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How wrong AD "experts" may be? Here

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sokol   Sunday, 11/11/18 10:22:15 AM
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How wrong AD "experts" may be? Here I post parts of a report from an Alzheimer"s conference that occurred in March 2016. AVXL 2-73 is briefly mentioned under the Emerging Therapeutic Targets section where it is said that: "5-HT6 receptor antagonists are likely the next treatments off the block." Axovant's drug and Lundbeck's drug fall within the latter category and are seemingly mentioned favorably. Near the end of what I quote below the author says this "His prediction is that within a few years we are likely to be using one or more of 5HT6 antagonists, LMTN (methylene blue derivatives), solanezumab and still recommending Souvenaid- and here the author is in agreement." Of course, we now know that both Axovant's and Lundbeck's clinicial trials failed, and it has been a few years without, to my knowledge, any use of methylene blue derivatives, etc. There is much more to this report than I comment about, and you can read it for yourself for other interesting things such as how much of an improvement may need to be shown for approval of a new AD drug. Read this and answer this question: How much, if any, of an improvement over a placebo may be need for any approval of AVXL 3-73?

http://www.drphilipmorris.com/new-developments-in-alzheimers-disease-research/

New developments in Alzheimer’s disease research Leave a comment »
The following article is from my senior colleague, A/Prof Michael Woodward, geriatrician at the Austin Medical Centre, Heidelberg Victoria. I wish to thank Michael for allowing me to post it on my website.

Springfield Advances in Alzheimer’s Treatment conference

Athens, March 2016

Conference report- Associate Professor Michael Woodward AM
........

Emerging Therapeutic Targets

5-HT6 receptor antagonists are likely the next treatments off the block. The closest to trial completion is the Lundbeck drug idalopridine, with three 6 month duration Phase III trials near recruitment closure. The Axovant drug, RVT-101, purchased from GSK, is moving ahead at breakneck speed. There is also a third drug in this class being developed by a small biotech company in India.

Inge de Jong presented the scientific rationale for this treatment approach, and likely underlying the very encouraging Phase II results of idalopridine. She showed that idalopridine potentiates the effect of donepezil on desirable gamma oscillation in regions of the brain important to cognition. This drug also affects other neurotransmitter systems, including glutamate and GABA and these are likely to contribute to its effects- ie the drug is not just working through 5HT6 and potentiating AChEI actions on cholinergic systems. Functional MRI also shows that when idalopridine is used with donepezil there is increased brain activity in regions of the brain underpinning cognition, including the hippocampi, amygdala and striatopallidal regions. These are actions not seen with donepezil alone and suggest that the combination has a unique and hopefully effective mode of action.

The Axovant drug , because it has cholinergic actions, may well work alone- ie not requiring co-administration of a cholinesterase inhibitor. Geetha Ramaswamy, from the company, presented the phase II results from the GSK trial and it is encouraging that both this and idalopridine have positive results in their phase II RCTs. As their drug has cholinergic activity it is also being trialled in DLB where there is a profound cholinergic deficit. It has 5HT2A activity and this receptor may underpin visual hallucinations, further supporting the potential benefit of RVT-101 in DLB. Only the data will tell though.

Souvenaid’s phase III trial in prodromal AD, the LipiDiDiet study, is now completed and the results were released at the conference. Tobias Hartmann from Hamburg presented the rationale for multi-nutrient intervention in prodromal AD- a condition where the brain is under amyloid/tau “attack” and rapidly runs out of the neuronal membrane/ synaptic precursors, exacerbated by the common dietary deficiencies of these in AD patients. Fortasyn Connect, which is the only component of Souvenaid, supplies these polyunsaturated fatty acids, uridine and other nutrients to enable the neurones to form synapses to potentially slow down the effects of the neurodegenerative process. Hikka Soininen from Kupio presented the trial results-this 2 year EU- funded RCT had approximately 300 randomized patients and is one of the first completed treatment trials in prodromal AD, using Dubois criteria. Disappointingly it was negative on the combined neuropsychological endpoint (the NTB) but there were positive secondary endpoints including memory and an almost significant CDR-SB (p= 0.051). The results were more positive in those with higher MMSE scores at baseline, but the numbers were becoming small when one added this subgroup analysis. There was a statistically significant reduction in the rate of hippocampal atrophy in the treatment group, supporting a biological rationale for the cognitive and functional improvements. Reassuringly the placebo and treatment curves seemed to be separating at 2 years on the functional and cognitive endpoints and as the study remains blinded, 3 and even 4 year results will be most interesting- especially to see if the original primary, the NTB, becomes positive. The preparation seemed entirely safe although there were, in absolute rather than percentage terms, a slightly higher number of strokes and other cardiovascular endpoints in the treatment arm. So, the doubters will feel vindicated by the primary but other folk will feel that the encouraging secondaries and the 2 year trend suggest the treatment will be a major step in prodromal AD management.

Other targets that have been subject to the harsh light of clinical research include the pyroglutamate modification of Aß and animal studies have used inhibitors of glutaminyl cyclase or monoclonal antibodies against this. Amyloid aggregation remains a target using tramiprosate- sadly the phase III trial results were negative but in Apo E4 heterozygotes the results are more encouraging. Iinflammation remains a robust target and masitinib has been used as another approach here. Anavex’s drug, targeting the sigmoid 1 mu- receptor, continues its non-blinded Phase IIa trial with a 52 week open label extension. Preliminary results demonstrate a favourable safety, bioavailability, dose-response curve and tolerability/risk profile. Analysis seems to indicate a cognitive benefit associated with ANAVEX 2-73. Cogstate, MMSE and EEG/ERP improved significantly at 5 weeks of treatment. The effect of changing from low to high dose was statistically significant with MMSE-? (p=0.0285) and ERP-? (p=0.0168) respectively.

Stem cells

These were darling of earlier AAIC meetings but seem to have dropped off the radar. However at this meeting Tristan Bolmont from Lausanne reinvigorated some enthusiasm, presenting results of trials where mesenchymal stem cells were given into transgenic mice bred to over-express amyloid. There was a clear reduction of Aß42 deposition. But mouse dementia seems a much easier condition to treat than human AD so watch this space and do not encourage your patients to seek unproven stem cell therapies just yet, despite the current interest and unprofessional promotion of such approaches.

What will be the Best Treatment for AD?
........
Lon Schneider returned and to this author’s mind had the final say. He began by simply saying the best treatment will be the one that works. But how well does it need to work? It is noteworthy that trials are being constructed, and reconstructed, to be statistically significant, and thus get a drug to market, even with small and potentially clinically insignificant effect sizes. Indeed the Lilly EXPEDITION 3 solanezumab trial, to be completed in November this year, has just dropped one of its 2 primary endpoints and one could somewhat cynically argue that this is to give it a greater chance of success- easier to improve one than two primary endpoints, as many other completed trials that only hit one endpoint have shown. But Lon would always see himself as a realist, and is no doubt visionary, rather than a cynic. He noted that we now have 390 AD therapy trials completed, in progress or about to commence, testing some 200 agents, and the trend is to design them to show the smallest possible benefit. Back to Lilly- he believes they have secured an undertaking that a 2 year ADAS-Cog improvement of 1.5 points, over placebo, would be sufficient for them to file for listing of solanezumab as an AD- disease modifying drug. Remember the AChEIs, including donepezil, were marketed on a 3-4 point benefit over placebo over 6 months. But they were far more progressed subjects. In question time Ezio Giacobini, the co-founder of this meeting, felt new drugs should be aiming at a 6 point ADAS-Cog benefit over placebo, and he felt that was imminent. In his opinion, the best drug would be better than donepezil and would simply be the first drug next approved by the regulatory authorities.

Lon noted that over 100 Phase IIb/III trials have proceeded on the basis of a negative Phase IIa trial albeit with a post-hoc rationale for the failed trial, and with no clear understanding of the drug mechanism of action- this somewhat gun-ho approach to trial progression is almost unique to this clinical research area. Again, EXPEDITION 3 follows failed EXPEDITION 1 and 2 trials. But this is his view, and not necessarily the author’s! His prediction is that within a few years we are likely to be using one or more of 5HT6 antagonists, LMTN (methylene blue derivatives), solanezumab and still recommending Souvenaid- and here the author is in agreement. He does believe we can develop drugs with large clinically significant effects if we better design trials (which need to be shorter, but better select subjects), pool data (as placebo data is currently being pooled between 6 large pharma and 9 regulatory agencies in an exciting initiative) and of course design better drugs that strongly engage their target. He notes that AD is not a single disease and is too mixed with normal ageing- we need to define the appropriate target/s in an individual and use drugs that engage these targets, probably in combination. He feels we can develop drugs that reduce AD risk in Aß/tau positive preclinical individuals by 25-30% and that this would be clearly clinically important. He fears that we may lurch away from amyloid as the target, to again waste years on tau as the new target- we need to learn from our amyloid experience if it does indeed disappoint us.

Conclusion

Again an exciting and rich Springfield- albeit the last (in future it will be combined with ADPD). I strongly believe that in the next 5 years these meetings will be focussing on bettering current disease-modifying drugs, and new symptomatic therapies- and will move away from the tau versus amyloid debate that to date has been fuelled by the lack of any effective preventative therapy for this most devastating disease. As one of Bengt Winblad’s patients said, what a shame Alzheimer himself died at 51- if he’d lived a few decades longer he may have cured the disease that was first described by him. Hope springs eternal.



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