October: Neuren Pharmaceuticals trials Trofinetide: 2 updates
1. Neuren Pharmaceuticals announced the financial support of Rettsyndrome.org for continued development of trofinetide as a treatment for Rett syndrome. With this funding Neuren Pharmaceuticals will conduct a pediatric trial in children below the age of 16. The study will determine the tolerability of higher doses and length of treatment in this age group, which will enable Neuren to determine the optimal dose to be used in the subsequent Phase 3 trial.
Neuren is working with the Food and Drug Administration (FDA) on the Phase 3 trial design that would support the potential approval of a New Drug Application.
2. The US Patent and Trademark Office issued a Notice of Allowance for a new patent concerning the use of trofinetide to treat Rett syndrome. The patent is expected to expire in January 2032, which offers Neuren Pharmaceutical additional protection to their current patent.
Trofinetide has orphan drug designation in the US and in Europe, which gives Neuren market exclusivity following market authorization for seven and ten years, respectively
(taken from Rettsyndrome.org blog)
June: Developing drug NLX-101 to treat breathing abnormalities; California, USA.
Neurolixis, a small biotech firm in southern California is developing the drug, NLX-101, to treat breathing abnormalities in people affected by Rett Syndrome. The drug targets a specific serotonin receptor (5-HT1A) located in regions of the brain that affect respiration, mood and cognition. It’s possible that, beyond breathing, the drug may also improve other core symptoms such as anxiety and movement disorders.
Their work is being funded by US Charity Reverse Syndrome Research Trust. Previous studies have determined dosage levels for human studies. The next step is for Neurolixis to manufacture and characterize clinical supplies of NLX-101, followed by testing the safety, tolerability and pharmacokinetics (the time course of the drug’s absorption, bioavailability, distribution, metabolism and excretion) in healthy volunteers and in people with Rett. By supporting this program, RSRT will help Neurolixis “de-risk” the project and make it more attractive to investors, who can support the next stage of development and expedite the process.
June: Trofinetide: a hopeful new drug; College of Medicine, Houston, Texas.
An exploratory phase 2, double-blind, placebo-controlled trial shows that the drug is safe, well tolerated, and effective in managing core symptoms of Rett Syndrome.
Many patients with Rett syndrome have breathing problems while awake. About 70% have epilepsy. The incidence of sudden unexpected death among patients with the syndrome is higher than in the general population. In knockout mice, the agent restored long-term potential, enhanced dendritic growth, and improved longevity. In healthy human volunteers, it has garnered a good safety and toleration profile.
The current study enrolled 56 female Rett patients, and participants were randomly assigned to one of three cohorts. The first included 9 patients who received placebo or 35 mg/kg of the drug twice daily for 14 days. The second group, with 18 patients, received placebo or 35 mg/kg of trofinetide twice daily for 28 days, and the third group, with 29 patients, received placebo or 70 mg/kg of the drug twice daily for 28 days.
The study found that according to parent reports, electrocardiograms, physical examinations, and laboratory evaluations, both doses — 35 mg/kg and 70 mg/kg — were safe and well tolerated after 28 days of treatment. There were no significant adverse side effects, dose related or time related.
It suggests that these results provide initial evidence that NNZ-2566 may be an effective drug for treating Rett syndrome, and that it supports further studies. A phase 2 study on safety and tolerability in children would likely be undertaken next, followed by a phase 3 study in children, adolescents, and adults.
May: Gene Therapy; a viable option? Cardiff & Edinburgh, UK.
In 2007 lab tests proved mice ‘infected’ with the mutant Mecp2 gene could be reversed. From this landmark study there is now research into whether gene therapy for Rett Syndrome is a viable option.
Gene Therapy involves making a ‘good’ copy of the MECP2 gene and delivering it to cells in the brains of girls with the MECP2 mutation. Once a cell has received this ‘good’ copy of the MECP2 gene it begins to express the MeCP2 protein. Tests on mice have shown positive effects – improved survival, reduced severity, improved locomotion etc. However the tests did show that there are still several challenges that need to be addressed before it could be used in patients; mainly how the ‘good’ gene is delivered to the cells – too little and it ‘hits’ too few cells; too much and too quickly causes toxic effects. This work is on going.
And there is new exciting approach to gene therapy that is growing pace – ‘gene surgery’. This involves deploying tools to ‘correct’ the mutation inside some of the brain cells affected by the MECP2 mutation, rather than giving these cells an extra copy of the gene. This should in theory be even safer and more effective than traditional gene therapy approaches. Yet it is also more difficult to achieve in a safe fashion so will require a lot more development work before there are clinical trials in our girls.
March: Ketamine Clinical Trail, Ohio, USA
“Ketamine? Isn’t that a tranquilliser? Ketamine is a sedative which is most often used as an anaesthetic in operations. However, at much lower doses it has been shown to significantly improve symptoms in disorders such as major depression and obsessive-compulsive disorder and to be effective in pain management.
So what’s that got to do with Rett Syndrome? Professor David Katz at Case Western Reserve University School of Medicine in Ohio, USA, has studied the impact of Ketamine on Rett mice. Rett mice show imbalances in nerve cell activity in their brain. In some areas of the brain there is too much activity and in some, there is not enough. Professor Katz gave Ketamine to Rett mice in an attempt to correct these imbalances. Even at low doses, this imbalance in brain activity was corrected. There were also significant improvements in neurological function, including breathing and reactions to sensory stimuli.
What will happen next? The Case Western Reserve and Cleveland Clinic researchers will soon be launching a two-year clinical trial using low doses of Ketamine in up to 35 individuals with Rett Syndrome.
The trial will focus primarily on measuring changes in breathing patterns and overall severity of the patients’ condition. Each participant will receive placebo as well as different doses of Ketamine in a random order. Comparing these results will enable researchers to work out if ketamine is effective as a treatment for Rett Syndrome and if so, what dose is best.
If the trial is successful, the next step will be to test whether the drug can be given on an on-going basis, rather than just a few doses.
Read the full Case Western press release about the Ketamine clinical trial here.
This work has been funded by the Rett Syndrome Research Trust.”
Taken from www.reverserett.org.uk
March: Overexpression of Long Gene, Harvard University, USA
“Every cell in our body contains the same genes. Yet a brain cell is distinctly different from a heart cell or a liver cell. What differentiates these cells are the genes that are either silenced or active and the degree of activation of the genes, also known as expression.
Scientists have known for many years that the “Rett protein”, MeCP2, regulates the expression of other genes. The big question has been, which genes?
Michael Greenberg of Harvard University, and his lab members Harrison Gabel and Benyam Kinde, may have an answer: long genes. The journal, Nature, is publishing this finding today.
Genes are made up of nucleotides (think back to high school biology: A,T,C,G) The average gene has about 20,000 nucleotides, but some have as many as a million. The scientists in the Greenberg lab found that the MeCP2 protein acts as a dimmer switch, dampening the expression of long genes. When the MeCP2 protein is absent, as in the case of Rett, with no dimmer switch to regulate it, long gene expression goes up. Any deviation from the normal expression pattern causes problems.
From this finding, the scientists suggest that Rett Syndrome may be caused by a widespread overexpression of long genes.
You may be asking yourself, why does this matter? It matters because there is a drug that can rebalance the expression levels of long genes. The Greenberg lab has already tested this drug in cells missing the MeCP2 protein with encouraging results. Experiments are now underway to test the drug in Rett mice.”
Taken from www.rettsyndrome.wordpress.com
February: Neuren Pharmaceuticals Phase III Clinical Trail, USA
Neuren Pharmaceuticals has been granted permission by the US federal government to continue trialing the now-named drug Trofinetide. This drug was known as NNZ-2566 when Neuren carried out a Phase II clinical trial in women with Rett syndrome, which produced some very positive results. It is the hoped that the next trial will be in a younger population and if found to be effective they will then work on a Phase III clinical trial.
Although the exact details of the results of the Phase II trail and the specifics of what the drug does have not been released to the public, it is known that this drug helps to increase the number of nerve cell connections (Rett girls have fewer connections to other nerve cells and the drug is acting to normalize the number of connections.) If the number of connections can be normalized, then the nervous system has greater potential for learning, motor function and all the other things the central nervous system does.
There is more information at https://www.rettsyndrome.org/blog/neuren-orphan-drug-status and http://www.rettsyndrome.org/blog/nnz-2566-success-breakdown
ALL THIS IS EXCITING NEWS AND TAKES US A STEP CLOSER TO OUR DREAM…
If you are passionate about research into finding a cure for Rett, then please donate to either http://curerett.org or http://www.reverserett.org.uk, thank you :)
We had a very positive meeting today with the ACE Centre, Oldham. They are a specialist charity who assess children with communication problems to ensure they have access to the most appropriate tools and resources to communicate.
They were pleased that Abbie is communicating, both through her basic expressive noises, eye contact and smiles, and also the more structured use of picture cards, which she uses to make a choice (e.g. a particular book) from a selection by eye-pointing. Abbie can manage choosing from 3 possible choices and we need to expand that up to 4, then 6, possibly 9.
The next big step is moving on from choosing things from pictures to using pictures conveying actions, wishes or comments such as ‘more’, ‘finished’, ‘I like’, ‘again’, ‘oops’, ‘stop’…. words that we already say to Abbie and ask her questions about, but words that we have never shown her in picture format.
And it makes sense in that as Abbie will only ever communicate through pictures (and eventually written words) she needs to be exposed at the earliest opportunity to these words in the format she can use – whether eye-pointing at a picture board or an eye-gaze computer.
This process is the foundation for Abbie communicating successfully, and once she has mastered the art of using the low-tech picture cards, the next step will be to assess her for more high-tech tools such as an eye-gaze computer. They did warn us today that this process can take anywhere between 12 and 24 months, and is very dependent on the individual child.
So we await the new picture cards arriving in the post! and try to get to grips with making them part of our everyday communication with Abbie. We will get her there!!
#achancetohavehersay
Abbie first visited Brainwave in May 2014, a few weeks after we had her diagnosis of Rett. Armed with this knowledge Brainwave could tailor her programme with what is achievable (i.e. they concentrated on her mobility rather than speech or holding things).
This visit built upon the exercises that we were given 6 months ago, as she had advanced beyond some. The ultimate goal is to get her to stand and then walk. But his needs breaking down into the minute detail that happens with every child, but Abbie needs each ‘fragment’ worked on separately and repeat, repeat, repeat!!
So today we came away with 8 exercises with 2 main long-term aims:
- From high kneeling to bring her foot up and plant with bent knee,
- To walk (with help) with less wooden action, using the right actions.
There are 4 Rett specialists in the UK and they hold regular Rett clinics around the country in Cardiff, Manchester and London.
Although we had to wait 5 months for a 1 hour session it was worth it. We went down to St Thomas’ in London and saw Dr. Hilary Cass, together with a speech and language therapist, a physiotherapist, and a representative from Rett UK who support these clinics.
It was great for Abbie to see specialists that deal with Rett everyday and could assess where she was on the spectrum of severity. (Abbie is only one of 3 known cases in Warrington so it’s understandable that our local health team, although very supportive, do not have a specialist knowledge of Rett syndrome).
Wow! They were very pleased with Abbie and considered her highly functioning. They were happy that she could sit up, crawl and kneel up and that she could eat and chew, albeit mashed/small pieces. They were especially pleased with her level of eye contact and that she was making choices. Dr. Cass believes Abbie will continue to progress and will – with a lot of help and encouragement - learn new skills, such as walking. They want her to try a splint on her left arm to stop her mouthing and see if she can ‘break the cycle’ of repetitive mouthing. This works with some girls and not with others, so watch this space!
We came away feeling very positive and very proud of our beautiful girl :)
