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Sanofi Shares Fall on Concern Over Lantus Cancer Risk
http://www.businessweek.com/news/2010-06-18/sanofi-shares-fall-on-concern-over-lantus-cancer-risk-update3-.html
By Albertina Torsoli
June 18 (Bloomberg) -- Sanofi-Aventis SA fell the most in a month in Paris trading on renewed concern that the Lantus diabetes treatment, the French drugmaker’s top-selling product, may be linked to an increased risk of cancer.
A study of 1,500 patients published this week in the journal Diabetes Care tied insulin glargine, as Lantus also is known, to a higher cancer risk, according to a note today from Hobart Capital Markets, a London brokerage. The study is “unclear” and “lacks precision,” Jean-Pierre Lehner, Sanofi’s chief medical officer, said in a telephone interview. The study can be “methodologically challenged,” the company said.
Sanofi shares slumped a year ago after Ralph DeFronzo, a researcher at the University of Texas Health Science Center, said on a conference call that studies would show Lantus was tied to cancer. As it turned out, the research published in the journal Diabetologia delivered mixed results, and the U.S. Food and Drug Administration said it didn’t show a link.
“There’s no difference in what this study is showing and what was published last year,” Nick Turner, an analyst at Mirabaud Securities in London, said in a telephone interview. “Clearly the risk is relatively light. If anything, this study shows that the risk could be mitigated with dosage, which is a positive.” He has a “neutral” rating on Sanofi’s stock.
Sanofi dropped 2.27 euros, or 4.4 percent, to 48.84 euros at 1:15 p.m. in Paris. The stock slid as much as 7.2 percent, the biggest intraday drop since May 20.
Additional Studies
Sanofi remains confident in the safety of Lantus, Lehner said. Three additional studies are under way, one in the U.S. and two in Europe, involving 1 million patients, he said. The drug had 3.1 billion euros ($3.8 billion) of sales last year.
“You can’t reach reliable conclusions with a study on 1,500 patients,” Lehner said today. “The possible secondary effects of insulin are a real problem and it will take years and years to shed light on the truth.”
Of the 1,500 patients in the study published this week, researchers focused on 112 with diabetes who developed cancer, comparing them to 370 patients matched for age, sex and weight to see if they could tease out any differences that may have contributed to tumor development. During the six-year review, the number of people exposed to each type of insulin was similar, the researchers said. A link to cancer was seen only in those getting higher doses of Lantus, and not other insulins such as Novo Nordisk A/S’s Levemir, the researchers said.
The researchers, led by Edoardo Mannucci from the Careggi Teaching Hospital’s diabetes agency in Florence, Italy, said the possible link between Lantus and cancer should be considered.
“We should all be aware that the epidemiological approach cannot provide definitive conclusions on the effects of any pharmacological treatment,” they wrote.
AMLN will split profits 50/50 with LLY but think they need to pay ALKM royalty on sales.
Exactly. I wouldn't underestimate Victoza in taking a big chunk of the GLP-1 market and certainly wouldn't think of it as a monopoly for bydureon. Will patients prefer the once-weekly formulation over a better pen delivery is yet to be seen.
I don't see a problem with a daily pill, think it is better than the gel. The problem of course is the side effects together with its marginal benefit that don't make it a good drug for long term use.
Scientific Meeting Calendar
NOTE: ANYONE MAY UPDATE THIS FILE
Edits: Removed old entries; Added ICO, ASRS, ESC, IASP
JUNE 2010
Psychopharmacologic clinical research - NCDEU
Boca Raton, FL
June 14-17, 2010
http://www.ncdeumeeting.org/NCDEU%202010.htm
European League Against Rheumatism - EULAR
Rome, Italy
June 16-19, 2010
http://www.eular.org/
Endocrine Society - ENDO
San Diego, CA
June 19-22, 2010
http://www.endo-society.org/
European Neurological Society - ENS
Berlin, Germany
June 19-23, 2010
http://www.ensinfo.org/
American Diabetes Association - ADA
Orlando, FL
June 25-29, 2010
http://www.diabetes.org/
European Association for Cancer Research - EACR
Oslo, Norway
June 26-29, 2010
http://www.eacr.org/
JULY 2010
International Conference On Alzheimer's Disease - ICAD
Honolulu, Hawaii
July 10-15, 2010
http://www.alz.org/icad/2010_icad.asp
International Congress on Obesity - ICO
Stockholm, Sweden
July 11-15, 2010
http://www.ico2010.org/registration.htm
AUGUST 2010
American Society of Retina Specialists - ASRS
Vancouver, Canada
August 28 - September 1, 2010
http://www.asrs.org/
European Society of Cardiology - ESC
Stockholm, Sweden
August 28 - September 1, 2010
http://www.escardio.org/congresses/esc-2010/Pages/welcome.aspx
World Congress On Pain - IASP
Montreal, Canada
August 29 - September 3, 2010
http://www.iasp-pain.org//AM/Template.cfm?Section=Home
OCTOBER 2010
American Association for the Study of Liver Diseases - AASLD
Boston, Massachusetts
October 29 - November 2, 2010
http://www.aasld.org/
NOVEMBER 2010
American Society of Human Genetics - ASHG
Washington, DC
November 2-6, 2010
http://www.ashg.org/
----
Procedure for Updating Calendar
When adding or modifying entries, please follow these steps:
1. Copy the complete text from the old calendar.
2. Make your additions or modifications, inserting any new items in chronological order.
3. Near the top of the message, give a very brief description of your changes (e.g. “Edits: Added entry for AASLD”).
4. Post the updated calendar in a new message as a reply to the message with the old calendar.
Boehringer Sex Pill May Not Aid Women, FDA Staff Say
http://www.bloomberg.com/apps/news?pid=20601124&sid=amNzIIW3oiBY#
By Molly Peterson
June 16 (Bloomberg) -- Boehringer Ingelheim GmbH’s sexual desire drug flibanserin may not be effective or safe, according to U.S. regulators weighing whether to approve the first pill designed to boost women’s libidos.
The drug “failed to demonstrate a statistically significant improvement” in sexual desire, Food and Drug Administration staff said in a review released today. It was also linked to appendicitis, depression and loss of consciousness. Side effects led about 15 percent of women to stop treatment with the drug, the review said.
While male sexual enhancement treatments led by Pfizer Inc.’s Viagra facilitate erections by increasing blood flow to the penis, flibanserin is designed to work in the brain. Boehringer’s libido pill, first tested as an antidepressant, lowers the level of one brain chemical, serotonin, and boosts production of two others, dopamine and norepinephrin.
“This points to the brain as the important organ in desire, as central to the feminine experience of sexuality,” said John Thorp, a professor of obstetrics and gynecology at the University of North Carolina School of Medicine and the lead investigator in North American drug trials sponsored by Ingelheim, Germany-based Boehringer. “This is a radical change.”
Boehringer, the world’s largest closely held drugmaker, asked the FDA to clear its pill to treat pre-menopausal women who suffer from hypoactive sexual desire disorder. Outside advisers to the FDA are scheduled to meet June 18 to review the drug.
Sex Drive
The condition, defined as a decrease in sex drive that causes problems in relationships, affects about 10 percent of women from the ages of 30 to 60, Thorp said. It is typically treated with therapy and with prescriptions of male hormones such as testosterone, an unapproved use, he said.
Taking male hormones can cause women to gain weight, grow facial hair, and face long-term health risks, Thorp said.
Noven Pharmaceuticals Inc.’s testosterone patch Intrinsa, licensed by Procter & Gamble Co., is sold in Europe for women whose uteruses have been removed. A U.S. version was put on hold in 2004 after an FDA advisory panel said the drug needed more study because existing research couldn’t rule out heart and breast cancer risks.
In clinical tests of 1,378 women in North America, 48 percent of patients who took flibanserin for six months reported improved desire, compared with 30 percent with a placebo, Boehringer reported at a May 18 meeting of the American College of Obstetricians and Gynecologists in San Francisco.
Female Libido
Female libido drugs may create an annual market of at least $2 billion, said Stephen Simes, chief executive officer of BioSante Pharmaceuticals Inc., in a June 9 presentation to investors. The Lincolnshire, Illinois-based company’s Libigel, a topical testosterone, is in the third and final stage of tests generally required for U.S. approval.
Viagra had sales of $1.89 billion last year, including $962 million in the U.S., Pfizer said Feb. 3. Cialis generated $1.56 billion in sales last year for Eli Lilly & Co., including $623.3 million in the U.S., the Indianapolis-based company reported Jan. 28.
“Viagra-like” drugs haven’t shown much success in women, said Jeffrey Jensen, a professor of obstetrics and gynecology at Oregon Health & Science University, in a telephone interview.
“That’s wrapped up in a whole bunch of stuff, not just plumbing,” Jensen said. “Treating male sexual arousal disorder is basically just plumbing -- getting blood flow to that area.”
I've checked AMLN's original PR and it's "average weight loss". No mention of medians and no misuse this time :)
Not only a lot of twists and turns for a medium-sized drug like Yaz, they also have a profit sharing agreement with Gideon Richter (think about 30%).
The PR said "average weight loss", why do you think these are medians?
In DURATION-4 study Bydureon (f/k/a exenatide LAR) reduced A1c similarly to metformin and Actos, and produced average weight loss like metformin.
Amylin shares fall after new Bydureon data hits
http://www.reuters.com/article/idCNN1521747120100615?rpc=44
* Diabetes drug tops one oral drug, comparable to 2 others
* Bydureon longer-lasting version of Byetta
* Amylin shares down nearly 4 pct
By Lewis Krauskopf
NEW YORK, June 15 (Reuters) - Amylin Pharmaceuticals Inc (AMLN.O) and Eli Lilly and Co's (LLY.N) experimental diabetes drug Bydureon proved better at reducing blood sugar levels than one currently marketed medicine, but only comparable to two others, according to data released on Tuesday.
Shares of Amylin were down nearly 4 percent after the companies released results of the 820-patient study, called Duration-4.
Bydureon, which is injected once a week and is a longer-lasting version of the companies' Byetta drug, also known as exenatide, belongs to the GLP-1 class of drugs that stimulate insulin production in order to regulate blood sugar levels.
The study is the fourth comparing Bydureon -- a critical potential growth driver for both companies -- to other diabetes drugs.
U.S. regulators are expected by Oct. 22 to decide whether to approve Bydureon, which was developed with technology from Alkermes Inc (ALKS.O).
Duration-4 compared Bydureon to three oral medicines for Type 2 diabetes: Merck & Co's (MRK.N) Januvia, Takeda Pharmaceutical Co's (4502.T) Actos, and metformin, which is available generically.
Study participants were not achieving adequate control of A1C -- a common measure of blood sugar -- through diet and exercise, and were not on any diabetes therapy when they entered the study.
After 26 weeks of treatment, patients who received Bydureon experienced a reduction in A1C of 1.5 percentage points from baseline, which was deemed significantly greater than the 1.2 percentage points reduction seen with Januvia.
However, patients taking metformin also experienced a reduction in A1C of 1.5 percentage points, while patients receiving Actos saw a reduction of 1.6 percentage points.
"The results indicate that Bydureon is better than Januvia but comparable to metformin and Actos" in reducing A1C levels, Leerink Swann analyst Joshua Schimmer said in a research note.
Patients taking Bydureon, Actos and metformin all achieved an average A1C of less than 7 percent, which is the glucose control target recommended by the American Diabetes Association.
Bydureon treatment produced an average weight loss of 4.5 pounds (2 kg), which was statistically significantly greater than the average 1.7 pounds (0.8 kg) patients lost with Januvia and the average 3.3 pounds (1.5 kg) patients gained with Actos. But patients receiving metformin experienced an average weight loss of 4.4 pounds (2 kg).
Weight loss is considered an extremely desirable side effect as obesity is a leading cause of Type 2 diabetes, and some treatments for the disease lead to weight gain, as Actos did in this study.
"Our conclusion is that Duration-4 may do more to reinforce generic metformin as the front-line diabetes drug of choice than to support asking for broad front-line use of Bydureon," Robert W. Baird analyst Thomas Russo said in a research note.
Aside from Bydureon and Byetta, the GLP-1 class is closely watched by Wall Street and includes Novo Nordisk's (NOVOb.CO) Victoza and taspoglutide, under development by Roche Holding AG (ROG.VX) and Ipsen SA (IPN.PA).
Amylin shares had risen 4.5 percent on Monday after analysts said data on diabetes drugs from potential competitors looks less threatening than some had expected. [ID:nN14209306]
"We still see Bydureon as likely the dominant GLP-1 agonist," Schimmer said, "but are struggling to quantify the extent of market expansion for the class, which is equally important for forecasting Bydureon revenue and AMLN's profitability."
New 'morning-after' pill effective, safe: FDA staff
http://www.reuters.com/article/idUSTRE65E2DD20100615
By Susan Heavey
WASHINGTON (Reuters) - A new, longer-lasting "morning-after" pill to prevent unwanted pregnancy appears to work with no unexpected side effects, U.S. health regulatory staff said in documents released on Tuesday.
Data shows the one-pill treatment, called ella and made by French drugmaker HRA Pharma, is effective when taken as many as five days after unprotected sex, Food and Drug Administration staff reviewers said in documents released ahead of a public meeting on the drug scheduled for Thursday.
At the meeting, an FDA panel of outside experts will decide whether to recommend the agency approve the emergency contraceptive for the U.S. market. If approved, Watson Pharmaceuticals Inc would sell the drug in the United States.
HRA Pharma's drug, approved last year in Europe under the name ellaOne, has re-ignited debate over "morning-after" pills in the United States, where reproductive issues are a constant political issue.
Women's health advocates have welcomed the potential for another contraceptive option, but some critics contend the drug is more akin to the abortion pill, sold by Danco Laboratories as Mifeprex and also known as RU-486 or mifepristone.
Teva Pharmaceutical Industries Ltd sells a rival product, called Plan B, a two-pill regimen with generic competition from Watson's Next Choice. Teva also sells a one-pill version of Plan B.
Both versions of Plan B, which are available over the counter for women at least 17 years of age, have only been proven to work for up to 72 hours after intercourse.
"There is a medical need for an efficient emergency contraceptive product which acts consistently over a prolonged time period," HRA Pharma said in a separate document released by the FDA.
The drugmaker has said its pill, also known by its chemical name ulipristal, works primarily by preventing ovulation of a woman's egg. But the drug's effect on the lining of the uterus -- critical for a fertilized egg to develop -- may also play a role, according to its label in Europe.
FDA staff scientists, in their review, concurred.
The agency's reviewers also said the company's studies showed no unexpected side effects in women, although reports of nausea, headache and abdominal pain were common. It was not clear what effect the drug had, if any, when a woman still became pregnant despite taking it, they added.
"Data on pregnancy outcomes after EC (emergency contraceptive) failure with ulipristal were too limited to draw any definitive conclusions regarding the effect of ulipristal on an established pregnancy or fetal development," they wrote.
"MORE LEEWAY"
Emergency contraceptive pills have been available in the United States for more than a decade.
Plan B, or levonorgestrel, was first approved in 1999. Efforts in 2001 to make it available without a prescription stirred fierce opposition from conservatives, and the bid stalled under the George W. Bush administration. Democrats angered by the delay threatened to block Bush's nominee to run the FDA. Easier access to the drug won approval in 2006.
HRA is not seeking to sell ella without a doctor's prescription.
Advocates for women's health have applauded the possibility of additional contraceptive options, saying a longer-lasting product could help women who want to avoid pregnancy.
For ella, "while you're going to have to go and get a prescription for it, it gives you a little bit more leeway in terms of putting your ability to put your life on hold and get this healthcare need taken care of," said Amy Allina, program and policy director for the National Women's Health Network.
Cost is also an issue. With Plan B sold over the counter, most women have to pay for the drug themselves -- roughly $50 -- rather than have their health insurance cover it, Allina said.
Anti-abortion groups oppose HRA Pharma's drug, saying it is closer chemically to mifepristone than Plan B and pressing the FDA to reject the product.
Like mifepristone, ella is a type of drug known as a selective progesterone receptor modulator (SPRM) that interferes with the hormone progesterone, which is critical for pregnancy.
If it is approved, it should be clearly labeled as an abortifacient, which would limit its distribution, the American Association of Pro Life Obstetricians & Gynecologists said in a letter to the FDA earlier this month.
"There is no doubt that ulipristal acts an abortifacient because the drug blocks progesterone receptors at three critical areas," an action that "interferes with the hormone action of progesterone to prepare the endometrium for implantation and to support the early pregnancy," the group wrote.
Proponents agree that ella is similar chemically to mifepristone but say the dose given does not interfere with a pregnancy already underway.
"There's just no evidence that it causes abortion," said Baylor College of Medicine professor Paul Fine, who also serves as medical director for Planned Parenthood in Houston and Southeast Texas.
On Thursday, the FDA's advisers will weigh HRA Pharma's data and offer recommendations before the agency later makes its approval decision.
Watson shares were up 50 cents, or 1.2 percent, to $43.20 in morning trade. Teva shares were up 6 cents to $53.34 in New York.
Novo Nordisk said on Monday it would resume supplies of its modern insulins to Greece after the country raised its prices for the drugs.
http://www.reuters.com/article/idUSLDE65D1LB20100614
FDA nod to new MS drug spells trouble for Teva
http://www.haaretz.com/print-edition/business/fda-nod-to-new-ms-drug-spells-trouble-for-teva-1.295789
Novartis' Gilenia threat [not so fast] to sales of Copaxone.
By TheMarker and Reuters
Novartis AG's experimental multiple sclerosis pill moved one step closer to winning U.S. approval on Thursday when a Food and Drug Administration advisory panel backed the drug to help reduce and delay patients' symptoms.
The FDA's outside advisers said that despite some concerns over potential risks the drug worked well enough to be considered an initial treatment option for all MS patients. They said that more data is still needed, especially on side effects.
The FDA will weigh the panel's recommendation as it makes its approval decision, expected by September. If approved, Novartis' Gilenia could be the first pill to treat U.S. patients, whose options now are limited to more invasive, injectable medications.
Novartis told the panel its pill is easier to take than injectable medicines already on the market and avoids the flu-like symptoms seen with some rivals.
Israel's Teva Pharmaceutical Industries is among the firms that currently market injectable drugs for the treatment of the degenerative disease. Not all patients can tolerate them, Novartis said.
Teva's revenues from Copaxone were $796 million in the first quarter of 2010, a 28% rise from the same quarter of 2009. U.S. sales rose 19% from the previous quarter, to $513 million. Total Copaxone sales were $2.8 billion in 2009, representing about 20% of Teva's total revenues and an estimated 25%-30% of its net profits for the year.
The main pharmaceutical "victim" of a successful launch of Gilenia, however, stands to be not Copaxone but rather interferon-based MS treatments such as Biogen Idec's Avonex as well as that company's Tysabri, delivered via intravenous infusion and considered a controversial option with its own side-effect issues.
In a study of patients who switched from Avonex to Gilenia, the relapse rate in year two was reduced by 31 percent and the number of new or newly growing brain lesions was reduced by 67 percent on the new drug.
Earlier last week Germany's Merck resubmitted its bid to the FDA in the hope of selling its MS pill, cladribine, after a delay last year. Other future rivals include experimental pills such as Teva's laquinimod, Biogen's BG-12 and Sanofi-Aventis SA's teriflunomide.
"Neurologists clearly want an oral option for their MS patients," Joshua Schimmer of Leerink Swann Research said in a research note.
Wall Street has predicted that Gilenia could be a potential blockbuster product for the Swiss drugmaker.
Forecasts, on average, point to sales of $987 million by 2014, according to Thomson Reuters data, although some analysts expect even bigger sales. Analysts at the Jefferies brokerage expect the drug to bring in $1.6 billion by 2014, while Nomura forecasts $2.1 billion in sales by 2014.
FDA staff had expressed some concern about side effects that arose in Novartis' clinical trials, including heart problems, fluid in the eye and a decrease in lung function. But FDA advisers said benefits of the novel treatment outweighed the risks as long as more studies are done.
They also expressed concern about the potential for complications if the drug were used in a wider population after approval, noting that diabetics and other high-risk patients were excluded from Novartis' trials.
Robert Temple, head of the FDA division that reviews neurological drugs, said the FDA would order additional data on such patients. "The excluded groups will have to be studied in some way. There's no question about that," he told the panel.
Novartis said it plans to continue to study the drug's safety with a 5,000-patient, five-year study, although panelists said the company's planned study was not enough.
The panelists' backing comes with other caveats, including a recommendation that patients be monitored for heart problems after they take their first dose. They also said routine exams would not be enough to monitor for other side effects, such as vision problems or declining lung function.
They also said the FDA should require Novartis to study a lower dose than the 0.5 milligram pill the company wants approved to see whether it would be as effective but possibly less risky.
Shares of Novartis closed up 1.7% on the New York Stock Exchange on Friday, to $48.25, after climbing 3.3% Thursday.
Teva raises stake in diabetes treatment developer
http://www.reuters.com/article/idCNLDE65D0BI20100614?rpc=44
June 14 (Reuters) - Teva Pharmaceutical Industries (TEVA.O) has exercised an option to raise its stake in Andromeda Biotech, which is developing a treatment for juvenile Type I diabetes, Clal Biotechnology Industries (CBI.TA) said on Monday.
Following the deal with Teva (TEVA.TA), Clal's stake in Andromeda will fall to 84 percent from 89 percent. Teva's share will rise to 16 percent.
According to the agreement, Teva and Clal will invest $17.5 million in Andromeda, of which $5.6 million will come from Clal and the rest from Teva. The money will be used to finance a confirmatory Phase III clinical trial to obtain marketing approval for DiaPep277 in Europe and the United States.
The deal values Andromeda at $170 million, Clal said.
Teva, the world's biggest generic drugmaker, last year received worldwide marketing rights for DiaPep277, whose market is estimated at hundreds of millions of dollars a year.
DiaPep277 is a unique peptide that prevents the destruction of insulin producing cells in the pancreas.
Once the drug is approved for marketing in Europe, Teva has an option to invest $44 million at a company valuation of $480 million, and when it is approved in the United States Teva can invest $52 million at a company valuation of $555 million.
One note on 23andme's killer application "relative finder" - if one's interest is to locate and connect with possible relatives or to have a kinship test, "family finder" (http://www.familytreedna.com/landing/family-finder.aspx ) is a cheaper way.
This part was not in NVS’ own PR on the FTY720 advisory panel:
Back to your original subject, I believe it depends on the data from the phase III in 1st line study where HLA-A*0201+ was not an inclusion criteria, and whether this study will be required for approval.
I think David meant HLA-A*0201 positive.
I was wondering how many were Teva's agents. We shouldn't count those either :)
Pharmasset Announces Submission of Abstracts to AASLD Liver Meeting Including an Interim Analysis of Roche's Phase 2b PROPEL Trial of RG7128
http://finance.yahoo.com/news/Pharmasset-Announces-prnews-55959860.html?x=0&.v=1
-- Analysis of data by Roche from all 408 patients concluded safety and tolerability profile of RG7128 administered for 8 or 12 weeks with standard of care (SOC) continues to be similar to SOC alone
-- RG7128 in combination with SOC demonstrated highly potent antiviral effects greater than SOC alone, patients with either HCV genotype 1 or 4
-- Roche has submitted two RG7128 abstracts to AASLD for the Annual Liver Meeting
Press Release Source: Pharmasset, Inc. On Wednesday June 9, 2010, 6:51 am EDT
PRINCETON, N.J., June 9, /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq:VRUS - News) announced today that the interim results from the PROPEL study conducted by its partner Roche demonstrate that RG7128 triple combination therapy was safe and well tolerated. In that study, the safety profile of RG7128 (1000mg BID or 500mg BID), when administered for 8 or 12 weeks with Pegasys (peginterferon alfa-2a) and Copegus (ribavirin), the standard of care (SOC), was similar to the safety profile of SOC alone. An interim analysis of the study included all safety data from all 408 patients who had completed the first 12 weeks of the study. The most common adverse events were no different than those frequently noted with SOC alone. There were no findings related to rash, anemia, bone marrow suppression, or nephrotoxicity across any of the arms.
The PROPEL study is evaluating the dose and duration of treatment of RG7128 in combination with SOC in patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 4 who have not been treated previously. The interim analysis also included on-treatment efficacy data demonstrating that >80% of patients had undetectable HCV RNA in all cohorts receiving the 12-week triple regimen compared to <50% for the placebo/SOC cohort. The safety and efficacy results from the interim analysis of the PROPEL Phase 2b study of RG7128 have been submitted by Roche as an abstract to AASLD for the Annual Liver Meeting (October 29 to November 2, 2010). The title of the abstract is:
"High rates of early viral response, promising safety profile and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study"
"We are encouraged by the reported efficacy, safety, and resistance data from this interim analysis of the PROPEL study," said M. Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We believe safety, absence of resistance, as well as antiviral potency will all be important considerations as HCV treatment incorporates direct acting antivirals in combination with interferon, and in potential interferon-free antiviral combination regimens."
No viral rebounds or resistance-related breakthroughs were noted during the first 8 or 12 weeks of triple combination therapy, consistent with the demonstrated high barrier to resistance in earlier RG7128 clinical studies. In clinical reports to date, the S282T mutation associated with RG7128 resistance in vitro has not been detected at baseline in HCV-infected patients enrolling in clinical trials. A separate abstract has been submitted by Roche including details of the resistance analyses that have been conducted during this study, including sequencing of the HCV RNA from all patients at baseline. The abstract is entitled:
"No evidence of drug resistance or baseline S282T resistance mutation among GT1 and GT4 HCV infected patients on nucleoside polymerase inhibitor RG7128 and Peg-IFN/RBV combination treatment for up to 12 weeks: interim analysis from the PROPEL study."
About the Phase 2b PROPEL Study
The Phase 2b study enrolled 408 patients with HCV genotypes 1 or 4, cirrhotic and non-cirrhotic, who have not been treated previously. The primary efficacy endpoint of the study is the proportion of patients who achieve an SVR, defined as HCV below the limit of detection (<15 IU/mL as measured by Roche TaqMan assay) 24 weeks after completion of all treatment. The study is being conducted in North America, Europe, and Australia. Patients were enrolled into one of 5 arms:
* 24 weeks of total treatment; RG7128 500mg BID in combination with SOC for 12 weeks, followed by 12 weeks of SOC ("12+12", RVR guided)
* 24 weeks of total treatment; RG7128 1000mg BID in combination with SOC for 12 weeks, followed by 12 weeks of SOC ("12+12", RVR guided)
* 24 weeks of total treatment; RG7128 1000mg BID in combination with SOC for 8 weeks, followed by a further 16 weeks of SOC ("8+16", RVR guided)
* 48 weeks of total treatment; RG7128 1000mg BID in combination with SOC for 12 weeks, followed by a further 36 weeks of SOC ("12+36", non-RVR guided")
* A control arm with SOC for 48 weeks.
Patients in the 24-week arms will discontinue all treatment at week 24 if they have achieved RVR, defined as HCV RNA below the limit of detection (<15 IU/mL) at week 4 and maintain these low levels of HCV RNA until week 22, a strategy known as "RVR-guided" treatment. Patients who do not meet these criteria will continue on the standard of care until week 48.
RG7128 is also currently being evaluated in a Phase 2b study in which RG7128 and SOC are given for a total of 24 weeks each ("24+0", RVR guided). The regimen will be assessed in treatment-naive HCV-infected patients with genotypes 1 or 4. Enrollment in this study was completed in early May. In addition, Roche anticipates the initiation of another Phase 2 study in HCV-infected patients with genotypes 2 or 3 by the end of 2010.
About Pharmasset ...
The ‘biobucks’ value of $1.1B will likely be a lot lower cause not all compounds (all are GKA) will eventually be taken to clinical trials.
It does sound like MON knows no one will buy a 50/50 ‘Refuge in a Bag’ version of VT Triple Pro. My answers give possible explanations to how did MON knew that.
Nothing on melanoma and varicella-zoster virus in the draft questions for the Gilenia advisory panel.
This idea is not new #msg-28309811
CBST/Cubicin patent litigation
CBST today announced that the U.S. District Court for the District of Delaware issued a claim construction order in the litigation between Cubist and Teva.
http://finance.yahoo.com/news/Cubist-Pharmaceuticals-bw-4280300217.html?x=0&.v=1
What's the official reason given by MON for not offering VT Triple Pro in a Bag?
This scenario can give another explanation (other than mutation) to how someone got such a variant
within the quasispecies, but it does not solve the riddle why this is the dominant variant and not present at low prevalence.
One more interesting phenomena regarding resistance in HCV:
Naïve patients infected with naturally occurring DAA-resistant variants as the pre-existing dominant strain have high baseline concentrations of viral RNA. "Normaly", these variants that confer resistance to DAA are associated with reduced replicative fitness. So it would be interesting to understand how they achieved their high replicative capacities prior to drug selection.
It is not really an example of the Survival of the Flattest phenomenon because it is not a case were mutation rate is increased and the outcome of competition switches to favour the genotype with the lower replication rate (lower fitness but more robust with respect to mutations).
VRTX's strategy makes sense since telaprevir-resistant variants were associated with single nucleotide substitutions, mutants emerged very quickly, and continuing treatment after breakthrough allows selection of multiple mutation, so checking as early as 2 weeks for suboptimal responders will minimize the risk of the selection of resistant variants.
Other points to take into consideration regarding telaprevir resistance in the future: there was a difference in risk of emergent drug-resistance between subtypes (1a more frequently than 1b), and typically different mutations between those subtypes. Also the pre-existing dominant strain in a patient's quasispecies can sometimes be the V36M or R155K variant (that has a reduced response to telaprevir), and even if a variant present at low prevalence within the quasispecies it can quickly become the dominant sequence if it offers a selective advantage.
First, I need to correct a typo, it should be - "Unless they compensate."
What I was suggesting is an explanation to the shift in variants population from baseline to breakthrough and relapse. What drives the relapse in that case imo, is incomplete suppression of viral replication under the selection stress of the drug.
High level resistant strains of HCV do not mutate to be low level resistance strains once the treatment stops, they are replaced by strains with higher fitness i.e better replication efficiency.
Resistance to telaprevir (from PROVE-2 data)
The preexisting dominant strain in patient's quasispecies was the WT but 2 variants were also present at baseline (in a very small percentage) and perhaps more that were not detected. After a short time of selection stress (telaprevir) highly resistant variants were selected and were seen while viral breakthrough. But there's a price to be paid even for a virus and so highly resistant variants typically are associated with a significantly impaired replicative fitness. Unless they do not compensate by additional mutation/s that restore replicative replication efficiency, then after termination of antiviral therapy they no longer have any advantage and are replaced by lower resistant variants and WT. So I don't think that relapse requires that the virus become at least low level resistant.
I don't think they do that.
Perhaps they just don't sell non-Bt seeds.
It is quite worrying that farmers are cheating big time. I'm sure none of the population genetic models considered total compliance with the refuge requirements but if large part of growers are cheating, the risk for resistant insects is high.
Ok, last one on MON quiz
MON is selling a lot more VT Triple Pro than SmartStax to corn growers in the Southern US cotton belt and that indicates that they are cheating.
MON quiz take two
A survey in which growers from the Southern US cotton belt are being asked what is the most important improvement they want to see in the VT Triple Pro. If the majority do not vote for reduced refuge, they are cheating...
I do not follow MON but my first guess would be that they keep track of the average yield per acre and if it is higher than expected (you don't see the adequate yield loss due to non BT acreage), then farmers were cheating (did not use the required refuge percentage).
The official reason given by Teva is economic. Hard to tell the real motive. Could be that this ANDA filed by Barr looks too problematic to Teva (see my old post here: http://siliconinvestor.advfn.com/readmsg.aspx?msgid=24447316 ).