What Next With Cortexyme’s Atuzaginstat?

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Not All Patients Respond To Treatment With Atuzaginstat…

This is the undebatable fact. But what it means that “not to reach the level of statistically significance”? It means that for the dose cohort the probaility of the dosed patients to have results like those in placebo cohorts is lower than 5%. The dispertion about the mean for those 226 patients did not meet this criteria. It sounds worse than what it implies after better look at the data. But first, I have some remorks on the demographics data.

The ADAS-Cog Mean reads impossible number. I think somebody screwed up because ~24 ADAS-Cog is similar to ~22 MMSE. Then again if you have 50% from MMSE between 12 and 18 and you take as average of 15 and if you take average of 19 to 24 MMSE and then get that averaged then you get MMSE 18.25 which is more like ADAS-Cog=40. I used partialy this graphic calculator. If indeed the MMSE average is 18.25 then we deal with very low scores. It would be interesting to see data for every patient just like it was provided by $AVXL AD phase2a and $SAVA AD Open Label.

But then again if you divide 24 ADAS-Cog by 2.33 (70/30) and subtruct it from 30 you get 19.7 MMSE. I don’t think this works in the real world as the graphic calculator by Steve Blasis at al. indicates. This data point should not have been calculated that way but it should come from testing.

Right below the top plots we get the data for the demographics of the cohorts or groups. I would like to point out that only about 25% of all dosed patients benefit from the drug as after 48 weeks, only 64% remains in the cohort or study. This also can be indication that these patients are located more toward lower MMSE scores spectrum or that due to side effect they quit. The other aspect of these plots is that if we take the bars at the end points as Standard Deviations than the Effect Size Cohen’s d can be calculated and it is in the vicinity of ES=3.00 (huge). The low numbers for p-values for 80 mg cohort (p=.02) support this. If the bars are not SD than these number for ES is meangless. We have to have in mind that Donezepil has been approved on ES=.28.

The primary difference is that we have different regulatory environment now than decads ago. The prices of drugs have risen so much that they threaten the solvency of healthcare system in the USA. The regulator will not approve either a costly drug or one not providing full benefits. Yes, I know these rules are only for small biotechs, not the Big Pharma. We are right now witnesses to the fight over diminishing resources in public health and unlimited desire for higher drug prices from Big Pharma, Something has to give. The company was right to expact just 50% reduction in the rate of deterioration but missed the fact that just relatively few would experience the benefits. Depending on how effective against P. gingivalis Atuzaginstat is, and how benefitial to patients (there is a difference here) it is, it still can be a blockbuster. Meantime, Cortexyme will sharpen its skills in desiging better drugs against this bacterium. A lot depends on finding the reason behind the liver enzyme levels. If indeed this is due to immune resonce then much can be expected from the drug. Another aspect of this study is that maybe we need to block both Lysine and Arginine proteases to show better results.

My forecast of the Atuzaginstat results was looking at the best possible case. The assumption being that all the patients will respond to the treatment. Unfortunately, this was not the case. I hope that future therapetic arsenal will include Atuzaginstat as it seems to have a role to play in this game but all hinges on regulators.

Currently, only $AVXL ‘s Blarcamesine and Simufilam by $SAVA can rescue patients. Blarcamesine has improved and retained some patients for 3 years on ADCS-ADL (Daily Living) scale. Retarding the rate of decline over many years can still give very meaningfull results as the average length of dementia is 3 to 4 years and usually is cut short due to death of other reasons. Mostly, these are people who decline ever so slightly due to age and then have sudden onslaught of dementia placing them in care of others. If those who responded to Atuzaginstat are the more advanced in age and severity then Atuzaginstat might much better drug than it seems. I hope these findings will be released at CTAD 2021. The evaluation of AD drug is quite complex as only two drugs till now have the ability to rescue some. I have to mention here Simufilam by $SAVA seems after a year to level off and the next question is whether it will rolll over and reverse of its benefits will occur. This would leave only Blarcamesine as the only drug able to rescue patients. Nevertheless, these rescued patients are limited to some potential 44% of sporadic cases. The number one condition is MMSE score above 20. For that reason it might be possible that Atuzaginstat might find a niche for itself if it can work on patient with more advanced disease where the redardation of the disease progress by 50% might epidemiologically can make sense.

Let us go over the findings from GAIN trial

1. Atuzaginstat lowers the virulence of P. gingivalis
2. Roughly 50% of AD patients are subject to the virulence of P. gingivalis
3. Side effects include liver enzyme increases but are mostly asymptomatic

My interpretation of findings

1. Atuzaginstat works as intended. It lowers the virulence of P. gingivalis.
2. Stoping the virulence is not enough to rescue the patients, it just lowers the rate at which the disease progresses.
3. Other drugs like $AVXL ‘s Blarcamesine should be used in a cocktail to provide therapeutic boost to CNS cells.
4. P. gingivalis seems to be an oportunistic infection for AD patients at rate of 50% but bearing more weight on the progress of the disease at 37% of patients. Atuzaginstat has found its niche. Biomarkers are ready.
5. P. gingivalis infection affects also blood vessels, heart, intestinal tract and liver. Till a drug directly killing the bug is found Atuzaginstat is the drug to go to lower the damage done by the infection. The statistical links are already known, for example between heart disease and Pg infection. The disease is chronic and depends on immune system phenotype. The drug can have effect on general health of peopel with the infection but without dementia.
6. The side effect might be connected with the immune system robustly attacking the infected cells (clearing pool of infected cells) in liver and gut. As in any system of regulation this kind of “failure” should rather be investigated to decisively classify either as sign of success or real failure.
7. Periodontal disease is the best known chronical condition leading to loss of teeth and general health. The population intended to treat here is very large so blockbuster status has not been lost yet. The concurrent periodontal study should reveal the extend of benefits going to patients on Atuzaginstat with periodontal disease. Follow these developments.