How promising is the pipeline?

By Dale Bredesen, M.D., Chief Scientific Officer for Apollo Health

On the heels of our successful randomized controlled trial for patients with mild cognitive impairment or early-stage dementia, which produced the best results of any treatment for cognitive decline to date, it is important to know how to continue to improve outcomes. The goal is of course a cure for every single person, but we are nowhere near that yet: in our recent trial, 90% of patients improved, but some had marked improvement whereas others had only modest improvement. And although some very late-stage patients do show at least some recovery, it is more and more difficult to achieve cognitive advances as the cognitive decline progresses. So one of the questions is whether it may help to combine specific, targeted therapeutics with the precision medicine protocol that we use? If so, what would be the best targets, and which therapeutics would offer the best chances for success, while minimizing unwanted side effects such as brain swelling and microhemorrhage?

The current pharmaceutical targets focus on amyloid, tau, inflammation, vascular health, and trophic support/neuroprotection. Here are a few examples:

•Diranersen: This is a medication that is administered intrathecally (via spinal tap) and reduces the production of tau. It failed in its clinical trial, but at one dose it did show a hint of slowing decline (26% slowing, similar to lecanemab). It is moving to a larger trial because it did reduce tau.

••My concern: Tau is a normal protein involved in stabilizing neuronal structure via its stabilization of microtubules, and p-tau is an anti-microbial protein, so it is protective. The finding that there was no increase in cognition reinforces the conclusion that this is not the best target for treatment of Alzheimer’s.

•Troculeucel: This approach takes your own NK (natural killer) immune cells, proliferates them outside your body, and then injects them back into your blood. These NK cells are part of the innate immune system, and the hope is that these will reduce inflammation in the brain. 

••My concern: The supportive data are conflicting, and in a common mouse model of Alzheimer’s, adding NK cells actually increased inflammation and impaired cognition.      

•Obicetrapib: This is an oral CETP inhibitor (cholesteryl ester transfer protein) that prevents the transfer of these lipids from HDL particles to ApoB-positive particles such as LDL and VLDL. The excitement around this drug candidate relates to the finding that it attenuated increases in p-tau over time. Furthermore, in those with ApoE 4/4, it actually led to a p-tau reduction, which is a very promising finding.

••My concern: There is no associated cognitive data from the trial, so it is not yet clear whether this p-tau effect will be accompanied by cognitive enhancement or not. 

•Valiltramiprosate: This drug candidate inhibits the oligomerization of amyloid-beta. The work follows on previous studies of homotaurine (tramiprosate), which failed in a clinical trial, but post-hoc analysis revealed that, in the group with ApoE 4/4, there was cognitive benefit. A precursor, valiltramiprosate, is in development as a potential drug treatment for Alzheimer’s, and although it failed to meet its primary endpoint in a recent trial, for those with ApoE 4/4 treated at the MCI stage, cognitive and imaging benefits were documented. 

••My concern: After homotaurine showed promise in those homozygous for ApoE4 (ApoE 4/4, which includes about seven million Americans), it should have been made widely available as a supplement — especially considering how little is available to help — but the FDA blocked its designation as a nutritional supplement (while approving aducanumab over the objections of its own panel of experts — nice job, FDA!). For those who are ApoE 4/4, valiltramiprosate represents a promising adjunctive therapy, to include as part of an overall precision medicine protocol.

•Foralumab: This is another anti-inflammatory approach. In this case, it is an anti-CD3 antibody (CD3 is produced by T-lymphocytes) that is administered intranasally, with the goal of reducing intracerebral inflammation.

••My concern: Although inflammation is clearly one of the key mechanisms driving Alzheimer’s, we typically see the best improvements when energetics are enhanced: metabolic flexibility, insulin sensitivity, mild ketosis, creatine, cerebral blood flow (enhanced by exercise, for example), oxygen saturation (treating sleep apnea, for example), mitochondrial function, hormone optimization, trophic support optimization, and related energetic support. Simply reducing inflammation may have a modest benefit, but is typically not optimal as a standalone treatment.

•GLP-1s (semaglutide, tirzepatide, and related): Initial trials of GLP-1s failed to improve cognition or slow decline, but further trials are ongoing.

••My concern: The failure of initial trials, and the lack of knowledge about long-term effects of taking GLP-1s, raise concern for their chronic use for Alzheimer’s. 

•TB006: This is another anti-inflammatory approach, in this case via intravenous infusion of a monoclonal antibody directed against Gal-3, which is involved in microglial activation. Although the Phase 1/2 clinical trial narrowly missed its primary endpoint, and did not improve cognition, it slowed decline by 63%. Therefore, it was granted expanded access (compassionate use) by the FDA, and is now available, although the effect is modest and the cost quite high (typically $20,000 for four monthly injections).

••My concern: Modest benefit, excessive cost.

•Remternetug: This is another anti-amyloid antibody (like lecanemab and donanemab).

••My concern: A recent Cochrane study of all of the many trials for anti-amyloid antibodies showed no meaningful clinical benefit, so this general approach is unlikely to be an optimal one, and other targets should be prioritized. As we understand the pathophysiology of Alzheimer’s disease better and better, the optimal targets for combining pharmacological approaches with precision medicine protocols should become more obvious, leading to enhanced outcomes.