in the wrong direction. Given the sobering facts about the costs of health care confronting us now and in the future, it appears prudent that any expanded indication for CRT in less symptomatic patients should be confined to patients with a QRS duration of more than 150 msec and in whom previous marked symptoms have been controlled with optimal medical therapy.
Shire has completed the NDA filing for velaglucerase.
http://www.reuters.com/article/rbssHealthcareNews/idUSL154008620090901
Matthew Herper on the issue
New Drugs Surprise In Barcelona
http://www.forbes.com/2009/08/29/brilinta-dabigatran-cardiology-business-pharmaceuticals-blood-thinners.html
Two experimental pills that weren't on anybody's radar screen six months ago delivered impressive clinical trial results at the annual meeting of the European Society for Cardiology in Barcelona.
These medicines are blood thinners, drugs that prevent the clots that cause heart attacks and strokes and one of the few big cardiology markets left. Brilinta, from London-based drug giant AstraZeneca, was shown in the study to prevent heart attacks and deaths better than Plavix, the second-best-selling drug in the world. Dabigatran, manufactured by privately held German company Boehringer Ingelheim, outperformed warfarin, a 60-year-old drug used to prevent strokes.
"Both these agents appear to be significant advances," says Deepak Bhatt, chief of cardiology at the Boston VA Healthcare System, who was not associated with either study. "The major challenge now will be picking the ideal agent for individual patients."
And both medicines, despite some real drawbacks, represent sneak attacks on more hyped drugs on which companies including Eli Lilly, Bayer and Johnson & Johnson are pinning high hopes. The New England Journal of Medicine is publishing articles on both agents, along with favorable editorials.
Brilinta is similar to Plavix, the $8.6 billion-per-year drug from Bristol-Myers Squibb and Sanofi-Aventis, in that it prevents blood cells called platelets from clumping together to form clots. But in a study of 18,600 patients who presented to the hospital with chest pain, 10% of those who got Brilinta had heart attacks, strokes, or died compared with 12% who received Plavix, a statistically significant 16% decrease.
"The efficacy is superb," says Steven Nissen, head of cardiology at the Cleveland Clinic, "and the bleeding [risk] seems pretty reasonable."
Plavix keeps working even after the drug is stopped. Brilinta stops working fairly quickly, potentially making it an appealing option in patients who show up in emergency rooms, in those at risk for bleeding, and in those who might need surgery.
Brilinta has a few marks against it. One problem with drugs in this class is that patients often stop taking them. Particularly for patients whose arteries are propped open with metal mesh stents, this can be dangerous, increasing the risk of heart attack. Brilinta must be taken twice a day; Plavix has once-daily dosing. About one-sixth of the patients in the study experienced shortness of breath, 50% more than on Plavix. That's a side effect that could make patients stop taking their drug.
Then there's the matter of price: Plavix is going to get very cheap when its patent expires in 2012, so health insurers will push its use.
Still, Brilinta could put a crimp on the prospects of another Plavix replacement, the recently launched Effient from Eli Lilly. Kirk Garratt, clinical director of interventional cardiovascular research at Lenox Hill Hospital in New York, notes that Brilinta significantly decreased the risk of death compared with Plavix, and that bleeding appears to have been less of a problem than with Effient. He expects both Brilinta and Effient will be prescribed often by doctors.
An even bigger surprise comes from Boehringer Ingelheim, off the map for most U.S. investors because it is based in Germany and is privately held--a new blood thinner for atrial fibrillation.
So-called a-fib is a troublesome heart rhythm afflicting 2.4 million Americans in which the top chambers of the heart, responsible for bringing blood back from the rest of the body, start to flutter. This produces blood clots that can lodge in an artery and cause a stroke.
The main treatment now is warfarin, a blood thinner derived more than a half-century ago from rat poison. It's annoying to use; doctors and patients must work to get blood levels exactly right to prevent clots without causing dangerous bleeding. Then they have to watch out for drugs and foods that interact with it, including broccoli and spinach.
Efforts to find a replacement for warfarin have ended up on the shoals. The last one was Exanta, an AstraZeneca drug that was nixed because it caused liver problems.
Along comes Boehringer's dabigatran, which works similarly to Exanta but doesn't cause liver problems. The top dose did a better job preventing strokes than warfarin, cutting the risk of strokes by one-third to 1.1% per year, without increasing bleeding. A lower dose caused less bleeding than warfarin and was equally effective. The study included 18,000 patients.
"It looks like we finally may have a safe, effective alternative for warfarin," says Robert Harrington, a professor of medicine at Duke. Adds Bhatt: "Doctors and patients want an alternative to warfarin, and I think dabigatran delivers."
Here, too, there are drawbacks. The rate of heart attacks was higher with dabigatran. That "will need further study," Harrington says. Doctors and patients knew who was getting which drug, which could raise questions with U.S. regulators. The study enrolled lots of patients who hadn't gotten warfarin before, which could make the warfarin group look comparatively worse. Study investigator Michael Ezkowitz of the Lankenau Institute for Medical Research in Wynwood, Pa., will present an analysis Wednesday that will try to get to the bottom of that issue.
The dabigatran results complicate things for two other would-be warfarin replacements that work by blocking an enzyme called Factor 10. One is being tested by Bayer and Johnson & Johnson, the other by Pfizer and AstraZeneca. On one hand, the dabigatran results increase the chance that these drugs will prove efficacious--on the other, a new competitor has been added to the mix
AZN’s Brilinta
One note regarding the PLATO study: in the U.S patients subgroup, which was only about 10% of patients in the study, there was a 25% higher chance for CV event for those on Brilinta than for those on Plavix.
In subsequent studies (Cunningham et al., Robert et al., Vincenzi et al., Thienelt et al., Bonner et al.), it has been shown that EGFR overexpression, as evaluated with IHC, has little or no correlation with the response to cetuximab. However, there's one work I'm aware of (Morono et al.) that showed, using FISH EGFR/CEN17 diagnostic test (by Dako), that EGFR gene amplification (copy number), correlates with clinical response to cetuximab.
I see. So, let me know when it's salable again.
Babylon says unsalable or nonsalable, but better ask our cheif editor - Roy.
2C19 screening is available since 2005 and works like this one will help bring it to docs' attention.
University of Maryland researchers identify gene variant linked to effectiveness of plavix
http://www.umm.edu/news/releases/cyp2c19_gene.htm
First study to use genome-wide scanning approach to locate gene that affects response to popular anti-clotting medication
Researchers at the University of Maryland School of Medicine have identified a common gene variant carried by as many as a third of the general population that is believed to play a major role in determining why people do not respond to a popular anti-clotting medication, Plavix. If the medication doesn't work, patients are at increased risk for subsequent heart attacks, strokes and other serious cardiovascular problems.
The results of the study, published in the Aug. 26, 2009, issue of the Journal of the American Medical Association (JAMA),
[http://jama.ama-assn.org/cgi/content/full/302/8/849?home]
confirm a previously reported link between people's decreased response to Plavix, also known as clopidogrel, and common variations of the CYP2C19 gene. The study is the first to identify a common variant of this gene by using a sophisticated technique called a genome-wide association study to rapidly scan hundreds of thousands of genetic markers in the DNA of participants. More than 400 members of the Old Order Amish community in Pennsylvania took part in the study.
"By scanning the entire genome, we found compelling evidence that the CYP2C19 gene is a key determinant of how people respond to this medication," says the lead author, Alan R. Shuldiner, M.D., professor of medicine and director of the Program in Genetics and Genomic Medicine at the University of Maryland School of Medicine in Baltimore. "We didn't detect any other common gene variants that appear to be as significant as CYP2C19, but our research suggests that people's response to clopidogrel is largely inherited and additional common and rare gene variants most likely are involved."
Dr. Shuldiner says he will continue his research to search for these gene variants. "The more we know about how genes affect people's response to medicines, the better able we are to develop effective new therapies and tailor treatment to an individual patient's genetic make-up," he says.
About 30 percent of the general population in the United States has the CYP2C19 variant identified in the study. Dr. Shuldiner says that it can be detected by a simple genetic test using DNA from blood or saliva. "If people have the gene variant, they might need to take a higher dose of clopidogrel or a different medication altogether," he says, adding that more research is needed before such testing becomes routine.
Plavix is one of the world's best-selling medications. It is used to prevent platelets from sticking together and causing blood clots in patients with cardiovascular disease who are at risk of having future heart attacks and strokes. (Platelets are fragments of bone marrow cells that help the blood to clot.) Despite its widespread use, up to 32 percent of people don't respond to the therapy and as a result, experience serious cardiovascular events. Researchers don't know the exact reason, but they believe that one important factor is the difference among individuals in their ability to metabolize the drug due to variation in the CYP2C19 gene.
"People who have this gene variant are less able to convert clopidogrel into its active form. They also have poorer platelet response to the medication and are at a 2.4-fold-higher risk of dying or having a serious cardiac event resulting from a blocked artery than those who don't have the variant," Dr. Shuldiner says.
E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine, says, "Dr. Shuldiner is a nationally recognized leader in pharmacogenetics research, and the results of this study are very impressive and important, given the huge number of people with cardiovascular disease who depend on Plavix to prevent future heart attacks and strokes. This research significantly advances the science in this area and moves us forward in our quest to offer individualized treatments to our patients."
Dr. Shuldiner and his colleagues analyzed the DNA of 429 healthy members of the Amish community in Lancaster County, Pa. They gave the study participants Plavix for seven days and then looked at how their blood platelets responded. They also studied the participants' DNA, searching for common gene variations. The researchers collaborated with investigators at the Sinai Center for Thrombosis Research in Baltimore, confirming their findings by studying a group of 227 people who received Plavix after having stents implanted to open blocked coronary arteries at Sinai Hospital.
Paul A. Gurbel, M.D., senior author of the study and director of the Sinai Center for Thrombosis Research, says that "patients with the CYP2C19 variant had a diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes." Patients with the gene variant were more likely (20.9 percent vs. 10 percent) to have a heart attack or other serious cardiovascular event in the year following initiation of treatment.
In 2003, Dr. Gurbel and his colleagues at Sinai were the first to report that some people don't respond to clopidogrel therapy. Two years later, they went on to demonstrate the important connection between this non-responsiveness and patients having adverse cardiovascular events.
"When we initially reported non-responsiveness to clopidogrel, the cause was unclear," adds Dr. Gurbel. "Since then, this field has rapidly evolved as demonstrated in this important study. The results of the study lend support to genotyping and platelet function testing as potential future strategies for optimal antiplatelet drug selection in treating patients with cardiovascular disease." This study is among the first to demonstrate in a single group of patients a link between a gene variant and responsiveness to clopidogrel that in turn is associated with outcomes after coronary stenting, he says.
Dr. Shuldiner says that about 30 percent of the Amish population has the CYP2C19 variant, which is similar to the general population. He notes that by studying the Amish – a genetically homogenous people, most of whom are related – researchers were able to estimate that 70 percent of the variation in clopidogrel response is due to genes and other shared factors among family members, such as their environment. In genetic research, 70 percent is considered extremely high "heritability," he says.
The researchers estimate that the CYP2C19 variant accounts for 12 percent of the platelet response to the drug, and other factors, such as age, body mass index and cholesterol levels in the blood, account for another 10 percent. But, Dr. Shuldiner says most of the difference in response to the medicine remains unexplained. "Additional studies in larger populations will be necessary to find additional genes that influence response to clopidogrel," Dr. Shuldiner says.
The research was funded in part by the National Institute of General Medical Sciences, which is part of the National Institutes of Health (NIH), and Sinai Hospital of Baltimore.
"This work was performed in a population that is superb for studying genetics, and the results were replicated in an unrelated and very different group in Baltimore," says Rochelle M. Long, Ph.D., of the National Institute of General Medical Sciences and director of the National Institutes of Health Pharmacogenetics Research Network. "The results will be very useful in the future to help predict which drugs to use in which patients, for optimal effect and prevention of cardiovascular disease."
Nycomed, Forest lung drug shows add-on potential
http://www.reuters.com/article/rbssHealthcareNews/idUSLR69456120090827
* 17 pct reduction in exacerbations with Daxas monotherapy
* Further lung function improvement if added to other drugs
* Oral drug seen used alongside existing bronchodilators
* Daxas may reach market in 2010, if approved by regulators
By Ben Hirschler
LONDON, Aug 28 (Reuters) - An experimental once-daily tablet from Nycomed [NYCMD.UL] and Forest Laboratories (FRX.N: Quote, Profile, Research, Stock Buzz) improves lung function in people with "smoker's lung" and may be a useful add-on to conventional inhaled drugs, experts said on Friday.
Privately owned Swiss drugmaker Nycomed, which is working towards a multibillion-dollar flotation, hopes Daxas will reach the market in 2010 and believes it has blockbuster potential.
It signed a deal earlier this month with Forest, giving the U.S. group rights to sell the drug in the United States as a treatment for chronic obstructive pulmonary disease (COPD).
Some analysts, however, have been wary of prospects for Daxas, given its troubled history and the failure of other drugs that work in a similar way, by inhibiting a enzyme called PDE4 linked to inflammation.
When used on its own, Daxas reduced exacerbations, or COPD attacks, that required medical intervention by 17 percent per patient per year compared with a placebo, according to results of two Phase III trial reported in the Lancet medical journal.
The drug, known generically as roflumilast, also increased by 48 millilitres the volume of air that patients would breath out in one second, a measure known as FEV1.
"It met our expectations and compares very favourably with other drug trials," researcher Klaus Rabe of the Leiden University Medical Centre in the Netherlands told reporters.
Still, the reduction in exacerbations came in at the lower end of what had been expected by analysts at Cowen, who had been looking for an 18 to 25 percent improvement.
The effect will inevitably be compared with other COPD medicines, notably Boehringer Ingelheim and Pfizer's (PFE.N: Quote, Profile, Research, Stock Buzz) Spiriva, which showed a 21 percent reduction in exacerbation risk in clinical tests, according to a Boehringer spokeswoman.
SIDE EFFECTS
In practice, Daxas is likely to be used alongside existing inhaled treatments, since two other trials published in the Lancet found it had a clear additional benefits when given with Spiriva and GlaxoSmithKline's (GSK.L: Quote, Profile, Research, Stock Buzz) salmeterol.
"It will definitely be used on top of existing medication because the unmet need is not to replace existing medication but to provide additional benefit," said Leonardo Fabbri of Italy's University of Modena and Reggio Emilia.
Nycomed had said in October Daxas was effective in the four Phase III trials but gave no details at the time.
PDE4 inhibitors are known to be associated with side effects -- notably diarrhoea, nausea, weight loss and headaches -- and the latest Daxas trials recorded adverse events in 67 percent of patients on the drug versus 62 percent for the placebo group.
"There is a proportion of 10 to 15 percent of patients who may not tolerate this drug," said Fabbri.
Nycomed has already submitted Daxas to European and U.S. regulators for approval and it hopes for registration in both jurisdictions next year.
Industry analysts believe an approval is by no means assured, given the history of the medicine. Daxas failed to show adequate benefit in an earlier clinical trial, prompting Pfizer to hand back rights to the product in 2005 to Altana (ALTG.DE: Quote, Profile, Research, Stock Buzz), which then owned it.
In addition, the record of other PDE4 drugs in lung disease is not good. Glaxo scrapped a similar drug called Ariflo in 2007, while Forest and Glenmark (GLEN.BO: Quote, Profile, Research, Stock Buzz) said last week oglemilast had failed in mid-stage Phase II tests.
Still, Daxas has progressed further than any other PDE4 in lung disease and Forest hopes it will help fill a revenue gap when the blockbuster antidepressant Lexapro, sold with Lundbeck (LUN.CO: Quote, Profile, Research, Stock Buzz), loses patent cover in 2012. (Editing by David Holmes)
Takeda to start key diabetes drug trial in Sept
http://www.reuters.com/article/rbssHealthcareNews/idUST32070320090828
TOKYO, Aug 28 (Reuters) - Takeda Pharmaceutical (4502.T: Quote, Profile, Research, Stock Buzz), Japan's largest drugmaker, said on Friday it is set to start an additional clinical study on a key diabetes drug candidate next month, setting a timeline that could see it receive U.S. approval in 2012.
Takeda had originally aimed to have the drug alogliptin or SYR-322 on the market ahead of the 2011 U.S. patent expiration of its blockbuster diabetes drug Actos but its application for approval suffered a setback when U.S. health regulators requested an additional safety test.
It expects to report data from the new study in about two years, it said in a statement.
"We would normally receive a response from the Food and Drug Administration six months after data submission, however, the timing depends on conditions," a Takeda spokeswoman said.
It will start the placebo-controlled examination, involving 5,400 Type 2 diabetes patients at a total 1,000 facilities in the United States, Europe and Asia, Takeda said, adding that U.S. regulators had agreed to the design of the trial.
Credit rating agency Moody's Investors Service on Thursday changed the outlook on its Aa1 rating for Takeda to negative, saying revenue growth and earnings may be pressured by a series of U.S. patent expirations for core products.
Noticed a big jump when they sold some of their Evogene shares. Apart from that cash infusion there was a change of CEO and a couple of scientific results, all preclinical. I'm not following ver closely. Are you holding them?
Geron Explains Hold on Stem-Cell Trial; Shares Rise
http://www.bloomberg.com/apps/news?pid=20601103&sid=axMDaltRudv4
By Rob Waters
Aug. 27 (Bloomberg) -- Geron Corp. rose 3.6 percent in Nasdaq trading after saying a hold placed by U.S. regulators on its plan for the first human embryonic stem-cell study was due to “non-proliferative” cysts in test animals.
The Food and Drug Administration cleared Geron in January to test its stem-cell treatment in patients with spinal cord injuries. The Menlo Park, California-based company announced the regulatory hold on Aug. 18.
Microscopic cysts seen in an early experiment in a few animals that received the cell-based treatment, GRNOPC1, were found in larger numbers of animals in a recent study. The cysts weren’t linked to complications, the company said today in a statement. A more recent study of rats using a new batch of test chemicals showed no cysts, Geron said in the statement.
Stephen Brozak, an analyst with WBB Securities LLC in Westfield, New Jersey, said investors would be reassured that the animals didn’t develop a type of tumor known as a teratoma.
“I think it provides people with a reasonable explanation,” Brozak said. “Everybody was afraid of the T- word, teratomas, and it clearly wasn’t that.” Brozak has a “strong buy” rating on the shares.
Geron rose 25 cents to $7.18 at 4 p.m. New York time in Nasdaq Stock Market composite trading. The shares fell 10 percent on Aug. 18 after the company announced the FDA’s hold.
There was an oral presentation at ASCO 2009: Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066. Abs.:
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=35242
No idea either, suppose to be in pre-IND studies. CEPH intend to file IND on ALK inhibitor (CEP-28122) for solid tumors in Q3.
Does anyone here follow this program?
Risperdal Consta and Invega Sustenna
JNJ has always referred to paliperidone palmitate as the better monthly depot formulation and to Risperdal Consta as a back-up plan and btw, they also intend testing it for a longer 12-week version.
NSCLC Biomarker
The reuters report didn't say that but the genetic test will probably look for patients who are positive for the Anaplastic Lymphoma Kinase (ALK) fusion gene (variants of EML4-ALK fusion gene).
http://clincancerres.aacrjournals.org/cgi/content/full/14/13/4275?maxtoshow=&HITS=100&hits=100&RESULTFORMAT=&titleabstract=kinase&searchid=1&FIRSTINDEX=0&fdate=//&resourcetype=HWCIT
It appears (update on Gaucher town hall meeting) that Genzyme also like PLX and Shire, filed a treatment IND for GENZ-112638 in July but withdrew the T-IND submission after the FDA told them to focus on their phase III trials (two are ongoing and a third one will start early 2010).
This information was given during the question&answers part at the Q109 CC. If you want to listen:
http://webcastingplayer.corporate-ir.net/PLAYER/PlayerHost.aspx?c=194451&EventId=2195534&StreamId=1302408&IndexId=&RGS=3&TIK=%7B51e898e3-e44e-4924-abe6-95899139eba3%7D&SID=%7B47617118-171b-4569-8eba-903293720817%7D&Configed=1
Edit: Just seen that dewophile has already answered your question but I'm leaving mine because of the link.
ACOR/Fampridine
I second that. Think the definition of 'responders' is likely to be much looser in the real world than it was in the clinical trials, and might include anyone who feels better on the drug.