Canavan Disease

BridgeBio disclosed results Thursday from a Phase 1/2 study of its gene therapy for Canavan disease, an extremely rare and devastating genetic disorder that causes the brain’s white matter to break down. The body needs a gene called ASPA to code for a key enzyme that breaks down an amino acid called N-acetyl-L-aspartic acid — or NAA. In people with Canavan, that gene is mutated, leading to damage of the white matter in the brain. It’s estimated to impact roughly 1 in 100,000 births, more frequently in the Ashkenazi Jewish population. With the infantile-onset form of the disease, most patients don’t live into their teens. Thus far, BridgeBio has treated eight children with the lowest dose of its virus-based gene therapy, called BBP-812, as well as three children at a higher dose. After treatment, children who got the lower dose saw the levels of NAA in their urine go down by 64% on average, and those who received the higher dose saw an average 73% decrease. In the cerebrospinal fluid, children who got the lower dose saw an average 70% decrease in NAA measures. (Fluid changes in the three who received the higher dose weren’t reported.) The data were presented at the European Society of Gene and Cell Therapy. Participants, who were dosed at 0 to 30 months of age, also saw “clinically meaningful” improvements in motor skills. That “stands in stark contrast to the characterized natural history of the disease, where the trajectory over this time period is essentially flat,” BridgeBio said in its announcement of the results. The program stands out against an increasingly challenging backdrop for rare disease gene therapies, where other academic-developed programs that were handed off to drug companies have been shelved or stalled, as Endpoints News has previously reported . In this case, BridgeBio’s subsidiary licensed the gene therapy from UMass Chan Medical School, where it was developed by researchers led by professor Guangping Gao. For Canavan disease, the company hasn’t yet selected a dose, according to BridgeBio’s CEO of gene therapy Eric David. It expects to use the next part of the study — a 15-patient expansion cohort — to apply for accelerated approval with the FDA. BridgeBio plans to use NAA as a surrogate biomarker for accelerated approval. It will also compare the results of its trial to a natural history study of the disease. In September, BridgeBio announced that it wasn’t moving forward with its other gene therapy for congenital adrenal hyperplasia following data that were “not yet transformational,” according to CEO Neil Kumar, cutting its gene therapy budget by $50 million as a result.

- Continued, progressive improvement in motor function and achievement of motor milestones at 12-months post-treatment represents an important and statistically significant change, in contrast to the disease course observed in BridgeBio’s ongoing CANinform natural history comparator study - Significant and sustained reductions in N-acetylaspartate (NAA) levels in urine, cerebrospinal fluid (CSF), and brain in all participants who received low dose; encouraging trends of further reduction in urine NAA in participants who received high dose BBP-812 - If approved, BridgeBio’s gene therapy for Canavan disease could be the first therapeutic option for children born with this fatal neurodevelopmental disorder PALO ALTO, Calif., Oct. 24, 2024 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio ), a commercial-stage biopharmaceutical company focused on genetic diseases, presented positive preliminary data from eleven participants dosed in the CANaspire Phase 1/2 clinical trial of BBP-812, an investigational intravenous (IV) adeno-associated virus serotype 9 (AAV9) gene therapy in development for the treatment of Canavan disease. Preliminary results from the study were presented in an invited, peer reviewed talk by the study’s principal investigator, Dr. Florian Eichler, M.D., director of the leukodystrophy service at Massachusetts General Hospital, Center for Rare Neurological Disease and principal investigator of CANaspire, today at the 31st Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) in Rome, Italy. “We continue to be encouraged by the results children are achieving in the CANaspire trial of BBP-812,” said Dr. Eichler. “Compared to the natural course of Canavan disease, in which most children do not achieve developmental milestones beyond that of a 6-month old, the fact that some children are sitting independently, taking steps, or even walking post-dosing is truly remarkable.” CANaspire is a Phase 1/2 open-label study designed to evaluate the safety, tolerability, and pharmacodynamic activity of BBP-812, in pediatric patients with Canavan disease. CANinform is an ongoing natural history study of more than 60 patients with Canavan disease, which was designed as a robust comparator for the CANaspire study in accordance with FDA’s guidance on the design and conduct of externally controlled trials. Highlights of the results presented at ESGCT 2024 include: Rapid and sustained reduction of NAA in urine and brain of participants post BBP-812 dosing Urine NAA was reduced to levels associated with mild Canavan disease (average reduction of 64% +/- 14% twelve months after receiving low dose and 73% +/- 13% three months after the high dose)NAA in CSF was reduced an average of 70% +/- 10% twelve months after receiving the low dose. Lower urine NAA levels have been maintained for nearly 3 years in the earliest dosed participants Improved myelination on T-2-weighted magnetic resonance imaging (MRI) observed in the majority of participants dosed with BBP-812Progressive and continued post-dose improvement in gross motor function (measured by Gross Motor Function Measure (GMFM)-88) and achievement of motor milestones (measured by Hammersmith Infant Neurological Examination (HINE)-2) This trajectory of progressive improvement stands in stark contrast to the characterized natural history of the disease, where the trajectory over this time period is essentially flatIn the low-dose cohort, these divergent trajectories result in statistically significant improvements in achieved motor function and milestones at 12-months after treatment with BBP-812, compared to what is observed in and predicted by the natural history of the disease; data from the high dose cohort are not yet available All participants demonstrated progress on administered developmental/motor assessments as measured by the GMFM-88, HINE-2, CDC milestones, or the Canavan Disease Rating ScaleBBP-812 continues to be generally well-tolerated, with a safety profile consistent with other systemically administered AAV9 gene therapies BBP-812 has been granted Regenerative Medicine Advanced Therapy (RMAT), Orphan Drug, Rare Pediatric Disease (RPDD), and Fast Track Designations from the FDA, as well as Orphan Drug Designation from the European Medicines Agency. With RPDD, if approved, BridgeBio may qualify for a PRV. About CANaspireCANaspire 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 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 NAA levels. Motor function and development will also be assessed. For more information about the CANaspire trial, visit TreatCanavan.com or ClinicalTrials.gov (NCT04998396). About Canavan DiseaseAffecting approximately 1,000 children in the U.S. and European Union, Canavan disease is an ultra-rare, disabling and fatal disease with no approved therapy. Most children are not able to meet developmental milestones, are unable to crawl, walk, sit or talk, and die at a young age. The disease is caused by an inherited mutation of the ASPA gene that codes for aspartoacylase, a protein that breaks down a compound called NAA. Deficiency of aspartoacylase activity results in accumulation of NAA, and ultimately results in toxicity to myelin in ways that are not currently well understood. Myelin insulates neuronal axons, and without it, neurons are unable to send and receive messages as they should. The current standard of care for Canavan disease is limited to supportive therapy. About BridgeBio Pharma, Inc.BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases. BridgeBio’s pipeline of development programs ranges from early science to advanced clinical trials. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com and follow us on LinkedIn, Twitter and Facebook. BridgeBio Pharma, Inc. Forward-Looking Statements This press release contains forward-looking statements. Statements BridgeBio makes in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), which are usually identified by the use of words such as “anticipates,” “believes,” “continues,” “estimates,” “expects,” “hopes,” “intends,” “may,” “plans,” “projects,” “remains,” “seeks,” “should,” “will,” and variations of such words or similar expressions. BridgeBio intends these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act. These forward-looking statements, including statements relating to expectations, plans and prospects regarding BridgeBio’s regulatory approval process for BBP-812, the ability of BBP-812 to be the first therapeutic treatment option for children born with Canavan disease and eligibility for a PRV, reflect BridgeBio’s current views about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to BridgeBio and on assumptions BridgeBio has made. Although BridgeBio believes that its plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, BridgeBio can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, BridgeBio’s ability to continue and complete its Phase 1/2 clinical trial of BBP-812 for the treatment of Canavan disease, BridgeBio’s ability to advance BBP-812 in clinical development according to its plans, the ability of BBP-812 to treat Canavan disease, the ability of BBP-812 to retain Fast Track Designation, RPDD, RMAT and Orphan Drug Designation from the FDA and Orphan Drug Designation from the European Medicines Agency, and potential adverse impacts due to global health emergencies, including delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy, the impacts of current macroeconomic and geopolitical events, including changing conditions from hostilities in Ukraine and in Israel and the Gaza Strip, increasing rates of inflation and rising interest rates, on our business operations and expectations as well as those risks set forth in the Risk Factors section of BridgeBio’s most recent Annual Report on Form 10-K, and BridgeBio’s other filings with the U.S. Securities and Exchange Commission. Moreover, BridgeBio operates in a very competitive and rapidly changing environment in which new risks emerge from time to time. These forward-looking statements are based upon the current expectations and beliefs of BridgeBio’s management as of the date of this press release and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. BridgeBio Contact:Vikram Balicontact@bridgebio.com(650)-789-8220

Analysis of Cerebral Spinal Fluid (CSF) from patients at pre-treatment baseline to post-treatment intervals up to 24 months demonstrates marked decrease in N-Acetylaspartate (NAA) Magnetic Resonance Imaging (MRI) assessments also show increases in brain white matter and myelin volume as well as functional improvements on validated scales The NAA reduction, MRI assessments and encouraging efficacy and safety data support further development of rAAV-Olig001-ASPA and discussions with regulatory authorities for a potential road map to registration NEW YORK, NY, USA I October 10, 2024 I Myrtelle Inc. (“Myrtelle” or the “Company”), a gene therapy company focused on developing transformative treatments for neurodegenerative diseases, today announced clinical trial findings showing a significant biomarker change in patients treated with the Company’s investigational gene therapy for Canavan disease (CD), rAAV-Oligo001-ASPA. Analysis of Cerebral Spinal Fluid (CSF) from seven patients, observed up to 24-month post treatment milestone revealed that each patient demonstrated a decrease of over 80% in N-Acetylaspartate (NAA) from their baseline measurement. Observations of these patients using Magnetic Resonance Imaging (MRI) also demonstrated increases in brain white matter and myelin volume over the same time intervals. The Company’s open-label Phase 1/2 First-in-Human (FIH) clinical trial is being conducted at Dayton Children’s Hospital (Dayton, Ohio) and includes baseline and post treatment assessments at 1, 3, 6, and 12 months the first year after surgery, and then once every 12 months for 5 years. Myrtelle’s FIH trial utilizes the Company’s proprietary rAAV vector to directly target oligodendrocytes, the brain cells affected in CD which are responsible for producing myelin – the insulating material that enables proper neuronal function. In CD, the production of myelin is impaired due to a mutation in the Aspartoacylase gene ( ASPA) that encodes the enzyme Aspartoacylase (ASPA) which is expressed in the brain solely in oligodendrocytes. The deficiency of ASPA enzyme results in multiple biochemical and anatomic changes, including inability to metabolize N-Acetylaspartate (NAA), a neurochemical that is abundant in the brain and plays an important role in myelin synthesis and brain bioenergetics. Myrtelle’s novel oligodendrocyte-targeting rAAV vector-based gene therapy is intended to restore ASPA function and hence the metabolism of NAA and myelination in patients with CD. Patients have also shown functional improvements on validated functional scales. Observed improvements in these treated patients are in contrast to the continuous clinical deterioration expected with the natural progression of CD. “The combination of changes in NAA levels and myelin volume offers a valuable tool for assessing early therapeutic efficacy in Canavan disease. Improvement in such important disease markers like NAA and myelin, together with functional gains in our patients, is encouraging given the progressive nature of Canavan disease. It drives us to continue our work to bring this potentially important therapy to the patients who currently do not have treatment options,” commented Olga Flamini, Co-CMO at Myrtelle. Myrtelle recently announced that rAAV-Olig001-ASPA was selected by the FDA for participation in the START pilot program in which the gene therapy candidate was one of four CBER-regulated products chosen. rAAV-Olig001-ASPA has also received RMAT, Orphan Drug, Rare Pediatric Disease, and Fast Track designations from the FDA, Orphan Drug Designation & Advanced Therapy Medicinal Product (ATMP) classification from the European Medicines Agency, as well as Innovative Licensing and Access Pathway (ILAP) from the United Kingdom Medicines & Healthcare products Regulatory Agency. ABOUT MYRTELLE Myrtelle Inc. is a gene therapy company focused on developing transformative treatments for neurodegenerative diseases. The company has a proprietary platform, intellectual property, and portfolio of programs and technologies supporting innovative gene therapy approaches for neurodegenerative diseases. Myrtelle has an exclusive worldwide licensing agreement with Pfizer Inc. for its Canavan disease program. For more information, please visit the Company’s website at: www.myrtellegtx.com . ABOUT CANAVAN DISEASE Canavan disease (CD) is a fatal childhood genetic brain disease caused by mutations in the ASPA gene ( ASPA ) which prevent the normal expression of aspartoacylase, a critical enzyme produced in oligodendrocytes. The lack of normal aspartoacylase expression negatively impacts brain bioenergetics and development, including myelin production. Patients with CD are impacted at birth but may appear normal until several months old when symptoms begin to develop. Poor head control, abnormally large head size, difficulty in eye tracking, excessive irritability, severely diminished muscle tone, and delays in reaching motor milestones, such as rolling, sitting, and walking, are the typical initial manifestations of CD. As the disease progresses, seizures, spasticity, difficulties in swallowing, and overall muscle deterioration emerge with most affected children developing life-threatening complications by approximately 10 years of age. Currently, there are no cures for CD, and only palliative treatments are available. More information on Myrtelle’s clinical trial in Canavan disease can be found on https://clinicaltrials.gov/ under the identifier NCT04833907 or by emailing PatientAdvocacy@MyrtelleGTX.com . SOURCE: Myrtelle