Research
RESEARCH INTO A TREATMENT FOR CANAVAN DISEASE
Canavan disease is caused by the absence of a vital enzyme known as aspartocylaste (ASPA) due to a mutation in the ASPA gene. ASPA breaks down N-acetylasparate acid (NAA); a non-functioning ASPA gene leads to extremely high levels of NAA in the brain and other parts of the body. This affects the central nervous system by disrupting the growth and maintance of the myelin sheath in the brain. The myelin sheath forms a protective coating around each nerve cell, ensuring the clear transmission of nerve impulses from one part of the body to another. The most promising research aims to replace the ASAP gene, leading to an increase in production of the ASPA enzyme, lower levels of NAA and better growth and preservation of the myelin sheath.
There are currently two companies working towards a gene replacement therapy for Canavan disease: Aspa Therapeutics and Myrtelle, Inc. If you have a child with Canavan disease, you may wish to contact either or both regarding enrollment in these trials. (Page down for details)
For updates as we receive them, click here.
CLINICAL TRIALS
The Canavan Foundation follows the progress of clinical trials for a treatment for Canavan disease with great interest, but does not independently evaluate or recommend any specific trial. If you are the parent of a child affected by Canavan disease, we suggest you learn as much as possible about the clinical trial process and each individual trial. We have provided links to each trial below. To learn more about clinical trials in general, visit the National Institutes of Health’s “Clinical Research Trials and You."
ASPA’s CANaspire Gene Replacement Therapy Trial
Dr. Guanping Gao, upon whose work the ASPA gene replacement therapy is based, with children who have Canavan disease.
Early positive data from BridgeBio's first two participants in CANaspire. (From a June, 2022 press release. Link to original content here.
BridgeBioPharma, Inc. a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, today announced promising pharmacodynamic data from the first two participants dosed in CANaspire, its Phase 1/2 clinical trial of BBP-812, an investigational intravenous (IV) adeno-associated virus serotype 9 (AAV9) gene therapy for the treatment of Canavan disease. Canavan disease is an ultra-rare and fatal disease with no approved therapies.
“Taken together, these robust decreases in urine, cerebrospinal fluid (CSF) and brain N-acetylaspartate (NAA), along with MRI signs of new myelination reported by the principal investigator are exciting and suggest we are on the right track when it comes to potentially making a difference for patients with this disease, and we look forward to gathering more data as the trial progresses,” said Genevieve Laforet, M.D., Ph.D., vice president of clinical development at Aspa Therapeutics, the BridgeBio Gene Therapy affiliate company developing the gene therapy for Canavan disease. “We are continuing to recruit and dose new participants for CANaspire and we are grateful to be able to collaborate with the advocacy organizations in the Canavan community in the pursuit of potential meaningful therapeutic advances for children with this cruel and fatal disorder.”
Data from the first two CANaspire participants show rapid and robust post-treatment decreases in NAA in urine, and importantly, in CSF and brain tissue as shown by magnetic resonance spectroscopy (MRS), to a degree not seen in available natural history data. Reduction in brain NAA is an early signal suggesting that BBP-812 administered IV has reached its intended target behind the blood-brain-barrier and is expressing functional aspartoacylase (ASPA) enzyme. There is evidence in the scientific literature that lower NAA levels are associated with milder disease. More time will be needed to see how these reductions in NAA translate to clinical outcomes.
From a safety standpoint, IV infusions of BBP-812 have been well-tolerated, and to date, no participants have experienced a treatment-related serious adverse event. BridgeBio reported:
- At Month 6 post-treatment, Participant 1 showed:
- 77% lowering of NAA in the CSF
- 15% reduction in NAA in brain white matter by magnetic resonance spectroscopy (MRS) imaging
- ~50% decrease in urine NAA
- At Month 3 post-treatment, Participant 2 showed:
- 89% reduction of NAA in CSF
- >50% decrease in NAA in brain white matter by MRS imaging
- 81% drop in urine NAA
“To see this biochemical change suggests that we are reaching cells critical to the disease process, a milestone in this disease. The ongoing myelination seen on MRI and the new interactions witnessed between children and their parents are both encouraging,” said Florian Eichler, M.D., director of the Leukodystrophy Service and principal investigator at Massachusetts General Hospital and lead investigator of the CANaspire trial.
While the data reported here are still early and the final safety and efficacy profile of the investigational gene therapy remains to be fully established, BridgeBio believes these data show the potential of BBP-812.
“BridgeBio’s early trial results are deeply encouraging for the Canavan community,” said Orren Alperstein, president of the Canavan Foundation, whose daughter Morgan died in 1997 of Canavan disease. “These preliminary but unprecedented decreases in brain and urine NAA suggest that meaningful progress is underway for patients and their families. The thoughtful and careful approach BridgeBio is taking in this trial continues to impress me.”
Data on the first two CANaspire participants will be presented on Friday, July 8, 2022, during Research Day at the National Tay Sachs & Allied Diseases Association Annual Family Conference in Denver, Colorado. A broader Phase 1/2 data readout, including safety and efficacy data and updates on the pharmacodynamic data, for Canavan disease is expected later in 2022.
About CANaspire
CANaspire is a Phase 1/2 open-label study designed to evaluate the safety, tolerability, and pharmacodynamic activity of BridgeBio’s AAV9 gene therapy candidate, BBP-812, in pediatric patients with Canavan disease. Each eligible patient will receive a single intravenous (IV) infusion of BBP-812. The primary outcomes of the study are safety, as well as change from baseline of urine and central nervous system N-acetylaspartate (NAA) levels. Motor function and development will also be assessed.
For more information about the CANaspire?trial, visit?TreatCanavan.com?or ClinicalTrials.gov (NCT04998396).
On March 19, 2022, Aspa shared the following message:
The Aspa Therapeutics team would like to share some preliminary observations from CANaspire, Aspa’s clinical trial of intravenous (IV) AAV9 gene therapy for Canavan disease. As a reminder, the aim of Aspa’s investigational gene therapy is to provide a healthy copy of the ASPA gene in order to restore the function of ASPA protein that is missing or impaired in Canavan disease. The lack of ASPA protein activity in Canavan disease prevents breakdown of a substance called N-acetylaspartic acid (NAA), leading to extremely high levels of NAA in the brain and other parts of the body. After treatment, the measurement of NAA levels in different locations in the body can tell us whether ASPA protein is now present and doing its job to break down NAA — and if so, where and how much. The hope is that restoring ASPA protein function will ultimately lead to improved brain development and function in children with Canavan disease.
While it is too early to comment on potential clinical or functional effects of our investigational gene therapy, thus far there has been no reported new onset or worsening of epileptic seizures that are a common feature of Canavan disease and tend to intensify over time in most patients.
An initial comparison of CANaspire participants’ pre- and post-treatment NAA levels shows a substantial decrease in NAA in the cerebrospinal fluid (CSF, the fluid bathing the brain and spinal cord). These CSF results are consistent with NAA reductions seen in the brain itself as measured by magnetic resonance spectroscopy (MRS), a kind of brain imaging. Reductions in NAA in the urine have also been observed. Taken together, these findings are consistent with the presence of functional ASPA protein in the brain and other parts of the body; however, the results are preliminary and require confirmation based on more participant data and longer follow-up. The treatment also has shown a favorable safety profile to date and has been well tolerated with no serious events either related or unrelated to the treatment.
The Aspa Therapeutics team is encouraged by these initial findings and wanted to share them with the community as we pledged to do at the outset of CANaspire. However, we all must remember that the trial is still in its early days and no conclusions can be drawn from the results thus far. We look forward to updating the community as the trial progresses and as we obtain more data on current and future study participants.
Please feel free to reach out to patientadvocacy@aspatx.com with any questions. More information about Aspa’s gene therapy program for Canavan disease and the CANaspire trial can be found at www.treatcanavan.com. For specific questions related to Aspa’s clinical program, please email: clinicaltrials@aspatx.com.
Myrtelle Receives FDA Fast Track, Rare Pediatric Disease, and Orphan Drug Designations for its Proprietary Gene Therapy for the Treatment of Canavan Disease
From a March 15, 2022 press release (link to original content here)
Myrtelle Inc., a clinical stage gene therapy company focused on developing transformative treatments for neurodegenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track, Rare Pediatric Disease (RPD), and Orphan Drug designations for its lead clinical-stage gene therapy, rAAV-Olig001-ASPA, for the treatment of patients with Canavan Disease (CD).
“FDA’s decision to grant these designations for our investigational gene therapy utilizing rAAV-Olig001-ASPA aligns with our mission to provide treatments for patients where few if any options exist and highlights the urgency of developing a treatment for patients with Canavan disease, a devastating disease of young children which results in short life expectancy,” said Nancy Barone Kribbs, Ph.D., Senior Vice President of Regulatory Affairs at Myrtelle Inc.
Myrtelle’s ongoing Phase 1/2 First-in-Human clinical trial utilizes a novel proprietary recombinant adeno-associated virus (rAAV) vector, AAV-Olig, that for the first time directly targets oligodendrocytes in the brain. Oligodendrocytes are the cells in the brain responsible for producing myelin, the insulating material that enables proper function of neurons. The production of myelin is affected in CD due to mutations in the Aspartoacylase gene (ASPA) coding for the Aspartoacylase enzyme (ASPA). The oligodendrocyte-targeted gene therapy is intended to restore ASPA function, enable metabolism of the abundant brain chemical N-Acetylaspartate (NAA), and support myelination. Myrtelle entered into an exclusive worldwide licensing agreement with Pfizer Inc. in 2021 to develop and commercialize this novel gene therapy for the treatment of CD.
More information here. A brochure can be downloaded here. You can also contact PatientAdvocacy@MyrtelleGTX.com.
IDENTIFYING CANAVAN PATIENTS WORLDWIDE
CANinform
CAN-Inform is a Canavan disease natural history study sponsored by Aspa Therapeutics. The study gathers information essential to developing safe, effective treatments to help children of all ages currently living with Canavan disease. If you or anyone you know has been affected by Canavan disease, you can learn more here. For a short informative video, click here. To contact the medical retrieval service directly, you can email CanavanMedRec@veristat.com or call 1-833-764-2267.
Canavan Patient Insight Network (PIN)
From their website:
The Canavan Disease PIN is a network to understand and share the health experiences of people with Canavan Disease. More than a traditional registry, a patient insights network helps us build an engaged Canavan Disease community, where patients are at the center. Participants take health surveys and learn about the experiences of others living with Canavan Disease.
Learn more here.
