Anavex Life Sciences Corp (AVXL)

[amstocks82]

Donepezil (Aricept), some analysis and comparison to Anavex 2-73

Donepezil (Aricept) - was the most popular Alzheimer's disease drug with sales of about $2 billion in 2013. Total Alzheimer's drug sales this year are estimated to be about $6.8 billion. For drugs like Aricept, the patent protection for the typical dosing regime has expired. The drug companies tried to remedy this by changing to a slightly higher dosage. By getting a higher dosage approved, this higher dosing regime would give them 5 year protection for the new higher dose. However, this didn't work.

Looking back to the original approval of Aricpet in 1996: http://www.eisai.com/news/news199602.html, the trial that the approval was based on was 476 patients for 30 weeks. The trial lasted a little over 6 months. They trial was radomized double blind with placebo trial and broken down to 3 different tiers. (The drug was given for 24 weeks followed by 6 weeks where the impact of not taking the drug was studied). In other words, they monitored cognition and health of patients to see what impact stopping the drug would have.

1) 5 mg of Aricept (approximately 150 people)

2) 10 mg of Aricept (approximately 150 people)

3) 0 mg of Aricept - placebo pill given (approximately 150 people)

Note: Anavex has proposed 300 people trial. Presumably, if they use the same method used for Aricept they would be randomized, double blinded with placebo. If they did it that way, they could test for example a pill of X mg (the X to be determined partly by the Pk/Pd testing) in 150 patients and 150 patients with the placebo.

Looking at a more modern study of Aricept: https://epub.ub.uni-muenchen.de/16928/1/10_1159_000017126.pdf where 250 patients per "cohort" were used, the study results of that were the same as for the original Aricept study.

One interesting thing about the Aricept study, during the 30 week study, 76% of the donepezil-treated patients completed the study compared to 80% of the placebo group. Aricept was given only in the first 24 weeks so 76% to 80% of patients completed taking Aricept for 24 weeks.

Comparing to Anavex's smaller 32 person study, 78% made it to 57 weeks. (25 people of the original 32 people in the trial made it to the 57 week period). I assumed Anavex would have a higher rate of fallout than they would in other similar trials such as that of Aricept since Anavex is providing the drug for longer periods than 24 weeks that a drug was provided by Aricept but this is not true. It is interesting but perhaps not significant given the small size. Random variation may be the reason that more remained in the A2-73 trial for this long of a period. Looking at the question statistically does not show a significant P value.

Note that it has been found (by a few studies) that Aricept improves cognition in the short term but has a smaller impact over the longer term. Basically what seems to happen is that for 6 weeks, there is a improvement over baseline for patients taking Aricept. After 6 weeks, cognition begins to decline again at about the same rate as before. However, the original improvement persists. Therefore, those who took Aricept have higher cognition values in the testing than does the group that took the placbo but the slope of the downward decline is similar. See Fig 1, page 240 on https://epub.ub.uni-muenchen.de/16928/1/10_1159_000017126.pdf

Looking at the 24 weeks of data, the drug companies published these comments:

"The Phase III study presented at the AAN enrolled 450 patients, with 150 patients randomized to one of three treatment arms; donepezil 5mg/day, donepezil 10mg/day or placebo. The trial was conducted over a 30-week period, and the primary endpoints were performance on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinician's Interview-based Impression of Change, with input from the patient carer (CIBIC-Plus).

Top-Line Data The researchers found that donepezil was well-tolerated over the course of the study. In addition, statistically significant improvements were observed with both the 5mg and 10mg donepezil groups compared to placebo on the ADAS-cog and the CIBIC-Plus scales. The drug reduced the number of treatment failures by up to 44% and increased the proportion of treatment successes by up to 245%, they said.

Overall, around 25% of Alzheimer's patients who received donepezil had meaningful improvements in memory and other cognitive skills, evidenced by a seven-point increase in the test scale. Furthermore, 81% of the donepezil patients experienced either no decline in cognitive ability or an improvement. Ranking the daily functioning scores, it was found that 56% of those in the placebo group worsened by the end of the study, compared to 32% on donepezil."

Note that recent studies tend to indicate that there is no impact for donepezil in the long term but that it tends to delay the progression of Alzheimer's disease in the shorter term - 18 months and possibly as long as 36 months. But after 18 months, the difference between those taking donepezil or a placebo group is very small statistically speaking. .

Further, it is noteworthy that they used a 24 week study period for donepezil. This is likely by design. That is because a few weeks after 24 weeks, the company would not be able to say that the majority of patients had no decline.

When comparing the chart of Anavex and donepezil treated patients on cogstat type tests, it is important to note that the minimum amount of donepezil to have some effect was thought to be around 3 mg. They tested two groups of patients - one group on 5 mg and another on 10 mg against a placebo group. Both tested tiers were above the 3 mg that was believed to have some effectiveness. With Anavex, the minimum effective dose was found to be 14 mg. Some of the patients in their chart were taking 10 mg. Thus, several patients were taking less than an effective dose.

But in comparison, synaptic activity continues to improve for Anavex after 24 weeks. Additionally, the MMSE and ADSL-ADL was much flatter.

Another interesting comparison is that one of the side effects fairly often reported with donepezil is insomnia. For A2-73, insomnia decreased.

There is controversy over exactly how donepezil works. The main method of action typically given is that it is a centrally acting reversible acetylcholinesterase inhibitor. An acetylcholinesterase inhibitor (often abbreviated AChEI) or anti-cholinesterase is a chemical or a drug that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. Additionally, donepezil is a sigma-1 receptor agonist.

Both donepezil and A2-73 are Sigma-1 receptor agonists. Except donepezil is also a acetylcholinesterase inhibitor. I have not found where A2-73's affinity for the Sigma-1 receptor was measured. The company indicates it has a "high affinity". But donepezil also has a high affinity. Another difference is that A2-73 has non-exclusive affinity to Sigma-1 receptors. What that means is it also has some affinity for the Sigma-2 receptors. There is much less written about agonists for the sigma-2 receptors so it is unknown exactly what impact this will be. Additionally, the chemistry of A2-73 may have some other more minor pharmacological impacts (my deduction from the chemistry and not from any comments from the company or other experts).

My overall view is that donepezil helps patients in two ways. The acetylcholinesterase inhibitor improves cognition. The second way (which appears to be "accidental" is that donepezil is also an agonist to the Sigma-1 receptor similar to A2-73. In the longer run, any longer term decline in cognition would be attributed to the sigma-1 aspect.

My overall view of A2-73 at this time is that it helps mainly by being an agonist to the Sigma-1 and possibly Sigma-2 receptors. It also may have some other impacts. Due to being designed to work as a Sigma-1 receptor, it is likely to have fewer side effects to donepezil and therefore, can be given in much higher dosages. Thus, even if the affinity to the Sigma-1 receptors were similar, A2-73 will overall have a higher impact from the Sigma-1 perspective. thus, if agonists to Sigma-1 receptors do have long term impacts as I suspect, it will have a greater impact. Additionally, if agonists to the Sigma-2 receptor have an effect on cognition, this could also have an impact. And A2-73 could help in other less well understood ways. (The same can be said for donepezil).

One final comment on genetics and drugs. It has been found that people differ somewhat in how well donepezil helps due to having genes that impact the rate at which the body removes donepezil from the blood stream. Thus, some higher responders to donepezil have higher levels of donepezil in their blood for longer than do other patients whose body removes it more quickly.

This is probably one of the main aspects being examined in the Pk/Pd study of A2-73. Blood tests taken a given number of hours after the drug is taken can show how fast the drug is removed. This rate may vary depending on genetics or health of the individual.