P.O. Box 50030 London, ON N6A 6H8 info@rett.ca (519) 474-6877

Taysha Rett Program Update

Sabrina Millson, President of Ontario Rett Syndrome Association quoted,

“This is a momentous day for the Rett syndrome community. As a mom to a daughter living with Rett syndrome and the president of the Ontario Rett Syndrome Association here in Canada, I know first-hand how this disease leads to debilitating symptoms, including difficulties in communication, mobility and breathing. The potential for a treatment that addresses the underlying cause of disease and slows progression or potentially prevents the onset of disease with early intervention is truly remarkable. We’re pleased to collaborate with Taysha Gene Therapies in an effort to bring a gene therapy treatment that could meaningfully change the lives of patients and their caregivers.”

Taysha-Gene-Therapies-Announces-First-Patient-Dosed-with-TSHA-102-in-the-REVEAL-Phase-1_2-Trial-Under-Investigation-for-the-Treatment-of-Rett-Syndrome

18th Rett Classic Registration

Register Now Before May 28, 2023.

2023 Hope Fund Grant Winners

The Ontario Rett Syndrome Association (O.R.S.A.) Board of Directors has unanimously approved the funding of two research grant totaling $150,000 from The Hope Fund for 2023. The Hope Fund has funded over $828,000 in Canadian research to date.

Grant applications were received and evaluated by O.R.S.A.’s Research Advisory Committee which is comprised of impartial and prominent neurologists, geneticists and scientists from across Canada. O.R.S.A. would like to thank all those individuals that applied for this grant.

The Hope Fund was established in 2014. The funds for this research grant were raised through donations and fundraising activities. O.R.S.A. continues to support research excellence and the development of a wide scope of Rett syndrome research across Canada.

We are pleased to award $100,000 to Dr. Ellis and Dr. Zani to support their research titled: Astrocyte-derived Extracellular Vesicles to Rescue Rett Syndrome Neurons.

LAY SUMMARY

Rett syndrome (RTT) astrocytes are less able to support maturation of synapses that interconnect neurons. Human astrocytes require the IGF1 receptor for optimal neuron support, and IGF1 is a promising RTT therapy. Astrocytes release small droplets called extracellular vesicles (EVs) containing messages in the form of genetic material called microRNA. EVs deliver the cargo to nearby neurons or into the bloodstream, and limited evidence suggests that healthy EVs rescue RTT neurons. Using ORSA and other funding, we produced astrocytes from healthy induced pluripotent stem cells (iPSC), isolated EVs and determined their microRNA cargo overlaps with those altered in RTT patient blood. We submitted a Stem Cell Network grant to test if healthy control EVs rescue RTT neuron activity.

To explore EV microRNAs as blood biomarkers for IGF1 drug treatment, it is essential to evaluate the EV cargo of RTT astrocytes. We are producing RTT patient astrocytes from stem cells and will determine which microRNAs have altered levels in RTT EVs compared to controls, and if IGF1 treatment normalizes the levels of microRNAs packaged into the RTT astrocyte EVs. The differential microRNAs corrected by IGF1 treatment will be candidate biomarkers, and their ability to rescue RTT neuron activity will be tested.


James Ellis, PhD

Hospital for Sick Children, Toronto Canada 

Dr. Ellis completed his BSc at McGill University and his PhD at the University of Toronto with Dr. Alan Bernstein developing retrovirus vectors for gene targeting. His Post-Doctoral Fellowship studying the beta-globin Locus Control Region was mentored by Dr. Frank Grosveld in London UK. Dr. Ellis established his own research team at the Hospital for Sick Children in Toronto in 1994 with a focus on gene therapy for Sickle Cell Anemia. He subsequently developed MECP2 vectors for Rett syndrome, and vectors with reporter genes that mark specific cell types. For example, the EOS vectors express specifically in pluripotent stem cells and facilitate generation of patient induced Pluripotent Stem (iPS) cells. The Ellis lab currently uses these iPS cells in collaborative research teams to model Rett syndrome, Autism Spectrum Disorders and cardiomyopathies. New research directions concentrate on post-transcriptional regulation during human neurodevelopment, and the transfer of microRNA via extracellular vesicles. Dr. Ellis is Research Integrity Advisor at the Hospital for Sick Children.  

Ellis Lab website http://lab.research.sickkids.ca/ellis/ 


Augusto Zani, MD, PhD 

Hospital for Sick Children, Toronto Canada 

Dr. Zani is a Neonatal and Paediatric Surgeon at the Hospital for Sick Children in Toronto, Associate Professor at the Department of Surgery, University of Toronto, and Scientist in the Development and Stem Cell Biology Program at the Peter Gilgan Centre for Research and Learning, SickKids, Toronto, Canada. His clinical interests are congenital anomalies and minimally invasive surgery, and his research focuses on neonatal and pediatric conditions with high morbidity and mortality rates. The Zani lab studies extracellular vesicles (EVs), which are nanoparticles released by all cells for intercellular communication. As EVs carry cargo similar to their cells of origin, EVs can be pathogenesis mediators, biomarkers of disease severity, and therapeutic agents. Among various EV-based projects, the Zani lab has recently been investigating the signatures of EVs isolated from induced plurip 

Zani Lab website: https://lab.research.sickkids.ca/zani/ 


We are also pleased to award $50,000 to Dr Marie LE ROUX and Dr. Elsa ROSSIGNOL, for RESEARCH PROJECT: Electrophysiological non-invasive biomarkers in Rett Syndrome evaluation. 

LAY SUMMARY 

This prospective single-center study, conducted at the CHU de Sainte Justine (Montreal, Quebec), aims to develop new non-invasive biomarkers of Rett syndrome progression in a pediatric cohort. Version date 11/22/2021 These biomarkers are based on functional and spectral connectivity including measurements of coherence and cortical integration in electroencephalogram, and mismatch negativity by auditory evoked potentials. Prospective data with repeated measurements one year apart will be collected in patients and age-matched controls, and disease evolution and level of severity (standardized scales as RSBQ and CGI) will be compared between both time points. These values will serve as a baseline for comparison in future therapeutic trials. Indeed, the first gene therapy in Rett Syndrome (REVEAL study, Taysha) is being launched at Ste-Justine, initially in adults, with a subsequent pediatric phase considered if the therapy is well tolerated in adults. Similar electrophysiological measurements will be conducted in the adult patients but an understanding of the evolution of such neural signatures in pediatric age groups is lacking. We thus propose to assemble a first large pediatric Rett syndrome cohort to document the natural evolution of these electrophysiological signatures over time, and to address how these biomarkers evolve with disease progression and therapies.


Dr. Elsa Rossignol

Dr. Elsa Rossignol is a pediatric neurologist at the CHU Sainte-Justine and an associate professor of clinics in the departments of Neurosciences and Pediatrics at the Université de Montréal. She is the recipient of the Canada Research Chair on the Neurobiology of epilepsy. Her research aims to clarify the molecular and cellular basis of pediatric epilepsies. Using Next Generation Sequencing in large cohorts of patients, her lab contributed to the identification of dozens of novel epilepsy genes. Furthermore, her lab uses multimodal approaches to study the network mechanisms by which mutations in these genes result in epilepsy and cognitive deficits, with a focus on their impact on network inhibition. Her recent work revealed the key role of cortical disinhibition in genetic generalized epilepsies with cognitive deficits, and the therapeutic benefits of re-establishing network inhibition on seizures, attention and cognitive flexibility. In addition, Dr. Rossignol is the Director of the Integrated Rett Syndrome Clinic at the CHU Sainte-Justine. Her clinical research on Rett syndrome aims to identify better biomarkers of disease progression, to optimize clinical scales to track disease state and to explore novel therapeutic options, including gene therapy. In particular, she is the lead PI for the REVEAL gene therapy trial for Rett syndrome (Taysha, NCT05606614). Altogether, as a clinician-scientist working in the field of rare diseases, Dr. Rossignol aims to advance care for children with genetic neurodevelopmental disorders including Rett syndrome.


Dr. Marie Le Roux

Dr. Marie Le Roux is a pediatric epileptology fellow at the CHU Sainte-Justine. She achieved her pediatric neurology residency in France, and a Master’s Degree in Neuroscience at Paris-Sorbonne University, France. She has particular interest in electrophysiology. She recently worked on high resolution EEG and source localisation in focal refractory epilepsies. Her main interest concerns electrophysiology in neurogenetic patients. She recently integrated the Rett Syndrome Clinic at the CHU Sainte-Justine. Her clinical research on Rett syndrome aims to identify non invasive biomarkers of disease progression through electrophysiology in order to help generate normative data in this population, which will serve as a baseline to compare post-therapy data in the context of future therapeutic interventions, including gene therapy.


“We are thrilled to award the 2023 Hope Fund Grant to Drs, Ellis, Zani, Le Roux Rossignol,” said Sabrina Millson, President of the Ontario Rett Syndrome Association. “Their proposals are both innovative and promising, and we believe they have the potential to make a significant impact on the Rett Syndrome community.”

The Ontario Rett Syndrome Board

DayBue Announcement

Acadia Pharmaceuticals Announces DAYBUE (trofinetide) is Now Available for the Treatment of Rett Syndrome 

— Commercial launch of DAYBUE offers Rett syndrome community the first and only approved therapy for Rett syndrome, a rare, neurodevelopmental disorder, which affects 6,000 to 9,000 patients in the U.S.1

SAN DIEGO–(BUSINESS WIRE)– Acadia Pharmaceuticals Inc. (Nasdaq: ACAD) today announced that DAYBUE (trofinetide) is now available for the treatment of Rett syndrome in adult and pediatric patients two years of age and older in the United States. DAYBUE has demonstrated the potential to improve the signs and symptoms of Rett syndrome. DAYBUE was approved by the U.S. Food and Drug Administration (FDA) on March 10, 2023, and is the first and only drug approved by the FDA for the treatment of Rett syndrome. 

“The Rett syndrome community has been waiting a long time for a drug to treat this debilitating disorder. We have worked hard to make DAYBUE available as quickly as possible following FDA approval,” said Steve Davis, Acadia’s Chief Executive Officer. “We are focused on providing robust patient support resources through Acadia Connect® to help caregivers and healthcare providers access this important new therapy.” 

“Following my experience as an investigator in the Lavender Phase 3 study I have already initiated the process of prescribing DAYBUE for my patients. I am thrilled to now be able to offer DAYBUE to more people living with Rett syndrome, outside of a clinical trial,” said Alan Percy, M.D., Professor of Pediatrics, Neurology, Neurobiology, Genetics, and Psychology at University of Alabama, Birmingham. “Having a therapy that has been shown to address multiple symptoms of Rett syndrome provides a promising treatment option that may lead to meaningful impact for patients and their families.” 

Acadia Connect® Patient Access and Support Services

As part of the company’s commitment to prioritizing patient access to treatments for those who need them most, Acadia expanded the Acadia Connect® program for those prescribed DAYBUE. The multi-faceted support program offers personal assistance, financial resources and prescription support to patients and caregivers starting and continuing appropriate DAYBUE therapy. Each dedicated support team includes a nurse care coordinator, a family access manager and 24/7 clinical pharmacist support. For more information, visit AcadiaConnect.comor call 1-844-737-2223, Monday to Friday, 8 a.m. to 8 p.m. Eastern Time. 

About Rett Syndrome

Rett syndrome is a rare, complex, neurodevelopmental disorder that may occur over four stages and affects approximately 6,000 to 9,000 patients in the U.S., with approximately 4,500 patients currently diagnosed according to an analysis of healthcare claims data.1-4 A child with Rett syndrome exhibits an early period of apparently normal development until six to 18 months, when their skills seem to slow down or stagnate. This is typically followed by a duration of regression when the child loses acquired communication skills and purposeful hand use. The child may then experience a plateau period in which they show mild recovery in cognitive interests, but body movements remain severely diminished. As they age, those living with Rett may continue to experience a stage of motor deterioration which can last the rest of the patient’s life.3 Rett syndrome is typically caused by a genetic mutation on the MECP2 gene.5 In preclinical studies, deficiency in MeCP2 function has been shown to lead to impairment in synaptic communication, and the deficits in synaptic function may be associated with Rett manifestations.5-7

Symptoms of Rett syndrome may also include development of hand stereotypies, such as hand wringing and clapping, and gait abnormalities.8 Most Rett patients typically live into adulthood and require round-the-clock care.2,9

About DAYBUE™ (trofinetide)

Trofinetide is a synthetic version of a naturally occurring molecule known as the tripeptide glycine-proline-glutamate (GPE). The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. In animal studies, trofinetide has been shown to increase branching of dendrites and synaptic plasticity signals.10,11 More information can be found at DAYBUE.com

Important Safety Information for DAYBUE™ (trofinetide)

Important Safety Information

  • Warnings and Precautions
  • Diarrhea: In a 12-week study and in long-term studies, an aggregate of 85% of patients treated with DAYBUE experienced diarrhea. In those treated with DAYBUE, 49% either had persistent diarrhea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhea severity was of mild or moderate severity in 96% of cases. In the 12-week study, antidiarrheal medication was used in 51% of patients treated with DAYBUE. 

    Patients should stop taking laxatives before starting DAYBUE. If diarrhea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue DAYBUE if severe diarrhea occurs or if dehydration is suspected. 
  • Weight Loss: In the 12-week study, 12% of patients treated with DAYBUE experienced weight loss of greater than 7% from baseline, compared to 4% of patients who received placebo. In long-term studies, 2.2% of patients discontinued treatment with DAYBUE due to weight loss. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE if significant weight loss occurs. 
  • Adverse Reactions: The common adverse reactions (≥5% for DAYBUE-treated patients and at least 2% greater than in placebo) reported in the 12-week study were diarrhea (82% vs 20%), vomiting (29% vs 12%), fever (9% vs 4%), seizure (9% vs 6%), anxiety (8% vs 1%), decreased appetite (8% vs 2%), fatigue (8% vs 2%), and nasopharyngitis (5% vs 1%). 
  • Drug Interactions: Effect of DAYBUE on other Drugs
  • DAYBUE is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with DAYBUE. Closely monitor when DAYBUE is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities. 
  • Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with DAYBUE. Avoid the concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities. 
  • Use in Specific Population: Renal Impairment
  • DAYBUE is not recommended for patients with moderate or severe renal impairment. 

DAYBUE is available as an oral solution (200mg/mL). 

Please read the accompanying full Prescribing Information, also available at DAYBUE.com

About Acadia Pharmaceuticals

Acadia is advancing breakthroughs in neuroscience to elevate life. For almost 30 years we have been working at the forefront of healthcare to bring vital solutions to people who need them most. We developed and commercialized the first and only approved therapies for hallucinations and delusions associated with Parkinson’s disease psychosis and for the treatment of Rett syndrome. Our clinical-stage development efforts are focused on treating the negative symptoms of schizophrenia, Alzheimer’s disease psychosis and neuropsychiatric symptoms in central nervous system disorders. For more information, visit us at www.acadia.com and follow us on LinkedIn and Twitter

Forward-Looking Statements

Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements include but are not limited to statements regarding the timing of future events. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks and uncertainties inherent in drug development, approval and commercialization. For a discussion of these and other factors, please refer to Acadia’s annual report on Form 10-K for the year ended December 31, 2022, as well as Acadia’s subsequent filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement and Acadia undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof, except as required by law. 

References

Acadia Pharmaceuticals Inc, Data on file. RTT US Prevalence. March 2022. 
2 Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open. 2020; 4: 1-14. 
3 Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018; 8: 170216. 
4 Acadia Pharmaceuticals Inc., Data on file. 
Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23(2): 185-188. 
6 Fukuda T, Itoh M, Ichikawa T, et al. Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol. 2005; 64(6): 537-544. 
7 Asaka Y, Jugloff DG, Zhang L, et al. Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis. 2006; 21(1): 217-227. 
8 Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010; 68(6): 944-950. 
9 Daniel C, Tarquinio DO, Hou W, et al. The changing face of survival in Rett syndrome and MECP2-related disorders. Pediatr Neurol. 2015; 53(5): 402-411. 
10 Tropea D, Giacometti E, Wilson NR, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA. 2009; 106(6): 2029-2034. 
11 Acadia Pharmaceuticals Inc., Data on file. Study Report 2566-026. 2010. 

Contacts

Media Contact: 
Acadia Pharmaceuticals Inc. 
Deb Kazenelson 
(818) 395-3043 
media@acadia-pharm.com

Investor Contact: 
Acadia Pharmaceuticals Inc. 
Mark Johnson, CFA 
(858) 261-2771 
ir@acadia-pharm.com

Source: Acadia Pharmaceuticals Inc.

DAYBUE in Canada

Is DAYBUE approved outside of the US?

At this time, DAYBUE is only approved in the US for the treatment of Rett syndrome in adults and children 2 years of age and older. If you have a child who is living with Rett syndrome, we understand your urgency to learn what possible treatments may be available for your child. While Acadia Pharmaceuticals Inc. owns the rights to trofinetide in North America (Canada, Mexico and the US), Neuren Pharmaceuticals owns the rights outside of North America.

If you live in the US: DAYBUE was FDA approved on March 10, 2023. By the end of April 2023, DAYBUE will be available by prescription through your doctor. Once you receive your child’s prescription for DAYBUE, you’ll be connected to the dedicated support team at Acadia Connect. The Acadia Connect team will be at your side every step of the way to support you in starting treatment with DAYBUE. You can reach Acadia Connect at 1-844-737-2223.

If you live in Canada: With the US approval complete, we are in the midst of developing a regulatory and commercial plan to commercialize trofinetide in Canada, and will provide further details on the timeline as we progress. For any additional inquiries, please do not hesitate to contact Acadia Medical Information at 1-844-4ACADIA (1-844-422-2342) Option 1 or medicalinformation@acadia-pharm.com

daybue-faq

18th Annual Rett Classic – Sunday June 11, 2023

We are excited to announce the date for our

18th Annual Rett Classic

Join us for golf, dinner, & friendship in support of O.R.S.A.
Sunday, June 11, 2023 at our NEW location in
Flamborough, ON.

Register Today!

https://www.canadahelps.org/en/charities/ontario-rett-syndrome-association/events/rett-classic/