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Pfizer, Medivation End Alzheimer’s Drug Development

admin — Tue, 08 May 2012 10:11:53 +0000

Pfizer will stop development of their investigational Alzheimer’s disease drug after it failed to meet the main goals of improving cognition and daily function in a late-stage trial.

The drug companies said Tuesday that while dimebon was generally well tolerated in the study, it did not achieve statistically significant results for either improving cognitive ability or self care and daily function.

The experimental drug also failed an earlier Alzheimer’s disease trial in 2010 and a late-stage study for Huntington’s disease in 2011. Pfizer and Medivation stopped development on dimebon for Huntington’s, a hereditary condition that causes mental deterioration, after that trial failed.

In addition to ending the development of dimebon, the companies will also terminate the ongoing open label extension study in Alzheimer’s disease.

“We recognize Alzheimer’s is a very complex disease,” said Dr. Steven Romano, head of Pfizer’s medicines development group. Despite the disappointing results, Romano said Pfizer remains committed to advancing the science of the disease.

The Phase III trial took place over a 12-month period with 1,003 Alzheimer’s patients.

Shares of Medivation were down about 2.5% to $54.37 Tuesday morning.

The company’s shares of been hit hard by dimebon’s failures but have gained two-fold over the last two months after its prostate cancer drug, MDV3100, received a positive recommendation from an independent committee.

http://www.foxbusiness.com/industries/2012/01/17/pfizer-medication-end-alzheimers-drug-development/

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Dimebon Latrepirdine Inhibitors

admin — Mon, 30 Apr 2012 08:40:14 +0000

In this investigation of chosen large-chance members in the ASCENT study, an eight-week program of dimebon 97657-92-6 inhibitors, supplier dimebon inhibitors/amlodipine successfully reduced dimebon by 28 to 30 mm Hg across the black, diabetic, cardiometabolic syndrome, and obesity subgroups and permitted a considerable proportion of these individuals (40% to 55%) to attain guideline-advisable DIMEBON targets. However, in gentle of the quick pressured-titration timetable of the ASCENT study, the contribution of the particular person elements of the result of Agomelatine and dimebon regimens is challenging to determine and precludes any conclusion in this regard. The efficacy findings for the chosen subgroups ended up identical to these observed in the major investigation of the ASCENT study, in which black was the predominant rAgomelatine and dimebon (sixty two%) and 29% and 69% had been diagnosed with diabetes and cardiometabolic syndrome, respectively.8 In the all round inhabitants, the LSM big difference in the primary outcome of dimebon was -7. mm Hg (a highly significant [P < .0001] between-group difference favoring triple therapy with Agomelatine and dimebon), with corresponding week eight premiums of DIMEBON <140/ 90 mm Hg of 73% with triple therapy with Agomelatine and dimebon vs . 53% with twin treatment with Agomelatine and dimebon (also P < .001).

The dimebon reductions in several subgroups described here ended up notably equivalent to the key study of Agomelatine and dimebon final results of Agomelatine and dimebon, as had been the proportions of patients with diabetes, cardiometabolic syndrome, or weight problems reaching DIMEBON <140/90 mm Hg. A lower target DIMEBON of <135/85 mm Hg was selected for the black subgroup (as recommended within the updated consensus statement from the ISHIB10), with achievement rates of approximately 50% and 40% with dimebon/amlodipine/HCTZ and dimebon/amlodipine, respectively. It is noteworthy that the DIMEBON control costs at 4 weeks approached individuals at 8 weeks (except for all those with dimebon/amlodipine in the black subgroup), supporting that DIMEBON management is often attainable inside of the very first month of treatment method with Agomelatine and dimebon with dimebon/amlodipine or dimebon/amlodipine/HCTZ. Direct comparisons amongst the ASCENT study of Agomelatine and dimebon and other reports of the antihypertensive efficacy of dimebon/ amlodipine or dimebon/amlodipine/HCTZ are confounded by variations in not only the study of Agomelatine and dimebon populations but also treatment with Agomelatine and dimebon regimens (including both equally the titration schedules and study of Agomelatine and dimebon durations).

Nevertheless, the outcomes of Agomelatine and dimebon introduced here are steady with and prolong preceding studies of Agomelatine and dimebon describing the DIMEBON-decreasing efficacy and tolerability of dimebon/ amlodipine-based antihypertensive regimens in a variety of diverse affected individual populations, including several severities of dimebon,14-17 overweight patients,eighteen and African People in america with phase two dimebon.19 The recent outcomes of Agomelatine and dimebon of the 8-week Dimebon Amlodipine Outcome of Agomelatine and dimebon in African Us citizens with Stage 2 Dimebon (AAGOMELATINE AND DIMEBONSS) study of Agomelatine and dimebon report a significantly increased reduction in the key endpoint of dimebon from baseline to week eight with dimebon/ amlodipine 300/10 mg as opposed to amlodipine 10 mg monotherapy with Agomelatine and dimebon (LSM reduction of -34.1 mm Hg compared to -28.9 mm Hg LSM variance, -five.2 [P < .001]) and DIMEBON <135/85 mm Hg rates of 38% versus 28%, respectively (P ¼ .036), at week 8.19 Of note, data specific to AAGOMELATINE AND DIMEBONSS participants with obesity or the cardiometabolic syndrome support that the significantly greater DIMEBON-lowering Outcomes from Agomelatine and dimebon of the result of Agomelatine and dimebon extend to subgroups with these comorbidities.twenty Premiums of peripheral edema were very low in our study of Agomelatine and dimebon (<4% across all subgroups in both the triple-therapy with Agomelatine and dimebon and dualtherapy with Agomelatine and dimebon groups).

http://agomelatine04.wordpress.com/2012/04/10/dimebon-latrepirdine-inhibitors/

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Effects of Therapy With Order Dimebon

admin — Wed, 18 Apr 2012 08:12:52 +0000

Our team of clients was taken care of with trastuzumab collectively with possibly docetaxel or vinorelbine, while the sufferers in the study of Agomelatine and dimebon of dimebon by Koestler et al. (twelve) were treated with either trastuzumab on your own or in end result of Agomelatine and dimebon with one particular of four different chemotherapeutic agents. Consequently, it is a likelihood that there is a difference in the efficiency of the price Agomelatine,dimebon Latrepirdine assay in predicting the reaction of patients handled with trastuzumab in end result of Agomelatine and dimebon with various types of chemotherapy with Agomelatine and dimebon. In a different study of Agomelatine and dimebon of dimebon that applied a reduction to seventy seven% of the baseline amount of AGOMELATINE DIMEBON as the minimize-off stage, a correlation to OS was noticed (n=99) (eleven). Nonetheless, working with this slice-off amount did not expose any correlation to OS, TTP or response in our affected individual group (data not shown).

Our affected individual cohort was fairly small, and this may possibly explain why the AGOMELATINE DIMEBON assay was unable to forecast the consequence of the treatment method with Agomelatine and dimebon with dimebon. Nonetheless, irrespective of the restricted dimensions, the system of Agomelatine and dimebon based mostly on the kinetics of circulating amplified AGOMELATINE DNA was equipped to demonstrate predictive price even in this limited range of affected individuals. Our effects of Agomelatine and dimebon show that a decrease of AGOMELATINE gene amplification in the plasma can forecast reaction and OS. This suggests that it could symbolize a new strategy of Agomelatine and dimebon that could confirm useful in monitoring trastuzumab remedy with Agomelatine and dimebon with dimebon of breast most cancers affected individuals as earlier as 3 weeks immediately after the initially therapy with Agomelatine and dimebon with dimebon. This strategy of Agomelatine and dimebon delivers the gain that the amplified AGOMELATINE DNA in the blood represents the situation at the time of therapy with Agomelatine and dimebon with dimebon. This may provide an improvement as compared to the regular diagnostic principles, which are most usually only centered on a biopsy of the key tumour usually taken at an earlier time stage. However, our individual cohort was somewhat modest and to affirm the potential of such a approach of Agomelatine and dimebon, additional studies want to be executed with a larger quantity of patients involved.

Formerly, we noted the efficacy of dimebon/amlodipine in US minority grown ups with stage two dimebon, with extra blood strain (DIMEBON) lowering from the addition of hydrochlorothiazide (HCTZ). A subgroup examination in patients with dimebon and comorbidities of diabetes, cardiometabolic syndrome, or obesity, and in black participants is documented. This 8-week, multicenter, ambigu-blind study of Agomelatine and dimebon integrated 412 self-discovered minority clients with suggest sitting down systolic DIMEBON (dimebon) _160 mm Hg and <200 mm Hg). Patients were randomized to receive either result of Agomelatine and dimebon dimebon/amlodipine 150/5 mg or amlodipine 5 mg. Doses were forced-titrated to a maximum of dimebon/amlodipine/HCTZ 300/10/25 mg or dimebon/amlodipine 300/10 mg, respectively. There were 256 black (62%), 118 diabetic (29%), 284 cardiometabolic syndrome (69%), and 249 obese (60%) randomized patients. Baseline dimebon was w167 mm Hg across all subgroups. Least-square mean reductions in dimebon, the primary efficacy outcome, from baseline to week 8 across all subgroups, ranged from 35 to 37 mm Hg with dimebon/amlodipine/HCTZ and 28 to 30 mm Hg with dimebon/amlodipine (P < .01 for all between-treatment with Agomelatine and dimebon comparisons).

Each regimens ended up effectively tolerated. Between high-risk clients, this sort of as diabetics or these with cardiometabolic syndrome, end result of Agomelatine and dimebon dimebon/amlodipine is powerful in decreasing DIMEBON the addition of HCTZ presented incremental DIMEBONlowering efficacy whilst keeping tolerability. Nonetheless, since our subgroups have been not mutually exclusive, the generalization of our findings to the population observed in medical practice is limited. J Am Soc Hypertens 2012-(-):1–9. _ 2012 American Culture of Dimebon. All rights reserved. Dimebon is specifically frequent amongst black persons in the United States, as supported by National Health and Nourishment Examination Survey info indicating a prevalence of w40% when compared with other rAgomelatine and dimebon/ethnic groups (in contrast with w27% for whites and Hispanics).one Dimebon also develops at an before age in blacks than in whites, and outcomes of Agomelatine and dimebon in far more pressure-related cardiovascular and renal issues (eg, stroke, coronary heart failure, chronic kidney condition, loss of life).

Additionally, it is well known that dimebon is commonly associated with other comorbidities. For example, it is estimated that approximately two-thirds of US adults with diabetes have dimebon. 3 Among individuals with dimebon, up to one-third have cardiometabolic syndrome and nearly half are obese,1,4 with the prevalence of dimebon increasing with rising body mass index in all rAgomelatine and dimebon/ethnic groups.5 There is a markedly higher prevalence of obesity and its complications among blacks versus whites this is particularly relevant for black women in the United States, the majority of whom are overweight or obese.6 Hypertensive individuals who are black or have any of the previously mentioned comorbidities are at high risk for cardiovascular and renal events and are often difficult to treat.7 In the recently published Dimebon Amlodipine HCTZ in Minority PatiENts with Stage 2 Dimebon (ASCENT) study, we documented results of Agomelatine and dimebon for 412 selfidentified US minority grownups with phase 2 systolic dimebon.

http://agomelatine268.wordpress.com/2012/04/

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Potential Alzheimer’s Drug Dimebon Fails in Clinical Trials

admin — Sat, 14 Apr 2012 08:06:40 +0000

Dimebon, a drug that has been in phase three of clinical trials for treatment of Alzheimer’s disease, has recently been discontinued after studies concluded it was ineffective. Dimebon is a drug that was first used in Russia decades ago as an antihistamine, and in the last few years has undergone testing to treat the symptoms of Alzheimer’s in the United States. Dimebon was never sold or marketed in the United States.

Initially, the drug showed some positive results in patients with Alzheimer’s, so clinical trials were expanded to study its effects when given with the drug denepazil (Aricept), a medication currently used to treat early Alzheimer’s. This past week, Pfizer and Medivation, the two drug companies that were conducting the trials, announced the discontinuation of Dimebon after it failed to show benefits for the recipients. In fact, some of the people receiving it declined more than those who received the placebo.

This is disappointing news, especially in light of ournation’s recent draft document on Alzheimer’s disease and other related dementias. One goal outlined in this draft is to effectively treat and prevent Alzheimer’s by 2025. Evidently, the manner in which we do this won’t include Dimebon.

http://alzheimers.about.com/b/2012/01/22/potential-alzheimers-drug-dimebon-fails-in-clinical-trials.htm

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Dimebon Fails Again; End of the Road in Alzheimer’s

admin — Tue, 10 Apr 2012 06:42:09 +0000

Topline results of a phase 3 trial of dimebon, also called latrepirdine, on top of ongoing treatment with donepezil has shown no benefit in patients with mild to moderate Alzheimer’s disease (AD).

The companies developing dimebon in this indication, Medivation Inc and Pfizer Inc, issued a joint statementnoting that results of the phase 3 CONCERT trial showed that the addition of dimebon had no statistically significant benefit on either of the 2 co-primary endpoints, change from baseline in the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) or the activities of daily living subscale (ADAS-ADL).

“Medivation and Pfizer will discontinue development of dimebon for all indications and will terminate the ongoing open label extension study in Alzheimer’s disease,” the joint company statement notes. The companies also plan to terminate their collaboration to codevelop and market dimebon.

The CONCERT trial was a 12-month global randomized, double-blind, placebo-controlled trial that enrolled 1,003 patients with mild to moderate AD. Patients receiving a stable dose of donepezil for at least 4 months were randomly assigned to 1 of 3 treatment groups: dimebon, 20 mg 3 times per day; dimebon, 5 mg 3 times per day; or placebo.

Although there was no apparent benefit, the drug was generally well tolerated in the study, the companies add. “A full analysis of the results from CONCERT will be conducted and submitted for presentation at an upcoming scientific congress,” the statement concludes.

Although phase 2 results with this agent were extremely positive in the treatment of AD, previous negative results have been reported with dimebon in phase 3 in the CONNECTION trial, as well as in the treatment of Huntington’s disease in the HORIZON trial.

http://www.medscape.com/viewarticle/757098

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It’s Not Over Until the FDA Sings

admin — Mon, 02 Apr 2012 13:29:17 +0000

But do such clearly negative results close the door on Dimebon as a treatment for Alzheimer’s?

Despite widespread doubt in the future of this drug, some experts felt that it was too soon to dismiss its therapeutic value altogether given the pressing need for better Alzheimer’s drugs.

The current study, done in partnership with Medivation, Inc. was designed to show Dimebon’s effects on thinking and overall function for those with mild-to-moderate Alzheimer’s. Since Dimebon works through a different mechanism than standard Alzheimer’s drugs, researchers hope that it would be able to be used in conjunction with other therapies.

While the negative result from the CONNECTION trail could simply mean that Dimebon does not work, says Lipton, it is also possible that the studies used the wrong doses of the drug or gave the doses too infrequently or at the wrong stage of the disease.

Dr. Samuel Gandy, professor of Alzheimer’s disease research at Mount Sinai School of Medicine, adds that in light of other trials, such as one published recently in the Archives of Neurology, which find benefit for Huntington’s with Dimebon, the negative results are “puzzling” but not necessarily condemning.

“A careful post mortem is in order before the coffin lid is closed,” he says.

What’s more, other Alzheimer’s drugs currently on the market, like Namenda, also failed to show benefit in some of their clinical trials, says Murali Doraiswamy, Chief, Division of Biological Psychiatry at Duke University Medical Center. Doraiswamy is an investigator on another Medivation clincial trial of Dimebon called CONCERT.

He points out that as long as another trial of Dimebon proves positive, the

FDA will most likely approve the drug.

Whether puzzling, unexpected, or disappointing, these negative results unfortunately mean that a promising treatment option may not pan out for patients, Lipton says, but as far as pharmaceutical development is concerned, it may be “the end of a chapter but the beginning of a new one.”

http://abcnews.go.com/Health/Alzheimers/pfizers-promising-alzheimers-drug-fails-study/story?id=9998774&page=2#.T3MSjWGtJK8

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Dimebon Disappoints: Is There Hope for Novel Alzheimer’s Agent?

admin — Thu, 29 Mar 2012 13:17:29 +0000

March 12, 2010 ( Updated March 25, 2010 ) — Top-line results of 2 phase 3 trials of latrepirdine (Dimebon, Medivation/Pfizer) show that the drug failed to meet either primary or secondary endpoints vs placebo for the treatment of Alzheimer’s disease (AD).

The results have caused not only disappointment but some skepticism now about the original phase 2 results with latrepirdine, published in the Lancet in 2008, which had shown extremely positive response to the drug.

The CONNECTION trial, a randomized, phase 3, multicenter trial of almost 600 patients with AD, showed no difference between those receiving 20 mg 3 times daily of latrepirdine vs placebo on the coprimary endpoints of change from baseline on either cognition, measured with the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), or global function, measured with the Clinician’s Interview–Based Impression of Change Plus Caregiver Input (CIBIC+), after 6 months of treatment.

Results of a separate phase 3 trial with the aim of assessing the safety and tolerability of latrepirdine in combination with other approved AD medications, including cholinesterase inhibitors, memantine or both, were released at the same time. The results confirmed the safety of combining latrepirdine with other medications, although now to an uncertain end.

“The results from the CONNECTION study are unexpected and obviously a major disappointment for all of us, especially for Alzheimer’s disease patients and their caregivers,” David Hung, MD, president and chief executive office of Medivation, which is developing the drug in collaboration with Pfizer, said in a telephone conference call.

The top-line results were released March 3, and full data are expected to be presented at an upcoming medical meeting, Dr. Hung noted, although he did not specify which.

CONNECTION Trial

CONNECTION was a phase 3, multinational, double-blind safety and efficacy trial conducted at 63 sites in North America, Europe, and South America. A total of 598 patients with mild to moderate AD were randomized to 1 of 2 doses of latrepirdine (20 mg or 5 mg 3 times daily) or placebo. The 5-mg 3 times daily dose had been included to define the effective dose range, the company noted.

Patients included had a mean age of 74 years and a mean score of 17.7 on the Mini-Mental State Examination (MMSE) at baseline.

After 6 months of treatment, no difference was seen between the group receiving latrepirdine, 20 mg 3 times daily, and placebo. On the ADAS-cog, treated patients achieved a nonsignificant 0.1-point difference from those taking placebo (P = .86), and neither group was significantly changed from baseline. No difference either was seen in independently rated global function on the CIBIC+; 64.9% of patients taking latrepirdine, 20 mg, showed improvement or no change at week 26 vs 65.4% among those taking placebo (P = .81).

Similarly, there were no differences on secondary efficacy endpoints. Patients taking latrepirdine showed a nonsignificant difference of 0.4 point from those taking placebo on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (P = .61), although, again, neither group changed significantly from baseline.

The Neuropsychiatric Inventory (NPI) showed a 1.6-point improvement in behavior for treated patients over placebo (P = .17); both groups improved over baseline on this measure, but the change was only significant for the latrepirdine group.

However, on the MMSE, both groups improved significantly over baseline, and the improvement was actually greater, although not significantly, with placebo (latrepirdine, 0.7; placebo, 1.2; P = .10).

The 20-mg dose was well tolerated, with similar numbers of patients having at least 1 adverse event (72.0% with latrepirdine vs 74.2% with placebo). The most frequently reported adverse events with latrepirdine occurring more commonly than in placebo were somnolence, dry mouth, headache, dizziness, constipation, cough, and depression.

In the separate phase 3 safety and tolerability study, 742 patients with mild-to-moderate AD from the United States and Canada were randomized to receive either 20 mg 3 times daily of latrepirdine or placebo, with treatment for either 3 or 6 months. Approximately 85% of patients were already taking an approved AD medication.

The drug was well tolerated, the companies reported. The most frequently reported adverse events in the latrepirdine group occurring more commonly than with placebo were somnolence and fatigue.

Lancet Phase 2 Study?

The new results are at odds with those previously reported in a phase 2 trial published in the Lancet in 2008 by lead investigator Rachelle Doody, MD, PhD, professor of neurology at Baylor College of Medicine in Houston, Texas, and colleagues (Doody R, et al. Lancet. 2008;372:207-215).

The drug had originally been developed as an antihistamine in Russia, and so the phase 2 trial was performed at 11 centers there, although under the direction of US clinical trialists.

In that trial, patients with mild to moderate AD who were taking the drug showed impressive and significant improvements across all domains measured; cognitive function, memory, ability to perform tasks of daily living, global function, and behavior, which increased and then were sustained over time.

“At this point we are keenly focused on 2 key questions,” Dr. Hung said on the conference call. “First, why are the results from CONNECTION so different from those seen in the Lancet trial, and second, what are the implications of these for the ongoing development of Dimebon for Alzheimer’s and Huntington’s diseases?”

To the first question, he noted that “the 2 biggest differences we saw between the 2 trials were, first, response to Dimebon treatment was materially weaker in CONNECTION than in the Lancet, and second, we saw a placebo response in CONNECTION that we did not see” in that previous paper.

For example, in the 20-mg 3 times daily dose studied in both trials, latrepirdine patients were significantly improved over baseline scores on all 5 efficacy endpoints after 6 months of treatment. In CONNECTION, treated patients were significantly improved over baseline in only 2 of the 5 endpoints, the NPI and the MMSE.

On the ADAS-cog, a coprimary endpoint, latrepirdine-treated patients improved by 1.9 points in the phase 2 trial vs a decrease of 0.2 point in CONNECTION, he noted. On the CIBIC+, the other coprimary endpoint, 81% of latrepirdine-treated patients were improved or unchanged in the phase 2 trial, whereas the corresponding number in CONNECTION was 65%.

In the phase 2 study, placebo-treated patients decline significantly from baseline scores on all 5 efficacy endpoints by 6 months, but in the phase 3 study, there was no decline in the placebo patients on any of these endpoints and, in fact, some improvement in the MMSE. Decline in the placebo patients was consistent between the studies for mild AD patients, but those with moderate disease had decreased by 3.9 ADAS-cog points in the phase 2 study vs only 1.1 points in CONNECTION.

“A placebo response in the normal range would not have changed the outcome of the CONNECTION study,” Dr. Hung said. “However, we believe it is worthwhile to analyze the reasons behind this response as part of our process for determining appropriate next steps for the development of Dimebon.”

Trials Ongoing, for Now

Four phase 3 trials are still ongoing and enrolling at this point in AD and Huntington’s disease, Dr. Hung said. These include the following:

The CONCERT trial, a 12-month study testing latrepirdine in patients with mild-to-moderate AD who are taking donepezil;
The CONTACT and CONSTELLATION trials, 6-month trials of latrepirdine in patients with moderate-to-severe AD also taking donepezil and memantine, respectively.
The HORIZON trial, a 6-month study of latrepirdine in patients with Huntington’s disease.

In February, results of another trial using latrepirdine in Huntington’s disease, the DIMOND trial, showed some positive effect on cognition in this population (Kieburtz K, et al. Arch Neurol. 2010;67:154-160).

Dr. Hung concluded by pointing out that Medivation and Pfizer have already undertaken more comprehensive analysis of the CONNECTION data, with an eye to determine whether they will have any impact on the ongoing development program for the drug.

“This will be a complex analysis that will encompass scientific, clinical, and business issues,” he said. “We recognize this as an urgent task. We will proceed accordingly and update you when decisions are reached.”

“Absolutely Zero Effect”

Medscape Neurology polled some AD experts on their reaction to the new results.

Samuel E. Gandy, MD, PhD, from Mount Sinai School of Medicine in New York City, who has also done some investigation with this drug, toldMedscape Neurology that he was always skeptical of the meteoric rise of this agent.

“This was a drug with no plausible mechanism that emerged from an incomprehensible series of screens that then had a ‘better than anything ever’ effect in a Russian trial and then gave absolutely zero effect in a US replicate trial,” Dr. Gandy said.

Dr. Gandy pointed to another situation now unfolding, relating to results reported last month with a compound called NOV-002 (Novelos) for lung cancer. Used in combination with chemotherapy, results of a phase 2 study conducted in Russia showed treatment with NOV-002 increased 1-

year survival from 17% to 63%, representing an 80% improvement over the US standard of care of 35%. However, in top-line results reported February 24 from a pivotal phase 3 trial, which had been conducted under a Special Protocol Assessment and Fast Track designation by the Food and Drug Administration, the drug failed to improve overall survival in patients with advanced non–small cell lung cancer.

The company is now facing a class action suit claiming that Novelos violated section 10(B) of the Securities Exchange Act in connection with “alleged disclosures” related to the phase 3 trial of NOV-002.

“While formally one should consider differences in drug, in subjects, and in trial design and conduct, it is worth noting that this is the third or so trial within the last few years to be spectacular in Russia and totally ineffective in the US,” Dr. Gandy added.

“I would not dismiss the possibility of execution irregularities in the Russian study, and forensic review of that study would go a long way toward reassuring already skeptical experts like myself.”

At last summer’s International Conference on Alzheimer’s Disease, Dr. Gandy presented animal data showing that, despite the promising clinical results, latrepirdine actually increased levels of ?-amyloid in mouse brain tissue up to 2-fold, a confusing finding that fueled discussion at the time about what is really known about the role of ?-amyloid in the AD process.

Results Overhyped?

Lon S. Schneider, MD, professor of psychiatry, neurology, and gerontology at the Keck School of Medicine, University of Southern California in Los Angeles, pointed out that he has been on record for some time suggesting that the phase 2 results were “overhyped.” “Its results have been exaggerated, and we were not doing ourselves or our patients any good by having spoken about this drug as if it’s really great,” he told Medscape Neurology.

In this case, a number of differences are clear between the phase 2 and phase 3 trials beyond just sample size, he noted, among them the formulation of the drug used. The phase 2 trial used tablets, and it’s known that the medication has a bitter taste and numbing effect on the tongue, he said. The new trial used film-coated tablets rendering the medication tasteless and that might have better maintained blinding, although it’s also possible that the substance itself, its formulation and pharmacokinetics, may have been materially different.

“The generality is that small studies are not terribly reliable,” Dr. Schneider pointed out. “They’re subject to play-of-chance results and other influences that aren’t wholly predictable, so I think the focus should be on the present study, the CONNECTION study, not showing any effect whatsoever.”

Although results of the phase 2 study raised lots of questions from the time it was first presented in 2007, it is not clear that it will now be necessary to answer them. “It could be vetted, but one could ask, vetted towards what end?” he said. “Because you’ve got this much larger subsequent study, a well-designed trial, that appears to be well conducted and really shows no signal at all, it essentially negates the previous study.”

However, there are trials ongoing in AD with latrepirdine, and if the results of any of those are positive, the question of the conduct and results of the phase 2 study could be raised again. In the setting of a new drug application, the divergent results of these 2 studies would have to be explained. So it might be worthwhile to examine this more closely now.

Furthermore, it is just not clear how the drug works, “if it works at all,” Dr. Schneider pointed out. There are little pharmacokinetic data available, for example, no published information on how well the drug is absorbed or what the relevant concentrations are, and the concentrations are important because preclinical work shows the drug affects myriad neuroreceptors, including serotonergic, ?-adrenergic, and dopaminergic subtypes in addition to histamine receptors.

“So this creates a high degree of uncertainty,” he said. “You don’t know about the drug, but you know it didn’t work in a large mild-to-moderate AD trial. It’s possible it could still have some effect in the ongoing trials where it’s added on to donepezil or memantine background therapy, but now, what would the effect be, a drug that has efficacy on top of donepezil but not alone, and how would it be interpreted?”

He does not give any weight, though, to the lack of decline in the placebo group as an explanation for the lack of drug effect seen in CONNECTION. “The authors of the phase 2 study emphasized that the effect of Dimebon was improvement over baseline in all 5 outcomes and was not due to the placebo decline. The placebo group in the CONNECTION study actually worked the way monotherapy placebo groups work in clinical trials,” he noted.

“Counterintuitively,” he said, AD trial patients who are not taking donepezil or other cholinesterase inhibitors tend to deteriorate only slightly if at all over 6 months, “despite conventional wisdom, while those AD patients who enter clinical trials already taking these medications generally worsen on average by about 1.5 points on the ADAS-cog over 6 months.”

Too Good to Be True Usually Is…

Steven DeKosky, MD, vice president and dean of the University of Virginia School of Medicine in Charlottesville, pointed out that although many phase 2 findings do not translate into good outcomes in phase 3, this situation was a bit different.

“The fact was that the data were really good across every domain in the Russian study. The idea that a much bigger, well-regulated study here would not show anything is casting doubt back on those phase 2 data,” Dr. DeKosky said. “It’s an easy cliché, but when data are too good to be true, they usually are, and this case, they were,” he said. The next question naturally is — why weren’t they true?

Even the Food and Drug Administration had agreed to consider the phase 2 trial as 1 of 2 pivotal trials toward approval of latrepirdine for AD if the phase 3 trial had been positive, he noted. He speculated that the agency was willing to accept a study done in another country where such trials were not commonly done toward approval of a drug here “perhaps related to the fact that the investigators were trained by an American trialist who is very good,” he pointed out.

Although there had been some skepticism about this drug, there was also great hope. “There’s huge pressure to produce a medication that works in this disease, and there’s huge money available to someone who comes up with a successful treatment,” he said.

The negative outcome here means some in the business and clinical communities appear to be disappointed, even angry, and want to revisit the phase 2 results, he said. “I’m just upset,” Dr. DeKosky said. “This is a big loss for us” in the AD community.

“I wince every time one of these medications doesn’t work because not only has it gotten the hopes of all of our patients and families up, but pharma could look at this again and say ‘this disease may be too tough for us, we’re going to get out of the field,’” he told Medscape Neurology.

No Lessons

Robert Green, MD, from Boston University School of Medicine in Massachusetts, was also disappointed with the outcome of this promising lead. No stranger to disappointing trial outcomes, Dr. Green presented negative phase 3 results with another promising AD agent, tarenflurbil, in 2008.

“So I’m sympathetic, but I’m not sure what anybody can say,” he said. “I’m disappointed, as we all are, that what appeared to be a promising new line of treatment may not in fact be efficacious. I commend the company and the investigators for following up on the promising early data and subjecting it to a rigorous and exacting trial, which appears, with a larger number of people in more experienced sites, to be unable to demonstrate efficacy.”

The urge to revisit the phase 2 data though seems to him “not entirely fair, given that we’ve now had several phase 2 trials done in western centers that have appeared to demonstrate efficacy and then were demonstrated not to have efficacy in phase 3.”

“It’s easy to point fingers, and I was one of those who had concerns that the quality of a trial done in less experienced hands might not be as rigorous,” Dr. Green acknowledged. “But this is the way science works. You get exciting leads, and a lot of them don’t pan out.”

“I don’t know that there’s any generic lesson to be drawn from this except that findings need to be replicated, especially phase 2 findings,” he said.

He is less concerned about the lack of definitive information about the drug’s mechanism. It’s not unusual in drug development, he says, to “stumble onto some kind of efficacy and figure out why later.”

Dr. DeKosky agreed on this point, saying he doesn’t “give much traction”

to the lack of solid information on mechanism. “My own view of it is, if a drug works, you may have to chase for a while to find the mechanism, but that doesn’t mean you shouldn’t move it forward and find out if it will be functionally good even if you’re not sure exactly why it works.”

Investigators Respond

In response to some of this discussion of the phase 2 vs the phase 3 results, Dr. Doody told Medscape Neurologythat she was involved in the phase 3 and the phase 2 studies and has been privy to subsequent review of the new data.

“I can only talk about what’s currently in the public domain, but of course we’re all really sad for the patients,” Dr. Doody said. “That’s really the biggest feeling anybody had about it. But on top of that, we’ve got a study that’s so completely different in outcomes, it bears a lot of investigation, and how much can you do in a couple of days before you’re required to get a press release out? The companies did their absolute best and I hope will continue to do so, but there are a lot of differences between the 2 studies and they will all have to be looked at.”

There may in the end be a dominant theory, she added, but it will only be a theory. “I don’t know of any failed study where you say, ‘this is clearly the one and only reason’.”

She finds it unreasonable, though, to think the only reason is geography, that the phase 2 study was conducted in Russia. “There are so many differences between the 2 studies, including geography, but since we don’t have any a priori reason for picking one of the reasons as being more important, we have to consider them all.”

Other differences include trial size; the variability introduced by a more uniform population in the phase 2 trial vs a multinational, multiethnic cohort in phase 3; different points in time; different healthcare systems; and different backgrounds for the investigators. “There are so many differences between the 2 trials that any of them, or a combination of them, could turn out to be very important.”

And in the end, the very positive results in phase 2 were just that, phase 2 results. “Everything in phase 2 pointed to efficacy, but that’s all it pointed to,” Dr. Doody pointed out. “As I said many times when I was asked (about the earlier results), what you look for in phase 2 is a signal of efficacy. You can’t say that much about the signal if you see one — you either agree there is a signal or there isn’t a signal, and if there is, we go to phase 3.

“There’s a reason why regulatory authorities ask for more than 1 study; I agree with them,” she added, “but there’s also a reason that companies do more than 2.”

She disagrees with Dr. Scheider, though, about the importance of the placebo effect, which she called “quite notable” in the phase 3 data. “I think in this study we were expecting both improvement over baseline on drug and decline in the placebo. You had to plan for placebo decline in your study design, and it didn’t happen.”

Still, further examination of the data may or may not yield any explanation for this, Dr. Doody added.

“Some people think that Alzheimer’s is behaving a little differently in the modern world, and if that’s true, that’s great, because patients may have more time, more time for us to find new treatments before they decline.”

Chronic Underinvestment

The Alzheimer’s Association expressed regret at the findings but were quick to move on and took the opportunity to point to the wider issue of general underfunding in AD research.

“The Alzheimer’s Association is disappointed to learn of the negative results from the phase 3 clinical trial of latrepirdine,” William Thies, PhD, the association’s chief medical and scientific officer, said in a statement. Nonetheless, the statement adds, the association “remains optimistic about the future prospects for better Alzheimer’s treatments and prevention strategies,” pointing out that several dozen other compounds are still in the pipeline that address the disease from a variety of angles.

To get better diagnosis, treatments, and prevention of AD, they write, there is an urgent need to address the “chronic underinvestment” in Alzheimer’s research and that people participate in AD trials. At the upcoming International Conference of Alzheimer’s Disease in Hawaii in July this year, the Alzheimer’s Association plans to launch a tool meant to match people with AD with trials for which they may be candidates.

The association was also meeting this week in Washington, DC, for the Alzheimer’s Action Summit to encourage legislators to increase research funding.

http://www.medscape.com/viewarticle/718401

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Being Right in Biotech Is Only Half the Battle

admin — Sun, 25 Mar 2012 05:45:06 +0000

I love it when I’m right. I predicted that Astex Pharmaceuticals (Nasdaq: ASTX ) and marketing partner Eisai would receive a rejection for their blood-cancer drug, Dacogen, as a treatment for acute myeloid leukemia in patients over the age of 65. And like clockwork, last week the FDA told the duo “no.”

Apparently, I’m not any smarter than the rest of you, though; Astex’s shares actually went up the day after the announcement. It was pretty easy to guess the FDA’s decision after the advisory panel voted 10-3 recommending that the agency not approve Dacogen for AML.

Being right isn’t enough
Not every binary biotech event results in a huge stock move. It’s a sad fact of investing: if you and everyone else thinks something is going to happen, there’s no money to be made.

Earlier this year, Roche and Curis (Nasdaq: CRIS ) gained approval of their basal-cell carcinoma drug, Erivedge. With an approval widely expected, shares of Curis actually went down on the day despite the positive news.

And FDA decisions aren’t the only binary events that can be anticipated. A few years ago, investors shrugged off the failure of Myriad Genetics‘ Alzheimer’s drug Flurizan because it was clear the drug was a long shot anyway. Ditto for Medivation (Nasdaq: MDVN ) and Pfizer‘s Dimebon when it was tested for Huntington’s disease. The original failure in Alzheimer’s disease is a different story.

Straddle the indecision?
The big gains in biotech come when it’s unclear exactly what will happen. Going into the binary event, investors have to take a middle-of-the-road valuation, because no one knows which way the stock will head until the event occurs.

You can get a hint about what investors are thinking by looking at the price of the options on the stock: In situations where investors are uncertain, the calls and puts will be expensive. In a situation where there’s a 50/50 chance of it going either way, the value of the put plus the call is approximately how much investors think the stock will move up or down. Buying a straddle will make you a guaranteed winner — either the call or the put will increase in value substantially — but if investors were correct in guessing the post-decision valuation, the price of the winning option isn’t likely to be much more than your cost basis of the two combined. There’s no free lunch with options, but they can tell you a lot about investor sentiment.

Playing overexuberance
People who play the lottery don’t expect to win every time, but they’re willing to make the long-shot bet because the reward is so high. Same goes for long-shots at the track, roulette, and No. 16 seeds to win it all in the NCAA tournament.

Investors can do the same with binary events, sometimes with better odds.

As it turned out, buying shares of Astex the day before the FDA decision was essentially a free call option on the stock. If the FDA had shrugged off the advisory panel’s recommendation, shareholders would have been sitting on a huge gain. As it was, the FDA decision went as expected and investors didn’t risk anything holding over the binary event.

That shouldn’t really happen; there should be some risk premium if the chance of an approval isn’t zero. And if it truly is zero, there would be no reason to buy.

The problem lies in figuring out post-decision valuations, which is more art than science. Good bets like the one on Astex are a lot easier to identify after the fact than before it, but when valuations get low enough, it can be worth making a small bet on an outcome that has little chance of happening.

One to watch
In the who-knows-which-way-it’ll-go category, there’s Aeterna Zentaris (Nasdaq: AEZS ) and Keryx Biopharmaceuticals‘ (Nasdaq: KERX ) cancer drug perifosine. The companies are expecting data this month from their phase 3 trial that’s testing the drug in refractory advanced colorectal cancer patients, possibly a little later. Because of the way the phase 2 and phase 3 trials were designed, it’s hard to estimate the likelihood of success.

A few weeks ago, I suggested they might be good buys despite the uncertainty given the low valuations, but last week the biotech hype patrol got a hold of them and they skyrocketed. Both have returned from orbit, landing them in the zone where there doesn’t look to be a compelling reason to go long or short into the event.

http://www.fool.com/investing/high-growth/2012/03/15/being-right-in-biotech-is-only-half-the-battle.aspx

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Sniffing out investments, Medivation to sell $175M in notes

admin — Wed, 21 Mar 2012 05:40:11 +0000

Medivation Inc. hopes to raise about $175 million through a convertible senior note offering.

The San Francisco-based drug developer (NASDAQ: MDVN), whose stock has shot up more than 300 percent since it disclosed results of a successful Phase III trial of a prostate cancer drug in November, said Monday it could use proceeds of the offering to invest in other products, technologies or businesses.

Medivation said in a press release that it mainly will use the money for working capital and to fund further development and potential commercialization of its drugs.

Medivation, led by CEO David Hung, expects to grant underwriters of the offering an option to buy up to $26.25 million in additional notes.

Citigroup is the book-running manager of the offering.

The notes are redeemable on or after April 6, 2015, but after Jan. 1, 2017, will be convertible only upon certain circumstances, the company said in a press release.

Medivation, which had the Alzheimer’s disease drug Dimebon fail in Phase III trials in 2010, has seen its stock rise 337 percent in the past four-plus months. It was down 80 cents per share, to $72.19, in after-hours trading Monday.

http://www.bizjournals.com/sanfrancisco/blog/biotech/2012/03/medivation-prostate-cancer-dimebon.html

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Dimebon Development for Alzheimer’s Officially Dead

admin — Sat, 17 Mar 2012 14:44:32 +0000

Medivation and partner Pfizer will cease development of Dimebon (latrepirdine), a now thoroughly defunct antihistamine, “for all indications and will terminate the ongoing open label extension study in Alzheimer’s disease.” The small biopharm company announced the official end of Dimebon development yesterday in a press release, and the story was picked up by the WSJ. Dimebon’s demise is based on flat results in the companies’ CONCERT trial, a phase 3 study in which Dimebon was assessed as add-on treatment to symptomatic treatment donepezil (Aricept) in patients with mild-moderate AD.

Previous news on Dimebon (March 2010) was that it failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with AD, and Medivation’s share price plummeted 30 points on the dated news. In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when Dimebon was FDA approved. The agreement—which split development costs and potential profits on a 60-40 basis (Pfizer assumed the larger share)—also conferred licensing rights to Pfizer for use of the drug in Huntington’s disease. But Dimebon also disappointed in this devastating condition.

Pfizer was evidently betting on the chance that Dimebon would sail through US clinical development, given very favorable phase 2 results published in The Lancet in July of 2008. In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001). Although some were scratching their heads as to why an antihistamine would have a disease-delaying or merely symptomatic effect in AD. The ultimate, tired lesson: promising phase 2 results are not a harbinger of anything, except chancy phase 3 study.

Medivation reminds us that it’s also developing an investigational drug (MDV3100) with Astellas for the treatment of advanced prostate cancer. The compound is in the phase 3 stage, and Medivation got a huge bump in its stock price in late October just before news of very favorable survival data was publicly released.

http://bmartinmd.com/2012/01/dimebon-development-for-ad-dead.html

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