Ketogenic Supplement Tricaprilin Fails in AD Trial

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MichaelR
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Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by MichaelR »

All:

Reporting from the Clinical Trials on Alzheimer's Disease 2017 conference:
Samuel Henderson of Accera Inc. in Boulder, Colorado, explained negative results for tricaprilin [ie, caprylic triglyceride], Accera’s latest formulation of caprylic triglycerides to boost ketone body metabolism with a dietary aid. [This is the successor to Axona -MR]. The Nourish-AD was a Phase 3 trial conducted at 61 sites in the U.S., in 413 people who met the NINDS-ADRDA diagnosis of probable AD.

At the end of the trial, the treatment and placebo groups performed equally on the primary outcome measure, cognition as per the ADAS-cog, and the secondary outcome measure, overall function as per the ADCS-CGIC. As with prior formulations of this dietary approach, adverse events included nausea, vomiting, and gastrointestinal discomfort.

At CTAD Henderson ascribed the negative result to low exposure and bioavailability, saying this new formulation generated insufficient amounts of ketone bodies in the brain. As happens frequently in six-month trials in AD, the tricaprilin trial, too, was further hobbled by a relative lack of cognitive decline in the placebo group.

Henderson noted the company still has faith in the rationale behind ketone body therapy for treating neurologic disease, and has developed yet another formulation for its approach.—Pat McCaffrey and Gabrielle Strobel
TRICAPRILIN: RESULTS OF A PHASE 3 STUDY IN MILD-TO-MODERATE ALZHEIMER’S DISEASE PATIENTS.

Samuel Henderson1, Michael Gold2, Judith Walker1, Sabrina Greer1, Janet Vogel1, Aaron Shenkin1
((1) Accera Inc, Boulder, CO, USA; (2) PPD Inc, Wilmington, NC, USA)

Background: Tricaprilin, a ketogenic compound, is in clinical development for the treatment of mild-to-moderate Alzheimer’s disease (AD). In a previous Phase 2b study, Tricaprilin demonstrated significant improvement relative to placebo in a sub-group of subjects (n=29 tricaprilin, 26 placebo) who were non-carriers of the epsilon 4 allele (ε4) of the APOE gene and received 20 grams of tricaprilin QD for 90 days. [MR: I've emphasized this point before: studies of keto diets in AD patients and high-risk groups have generally failed, and to the extent that there have been hints of an effect by genotype they have tended to seem to only work in APOEε4 non-carriers ].

Methods: We conducted a 26 week, double-blind, randomized, placebo-controlled, Phase 3 trial involving patients with mild-to-moderate Alzheimer’s disease. The study population included men and women between the ages of 66 and 90 years old who met the NINCDS-ADRDA criteria for probable AD. Use of cholinesterase inhibitors and/or memantine was permitted (in stable doses). Eligible subjects were stratified by APOEε4 carriage status (+, -) and baseline MMSE score (14-20, 21-26).

Subjects were randomized 1:1 to receive either oral tricaprilin at 20 grams/day or a matching isocaloric placebo. Upon completion of the double-blind treatment phase, participants were eligible to receive tricaprilin in an optional 26 week open-label extension. The primary analysis population was the APOEε4 non-carriers and the primary outcome measures were the ADAS-cog(11) and ADCS-CGIC. Secondary outcomes included the ADCS–ADL, QoL-AD, RUD-Lite, Clock Draw Interpretive Study (CDIS), and the MMSE.

Results: The study enrolled 285 APOEε4 non-carriers and 128 carriers at 61 sites in the USA. Eighty percent of APOEε4 non-carriers completed the study. In the primary analysis population, the mean age (SD) was 76.9 (6.88) and the MMSE score at baseline was 21.2 (3.50). No significant differences between tricaprilin and placebo in change in ADAS-Cog at 26 weeks (least squared means: tricaprilin 1.1; placebo 0.3; p=0.25) or in ADCS-CGIC (p=0.27) were detected.

Conclusion: The study did not meet primary and secondary endpoints. Subsequent analyses revealed two factors that may have influenced study outcome: (1) the formulation used in the study produced lower levels of ketones than formulations used in the earlier studies; (2) there was a marked lack of cognitive decline among the APOEε4 non-carriers. Detailed results of this trial will be presented as well as plans for continued development.
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Julie G
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by Julie G »

Nice to see you posting, Michael. Thanks for sharing. I'd be curious to learn what the actual BHB levels were.
Conclusion: The study did not meet primary and secondary endpoints. Subsequent analyses revealed two factors that may have influenced study outcome: (1) the formulation used in the study produced lower levels of ketones than formulations used in the earlier studies; (2) there was a marked lack of cognitive decline among the APOEε4 non-carriers.
As I recall from Henderson's earlier work, E4+ folks achieved levels less than 0.5mM after a full 90 days of using Henderson's product. Anyone who's dabbled with ketosis knows this is a minuscule level. If levels were even lower here, it's not surprising that they failed to show effect especially in our more disadvantaged E4+ group.
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

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I’m still struggling with why the amount of BHB matters if it’s the “storage” form, as long as you have some. It’s easy enough to go higher, but can’t figure out the logic why having more in storage is better (not that we have long-term studies to support higher levels, but a rationale?).
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

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circular wrote:I’m still struggling with why the amount of BHB matters if it’s the “storage” form, as long as you have some. It’s easy enough to go higher, but can’t figure out the logic why having more in storage is better (not that we have long-term studies to support higher levels, but a rationale?).
I tend to view circulating BHB as an "active form" of ketones (even preferentially competing with glucose for fueling cellular metabolism), where it's not quite tucked away into storage waiting for activity like muscle glycogen, intramuscle creatine stores, or body fat. From this perspective, I could see higher values up around 1mmol being more therapeutic than say a 0.2mmol/L BHB value... but I'm not quite sure what to make of say, a 0.4-0.6mmol/L level, where you're certainly in ketosis, but far from say "raging ketosis." I suppose going by feel makes sense, so long as you can feel the difference. From my experience, supplemental MCT oil only mildly elevates ketones for a few hours. If I recall, exogenous ketones also increase postprandial insulin secretion, so there could be odd metabolic side effects when consuming MCT / Ketones over carbs if insulin is associated with AD pathology.
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by MichaelR »

circular wrote:I’m still struggling with why the amount of BHB matters if it’s the “storage” form, as long as you have some.
Putting aside the fact that BHB is not technically a ketone at all: BHB is only a "storage" form of ketones (meaning, that it has to be converted to AcAc for use as fuel) in the periphery: the brain can use BHB directly. I'm here saying anything about BHB as being a good thing or not, but if the theory at least is that you're providing ketones as an alternative fuel for neurons in response to brain glucose hypometabolism, then for this purpose BHB is an "active" fuel molecule, not a storage form.
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by circular »

Okay, so I can shift from thinking of it as "active" to the brain and "storage" for peripheral tissues, but it still begs the question, if there is always at least, say .3 or .5 mM, then there seems to always be enough in the brain, or it would have preferentially taken that up and left the serum with 0?
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

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circular wrote:Okay, so I can shift from thinking of it as "active" to the brain and "storage" for peripheral tissues, but it still begs the question, if there is always at least, say .3 or .5 mM, then there seems to always be enough in the brain, or it would have preferentially taken that up and left the serum with 0?
Good question. I might be wrong, but I believe a higher serum level of BHB corresponds to a higher utilization of BHB over glucose and vice versa, where if there is glucose hypometabolism associated with AD, there could be a benefit to relying less on glucose. I have noticed with heavy exercise, I can affect serum glucose / ketones (BHB drops as muscles suck it up), but I haven't noted this effect with heavy thinking. :)

It is interesting to read the exogenous ketone reports of what happens when people take a shot of BHB esters, which quickly rockets toward 6mmol/L, rather than the 0.4 or so you get from MCT. These reports do often sound like there's a bit of magic on the upper end.

In addition to looking at BHB as a fuel source, a state of ketosis has a large effect on cellular signaling (HDACi, etc) / epigenics... I'd be curious if there's a relationship with the depth of ketosis (even if we are just looking at fuller "ketone stores") and these downstream changes.
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by Orangeblossom »

It says here levels lower than in previous trials and looks like they are adjusting it again for the future..

http://www.accerapharma.com/accera-anno ... s-disease/
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by Kenny4/4 »

Are there any studies that show Ketosis preventing or slowing alzheimer's for us 4's?
They all seem to work for non 4's but not us.

I've done Ketosis for 3 months now and it's pretty cool as you get a "high" off it (kind of jokey and you get the giggles).
Why does everyone "believe" or want to believe in Ketosis?
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Re: Ketogenic Supplement Tricaprilin Fails in AD Trial

Post by Julie G »

Good question, Kenny. There are no RCTs showing that ketosis helps our genotype, just multiple case studies like this one. Lots of folks on our site (hand waving!) also report positive cognitive benefits. Given our reduction in cerebral glucose utilization starting as early as our 20s, it mechanistically makes sense that this approach might help.

It's worth noting that the studies that have been done, to date, have been poorly conducted with subjects reaching extremely very low levels of ketosis. I suspect that we still have lots to learn here.
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