Safely increase Aricept dosage

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Chase

DEMENTIA DRUGS: Donepezil (Aricept) boosts memory & thinking in Alzheimer's. More donepezil means more boost - along with intensified side-effects. A key trial shows how donepezil can be safely boosted when combined with solifenacin. Find out more.

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IRVINE, California -- Donepezil helps Alzheimer's and other types of dementia. Doctors often minimize its use because it can have a variety of side-effects. Progressive research shows that by adding solifenacin to each pill of donepezil, a patient could potentially boost the dosage by as much as 400% without added side-effects.

Here's a simplified explanation of how it works.

Early-to-Midstage Alzheimer's
Brand Name	Generic Name
Aricept®	donepezil
Exelon®	rivastigmine
Remynil or Razadyne®	galantamine
Drugs for Moderate-to-Severe Stage
Namenda® or Ebixa®	memantine

1. Acetylecholine is used by the brain to send messages from cell to cell.
2. If there is not enough acetylecholine in the brain, memory and thinking start to fail.
3. Alzheimer's often experiences dangerous drops in acetylcholine.
4. Donepezil helps boost the level of acetylcholine throughout the body.
5. This can help an Alzheimer's brain get back to normal. However, it can also overload other systems in the body, causing nausea, weight-loss and other side-effects.
6. The brain is separated from the rest of the body by the "blood-brain barrier".
7. A pill of donepezil travels from the stomach to the entire body. It passes through the blood-brain barrier, boosting acetylcholine in the brain.
8. Solifenacin is another drug that blocks donepezil. However, it CANNOT pass through the blood-brain barrier.
9. Therefore, it seems that solifenacin cannot get to the brain and as a result, cannot block donepezil in the brain.
10. At the same time, solifenacin can block donepezil everywhere else in the body, stopping side-effects like nausea in the stomach.
11. The result is no nausea or other side-effects in the body. The patient just gets the good effect in the brain.

For now, researchers call this combination of donepezil-plus-solifenacin by the name CPC-201. The new combination will mean that the brain can get the benefits of a lot more donepezil with fewer side-effects.

Chase Pharmaceuticals Corporation (Chase) announced its results from a Phase 2 study of CPC-201.

400%

The CPC-201 Phase 2 results, presented by Thomas Chase, MD, chief scientific officer and co-founder of Chase, and the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke, confirmed that solifenacin attenuated donepezil adverse events, enabling the tolerable administration of doses of donepezil to as much as 400 percent of the current standard treatment of donepezil. Secondary endpoints provided signals of enhanced efficacy, as would be predicted from increased tolerable dosing of donepezil. The data were presented during an oral session at the 2016 Alzheimer’s Association Conference (AAIC) in Toronto, Canada (Abstract a12446).

The primary endpoint of this Phase 2 single-blind, crossover trial was to safely increase the tolerated dose of donepezil from 10 mg/day up to as much as 40 mg/day. This trial consisted of 41 moderate (MMSE 10-20) Alzheimer’s type subjects who were being successfully treated with 10 mg/day of donepezil. The anticholinergic solifenacin was first titrated to 15 mg/day and then donepezil escalated to each subject’s maximum tolerated dose or to the protocol limit of 40 mg/day. Subjects then continued for a three-month maintenance period. All subjects were able to tolerably maintain above the currently approved doses of donepezil and 85 percent of subjects reached and tolerated the maximum allowable donepezil dose of 40 mg/day. Moreover, in the maintenance phase of the trial, subjects experienced significantly less dose-limiting side effects than those that would be predicted for 10 mg/day of donepezil. 

A Real Difference

Although this Phase 2 study was not designed nor powered to provide meaningful estimates of anti-dementia efficacy, both the ADAS-Cog and the CGI-I scales in the study yielded positive signals of enhanced efficacy. 

During the dose maintenance phase, at a median donepezil dose of 40 mg/day, total gastrointestinal adverse events were greatly attenuated and about 80 percent below those predicted from trials of previously approved doses of 10 mg/day of donepezil. As would be expected with a cholinergic blocker that does not cross the blood-brain barrier, solifenacin had no effect on cognitive function and there were no drug-related serious adverse events (SAE) or clinically significant cardiovascular or laboratory abnormalities. There were no drug related drop­outs and no new AEs or evidence of solifenacin toxicity.

“Pre-clinical studies have repeatedly shown that there is a strong dose/efficacy relationship associated with AChEIs. Further, PET scan studies in humans show that at the typical dose of 10 mg/day of donepezil, the central enzymatic inhibition is no greater than about 30 percent, substantially lower than that which would be expected from optimal dosing. Yet, historically, it has not been possible to tolerably increase the dose of donepezil to meaningfully higher levels,” said Douglas Ingram, chief executive officer of Chase. “We believe we have the means to finally unlock the true potential of optimally dosed AChEIs. Moreover, we are employing an efficient development and regulatory pathway and plan to commence a superiority trial versus the current gold-standard treatment for Alzheimer’s, 10 mg/day of donepezil. If successful in Phase 3, CPC-201 could be the new standard for the symptomatic treatment of Alzheimer's disease and benefit millions of suffering patients.”

What Do Aricept, Exelon & Razadyne Do?

Teepa Snow
MEDICATION VIDEO
See Teepa Snow talk about the top medications for Alzheimer's & dementia. In plain English, she explores what they do and how they work. Get clarity on Aricept, Exelon and Razadyne (generic donepezil, rivastigmine and galantamine).

Technical Talk

“We believe that adverse events have long limited AChEI dosing to suboptimal levels, in turn limiting the efficacy of donepezil and other AChEIs,” said Thomas Chase, M.D. “Our Phase 2 findings, together with those from our earlier Phase 1 studies, robustly support our hypothesis that the co-formulation of a peripheral anticholinergic with donepezil enables the safe and tolerable administration of multiples of the current standard of care doses of AChEI such as donepezil.”

The mean change in ADAS-Cog over the course of the study showed improvement versus subject baseline and, adjusted for underlying disease progression using a multi-study meta-analysis, subjects showed a mean (± SEM) benefit of 2.45 points over 10 mg/day donepezil or 5.4 ± .84 points compared to predicted untreated disease progression. Combined Clinical Global Impression (CGI-I) scores from investigators and caregivers at 26 weeks averaged 3.1 ± .20 points, thus improving by .94 ± .20 points (p < .001; n = 16). The responder rate (as measured by those who either did not worsen or improved over the course of the study) was over 90 percent.

MORE INFORMATION:

About CPC-201
Chase’s lead candidate, CPC-201, is a patent-protected combination of donepezil (an AChEI), one of the few pharmaceuticals proven to improve cognition in Alzheimer’s patients, and solifenacin, a peripherally acting cholinergic blocker.

Dementia-Quadrupling Donepezil

Caregivers, and healthcare professionals,here is some great information

Here is a great dementia resource for caregivers and healthcare professionals,

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Follow alzheimersideas on twitter

Alzheimer's and Dementia Weekly
Donepezil (Aricept) boosts memory & thinking in Alzheimer's. More donepezil means more boost - along with intensified side-effects. A new trial shows how donepezil can be safely boosted when combined with solifenacin. Find out more.

---

IRVINE, California -- Donepezil helps Alzheimer's and other types of dementia. Doctors often minimize its use because it can have a variety of side-effects. New research shows that by adding solifenacin to each pill of donepezil, a patient could potentially boost the dosage by as much as 400% without added side-effects.

Here's a simplified explanation of how it works.

Early-to-Midstage Alzheimer's
Brand Name	Generic Name
Aricept®	donepezil
Exelon®	rivastigmine
Remynil or Razadyne®	galantamine
Drugs for Moderate-to-Severe Stage
Namenda® or Ebixa®	memantine

1. Acetylecholine is used by the brain to send messages from cell to cell.
2. If there is not enough acetylecholine in the brain, memory and thinking start to fail.
3. Alzheimer's often experiences dangerous drops in acetylcholine.
4. Donepezil helps boost the level of acetylcholine throughout the body.
5. This can help an Alzheimer's brain get back to normal. However, it can also overload other systems in the body, causing nausea, weight-loss and other side-effects.
6. The brain is separated from the rest of the body by the "blood-brain barrier".
7. A pill of donepezil travels from the stomach to the entire body. It passes through the blood-brain barrier, boosting acetylcholine in the brain.
8. Solifenacin is another drug that blocks donepezil. However, it CANNOT pass through the blood-brain barrier.
9. Therefore, it seems that solifenacin cannot get to the brain and as a result, cannot block donepezil in the brain.
10. At the same time, solifenacin can block donepezil everywhere else in the body, stopping side-effects like nausea in the stomach.
11. The result is no nausea or other side-effects in the body. The patient just gets the good effect in the brain.

For now, researchers call this combination of donepezil-plus-solifenacin by the name CPC-201. The new combination will mean that the brain can get the benefits of a lot more donepezil with fewer side-effects.


Chase Pharmaceuticals Corporation (Chase) announced its results from a Phase 2 study of CPC-201.

400%

The CPC-201 Phase 2 results, presented by Thomas Chase, MD, chief scientific officer and co-founder of Chase, and the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke, confirmed that solifenacin attenuated donepezil adverse events, enabling the tolerable administration of doses of donepezil to as much as 400 percent of the current standard treatment of donepezil. Secondary endpoints provided signals of enhanced efficacy, as would be predicted from increased tolerable dosing of donepezil. The data were presented during an oral session at the 2016 Alzheimer’s Association Conference (AAIC) in Toronto, Canada (Abstract a12446).

The primary endpoint of this Phase 2 single-blind, crossover trial was to safely increase the tolerated dose of donepezil from 10 mg/day up to as much as 40 mg/day. This trial consisted of 41 moderate (MMSE 10-20) Alzheimer’s type subjects who were being successfully treated with 10 mg/day of donepezil. The anticholinergic solifenacin was first titrated to 15 mg/day and then donepezil escalated to each subject’s maximum tolerated dose or to the protocol limit of 40 mg/day. Subjects then continued for a three-month maintenance period. All subjects were able to tolerably maintain above the currently approved doses of donepezil and 85 percent of subjects reached and tolerated the maximum allowable donepezil dose of 40 mg/day. Moreover, in the maintenance phase of the trial, subjects experienced significantly less dose-limiting side effects than those that would be predicted for 10 mg/day of donepezil. 

A Real Difference

Although this Phase 2 study was not designed nor powered to provide meaningful estimates of anti-dementia efficacy, both the ADAS-Cog and the CGI-I scales in the study yielded positive signals of enhanced efficacy. 

During the dose maintenance phase, at a median donepezil dose of 40 mg/day, total gastrointestinal adverse events were greatly attenuated and about 80 percent below those predicted from trials of previously approved doses of 10 mg/day of donepezil. As would be expected with a cholinergic blocker that does not cross the blood-brain barrier, solifenacin had no effect on cognitive function and there were no drug-related serious adverse events (SAE) or clinically significant cardiovascular or laboratory abnormalities. There were no drug related drop­outs and no new AEs or evidence of solifenacin toxicity.

“Pre-clinical studies have repeatedly shown that there is a strong dose/efficacy relationship associated with AChEIs. Further, PET scan studies in humans show that at the typical dose of 10 mg/day of donepezil, the central enzymatic inhibition is no greater than about 30 percent, substantially lower than that which would be expected from optimal dosing. Yet, historically, it has not been possible to tolerably increase the dose of donepezil to meaningfully higher levels,” said Douglas Ingram, chief executive officer of Chase. “We believe we have the means to finally unlock the true potential of optimally dosed AChEIs. Moreover, we are employing an efficient development and regulatory pathway and plan to commence a superiority trial versus the current gold-standard treatment for Alzheimer’s, 10 mg/day of donepezil. If successful in Phase 3, CPC-201 could be the new standard for the symptomatic treatment of Alzheimer's disease and benefit millions of suffering patients.”

What Do Aricept, Exelon & Razadyne Do?

Teepa Snow
MEDICATION VIDEO
See Teepa Snow talk about the top medications for Alzheimer's & dementia. In plain English, she explores what they do and how they work. Get clarity on Aricept, Exelon and Razadyne (generic donepezil, rivastigmine and galantamine). 

Technical Talk

“We believe that adverse events have long limited AChEI dosing to suboptimal levels, in turn limiting the efficacy of donepezil and other AChEIs,” said Thomas Chase, M.D. “Our Phase 2 findings, together with those from our earlier Phase 1 studies, robustly support our hypothesis that the co-formulation of a peripheral anticholinergic with donepezil enables the safe and tolerable administration of multiples of the current standard of care doses of AChEI such as donepezil.”

The mean change in ADAS-Cog over the course of the study showed improvement versus subject baseline and, adjusted for underlying disease progression using a multi-study meta-analysis, subjects showed a mean (± SEM) benefit of 2.45 points over 10 mg/day donepezil or 5.4 ± .84 points compared to predicted untreated disease progression. Combined Clinical Global Impression (CGI-I) scores from investigators and caregivers at 26 weeks averaged 3.1 ± .20 points, thus improving by .94 ± .20 points (p < .001; n = 16). The responder rate (as measured by those who either did not worsen or improved over the course of the study) was over 90 percent.

MORE INFORMATION:

About CPC-201
Chase’s lead candidate, CPC-201, is a patent-protected combination of donepezil (an AChEI), one of the few pharmaceuticals proven to improve cognition in Alzheimer’s patients, and solifenacin, a peripherally acting cholinergic blocker.

SOURCE:

About Chase
Chase Pharmaceuticals Corporation is a clinical-stage biopharmaceutical company focused on the development and commercialization of improved treatments for neurodegenerative disorders. Chase’s development program, if successful, will profoundly improve the symptomatic treatment of Alzheimer's disease. The company was co-founded by Thomas Chase, MD, the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke and Kathleen Clarence-Smith, MD, PhD, the former head of CNS development at each of Sanofi, Hoffmann-La Roche and Otsuka. Chase is led by its chief executive officer and president, Douglas Ingram, formerly the president of Allergan, Inc.

Chase has closed over $24 million in funding to date, with approximately $22 million through a Series B financing led by New Rhein Healthcare Investors, LLC and including, among others, Edmond de Rothschild Investment Partners, Cipla Ventures and Brain Trust Accelerator Fund.

EDITED BY:
Peter Berger

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I

Adding Second Drug No Help in Alzheimer's

Here is a great dementia resource for caregivers and healthcare professionals,

You will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care professionals to get an easyceu or two

Follow Alzheimers1 on twitter

Medpage Today

Action Points
In moderate-to-severe Alzheimer's disease, continuing treatment with donepezil, a cholinesterase inhibitor, had some benefits, but adding memantine (Namenda) did not.
Note that memantine yielded similar benefits compared with placebo but the combination of memantine and donepezil was no better than donepezil alone.

For patients with moderate-to-severe Alzheimer's disease, continuing treatment with donepezil -- a cholinesterase inhibitor -- has some benefits, but adding memantine (Namenda) does not, a randomized trial showed.

Compared with stopping donepezil, continuing treatment for a year resulted in significant improvements in cognition and performance of the activities of daily living (P<0.001 for both), according to Robert Howard, MD, of King's College London, and colleagues.

Memantine yielded similar benefits compared with placebo but the combination of memantine and donepezil was no better than donepezil alone, the researchers reported in the March 8 issue of the New England Journal of Medicine.

In an accompanying editorial, Lon Schneider, MD, of the University of Southern California in Los Angeles, said the results with donepezil in the trial may not apply to other cholinesterase inhibitors because of differences in pharmacokinetics and mechanisms of action.

"Nor should the ... results be interpreted as evidence of the efficacy of indefinite treatment with donepezil," he noted. "More research is needed to assess the long-term benefits, the potential for harm and physiological tolerance, and the safe discontinuation of cholinesterase inhibitors as Alzheimer's disease progresses."

Cholinesterase inhibitors -- including donepezil -- have shown some benefits in patients with mild-to-moderate Alzheimer's disease, although no treatments have been able to halt disease progression.

When the disease worsens, clinicians must make a decision about continuing treatment, which is complicated by a greater risk of adverse outcomes, the need for permanent pacemakers, and hip fractures when treatment is not stopped.

In the DOMINO study, Howard and colleagues evaluated the effects of continuing donepezil with or without the addition of memantine in 295 patients with moderate-to-severe Alzheimer's disease who had been treated with donepezil for at least three months.

The patients were living in the community and either had a live-in caregiver or someone who visited them at least once a day.

The researchers assigned the patients to one of four groups for one year:

Continue donepezil at a dose of 10 mg daily and start placebo memantine
Continue donepezil and start memantine at a dose increasing to 20 mg daily
Gradually discontinue donepezil and receive placebo donepezil and placebo memantine
Gradually discontinue donepezil, receive placebo donepezil, and start memantine
The coprimary outcomes of the trial were changes on the Standardized Mini-Mental State Examination (SMMSE) and on the caregiver-rated Bristol Activities of Daily Living Scale (BADLS). The minimum clinically important differences were defined as 1.4 points and 3.5 points, respectively.

Compared with patients who stopped donepezil, those who continued treatment scored 1.9 points better on the SMMSE and 3 points better on the BADLS. Only the difference on the SMMSE exceeded the minimum clinically important threshold.

In his editorial, Schneider said the 1.9-point difference "is potentially important because many of the patients were severely impaired, on the cusp for needing nursing home care, and slightly worse cognitive function could affect their ability to remain at home."

Compared with patients who received placebo memantine, those who started the drug scored 1.2 points better on the SMMSE and 1.5 points better on the BADLS (P≤0.02 for both), although both figures fell short of being clinically important.

Combining donepezil and memantine was not superior to donepezil alone.

"Although memantine appears to be helpful for the treatment of moderate-to-severe Alzheimer's disease when used alone or when replacing donepezil, the results of the DOMINO trial do not support the typical use in the U.S., and an FDA-approved use, as add-on therapy to established donepezil treatment," according to Schneider, who noted that the finding conflicts with a previous, shorter trial.

Howard and colleagues pointed out that neither donepezil nor memantine halted the overall loss of cognitive function and functional abilities.

Compared with the changes in patients who received placebo for both drugs, the gains seen in the SMMSE score with donepezil and memantine represented just 32% and 20%, respectively, of the total decline during the study. The figures for the BADLS scores were 23% and 11%, respectively.

There were 188 serious adverse events, but only six were considered possibly related to the study drugs. Rates did not differ between groups.