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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Dimebon Dimebolin Information Availability

Pfizer and Medivation reported Monday that the experimental drug Dimebon (latrepirdine) failed to meet either of the main goals in a late-stage trial for patients with Huntington disease. Medivation CEO David Hung said that the companies would “discontinue development of Dimebon in Huntington disease, including the ongoing open-label extension study.”

The HORIZON trial randomised 403 patients with Huntington disease to receive Dimebon three-times daily or placebo for six months. Data suggested that no statistically significant improvements were observed between the two groups in a measure of cognition or clinician’s impression of improvement in global function.

Hung noted that the Phase III CONCERT trial investigating the agent in patients with mild-to-moderate Alzheimer’s disease would continue, with top-line data expected “in the first half of 2012.” The drug previously failed to show effectiveness in treating Alzheimer’s disease in the late-stage CONNECTION trial.

http://www.firstwordplus.com/Fws.do?articleid=B46580191B5548278A60D2204BF85ACB

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Dimebon

Medivation and partner Pfizer are discontinuing development of dimebon (latrepirdine) for the treatment of Huntington disease due to its failure to show benefits in the Phase III Horizon trial. The Horizon trial found dimebon therapy had no beneficial effects in terms of either the mini-mental state examination (MMSE), which measures cognition, or the clinician’s interview-based impression of change plus caregiver input (CIBIC-plus) assessment, which measures global function. An ongoing open-label extension study will also be stopped.

Medivation and Pfizer are separately evaluating dimebon in a Phase III Concert study in Alzheimer disease patients and an associated open-label extension study. Topline data from Concert are expected during the first half of 2012.

Medivation teamed up with Pfizer to develop dimebon for the treatment of Alzheimer disease and Huntington disease back in 2008. Medivation received an up-front cash payment of $225 million and potentially another $500 million in development and regulatory milestones.

http://www.genengnews.com/gen-news-highlights/phase-iii-failure-leads-medivation-and-pfizer-to-ditch-dimebon-for-huntington-disease/81244981/

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A potential Alzheimer’s drug that had seemed to perform spectacularly well in a medium-scale clinical trial has now been shown in a larger and more conclusive trial to have no apparent effect on the disease.

The surprising failure of the drug, known as dimebon, is yet another disappointment for Alzheimer’s researchers as well as patients and their families. It also raises questions about the conduct and design of Alzheimer’s clinical trials, particularly in Russia where the initial dimebon trial took place.

“The prior doubts about the Russian trial appear to have been borne out,” says Sam Gandy, an Alzheimer’s researcher at Mount Sinai School of Medicine.

Dimebon (generic name latrepirdine) was originally developed and briefly used as an antihistamine in Russia in the 1980s. It began to be re-evaluated as a potential Alzheimer’s drug in the 1990s, after Russian researchers reported that it seemed to boost the levels of memory-related neurotransmitters in lab tests on brain cells.

A San Diego-based company, Medivation, Inc., eventually began clinical trials of dimebon in Russia, where the drug was already approved for use. In 2008, astounding results were reported in 183 Russian patients whose Alzheimer’s dementia was classified as “mild-to-moderate.” Half had received dimebon at a dose of 20 mg thrice daily, and half had received a thrice-daily placebo. After six months, the dimebon group scored much higher on standard tests of cognition and quality of life, and follow-up studies suggested that the progression of the disease had been stopped. The apparent “treatment effect” was the largest ever reported for an Alzheimer’s drug trial.

Some researchers expressed concern that such a powerful result was too good to be true, particularly since no one really knew how dimebon worked against Alzheimer’s. However, several well-known U.S. clinical trial experts had observed the Russian study and vouched for its validity. Other researchers soon reported evidence from laboratory studies that dimebon might be able to boost the general survival ability of neurons in a way that could make them resistant to other neurodegenerative diseases too (see “Hope and Caution on Russian Antihistamine Drug for Alzheimer’s”).

Unfortunately, dimebon seemed only weakly effective in a small-scale clinical trial in people with Huntington’s disease; its results were reported in February. And on March 3, dimebon’s candidacy as an Alzheimer’s drug was most likely terminated.

On that day, Medivation reported results from a large, apparently definitive trial of dimebon in 598 people with Alzheimer’s in North America, South America, and Europe. Those results suggest that dimebon, while safe, is completely ineffective against Alzheimer’s disease. The data failed to show even a hint of a consistent impact on patients’ cognition and quality of life, compared to a placebo.

In recent years, a number of Western drug companies have used Russian hospitals as a relatively inexpensive proving ground for early-stage drug development. However, in at least one other case, a positive result from a Russian trial has failed to translate to a larger, more rigorous Western trial.

Gandy says he wonders whether “something is systematically wrong over there.”

In the case of dimebon, not only the early clinical trial results but also a significant amount of laboratory work appears to be of questionable value. Over the past few years, researchers who were eager to find dimebon’s mechanism of action against dementia have reported, for example, that it blocks the toxicity of amyloid beta aggregates found in Alzheimers, or that it enhances the survival of mitochondria. If nothing else, the case underscores the weakness of such laboratory evidence in the absence of data in people that confirms it.

“At the moment I don’t think that any of these effects is clinically important,” said Gandy, whose own research group recently found that dimebon actually increases amyloid beta levels outside cells, in lab dish and animal experiments.

To some researchers, the dimebon failure, and the failure of many other Alzheimer’s drug candidates to date, points to a larger problem:  The treatments are started too late in the course of the disease.

“What you want in such trials are people who are just starting to lose neurons, but typically by the time an Alzheimer’s patient goes to see a neurologist, his or her brain has already been severely damaged,” says Jeffery Kelly, an investigator at the Scripps Research Institute in La Jolla, California, whose work has focused on amyloid-associated conditions. “Considering the way the Alzheimer’s trials are being done now, I’m not sure that even a great drug could be discerned as such.”

Gandy agrees:  “I think that our best chance for impact on this disease is presymptomatic intervention and prevention.”

http://www.dana.org/news/features/detail.aspx?id=25798

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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.”

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

http://www.dimebonalzheimers.com/

Winnipeg Alternative Therapies

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.

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

http://www.dimebonalzheimers.com/

Winnipeg Alternative Therapies

Winnipeg Manitoba  Mainstay Hotels

NDIANAPOLIS (TheStreet) — Eli Lilly(LLY) was forced to halt development of an experimental Alzheimer’s disease drug after an early look at results from two late-stage clinical trials determined the drug to be ineffective.

Lilly shares fell 2% to $34.75 in Tuesday’s pre-market trading on news of the setback for the Alzheimer’s drug semagacestat, one of two drugs being in the company’s pipeline that are in late-stage studies against the neuro-degenerative disease.

The failure of semagacestat will also heighten concerns about Lilly’s future growth given the looming loss of patent protection through 2014 on drugs that presently account for 60% of the company’s revenue.

Tuesday, Lilly said it would take a charge of 3-4 cents a share in the third quarter to account for the halting of the semagacestat clinical trials. The company reiterated 2010 guidance of $4.44 to $4.59 a share on a reported basis.

The two phase III clinical trials of semagacestat enrolled more than 2,600 patients with mild to moderate Alzheimer’s, randomizing them to treatment with semagacestat or a placebo. An interim analysis of the studies found that semagacestat-treated patients were performing worse on tests of cognition and ability to complete daily living tasks compared to patients treated with a placebo. In addition, semagacestat patients were at a higher risk for developing skin cancer.

Lilly said Tuesday that phase III trials involving the company’s other late-stage Alzheimer’s drug solanezumab are continuing. Both semagacestat and solanezumab are designed to reduce the levels of amyloid beta plaques, protein substances that attach to and destroy neurons in the brain. Amyloid beta is thought to one of the causes of Alzheimer’s.

Semagacestat works by inhibiting an enzyme, gamma secretase, which the body uses to form amyloid beta plaques.

Earlier this year, Pfizer(PFE) and Medivation(MDVN) said a phase III study of their Alzheimer’s drug Dimebon also failed, although additional clinical trials of that drug continue.

Dimebon

http://www.dimebonalzheimers.com/

overtimeautoapprovals

24hourautofinance.com

Edmonton 2010 Mazda Tribute

Pfizer Inc. and Medivation Inc. studying a 27-year-old hay fever treatment for patients of Alzheimer’s disease, say it is possible it may also help those with Huntington’s.

According to research published in the Archives of Neurology today, the drug Dimebon is said to improve mental functioning and awareness in patients with Huntington’s, a degenerative neurological disorder running in families.

Karl Kieburtz, lead author of the study says, since there are no treatments for the psychological effects of Huntington’s affecting 25,000 people in North America, these findings are immensely encouraging and offer hope. Typically, beginning in middle age, symptoms of Huntington’s include muscle twitching, aggression, depression, orientation and memory loss.

The drug will be studied in a larger, long-term study to find out whether the benefits are due to the drug’s efficacy or simply due to chance.

However, because of Dimebon’s effect on mitochondria i. e. parts of cells that convert food into energy, improving cell function and helping them withstand stress, scientists believe it may help patients of Huntington’s disease, as well as those with Alzheimer’s.

For the study, 91 patients taking either Dimebon or a placebo for three months were evaluated, and it was found those taking Dimebon seemed more likely to give the correct answer to questions about what year it was, where they were, while counting backward and recalling words over a brief period of time.

No impact of the drug was found on a broader assessment measuring motor function, cognition and behaviour, nor was any benefit noticed while measuring cognition in Huntington’s patients taking the test developed for patients of Alzheimer’s disease.

San Franscisco-based Medivation and Pfizer in New York, as part of the third and final stage of testing required to get U. S. regulatory approval for Dimebon are working on a six month study involving 350 Huntington’s patients.

An experimental drug called latrepirdine used since 1983 to treat hay fever in the former Soviet Union, but not any more, was acquired by Medivation and Pfizer, who purchased the rights to the drug, after Russian researchers screening compounds for potential effects on the brain found it appeared to stabilize mitochondria, the power source of brain and other cells.

The results of the larger Phase 3 trial now under way are expected later this year.

Dimebon Alzheimer’s Disease

http://www.dimebonalzheimers.com