"Rett-Buster" -- Hope of a Treatment Drug (NNZ 2566)
Ok guys and girls, several are asking about the new drug trial that just completed late last year. I’ll give my take on it, but the standard disclaimers apply:
I’m not a doctor, I just play one when I can’t sleep
I’m only as good as Google
It must be true, I read it on the Internet
The drug is currently known as “NNZ 2566”, and is produced by a New Zealand-based pharmaceutical company called Neuren. Not a very catchy name (NNZ 2566), but I suspect the CEO doesn’t want marketing guys spending big $$$ naming the drug until they can really sell it. So I surmise that “NNZ” represents “Neuren New Zealand”, and the number was next in line – that’s all a guess. I want to name it, so let’s call it Rett-Buster.
Rett-Buster just completed a Phase II clinical trial at three separate hospitals (Baylor, UAB, and Gillete Children’s Hospital). Our guy/super-hero, Dr. Alan Percy at UAB was right in the middle of it, and RettSyndrome.org funded a significant part of the trial. We are all painfully aware that new drugs take a long time to develop, test, and approve (via the FDA) for use in the general US population. Killing people with new drugs is bad, so the entire process is typically measured in years. Phase II is one of the first phases where the drug is actually given to humans, and in the case of our Rett-Buster, the Phase II trial was designed primarily to prove that the drug is SAFE. Now in this particular trial, there was also a secondary goal, with very precise and controlled measurement criteria, that included assessment of the drug’s EFFECTIVENESS. This is where it gets cool… more in a minute.
First a little refersher. Any Rett-follower worth their salt knows that the problem is on one of the two X-chromosomes (girls have two), and specifically on the gene that produces a protein called MECP2. The tricky thing with Rett is that the MECP2 gene randomly mutates in one of about 250 or so different ways... causing either an altered protein or not enough protein or a confusing protein, or a shortened protein, or in general – a protein that just doesn’t do the job it’s supposed to do. Depending on how it mutates (and any number of other genetic factors like X-skewing, other mutations on other genes, etc.) it becomes very difficult to predict how any single Rett girl will be affected. Too many variables, not enough equations (remember your algebra).
“What” the MECP2 protein does is fairly well understood; “how” it does it is still a little fuzzy. But when it doesn’t do it correctly, the end result is that signals from the brain don’t quite make the connections on the road to where they’re going (the lungs, the heart, the muscles, or even within the brain itself). Wiki says: “This defect probably disrupts the normal functioning of nerve cells, leading to the signs and symptoms of Rett Syndrome.” So there you go… generally good brain, but a bad delivery system, and all because of one screwed up protein. We could pull an all-nighter on MECP2 and barely scratch the surface, so let’s leave it there.
So theoretically we cure Rett Syndrome by fixing the MECP2 problem. Add more, fix the bad ones, turn on the other “good” X-chromosome… whatever… sounds easy but it’s not. There is a lot of research going on related to really fixing the MECP2 in the cell (go read about the “mouse model” experiment where the faulty MECP2 was “fixed”). These approaches still have a long road in front of them, but we are forever hopeful. In the interim, we treat symptoms with therapy, and known drugs for that symptom (i.e., seizure meds, heart meds, etc.), none of which really solve the underlying biological deficiency of bad MECP2, and the resultant faulty nerve cell function.
OK buckle up…. Rett-Buster is a synthetic “analogue” of a naturally occurring peptide (Glypromate) derived from IGF1 (Insulin Growth Factor 1) – a growth factor produced in brain cells. Glypromate plays a key role in the brain’s response to injury and stress. Forget about trying to understand analogues and peptides and Glypromate and IGF1… the bottom line is that the chemical in Rett-Buster(essentially a synthetic Glypromate) is able to cross the blood-brain barrier and theoretically “repair” some of the broken nerve cell responses… fix the signal delivery system. It does not fix the bad MECP2 (which in our moments of hope and greed is what we really want), but based on the Phase II trial effectiveness criteria, it does appear to successfully alter the “transport system” in a positive way.
Here’s your quick bullets on Rett-Buster and the Phase 2 trial:
In prior animal studies, NNZ 2566 was proven to exhibit a wide range of positive effects including reduction of neuro-inflammation, normalizing the role of microglia, and improving deficits in synaptic function
Phase II - Small study/short study – 67 Rett girls at three different hospitals for 28 days. Ages were 16-45 (as you might imagine, first safety studies are not done on children)
For you technicians – Phase II, double-blind, placebo controlled, parallel group, dose-escalation
For you non-technicians – good scientific methods and practice, some got the drug and some did not, some got a higher dose than others
Result – deemed safe (at least for the period of the study)
Result – deemed effective (at the highest dosage level)
Study completed in September 2014
What got better? – a little harder to answer that – each girl that really got the drug had different improvements, but the key is that they all improved by some measure… here’s the quote from RettSyndrome.org blog:
“At the high dose, the behaviors changed (improved) from the placebo control. Behaviors in each patient are different so to say one particular behavior changed would be incorrect because no two persons’ behaviors are exactly the same. The physiological measures also showed changes and trended toward improvement, but that is still being analyzed. The most important thing to remember is no one knows how this all works other than the nerve connections are a necessary part of everything we do. If NNZ-2566 increases the number of nerve cell connections, then each patient in the trial may exhibit different progressions in their everyday life. However, each patient may not progress at the same rate because of individual to individual difference in experiences and how those experiences are stored in the neural connections. The goal of the study and future NNZ-2566 studies is to correct Rett biology! The nerve connections in Rett are fewer than normal as stated above. This drug in its actions helps to form more connections. By forming more connections, we are trying to normalize the Rett biology… then the nervous system has greater potential for learning, motor function and all the other things the central nervous system does. It is important to know this drug is not designed to specifically treat one of the symptoms of Rett,… But rather it is designed to correct the deficiency in nerve connections globally in Rett. If the number of connections can be improved, then there is the possibility that those symptoms will be improved by having a greater neural network to stabilize the entire central nervous system."
So, when you go study the “effectiveness measurement criteria”, you can do a little connecting-the-dots and come to the conclusion that potentially lots of things improved – motor function control, frequency of hand-wringing, breathing, brain function as measured by EEG, cardiac response, etc. were all part of the effectiveness measurements. Good news.
One other interesting fact – Rett-Buster is potentially not just for Rett Syndrome. Neuren is also studying the drug’s effectiveness in cases of Fragile X Syndrome (another X chromosome mutation) and Traumatic Brain Injury (TBI), and is actually receiving funding from the US Army to conduct the TBI study - obviously, war produces a lot of TBI. Nice to know that Uncle Sam is throwing some money at this too – albeit for a different reason – but we’ll take it.
What’s next? – more trials, potentially on younger age groups (like our little Blakely-boo), or a more extended study of effectiveness… but based on the encouraging/positive Phase II result, Neuren (working together with RettSyndrome.org) is expected to apply for “Orphan Drug Status” and “Break-through Drug Status” from the FDA. I won’t get into the details of those designations right now (they are somewhat self-evident), other than to say it puts the drug on a faster schedule for eventual FDA approval, assuming success in the next-phase trials.
Exciting stuff for all of Team Blake… keeps us and every other Rett family motivated, digging, praying, working, and raising money for the cure. More to come when we hear about the next steps for Rett-Buster!!! See the link below for the RettSyndrome.org blog on all of this. There is a video clip of the RettSyndrome.org Chief Science Officer (Steve Kaminsky) explaining everything I just tried to explain. And he really is qualified !!!
Written by: Kevin Pierce -- Blakely's PapaCoach and our resident Google PHD... and narrator of Disney Princess stories.