Spruce Biosciences Advances Toward 2026 BLA Submission for Tralesinidase Alfa in Sanfilippo Syndrome Type B
Spruce Biosciences, Inc., a late-stage biopharmaceutical company focused on developing and commercializing innovative therapies for neurological disorders with significant unmet medical needs, has announced important regulatory and manufacturing progress supporting its plan to submit a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for tralesinidase alfa enzyme replacement therapy, also known as TA-ERT.
The company expects to submit the BLA during the fourth quarter of 2026 for the treatment of Sanfilippo Syndrome Type B, or MPS IIIB, a rare and devastating inherited neurological disorder that primarily affects children. Spruce said it has completed two pre-BLA meetings with the FDA, providing greater clarity regarding the anticipated content of the regulatory submission, manufacturing requirements and the proposed development pathway for TA-ERT.
The recent regulatory discussions represent an important milestone for Spruce as the company works toward potentially bringing the first disease-modifying treatment specifically designed for children living with MPS IIIB to patients and their families.
Javier Szwarcberg, M.D., M.P.H., Chief Executive Officer of Spruce Biosciences, said the company has been encouraged by its constructive engagement with the FDA and believes the recent discussions have provided greater confidence regarding the path toward the planned BLA submission.
According to Szwarcberg, Spruce has also made substantial progress in chemistry, manufacturing and controls (CMC), including the transfer of manufacturing technology to a commercial-scale manufacturer. The FDA has determined that the company’s analytical comparability strategies are reasonable following the technology transfer.
The company has also reached alignment with the FDA on the overall content and format of the planned BLA, including how integrated efficacy and safety summaries will be presented.
Preparing for Potential Accelerated Approval
A central component of Spruce’s regulatory strategy is its plan to pursue accelerated approval for TA-ERT based on reductions in cerebrospinal fluid heparan sulfate non-reducing ends, commonly referred to as CSF HS-NRE.
Sanfilippo Syndrome Type B is associated with a deficiency in the enzyme alpha-N-acetylglucosaminidase, which results in the accumulation of heparan sulfate in cells and tissues. This buildup can contribute to progressive damage within the central nervous system and is associated with the severe neurological manifestations of the disease.
Spruce is evaluating CSF HS-NRE as a biomarker that may provide an indication of the biological activity of TA-ERT. Under the company’s proposed accelerated approval pathway, reduction in this biomarker could serve as the basis for regulatory approval if the FDA determines that it is an appropriate surrogate reasonably likely to predict clinical benefit.
The accelerated approval pathway is designed to allow certain therapies for serious conditions to potentially reach patients earlier when they address an important unmet medical need and are supported by evidence using a surrogate endpoint. Such approvals generally require confirmatory studies to verify clinical benefit.
Spruce said it has previously aligned with the FDA on the design of a confirmatory study for TA-ERT. The company and agency have also agreed that the confirmatory study may be initiated while the BLA is under FDA review.
This approach could allow Spruce to continue generating clinical evidence while the regulatory review process is underway.
FDA Meetings Provide Greater Regulatory Clarity
The two recent pre-BLA meetings were focused on key elements of the upcoming submission. According to Spruce, the FDA provided feedback that supports the company’s current regulatory strategy.
One major area of discussion was the analytical comparability strategy for TA-ERT following the transfer of drug substance and drug product manufacturing to a new commercial-scale manufacturing partner.
The FDA found Spruce’s proposed analytical comparability strategies reasonable, an important development because demonstrating consistency between manufacturing processes is a critical part of the regulatory review for biologic therapies.
The company also received alignment regarding the structure and content of the BLA. This includes the planned organization of integrated efficacy and safety summaries, which will bring together clinical evidence from Spruce’s development program.
By obtaining this feedback before submitting the BLA, Spruce has been able to further refine its regulatory package and identify the remaining activities required for submission.
The company believes this regulatory alignment reduces uncertainty as it approaches the fourth quarter of 2026 filing target.
Significant Progress in Manufacturing
In parallel with its FDA interactions, Spruce has continued to make progress on manufacturing activities for TA-ERT.
The company has completed the transfer of both drug substance and drug product manufacturing to a leading global biologics manufacturer. The transfer is intended to establish commercial-scale production capabilities that could support both the planned BLA submission and a potential future commercial launch.
Manufacturing capacity and consistency are particularly important for biologic therapies because regulators must evaluate whether the manufacturing process can reliably produce a product with the appropriate quality, purity, potency and other characteristics.
Following the technology transfer, Spruce successfully completed production of drug product registrational batches. The company has also advanced its analytical control strategy, which is intended to provide the regulatory foundation necessary to support potential approval of TA-ERT.
Spruce and the FDA previously agreed on an approach for submitting process performance qualification, or PPQ, data. PPQ is an important stage in establishing that the commercial manufacturing process can consistently perform as intended.
Under the agreed plan, data from the first PPQ batch will be included in the BLA submission, while data from the second PPQ batch will be submitted before the midpoint of the FDA’s review.
Spruce successfully completed manufacturing of its first PPQ batch in July 2026. The company expects to complete manufacturing of its second PPQ batch during the fourth quarter of 2026.
The remaining CMC activities required to support the BLA have been identified, and Spruce said they remain within its current operating plan.
Potential Treatment for a Devastating Rare Disease
MPS IIIB is a rare lysosomal storage disorder caused by genetic mutations that result in insufficient activity of the enzyme alpha-N-acetylglucosaminidase. The resulting accumulation of heparan sulfate can progressively affect the brain and other parts of the body.
Children with MPS IIIB can develop a range of neurological and behavioral symptoms as the disease progresses. These may include developmental delays, cognitive decline, behavioral changes and other neurological complications. The progressive nature of the disease can have a profound impact on affected children, their families and caregivers.
The lack of approved disease-modifying treatment options specifically targeting the underlying pathology of MPS IIIB creates a significant unmet medical need.
Spruce believes TA-ERT has the potential to address this need by providing enzyme replacement therapy intended to target the biological deficiency associated with the disease.
The company is therefore moving its development program forward with urgency, with the objective of potentially providing children and families with a new therapeutic option.
Clinical Development and Natural-History Data
Spruce’s regulatory strategy is supported by data generated through its completed clinical studies as well as natural-history information describing the progression of MPS IIIB.
The FDA has previously indicated that integrated data from Spruce’s completed clinical studies, when considered together with natural-history data, could potentially constitute an adequate and well-controlled body of evidence to support review of TA-ERT’s effect on CSF HS-NRE.
This regulatory feedback is important because natural-history studies can help establish the expected course of a rare disease in the absence of an effective treatment. For ultra-rare or rare pediatric diseases, obtaining large randomized controlled trial populations can be challenging because of the limited number of eligible patients worldwide.
By integrating clinical trial evidence with natural-history data, regulators may be able to better evaluate whether an investigational therapy produces a meaningful biological effect compared with the expected progression of the disease.
Spruce said its ongoing strategy remains aligned with the FDA’s previous feedback regarding the potential use of CSF HS-NRE reduction as the basis for accelerated approval.
Confirmatory Study Planned
While the accelerated approval pathway could potentially provide an earlier route to regulatory authorization, Spruce will also be required to generate additional evidence to confirm the clinical benefit of TA-ERT if accelerated approval is granted.
The company has already reached agreement with the FDA on the design of a confirmatory study. Importantly, the FDA has agreed that the confirmatory trial can begin during the BLA review process rather than waiting until after a potential approval.
This could allow Spruce to move more efficiently toward the next phase of clinical development and provide additional evidence regarding the long-term effects of TA-ERT.
The confirmatory study will be an important component of the overall development strategy because demonstrating a reduction in a biomarker alone does not necessarily establish the full clinical impact of a therapy. Long-term clinical outcomes and functional measures will therefore remain important considerations as development continues.
Multiple Regulatory Designations
TA-ERT has received several regulatory designations that recognize the seriousness of MPS IIIB and the potential need for new treatment options.
In the United States, the therapy has been granted Breakthrough Therapy, Fast Track, Rare Pediatric Disease and Orphan Drug designations.
These designations can provide various forms of regulatory support or incentives during the development and review process. For example, Breakthrough Therapy designation is intended for therapies that may offer substantial improvement over available treatments for serious conditions, while Fast Track designation is designed to facilitate the development and review of medicines addressing serious conditions with unmet medical needs.
The Rare Pediatric Disease designation is particularly relevant given that MPS IIIB primarily affects children. If TA-ERT receives approval and meets the applicable requirements, Spruce may be eligible for a rare pediatric disease priority review voucher.
TA-ERT has also received Orphan Drug Designation in the European Union, reflecting the rarity of the disease and the need for additional treatment options.
Biomarker Strategy Gains Additional Support
Spruce also pointed to the FDA’s recent accelerated approval of a therapy for a related neuronopathic form of mucopolysaccharidosis as supporting the broader regulatory rationale for its biomarker strategy.
That recent regulatory decision was based on a reduction in a cerebrospinal fluid heparan sulfate biomarker. Spruce believes this precedent is consistent with the FDA’s willingness to consider biomarkers associated with heparan sulfate accumulation as surrogate endpoints that may be reasonably likely to predict clinical benefit in certain neurological lysosomal storage disorders.
While regulatory decisions are made based on the specific evidence and circumstances associated with each therapy, the precedent provides additional context for Spruce as it prepares its BLA.
With its two pre-BLA meetings completed, manufacturing technology transfer substantially advanced and the regulatory submission framework established, Spruce Biosciences remains on track for its planned fourth-quarter 2026 BLA submission for TA-ERT.
The company still has important activities to complete, including manufacturing of the second PPQ batch and finalization of remaining CMC documentation and regulatory materials. However, Spruce said these activities are well defined and remain within its current operating plan.
If the BLA is submitted and accepted for review, the subsequent FDA evaluation will determine whether the available evidence supports approval of TA-ERT under the proposed accelerated pathway.
For children living with MPS IIIB and their families, the development of a potentially disease-modifying therapy could represent a major advancement in the management of this devastating neurological disorder.
Spruce’s progress toward a BLA reflects several years of clinical, regulatory and manufacturing development. The company’s strategy combines clinical evidence, natural-history data and biomarker analysis with a planned confirmatory study intended to further establish the potential clinical benefit of TA-ERT.
As the fourth quarter of 2026 approaches, the company is focused on completing the remaining regulatory and manufacturing activities necessary to submit its application. The outcome of the FDA review will be an important milestone for Spruce and for the broader MPS IIIB community.
The combination of FDA engagement, commercial-scale manufacturing readiness, multiple regulatory designations and alignment on a potential accelerated approval pathway positions TA-ERT for an important next stage of development. If successful, the program could potentially introduce a new treatment approach for children affected by MPS IIIB, a rare disease for which significant unmet medical needs continue to exist.
About Sanfilippo Syndrome Type B (MPS IIIB)
Sanfilippo Syndrome Type B (MPS IIIB) is an ultra-rare, serious, and fatal genetic disease characterized by deficiency in alpha-N-acetylglucosaminidase (NAGLU), an enzyme required for the catabolism of heparan sulfate in lysosomes. It is estimated that MPS IIIB affects fewer than one in 200,000 people in the United States. The accumulation of toxic levels of cerebral spinal fluid heparan sulfate in the brain is the underlying pathophysiology of MPS IIIB. Although signs and symptoms of MPS IIIB can vary amongst affected individuals, progressive neurodegeneration typically follows a predictable path to brain atrophy, cognitive and developmental impairment, hyperactivity with aggressive and destructive behavior, delayed speech, hearing loss, and motor skill deficits.
Somatic manifestations include coarse facial features, hepatosplenomegaly, and gastrointestinal symptoms. The final stage of MPS IIIB is typically marked by severe dementia, loss of motor function, and seizure activity, with patients largely bed-ridden and requiring constant care, requiring feeding tubes for hydration and nutrition, and ultimately leading to death. The estimated life expectancy of individuals with MPS IIIB ranges from 15 to 19 years of age. Currently, there are no FDA-approved therapies for MPS IIIB, and management of the disease consists of limited palliative care to improve quality of life.
About Tralesinidase Alfa Enzyme Replacement Therapy (TA-ERT)
TA-ERT is a fusion protein comprised of recombinant human NAGLU (rhNAGLU). TA-ERT is intended as an enzyme replacement therapy for the treatment of patients with MPS IIIB who lack rhNAGLU enzyme activity. TA-ERT is anticipated to restore rhNAGLU enzyme activity in the central nervous system following intracerebroventricular injection. rhNAGLU typically lacks the mannose-6 phosphate (M6P) residues that are essential for efficient cellular uptake via the M6P receptor pathway.
As a result, the naked enzyme is poorly absorbed by cells, including neurons. To address this challenge, TA-ERT is fused to an insulin-like growth factor 2 peptide, which binds to the cation-independent M6P receptors on cell surfaces. This fusion enables the enzyme to be internalized and delivered to the lysosome, thereby enhancing its therapeutic potential for treating MPS IIIB.
By restoring NAGLU enzymatic activity and promoting clearance of lysosomal heparan sulfate and heparan sulfate non-reducing end in the brain, TA-ERT therapy is expected to preserve neuronal cell health and potentially halt or slow the neurological decline and improve clinical outcomes in affected patients. TA-ERT has been evaluated in three clinical studies in participants with MPS IIIB: the interventional study 201 and extension studies 202 and 401. TA-ERT has been administered to 22 individuals diagnosed with MPS IIIB, and was generally well tolerated across six years of integrated safety data.
About Spruce Biosciences
Spruce Biosciences is a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for neurological disorders with significant unmet medical need. Spruce’s lead product candidate, TA-ERT, is in late-stage development for the treatment of MPS IIIB, a devastating pediatric neurodegenerative disorder for which there are no FDA-approved therapies. TA-ERT has received Breakthrough Therapy Designation, Rare Pediatric Disease Designation, Fast Track Designation and Orphan Drug Designation from the FDA, as well as Orphan Drug Designation in the European Union. To learn more, visit www.sprucebio.com and follow us on X, LinkedIn, Facebook and YouTube.