I posted a video presentation a while ago by Dr. Michael Tranfaglia, Medical Director and Chief Scientific Officer of FRAXA on IND's for Fragile X, titled: The Investigational New Drugs - What do they Do?
If you haven't had a chance to watch it yet, I highly recommend you do.
I took away many gems from this presentation, which mostly highlighted why I invested in Neuren Pharmaceticals in the first place.
Here are some of the important highlights from the video that I have jotted down and how the current Fragile X molecules in the clinic compare to NNZ-2566.
Stay with me though, as I lead up to the Fragile X molecule comparisons. First a bit on the science, then the comparisons.
* Mark Bear and Ken Huber discovered, shortly before 2000 that there was a specific kind of defect in synaptic plasticity in Fragile X, that is, there is a specific defect in how the connection between neurons in Fragile X people and Fragile X mouse, respond to experience.
* Normally when you have an experience it changes your anatomy in very subtle ways and all those changes in anatomy relating to your experiences to making a person who he is. And that's how our brains become the way they are.
* Dr. Tranfaglia illustrates this effect of FMRP (Fragile X Mental Retardation Protein) when it's absent. He highlighted that when we see a kind of schematic of the synapse, where we have receptors at the top i.e., mGlur1, mGlur5 and AMPAR receptors, these are the main Glutamate receptors and mGlur1 & mGlur5 control the endocytosis, or the removal from the cell surface of these AMPAR receptors.
Note: A Synapse is a junction between two nerve cells, consisting of a minute gap across which impulses pass by diffusion of a neurotransmitter.
* He went on to say that normally this is happening all the time and they're kind of cycling in and out of the membrane of these AMPAR receptors. He also said that more AMPAR receptors tend to make a more mature synapse.
* There are even some people who would go so far as to say more AMPAR receptors make you smarter, he said. So drugs that enhance AMPAR receptor function, are smart drugs.
* Many have actually tested those and have actually done clinical trials of AMPAR kinds which enhance AMPAR receptor function.
* He went on to say that in Fragile X there's too much of the endocytosis of AMPAR receptors. If you don't have enough of these on the surface, it results in an immature synapse.
* So what normally happens is mGlur5 stimulation, results in translation of proteins and these proteins which he referred to as LTD proteins, result in persistent internalization of these AMPAR receptors and a kind of long term depression of the synapse. This decreases synaptic function and it does that in a stable way when there's protein synthesis.
* Normally FMRP, the Fragile X protein, actually inhibits this process and it keeps it regulated and it's actually very very tightly regulated. But of course in Fragile X, FMRP is absent.
* And in the absense of FMRP, you get an increase in protein synthesis, and an increase in this persistent internalization of AMPAR receptors, increase in long term depression and essentially a very immature kind of synapse. So synapses, that cannot mature in response to experience.
* He went on to say that this is a very subtle effect because kids with Fragile X can learn, they can actually learn things and they can respond to experiences with changes in behaviour.
* This is just one mechanism in synaptic plasticity, but it is one mechanism that is especially significantly affected in Fragile X.
* Dr. Tranfaglia highlighted another cartoon of a synapse where at the top there was the axon, the pre-synaptic neuron. At the bottom there was the dendrite or the post-synaptic neuron. In the middle between two cells, is where the chemical signals get transmitted. This is where glutamate is spewed out into the synaptic space between the two cells.
* It's received by mGlur5 receptors and it's also received by AMPAR receptors. And AMPAR receptors cause an influx of ions when a glutamate binds to it. mGlur, when a glutamate binds to it, results in a protein cascade and that's mostly shown by many other proteins that are attached to the bottom of mGlur5. So, an increase in protein synthesis when FMRP isn't around to regulate this.
* Dr. Tranfaglia mentioned that the slide he was referring to was taken from a paper that was talking about an autism mouse model, because other forms of autism, in mouse models at least appear to respond to mGlur5 antagonist as well.
* What he also mentioned is that there are a couple of different ways that you can fix this problem. You could decrease the amount of glutamate that's being released by the top cell and that's what GABA-B agonist like baclofen and arbaclofen do. You could block the mGlur5 receptor and that's what the Roche drug and the Novartis drug do. Or you could increase the function of the AMPAR receptors by stimulating that.
Ok, so now that we have an understanding of the science behind these drugs, let's look at how they compare to the NNZ-2566 drug.
What novel molecules are in the clinic for Fragile X?
* There are a few trials of approved drugs but they're purely targeting symptomatic treatment.
* There's the Seaside Therapeutics program, but that has now failed.
* There's one GABA antagonist (Marinus) and two mGlur antagonists (Roche and Novartis).
* A GABA antagonist doesn't look too promising after the results from Seaside Therapeutics, but there's still a lot we don't really know about that program, so I'll reserve comment for a later stage. I expect we'll hear more on this soon.
*As to the two mGluR antagonists, Roche and Novartis, there really hasn't been much heard about the results in the clinic so it's hard to comment at this point in time.
I've been doing some research on a few of the preclinical studies with mGluR antagonists and they have certainly been promising, however, in one study, researchers cut expression of mGluR1 and mGluR5 by half by genetic means, the fmr1 knockout mice had more seizures and only modest improvements in behavioural measures.
See article below:
Mouse study raises questions about fragile X treatment
Deborah Rudacille
18 July 2011
http://sfari.org/news-and-opinion/news/2011/mouse-study-raises-questions-about-fragile-x-treatment
What I really wanted to highlight with this rather long post, is that mGlur antagonists have one specific mechanism of action whereas NNZ-2566 has a broader range of actions, IL-6 inhibition, increased IGF-1 expression and normalization of ERK and AKT activation of mGlur as well as normalizing microglial function. (Refer to the April 15 announcement for greater detail).
Of course we need that signal of clinical efficacy first, but having said that, I am very encouraged, optimistic and excited by the initial results to date, and sense we have a very powerful molecule ready to go to head to head with the 'big boys' in the clinic.
Regards,
Tony
(20min delay)