Scientific Alzheimer’s disease and a-msh studies (for future reference)

Alexius

Well-known member
Not directly related to AD, but rather to CNS disorders in general.
After reading the rejection of this https://globaldossier.uspto.gov/#/details/US/15522260/A/94964 patent, the following question came to my mind:
Most of the rejections refer to the fact that (according to the authorities) there is insufficient evidence (neither in animal nor in human trials) that a-MSH has a chance of success in the diseases mentioned.
Is there any chance that
a) Clinuvel has done animal studies since final rejection, which sufficiently proof the potential efficacy of afamelanotide?
or
b) Clinuvel seeks an "agreement" with the authorities such as: If first human studies produce positive results (stroke is also one of the diseases mentioned!), Clinuvel is allowed to ask for reopening the application?

If b) applies: What would prevent them from announcing all CNS diseases mentioned in their patent as "6th indication"? This might explain the timely delay they are facing...I still can´t get over PWs smile when talking about the sixth, it has to be something groundbreaking.

Disclaimer: I personally know 0,0 about patent applications and authorities, so the previous theses might be pure none-sense.
 

macgyver

Well-known member
@Alexius I think in the Biogen studies for their drug Aduhelm they had something like 3000+ patients involved which would be a costly undertaking for one indication let alone several. I know what you're asking: could the CNS disorders fall under one banner and be treated as such. If I read the Luger patent applications correctly, they do group inflammatory and neurodegenerative disorders together and then MS. But since Luger's and Clinuvel's patents were rejected, Luger's MS patent application was amended to exclude a broad claim for inflammatory/neurodegenerative disorders to appease the Examiner and yet the application has still come to grief (Luger's MS patent application is the only one still alive having already been rejected once). Knowing that, it's a struggle to see how a drug authority would say yes to an overarching CNS program for the 6th indication. On the other hand, should MS be approved as an indication for a-msh, I can see short approval paths for AHLE and ELE as they are demylinating diseases as well. (Both mentioned in one of Luger's patents and of which ELE was used as a substitute disorder for MS with accompanying mouse models to try and win the patent).

What's curious is that for Alzheimer's disease patents concerning a-msh there are none in play. Clinuvel's was abandoned, and Luger's application has been pared back with CNS disorders removed except for MS, AHLE and ELE. Why? After reading into the patent further, Luger talks a lot about the BBB, reducing inflammation causing neuronal death, progression of neurodegenerative disorders etc, but nothing specific about the pathology of Alzheimer's disease. I had a look at the research paper from Luger and Karin Loser and there is nothing in there (as far as I can see) that talks specifically about the effects of a-msh on Alzheimer's disease. (please someone correct me if I'm wrong on this, it just appears Luger's patent is directly related to his research at the University of Muenster and in the research it mentions the ELE mouse models). Knowing this, I think Luger tried a blanket patent application to hem AD in to the patent but failed.

There is substantial research from the likes of Daniella Guiliani and the well known paper showing some reduction of plaques in AD bred mice (https://www.jneurosci.org/content/jneuro/34/20/6736.full.pdf). I don't know why a patent application hasn't been submitted from those results, maybe it's in the internet somewhere. Google Patents throws up 18,000+ results for AD. Even I'm not keen on digging that much:LOL:

So as it stands at the moment, from what I can see, AD is a free-for-all. And the company who can bring a melanocortin peptide to the AD market first will be able to submit a patent application based on their findings from AD/a-msh trials if one doesn't currently exist. If Clinuvel came to terms with Luger, perhaps they intend to go for MS first and then tackle AD later. If they go for AD alone, the risk is elevated but the potential is immense.
 
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macgyver

Well-known member
Following the FDA's controversial decision to grant approval to Biogen's drug Aduhelm, I'm betting a lot of shareholders in various pharma companies are possibly excited about future prospects not least of all because the FDA will pass any turkey now. I don't think I've ever seen such a self inflicted injury to a Western regulatory body's reputation as damaging as this. The optics are poor indeed. But in an attempt to hose down my own expectations and giddiness at possible ramifications for Clinuvel concerning AD, I wanted to better understand just how much of a possibility it is for Clinuvel to treat this disorder compared to Biogen's Aduhelm.

In the paper from the link posted in the previous post (Melanocyte Stimulating Hormone Prevents GABAergic Neuronal Loss and Improves Cognitive Function in Alzheimer’s Disease), the main benefits that resulted from this study were: restoring GABAergic function leading to increased cognition, and alleviating anxiety levels in the experimental mice. A key feature of this study IMO was there was no significant reduction in insoluble or soluble amyloid plaque proteins between the control group and the a-msh treated group. However, the improvement in cognition and anxiety levels suggests, according to the authors, "preservation of behaviour independent of amyloid plaque/proteins". That appears to be in direct contrast to Biogen's drug, which is known only to remove amyloid plaque clumps, which in itself is not indicative of improved cognition. Even Biogen's data concerning evidence of improved cognition is negligible. A-msh led to an improved neurological outcome for the mice regardless of levels of amyloid proteins.

Concerning the reduction of amyloid protein levels, the experimental mice in the aforementioned study were engineered to express 3 copies of APP (amyloid precursor protein). In Daniella Giuliani's paper from 2014 (Melanocortins protect against progression of Alzheimer’s disease in triple-transgenic mice by targeting multiple pathophysiological pathways), the experimental mice in that study were engineered to express one copy of APP only. These mice were treated with a prophylactic treatment of a potent a-msh analog before the onset of amyloid pathology occurred, which led to reductions in amyloid deposits. Or in other words:

- one group of mice bred to over-produce amyloid proteins and treated with a-msh therapeutically will not see significant reductions in amyloid proteins, yet they will see relative improvements in cognition and anxiety levels,

- the other group of mice producing normal levels of amyloid proteins treated prophylactically will see both a reduction in amyloid deposits and improved cognition.

According to the authors of the first study, there are several studies in which different treatments were used (i.e. beta peptide immunisation) leading to improved cognition regardless of the amount of amyloid proteins present. Clinuvel's abandoned CNS patent was intended to specifically target juvenile forms of CNS disorders, especially AD before the age of 65. This says to me their calculus is based around the prophylactic treatment of AD rather than as a therapeutic option. However, the scope is there for afamelanotide (or a more potent analog) to be used therapeutically as well as it can lead to a measure of improved cognition in more advanced AD sufferers irrespective of amyloid protein/plaque levels.

It would be remiss to disregard Aduhelm entirely without reading through its data and outcomes to better understand how it works. But at the moment, from what I can tell reading anecdotal evidence and the fact the FDA advisory board overwhelmingly voted against recommending it for use in AD, (not to mention 3 members resigning in protest), the drug doesn't lead to what I would consider meaningful improvement across a range of pathophysiological processes of AD. In contrast, a-msh seemingly goes beyond by improving cognition and other neurological aspects in advanced AD while in juvenile AD it can reduce amyloid proteins as an additional benefit.

With all things considered, I think its worth the risk to at least investigate with a small study a prophylactic treatment for juvenile AD perhaps centred around Scenesse (since its approved already). The risk will be manageable and within Clinuvel's capability, but of course it remains to be seen whether non-human experimental results can translate successfully to human trials. CNS and AD were certainly on PW's mind as the abandoned patent proves, hopefully Biogen's approval has emboldened him to take the gamble.
 
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macgyver

Well-known member

Herpes a possible contributor to Alzheimer’s disease. Genital herpes and AD?? Wow. Just when you think things couldn’t get worse…

“Two critical elements of the infectious hypothesis are that the infectious agent must persist for years or periodically infect the host and that the immune response to this agent involves the nervous system. HSV1 infections meet these two requirements. It is a ubiquitous human infection that infects the nervous system and established a reactivable latent infection. Despite a strong immune response, the infection is not cleared and lasts for the life of the host.”

“Neuroinflammation is an important component of the infectious hypothesis of AD. It is defined as an inflammatory response in the nervous system to infection or injury. Neuroinflammation is considered a major driving factor in neurodegeneration and AD pathology, which starts early in the course of the disease, prior to the formation of Aβ plaques in the brain. It may be triggered by infectious agents including viruses”.

“In addition, NSD-MSH treatment reduced the levels of Aβ and tau phosphorylation, inflammation, neuronal apoptosis, and improved cognitive functions in 3Txg transgenic mice compared to control groups (147). All together, these findings suggested that NDP-MSH promotes the development of microglia into an anti-inflammatory M2-like phenotype”.
 
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macgyver

Well-known member
The FDA has done an about-face regarding Aduhelm, the AD drug from Biogen. Now the FDA are approving it for use in early stages of AD only in lieu of widespread use for all eligible AD patients. What does it mean for Clinuvel? Not sure, but if AD is the 6th indication, we would see an interesting competition to see which drug worked better, and possibly leaving the FDA with egg on their face. My money is on a-msh.
 

macgyver

Well-known member

Not specifically a-msh related, in the above article a study was conducted with participants eating a diet mainly consisting of nuts/legumes and leafy green vegetables, (Mediterranean style diet) while avoiding fats like butter and cheese. Post mortems revealed that even though the participants had enough amyloid proteins to warrant a diagnosis of the onset of Alzheimer’s disease, “some of the participants never developed clinical dementia. The MIND diet supports cognitive function regardless of the underlying pathologies of Alzheimer’s disease”.

This is mirrored in the studies conducted by Giuliani et al that showed improvement in cognition in transgenic mice without a reduction in amyloid proteins present in their brains. I’m beginning to wonder if there might be an opportunity for afamelanotide to be used in a secondary stage of Alzheimer’s to reduce inflammation and halt progression so as to prolong the life of the patient and, if remotely possible, improve cognition.
 
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macgyver

Well-known member
I believe this is the first time I've seen periaqueductal grey mentioned by Clinuvel, I don't recall seeing it before or at least where a list of receptors and their expressions is concerned. I looked at dementia related papers for the periaqueductal grey, generally the theme across the papers is that Alzheimer's disease attacks the area as well other parts of the brain stem. The periaqueductal grey is a control centre for various functions including behaviour towards threatening situations, autonomic functions etc. It is reported in one paper AD patients displaying aggressive behaviour are likely to have plaques and as a small percentage neurofibrillary tangles in this region. Damage to this region is also seen in multiple system atrophy and Lewy body dementia. Its not clear how much of a part this region plays in the overall symptoms of AD, but if the region expresses MC1R and is susceptible to damage from AD then it is certainly an area that could show potential as part of an encompassing neurological treatment with afamelanotide for Alzheimer’s disease.


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