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Muscarinic Agonists Come Back Around

Allergan, now that they’re not going to be Pfizer, has wasted no time signing a big deal with Heptares for Alzheimer’s. Heptares, as the receptor-centric people in the readership will know well, has been working on GPCR structure for some years now, and applying this knowledge to their own drug discovery efforts. They have what they believe are selective muscarinic agonists, which could be useful in Alzheimer’s and several other CNS diseases, and have been actively looking to partner with someone on the (no doubt lengthy) clinical development of these. Heptares gets $125 million now, and milestones that could reach into the low billions should something (a) show efficacy, (b) make it through the clinic, (c) get approved and (d) sell. That last one should follow should the first three come through, since there’s little or nothing for Alzheimer’s patients as it stands.

So how useful will M1 and M4 agonists be? That is the big question. I was working in the field when Eli Lilly was trying to get a selective M1 agonist (xanomeline) going, and selectivity in that receptor family is not easy to attain. The side effects will hammer you if you’re not, though, which in the end is what happened with Lilly. They did come up with some clinical data to suggest that the mechanism might be useful in Alzheimer’s before the whole program wiped out, though, which is what brought Heptares back around for another try.

And if anyone’s going to get selectivity, they’re probably the ones. They have some Phase I data that suggest that they’re engaging the target without the sorts of side effects that were seen in the Lilly effort, and these results are surely a big part of why Allergan signed up with them. In fact, I’m willing to stipulate that Heptares has a selective M1 agonist, for purposes of argument, although more data will be needed to make sure of that. But let’s assume that they do: how well will that work?

Here’s where the brow-furrowing starts. Even back in the 1990s, there was some room to wonder about this. M1 is the main postsynaptic receptor in the cholinergic signaling system, so one thing a selective M1 agonist would do is be a straight-up acetylcholine replacement. But there’s more to it than that – there pretty much has to be, because acetylcholine is released in discrete pulses on the presynaptic side, and just dumping in more (or a replacement) wouldn’t be expected to be a very useful signaling mode. I believe that one rationale for an M1 agonist is that it would increase the tone of the whole signaling network, priming the postsynaptic neurons to be able to respond to lower doses of acetylcholine from across the synapse.

Lower doses you will have, most likely, because the whole cholinergic system is known to be hit pretty hard by Alzheimer’s. That, in the end, is one of the worries about targeting it as a therapy. If you don’t have a disease-altering mechanism (and no one does), then you might be boarding a sinking ship by going after the cholinergic neurons. Nonetheless, that’s what Aricept does (donepezil, Pfizer and Eisai’s existing Alzheimer’s therapy, now generic), inhibiting acetylcholine breakdown in the synapse. It doesn’t work that well. Back in the 1990s, another approach was to try to make selective muscarinic M2 antagonists, because that was the presynaptic autoreceptor that sensed acetylcholine in the synapse and told the upstream neuron to stop releasing it. Blocking that, it was thought, would potentiate the signals, making them longer and more powerful, and overcome problems downstream. No one got that one to work, either, but to the best of my knowledge it never got a real trial in Alzheimer’s patients.

So here’s my question: how sure are we that potentiating cholinergic neuron signaling is going to help Alzheimer’s patients? There’s a bit of hope from the efficacy seen with donepezil, although that’s mildly palliative at best and goes away after a period of treatment, and some hope from Lilly’s agonist program, which went pretty far into the clinic in mild-to-moderate Alzheimer’s patients, insofar as they could be identified back then. No idea if that efficacy, if efficacy it was, holds up either, or for how long. What I’m saying is that this really is something of a leap of faith.

On the other hand, leaps of faith are about all we’ve got in Alzheimer’s, and it will be good to see this hypothesis finally put to a test again after more than twenty years. More clinical data are expected later this year, but it’s going to be a while before we see results from either of the Heptares agonist candidates in actual Alzheimer’s patients. Allergan’s up-front money is not huge here, which seems appropriate, given the history of the field. But their downstream milestone payments are huge, which seems appropriate, given the size the market. This will be very interesting to watch.

27 comments on “Muscarinic Agonists Come Back Around”

  1. Dave says:

    There’s been some interesting (non-)news regarding Amyloid Protein antagonists coming out of Israel recently (I say non-news, since it’s all pretty ambiguous hand-waving, with a decided lack of details, about some effects in mice, which, in general, have a different Alzeheimer’s Disease mechanism.).

    http://www.haaretz.com/israel-news/science/.premium-1.712763

    1. Andre says:

      Dave, I (and probably most readers) could not access the report in Haaretz. Could you post the PDF of the article? Alternatively, is there a scientific publication associated with the report? Is there a company involved? If not, who heads the laboratory that generated the data?

      1. Kevin J. Rice says:

        Haaretz article, quoted WITHOUT permission but with attribution:

        A new drug under development by Israeli scientists to fight Alzheimer’s disease has led to the complete disappearance of symptoms in mice used as a model for the sickness. These mice have shown similar cognitive capabilities to healthy ones after taking the drug. The study of the mice was conducted after excellent results were reached with neuron cultures, in which a tiny concentration of the drug succeeded in preventing the destruction of nerve cells — which had been exposed to damage characteristic of oxidative stress or amyloid beta plaques.

        For now, it is much too early for the new drug to help Alzheimer’s sufferers, but the scientists say their preliminary findings present a worthy candidate for a future treatment for a disease that is incurable today.

        “I describe the molecule we developed as a sort of ‘Swiss army knife.’ It is capable of carrying out a large number of therapeutic tasks and works on a number of targets at the same time,” Prof. Bilha Fischer, a chemistry professor at Bar-Ilan University, told Haaretz. Fischer is developing the new drug in cooperation with Prof. Daniel Offen, a neuroscientist at Tel Aviv University Medical School.

        Medical science has been this optimistic before about finding a cure for Alzheimer’s, but in most cases the scientists, patients and their families have suffered serious disappointment. The bitter truth is that over 99 percent of all clinical trials for Alzheimer’s treatments end in failure. For now it is not only incurable, but a major mystery and irreversible. The chemical basis for the disease is still unclear. The research is directed in many directions and based on very different assumptions and approaches.

        One focus in recent years is based on the “amyloid assumption,” which says the amyloid beta peptide plays a major role in the development of the disease. The accumulation of the “sticky” amyloid protein plaques is responsible for the damage, by building up into clumps that can cause inflammation in the brain and the death of neurons. These plaques are the main target of most Alzheimer’s research today. Almost 90 percent of the scientific resources in Alzheimer’s research are devoted to developing drugs and treatments to reduce the concentrations and activity of amyloid beta in the brain.

        If some progress is being made in the battle against Alzheimer’s, it can be found mostly in the development of tools for early diagnosis of the disease, as well as in research on the link between lifestyle changes for patients and a slowing of the disease. Drug development still lags far behind. “Today, there are drugs whose effectiveness is very limited. They affect only about 20 percent of the patients and for a period of a year to two,” says Fischer.

        The main reason for this lack of progress is the multi-dimensionality of the disease and the inability to treat it through only one dimension, a single therapeutic target, as has been done in most trials so far, she says. In addition, many of those developing therapeutic approaches are not chemists or pharmaceutical developers, but biologists who adopt approaches such as using antibodies against beta amyloid for treatment. “We come from the direction of development of small molecules as drugs,” explains Fischer.

        The new molecule succeeds in effectively breaking up the accumulation of the amyloid beta, which damages nerve transmission, while at the same time also succeeds in activating specific proteins that provide a defense for neurons from various materials characteristic of Alzheimer’s. “In the lab we saved neurons [of new-born rats] which normally would die under conditions of oxidative stress or in the presence of amyloid beta. These cells survived quite well when treated even with very low concentrations of our material,” says Fischer.

        The series of tests conducted on the mice included testing their orientation ability, behavior, learning and memory — and for all of which the results were positive, and the mice’s cognitive abilities were similar to those of healthy mice, she says. “It was encouraging. We need to remember that the disease starts 20 years before it is diagnosed. Since the diagnosis ability today is better than the ability to cure, the scenario we can hope for is that as we can diagnose the disease in earlier stages, so we can prevent the progress of the disease using the drug. It could be an enormous achievement in dealing with this challenging disease,” she says.

        The amyloid beta, even though great resources are being poured into understanding and fighting it, is not the only target — and it does not reveal the sources of the disease and the mechanisms that cause it. One of the other interesting directions being studied concerns the immune system. In recent years, the approach that the development of Alzheimer’s is linked to a disruption of the dialogue between the brain and immune system is taking hold. This approach contradicts what was once the accepted position that a complete separation exists between brain cells and the immune system.

        “Twenty years ago I claimed it was not possible evolutionarily for the brain to give up on the help of the immune system,” says neuro-immunologist Michal Schwartz of Weizmann Institute of Science. In addition to the plaque build-up there is local inflammation, and while such an immune response is usually good, when it does not end is becomes pathological, she said.

        Ido Efrati
        Haaretz Correspondent
        read more: http://www.haaretz.com/israel-news/science/.premium-1.712763?date=1460228547745

  2. Lane Simonian says:

    G protein-coupled receptors are damaged in Alzheimer’s disease by cysteine oxidation. These include receptors involved in the release of neurotransmittors needed for short-term memory (muscarinic acetylcholine), sleep (melatonin), mood (serotonin), social recognition (oxytocin), and alertness (dopamine). So unless you reverse oxidation to muscarinic acetylcholine receptors, an agonist is not going to do much if any good.

    Both acetylcholinesterase and gamma secretase activity appear to depend on the release of intracellular calcium. In most cases that release declines as Alzheimer’s progresses so that acetycholinesterase inhibitors no longer work since their target is no longer an issue. As the disease progresses, oxidation and/or nitration inhibit the transport of choline and inhibit choline acetyltransferases.

    The two main problems regarding the retrieval of short-term memory in Alzheimer’s disease are the following: acetylcholine is no longer being produced and it is no longer being released. The upshot is that short-term memories are still there but the compound that helps retrieve them is basically depleted.

    1. Mark Thorson says:

      To the man with an oxidative hammer, every protein is a nail.

      1. Pennpenn says:

        I wonder if there’s a betting pool here on how many words it takes Lane to get to something that starts with oxida- in any discussion of Alzheimer’s?

  3. Anonymous Researcher snaw says:

    Lane, I don’t think you’re likely to be right, but it’s not as though Big Pharma has a whole heck of a lot to offer for AD either. Lord how difficult testing the Amyloid Hypothesis has been. And expensive.

    I sure hope somebody comes up with a disease-modifying treatment for AD before I’m in that age group. I’ve seen up close what AD did to people about whom I cared a lot, as have many readers of this blog.

  4. Bryan Roth says:

    Derek: these are likely positive allosteric modulators (PAMs) or PAM-agonists and not direct agonists..so they would have some activity early in the course of the disease but when all cholinergic tone is lost (or nearly so, which happens eventually) they would lose effectiveness.

    Xanomeline has a number of non-muscarinic targets and is a pan-muscarinic agonist (Psychopharmacology (Berl). 2005 Apr;178(4):451-60. Epub 2004 Oct 13.) so even though many believe its actions are due to M1/M4 agonism this is by no means clear in human AD (Br J Pharmacol. 1998 Dec;125(7):1413-20.
    Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Watson J1, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ, Jerman J, Middlemiss DN, Riley GJ, Brown AD; .)

    1. TX raven says:

      Bryan,
      If these compounds are truly allosteric agonists, they may get around the agonist tone issue. Even if they work in early AD delaying onset, that wouldn’t be bad at all.
      Definitely, they are expected to be different to an orthosteric agonist.
      Still, the lack of mechanistic disease understanding makes this a huge bet.

    2. biochem says:

      If these compounds are specific only to early disease / prevention, then they will have to meet a very high safety bar. Patients taking it will be taking it for years and taking it during years in which their quality of life is still good. This drug can’t significantly impact that. The side effects will need to be mild. Not an easy hurdle to meet for a neurological med.

  5. Lane Simonian says:

    The damage to g protein-coupled receptors and choline acetyltransferases may be due to either cysteine oxidation and/or tyrosine nitration.

    http://www.ncbi.nlm.nih.gov/pubmed/16043170

    http://www.ncbi.nlm.nih.gov/pubmed/11562447

    “These findings suggest that the oxidation and/or nitration of beta-adrenoceptors impair the ability of isoproterenol to bind to and/or activate these G protein-coupled receptors.”

    The same also applies to muscarinic acetylcholine receptors. To use a common analogy, a key cannot open a door when the lock is jammed, you have to “unjam” the lock first.

    In a strange way, there is a positive to Alzheimer’s disease. So many people who are researching it have or had a relative with the disease and are afraid of getting it themselves. This is a powerful incentive for trying to understand the disease.

    1. Lane Simonian says:

      This is a more pertinent example:

      “Oxidative stress has been implicated as a contributing factor to neurodegeneration in Alzheimer’s disease. An endogenous, low molecular weight (LMW) inhibitor from Alzheimer’s brain inactivates the human brain muscarinic acetylcholine receptor (mAChR). The inhibitor prevents agonist and antagonist binding to the mAChR as assessed by radioligand binding studies. ..”

      ” Natural antioxidants and pyrophosphate analogs may improve the effectiveness of acetylcholinesterase inhibitors and prove useful in the treatment and prevention of Alzheimer’s disease since the muscarinic acetylcholine receptor is required for memory, and decreased cholinergic function is a critical deficit in Alzheimer’s disease.”

      Anavex is another company working on compounds that are muscarinic acetylcholine receptor-1 agonists (and muscarinic acetylcholine receptor-2 and 3 antagonists and sigma receptor-1 agonists). However, probably much more importantly, these particular compounds impede the formation of peroxynitrite and inhibit caspase-3 activity.

  6. Morten G says:

    Heptares StaRs (r) *jazz hands*

    (Sorry, I think it’s a really good technology but the name always makes me want to do jazz hands)

  7. Andre says:

    I can image lots of potential side-effects, if one were to take muscarinic receptor agonists as an AD treatment over years. For example, gastric acid production in the stomach is stimulated by the release of acetylcholine from vagal nerves endings to stimulate M1 receptors of ECL cells, which in turne release histamine to activate acid production in parietal cells. Furthermore, acetylcholine stimulates directly M3 receptors on parietal cells to increase acid production (https://en.wikipedia.org/wiki/Gastric_acid). This is just one example. In general, acetylcholine signalling plays a major role in regulating various digestive tract functions. In my personal view, muscarinic receptor agonists as AD targets dead on arrival. There is no validation in an animal model nor is there any human genetics supporting any benefit in slowing AD development or progression. I fear that again billions will go down the drain. At the same time the responsible CEOs will pocket huge salaries for misconceived drug development pipelines….

  8. Andre says:

    Just a follow-up on my last comment. Xanomeline (LY-246,708; Lumeron, Memcor) was dropped from AD development due to gastrointestinal side effects that led to a high drop-out rate in clinical trials (https://en.wikipedia.org/wiki/Xanomeline). Good luck trying avoid these very same problems with next generation muscarinic receptor agonists….

    1. Lyle Langley says:

      The issues with xanomeline were/are thought to be mediated through M2/M3 and thus if one could get a selective M1 agonist or PAM they may be able to overcome the GI SLUDGE issues. There are others that believe M1 is the culprit as well. Many groups are going after PAMs to overcome some of the issues and not knowing the actual structure of the Hepatares compound – from the patent literature I don’t believe these are PAMs, they are more likely allosteric agonists, or true agonists and thus selectivity may be an issue.

      1. Andre says:

        As mentioned above, ECL cells express M1 receptors, which are activated after vagal nerve release of acetylcholine. This will trigger histamine release and activation of gastric parietal cells. They will increase gastric acid production. Thus, M1-specific agonists are likely to have gastrointestinal side effects. Correct me if I am missing something!

    2. A company called Karuna Pharmaceuticals is intending to take xanomeline back into the clinic for schizophrenia, combined with trospium chloride to block the M2/M3-mediated GI effects. It will be interesting to see if this really does mitigate the effects.

  9. AD guy says:

    Im not sure how you would do a clinical trial in AD with a muscarinic allosteric agonist- presumably it would have to be done in subjects already on cholinesterase inhibitors as it would be unethical to take them off the drug.

    1. Lyle Langley says:

      One way to do this is to go in combination with a cholinesterase inhibitor and look to lower the dose as a first pass. Looking to do a “sparing” trial would potentially get your drug on the market and lessen any side effect profile of both drugs. Then go in for stand-alone therapy. I know there are data showing this can be done in rodents. This is one strategy in the Parkinson’s field with L-DOPA.

      1. TX raven says:

        Funny you say this is a strategy for PD.
        I got tired of convincing clinicians to do this, and they got tired of saying it cannot be done.

        1. Lyle Langley says:

          Then you are talking to the wrong clinicians. There hasn’t been one that I’ve talked to that has not suggested this strategy. Talk with the PD community and they will agree that if one can lessen the amount of L-DOPA needed for efficacy (sparing) it would be a welcomed addition. I believe the A2A antagonist from Schering used this same strategy (co-dosed with L-DOPA) in their clinical trials – the compound failed, though for other reasons.

  10. anon says:

    Want some input on the implications of opening up the BBB.
    Could this mean combining Lexiscan and an anti-amyloid antibody (such as solaneuzumab) might be more effective and with less risk of ARIA?

    https://www.sciencedaily.com/releases/2016/04/160408132649.htm

  11. stupid man sitting in a tobacco field says:

    how can one discover a treatment for an illness without knowing what causes the illness to begin in the first place. Could alzheimers be the results of chronic nutritional deficency? Could it be that the brain is not getting the nutrients it needs to remain healthy? I work in a pharmacy and all these older people are taking these proton inhibitors or other anti-acids which could be preventing elderly people from properly digesting their food and getting the nutrients that they need to maintain a healthy brain. Would taking high doses of anti-oxidant vitamins/compounds help reduce brain inflammation and formation of amyloid plaques? which nation has the lowest incidence of Alzheimers? Is there anything about their diet that could suggest a treatment for Alzheimers?

    1. Design Monkey says:

      > which nation has the lowest incidence of Alzheimers?

      Swaziland, probably. Because they have more than 25% HIV infection prevalence, life expectancy less than 50 years, and simply don’t live long enough to get much of Alzies.

  12. anon2 says:

    taurx’s LMTX appears to have done quite well in a subgroup on monotherapy in its phase 3 trials as presented at ICAD2016 today in Toronto. Is this the Alzheimer’s result that we have all been waiting for?

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