Open-Label Multicenter Extension Study to Further Evaluate Safety, Tolerability and Efficacy of Intracerebroventricular AX 250 Treatment in Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B) Patients

This is a Phase 3B/4, multicenter, multinational, open label study to further evaluate intracerebroventricular (ICV) delivered AX 250 treatment in MPS IIIB subjects that complete Study 250-202 for up to an additional 3 years (144 weeks) of treatment with AX 250 administered by ICV infusion every other week. Subjects will be evaluated for neurocognitive function, communication, adaptive behavior, quality of life, imaging characteristics and biochemical markers of disease burden. Safety will be assessed by adverse events, clinical labs, and physical exams.

Start Date02 Dec 2022

Sponsor / Collaborator

Allievex Corp.

NCT03784287

/ Unknown statusPhase 2

A Multicenter, Multinational, Extension Study to Evaluate the Long Term Safety and Efficacy of Intracerebroventricular AX 250 in Patients With Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)

The primary objectives of this study are to evaluate the long-term safety and tolerability of AX 250 administered to subjects with MPS IIIB by an implanted ICV reservoir and catheter and to evaluate the impact of long-term AX 250 treatment on cognitive function in patients with MPS IIIB as assessed by developmental quotient (DQ).

Start Date19 Feb 2018

Sponsor / Collaborator

Allievex Corp.

NCT02754076

/ CompletedPhase 1/2

A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Intracerebroventricular AX 250 in Patients With Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)

The study's primary objectives are to evaluate the safety and tolerability of AX 250 administered to subjects with MPS IIIB via an ICV reservoir and catheter and to evaluate the impact of AX 250 on cognitive function in patients with MPS IIIB as assessed by the Development Quotient.

Start Date01 Apr 2016

Sponsor / Collaborator

Allievex Corp.

100 Clinical Results associated with Tralesinidase alfa

100 Translational Medicine associated with Tralesinidase alfa

100 Patents (Medical) associated with Tralesinidase alfa

Literatures (Medical) associated with Tralesinidase alfa

17 Jan 2023·The Journal of clinical investigation

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B

Article

Author: Koehn, Anja ; von Cossel, Katharina ; Maricich, Stephen M ; Zanelli, Eric ; Couce, Maria Luz ; Nestrasil, Igor ; Kaufman, Brian ; Harmatz, Paul ; Shaywitz, Adam J ; Cleary, Maureen ; de Castro Lopez, Maria J ; Okur, Ilyas ; Lin, Shuan-Pei ; Solano, Martha ; Muschol, Nicole ; Batzios, Spyros ; Kovalchin, Joseph ; Ezgu, Fatih ; Kuca, Bernice

BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

01 Jan 2023·Toxicology reports

Safety, pharmacokinetics and CNS distribution of tralesinidase alfa administered via intracerebroventricular infusion to juvenile cynomolgus monkeys

Article

Author: Henshaw, Joshua ; Zanelli, Eric ; Melton, Andrew C ; Boyd, Robert B ; Pinkstaff, Jason ; Chandra, Sundeep ; O'Neill, Charles A ; McCullagh, Emma ; Wait, Jill Cm ; Butt, Mark T ; Trombley, Jami L ; Grover, Anita ; Kovalchin, Joseph ; Adams, Eric L ; Cherukuri, Anu ; Reed, Randall P ; Nguyen, Annalisa

Mucopolysaccharidosis Type IIIB (MPS IIIB) is an ultrarare, fatal pediatric disease with no approved therapy. It is caused by mutations in the gene encoding for lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Tralesinidase alfa (TA) is a fusion protein comprised of recombinant NAGLU and a modified human insulin-like growth factor 2 that is being developed as an enzyme replacement therapy for MPS IIIB. Since MPS IIIB is a pediatric disease the safety/toxicity, pharmacokinetics and biodistribution of TA were evaluated in juvenile non-human primates that were administered up to 5 weekly intracerebroventricular (ICV) or single intravenous (IV) infusions of TA. TA administered by ICV slow-, ICV isovolumetric bolus- or IV-infusion was well-tolerated, and no effects were observed on clinical observations, electrocardiographic or ophthalmologic parameters, or respiratory rates. The drug-related changes observed were limited to increased cell infiltrates in the CSF and along the ICV catheter track after ICV administration. These findings were not associated with functional changes and are associated with the use of ICV catheters. The CSF PK profiles were consistent across all conditions tested and TA distributed widely in the CNS after ICV administration. Anti-drug antibodies were observed but did not appear to significantly affect the exposure to TA. Correlations between TA concentrations in plasma and brain regions in direct contact with the cisterna magna suggest glymphatic drainage may be responsible for clearance of TA from the CNS. The data support the administration of TA by isovolumetric bolus ICV infusion to pediatric patients with MPS IIIB.

01 Sep 2022·The Journal of pharmacology and experimental therapeutics

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB

Article

Author: Labounek, Rene ; Crawford, Brett E ; Cherala, Ganesh ; Cherukuri, Anu ; Vuillemenot, Brian R ; Parsons, Rebecca L ; Paulson, Amy ; Prill, Heather ; Cooper, Jonathan D ; Zhou, Huiyu ; Lawrence, Roger ; Hess, Andrew S ; Jamil, Maryam ; McCullagh, Emma ; Snella, Elizabeth M ; Ellinwood, N Matthew ; Zanelli, Eric ; Pinkstaff, Jason ; Smith, Jodi D ; Kovalchin, Joseph ; Wait, Jill C M ; Nestrasil, Igor ; Assis, Ana B ; Egeland, Martin T ; O'Neill, Charles A ; Jeffery, Nicholas D ; Jens, Jackie K ; Chandra, Sundeep ; Millman, Suzanne T ; Liu, Xiao Ying ; Mueller, Bryon A ; Grover, Anita ; Hostetter, Shannon J ; Butt, Mark T ; Melton, Andrew C ; Nelvagal, Hemanth R ; Valentine, Bethann N

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.

News (Medical) associated with Tralesinidase alfa

10 Nov 2025

·investors.sprucebio.com

Spruce Biosciences Reports Third Quarter 2025 Financial Results and Provides Corporate Updates

Granted Breakthrough Therapy Designation for Tralesinidase Alfa Enzyme Replacement Therapy (TA-ERT) for the Treatment of Sanfillipo Syndrome Type B (MPS IIIB) Biologics License Application Submission of TA-ERT for the Treatment of MPS IIIB on Track for the First Quarter of 2026 Completed $50.0 Million Private Placement Financing Backed by Dedicated Healthcare Investors SOUTH SAN FRANCISCO, Calif. --(BUSINESS WIRE)--Nov. 10, 2025-- Spruce Biosciences, Inc. (Nasdaq: SPRB), a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for neurological disorders with significant unmet medical need, today reported financial results for the third quarter ended September 30, 2025 and provided corporate updates. “We have made significant progress this year with the receipt of Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for our tralesinidase alfa enzyme replacement therapy (TA-ERT), followed by the syndication of a $50 million private placement financing backed by an impressive group of healthcare investors. These important corporate milestones underscore the transformative moments in our collective efforts to advance TA-ERT as potentially the first disease-modifying therapy to treat children with MPS IIIB,” said Javier Szwarcberg , M.D., M.P.H., Chief Executive Officer of Spruce Biosciences . “The recent financing provides the capital resources to advance TA-ERT well beyond a biologics license application (BLA) submission expected in the first quarter of 2026.” Dr. Szwarcberg continued, “I am very proud of our team for the advancements we have made this year, appreciative of the unwavering support from our Board and investors, and grateful to the patients and families who took part in the TA-ERT clinical trials. We look forward to an impactful 2026 as we move towards bringing to market a new, life-changing treatment option for children affected by MPS IIIB.” Corporate Updates $50.0 Million Private Placement Financing Backed by Dedicated Healthcare Investors . In October 2025 , the company entered into a definitive securities purchase agreement for a private placement that resulted in gross proceeds of approximately $50.0 million , before deducting offering expenses. Under the securities purchase agreement, the investors purchased 502,181 shares of the company’s common stock. In lieu of shares of common stock, as a portion of their investment, certain investors purchased prefunded warrants to purchase up to 233,144 shares of common stock. The prefunded warrants are exercisable for a period of five years following the date of issuance. U.S. FDA Breakthrough Therapy Designation Granted to TA-ERT for the Treatment of MPS IIIB. Granted to Spruce in October 2025 , the FDA Breakthrough Therapy Designation is designed to expedite the development and regulatory review of promising therapies for serious or life-threatening conditions where preliminary clinical evidence suggests the potential for substantial improvement over existing treatments. The designation facilitates more intensive FDA guidance, cross-disciplinary collaboration, and eligibility for rolling submission and priority review. Relisted “SPRB” on the Nasdaq Capital Market. In September 2025 , the company resumed trading on the Nasdaq Capital Market under the ticker symbol “SPRB” and CUSIP 85209E 208, following a one-for-75 reverse stock split. Third Quarter 2025 Financial Results Cash and Cash Equivalents: Cash and cash equivalents as of September 30, 2025 , were $10.7 million , which does not include approximately $50.0 million in gross proceeds from the October 2025 private placement financing. Cash and cash equivalents as of September 30, 2025 , plus proceeds from the October 2025 private placement financing are expected to fund the company’s current operating plan into the fourth quarter of 2026. Research and Development (R&D) Expenses: R&D expenses for the three and nine months ended September 30, 2025 , were $5.0 million and $15.4 million , respectively, compared to $6.6 million and $25.0 million for the same periods in 2024. The decrease in R&D expenses was primarily related to the cessation of development activities of tildacerfont for the treatment of congenital adrenal hyperplasia (CAH), offset by development activities related to TA-ERT for the treatment of MPS IIIB. General and Administrative (G&A) Expenses: G&A expenses for the three and nine months ended September 30, 2025 , were $3.2 million and $10.0 million , respectively, compared to $3.5 million and $11.3 million for the same periods in 2024, primarily driven by a decrease in stock-based compensation expense. Total Operating Expenses: Total operating expenses for the three and nine months ended September 30, 2025 , were $8.2 million and $25.4 million , respectively, compared to $10.0 million and $36.3 million for the same periods in 2024. Operating expenses include non-cash stock-based compensation expenses of $0.4 million and $0.9 million for the three and nine months ended September 30, 2025 , respectively, compared to $1.1 million and $4.4 million for the same periods in 2024. Net Loss: Net loss for the three and nine months ended September 30, 2025 , was $8.2 million and $24.3 million , respectively, compared to $8.7 million and $29.5 million for the same periods in 2024. Capital Structure: Common shares outstanding as of September 30, 2025 , were 563,491, which excludes 25,512 outstanding restricted stock units and 28,118 outstanding prefunded warrants to purchase common stock. In connection with the October 2025 private placement financing, 502,181 shares of common stock and 233,144 prefunded warrants to purchase common stock were issued to certain investors. 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. To learn more, visit www.sprucebio.com and follow us on X, LinkedIn, Facebook and YouTube. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the timing and likelihood of regulatory filings and approvals for TA-ERT, including the anticipated biologics license application submission of TA-ERT for MPS IIIB in the first quarter of 2026; TA-ERT’s potential to be the first disease-modifying therapy to treat MPS IIIB; TA-ERT’s potential to be a new, life-changing treatment option for children affected by MPS IIIB; and the Company’s ability to fund its operating plan into the fourth quarter of 2026. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “anticipate”, “will”, “potential”, “intend”, “expect” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Spruce’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Spruce’s business in general, the impact of geopolitical and macroeconomic events, and the other risks described in Spruce’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Spruce undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. SPRUCE BIOSCIENCES, INC. CONDENSED BALANCE SHEETS (unaudited) (in thousands, except share and per share amounts) September 30 , December 31 , 2025 2024 ASSETS Current assets: Cash and cash equivalents $ 10,669 $ 38,753 Prepaid expenses 932 3,177 Other current assets 2,915 2,276 Total current assets 14,516 44,206 Right-of-use assets 735 934 Other assets 62 69 Total assets $ 15,313 $ 45,209 LIABILITIES AND STOCKHOLDERS’ EQUITY Current liabilities: Accounts payable $ 1,386 $ 1,295 Accrued expenses and other current liabilities 7,502 12,329 Term loan, current portion 539 1,622 Total current liabilities 9,427 15,246 Lease liabilities, net of current portion 500 736 Term loan, net of current portion — 124 Other liabilities — 282 Total liabilities 9,927 16,388 Commitments and contingencies Stockholders’ equity: Preferred stock, $0.0001 par value; 10,000,000 shares authorized and no shares issued or outstanding as of September 30, 2025 and December 31, 2024 — — Common stock, $0.0001 par value; 200,000,000 shares authorized as of September 30, 2025 and December 31, 2024 ; 563,491 and 563,042 shares issued and outstanding as of September 30, 2025 and December 31, 2024 , respectively — — Additional paid-in capital 279,974 279,089 Accumulated deficit (274,588 ) (250,268 ) Total stockholders’ equity 5,386 28,821 Total liabilities and stockholders’ equity $ 15,313 $ 45,209 SPRUCE BIOSCIENCES, INC. CONDENSED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (unaudited) (in thousands, except share and per share amounts) Three Months Ended September 30 , Nine Months Ended September 30 , 2025 2024 2025 2024 Collaboration revenue $ — $ 602 $ — $ 4,214 Operating expenses: Research and development 5,011 6,554 15,418 24,961 General and administrative 3,218 3,456 9,995 11,330 Total operating expenses 8,229 10,010 25,413 36,291 Loss from operations (8,229 ) (9,408 ) (25,413 ) (32,077 ) Interest expense (19 ) (71 ) (84 ) (251 ) Interest and other income, net 36 808 1,177 2,851 Net loss and comprehensive loss (8,212 ) (8,671 ) (24,320 ) (29,477 ) Net loss per share, basic and diluted $ (14.58 ) $ (15.75 ) $ (41.25 ) $ (53.68 ) Weighted-average shares of common stock outstanding, basic and diluted 563,066 550,645 589,520 549,116 View source version on businesswire.com: https://www.businesswire.com/news/home/20251110552861/en/ Media Carolyn Hawley Inizio Evoke Comms Carolyn.Hawley@inizioevoke.com media@sprucebio.com Investors Samir Gharib President and CFO Spruce Biosciences, Inc. investors@sprucebio.com Source: Spruce Biosciences, Inc.

Financial StatementBreakthrough Therapy

20 Oct 2025

·www.businesswire.com

Spruce Biosciences Receives U.S. FDA Breakthrough Therapy Designation for Tralesinidase Alfa Enzyme Replacement Therapy (TA-ERT) in Sanfilippo Syndrome Type B (MPS IIIB)

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Spruce Biosciences, Inc. (Nasdaq: SPRB), a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for neurological disorders with significant unmet medical need, today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to tralesinidase alfa enzyme replacement therapy (TA-ERT) for the treatment of Sanfilippo Syndrome Type B (MPS IIIB). “We are pleased to receive U.S. FDA Breakthrough Therapy Designation as we prepare to submit the Biologics License Application of TA-ERT for the treatment of MPS IIIB in the first quarter of 2026. This designation highlights TA-ERT’s potentially transformative clinical impact as the first disease-modifying therapy to treat MPS IIIB in children impacted by this devastating condition,” said Javier Szwarcberg, M.D., M.P.H., Chief Executive Officer of Spruce Biosciences. “The integrated group-level clinical data demonstrates a rapid, profound, and durable effect of TA-ERT in normalizing CSF HS-NRE, the pathogenic factor leading to neurodegeneration, and stabilizing cortical grey matter volume and cognitive function in children with MPS IIIB.” BTD is designed to expedite the development and regulatory review of promising therapies for serious or life-threatening conditions where preliminary clinical evidence suggests the potential for substantial improvement over existing treatments. The designation facilitates more intensive FDA guidance, cross-disciplinary collaboration, and eligibility for rolling submission and priority review. About Sanfilippo Syndrome Type B (MPS IIIB) MPS IIIB is an ultra-rare, serious, and fatal genetic disease characterized by deficiency in N-Acetyl-Alpha-Glycosaminidase (NAGLU), an enzyme required for the catabolism of heparan sulfate (HS) in lysosomes. It is estimated that MPS IIIB affects fewer than 1:200,000 people in the United States (U.S.), but the true incidence and prevalence are difficult to ascertain because MPS IIIB is a disease currently not included in newborn screening. 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) Tralesinidase Alfa Enzyme Replacement Therapy (TA-ERT) is a fusion protein comprised of recombinant human alpha-N-acetylglucosaminidase (rhNAGLU). TA-ERT is intended as an enzyme replacement therapy for the treatment of patients with MPS IIIB (Sanfilippo Syndrome Type B) who lack rhNAGLU enzyme activity. TA-ERT is expected to restore rhNAGLU enzyme activity in the central nervous system following intracerebroventricular injection. rhNAGLU typically lacks the mannose-6 phosphate 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 mannose-6-phosphate 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. Twenty-two individuals with MPS IIIB have been administered TA-ERT therapy. TA-ERT has demonstrated an adequate safety profile based on integrated five years of 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. To learn more, visit www.sprucebio.com and follow us on X, LinkedIn, Facebook and YouTube. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the ability to seek accelerated approval of TA-ERT for MPS IIIB based on existing clinical data, and TA-ERT’s potential to preserve neuronal cell health and potentially halt or slow neurological decline and improve clinical outcomes in affected patients. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “potential,” “intend,” “on track,” “expect” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Spruce’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Spruce’s business in general, the impact of geopolitical and macroeconomic events, and the other risks described in Spruce’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Spruce undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Breakthrough TherapyPhase 3

15 Aug 2025

·pipelinereview.com

Spruce Biosciences Announces Integrated Long-Term Clinical Data of Tralesinidase Alfa Enzyme Replacement Therapy (TA-ERT) Demonstrating Profound and Durable Efficacy and Safety in Patients with Sanfilippo Syndrome Type B (MPS IIIB)

TA-ERT Profoundly and Durably Lowered Cerebral Spinal Fluid Heparan Sulfate Non-Reducing End (CSF HS-NRE), the Factor Responsible for Neurodegeneration in MPS IIIB U.S. FDA Confirmed that CSF HS-NRE is a Surrogate Biomarker Reasonably Likely to Predict Clinical Benefit and Could Serve as Basis for Accelerated Approval Cognition and Cortical Grey Matter Volume Were Stabilized in Patients Treated with TA-ERT Relative to Declines Observed in Untreated Patients SOUTH SAN FRANCISCO, CA, USA I August 14, 2025 I Spruce Biosciences, Inc. (OTCQB: SPRB), a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for neurological disorders with significant unmet medical need, today announced results from a long-term data integration of tralesinidase alfa enzyme replacement therapy (TA-ERT) clinical program in patients with Sanfilippo Syndrome Type B (MPS IIIB). Spruce integrated and evaluated group-level efficacy data for cerebral spinal fluid heparan-sulfate non-reducing end (CSF HS-NRE), cortical grey matter volume (CGMV), and Bayley-III Cognitive Raw Score (BSID-C), the cognitive subscale of the Bayley Scales of Infant and Toddler Development – Third Edition (Bayley-III), as well as safety data over a five-year period from clinical studies 201, 202, and 401. Data from treated patients (n=22) in the studies 201, 202, and 401 was compared with data from untreated patients with MPS IIIB in natural history studies 901 and 902. “These data demonstrate a rapid, profound, and durable effect of ICV-administered TA-ERT on normalizing CSF HS-NRE, the pathogenic factor leading to neurodegeneration, and in stabilizing CGMV and cognitive function, relative to the declines observed in untreated children with Sanfilippo Syndrome Type B (MPS IIIB) in the natural history studies,” said Paul Harmatz, M.D., Principal Investigator in studies 901, 201, and 202 and Professor in Residence, Department of Pediatrics, University of California, San Francisco (UCSF) and UCSF Benioff Children’s Hospital Oakland. “This is an important development toward relief for children and families whose lives are impacted by this devastating condition.” “Convincing positive outcomes have been experienced by families who resoundingly state that the benefits of TA-ERT outweigh risks in their real-world experiences,” said Cara O’Neill, M.D., FAAP, Co-Founder and Chief Science Officer of Cure Sanfilippo Foundation. “Biomarker data, along with promising clinical outcomes, are significant and meaningful from the perspective of the patient community. Currently, there is no U.S. FDA-approved therapy for the treatment of MPS IIIB, and disease management consists of limited palliative care. We are eager to see TA-ERT advance under the accelerated approval pathway.” Cerebral Spinal Fluid Heparan-Sulfate Non-Reducing End (CSF HS-NRE) Integrated group-level data from clinical studies 201, 202, and 401 demonstrate that TA-ERT therapy significantly reduced to normal or near normal CSF HS-NRE levels over a five-year period (Figure 1). At 240 weeks, CSF HS-NRE decreased 91.5 ng/mL from baseline (95% CI: -102.10, -80.90; p<0.0001). Most participants experienced normalization of CSF HS-NRE levels eight weeks after initiating therapy. In a 2024 meeting with the U.S. Food and Drug Administration (FDA), the FDA confirmed that CSF HS-NRE is a surrogate biomarker reasonably likely to predict clinical benefit and could serve as a basis for accelerated approval. Cognitive Function In untreated patients with MPS IIIB, cognitive function peaks at around four years of age and then declines over time. In contrast, children with established disease treated with TA-ERT experienced stable cognitive function over time (Figure 2). Untreated children in the natural history studies showed a decline in cognition beginning at approximately five years of age that progressively worsened over time, while cognition in the TA-ERT treated group remained stable. Using a model-based approach, the mean (95% CI) BSID-C over six to 10 years of age was significantly higher in patients treated with TA-ERT, relative to untreated, age-matched children, with differences evident at six years of age (group difference: 10.67, 95% CI: 3.23, 18.11; p=0.005). At 10 years of age, the difference in BSID-C scores between groups increased to 34.66 (95% CI: 24.38, 44.93; p<0.0001). Although TA-ERT treatment stabilized BSID-C scores on average, increases in BSID-C scores were more commonly observed in subjects who initiated therapy at younger ages with higher baseline cognitive function and prior to the establishment of meaningful neurodegeneration. The BSID-C is anticipated to be the primary endpoint for the post-marketing clinical trial. Cortical Grey Matter Volume (CGMV) TA-ERT therapy was also associated with stabilization of CGMV, relative to the decline in CGMV observed in untreated children due to the progressive neurodegenerative nature of MPS IIIB (Figure 3). While CGMV should increase with age in children up to five years of age, there was an average loss of ~32 mL over 48 weeks in untreated children with MPS IIIB observed in study 901. Consistent with TA-ERT’s mechanism of action, decreases in CGMV were observed during the initial 24 weeks of TA-ERT treatment, likely reflecting intracellular clearance of cerebral spinal fluid heparan sulfate (CSF HS) and CSF HS-NRE. CGMV stabilized from weeks 48 to 240 with TA-ERT treatment. Safety TA-ERT therapy exposure for up to 7.3 years has demonstrated an adequate safety profile in a serious and fatal disease for which no treatment is currently available. The mean (SD) exposure to TA-ERT was 4.2 (2.0) years. No deaths occurred throughout study 201 and its long-term extension studies 202 and 401. The most frequent treatment-emergent adverse event (TEAE) by preferred term (reported in ≥40% of participants) was vomiting (22 [100%]), followed by pyrexia (20 [90.9%]), upper respiratory tract infection (17 [77.3%]), pleocytosis (11 [50.0%]), COVID-19 infection (10 [45.5%]), and diarrhea (9 [40.9%]). Four (18%) patients discontinued treatment, although three (14%) discontinuations were due to hydrocephalus, a known complication of MPS IIIB. Adverse events related to the ICV device were consistent with other therapies administered by the ICV route. About Sanfilippo Syndrome Type B (MPS IIIB) MPS IIIB is an ultra-rare, serious, and fatal genetic disease characterized by deficiency in N-Acetyl-Alpha-Glycosaminidase (NAGLU), an enzyme required for the catabolism of heparan sulfate (HS) in lysosomes. It is estimated that MPS IIIB affects fewer than 1:200,000 people in the United States (U.S.), but the true incidence and prevalence are difficult to ascertain because MPS IIIB is a disease currently not included in newborn screening. 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) Tralesinidase Alfa Enzyme Replacement Therapy(TA-ERT) is a fusion protein comprised of recombinant human alpha-N-acetylglucosaminidase (rhNAGLU). TA-ERT is intended as an enzyme replacement therapy for the treatment of patients with MPS IIIB (Sanfilippo Syndrome Type B) who lack rhNAGLU enzyme activity. TA-ERT is expected to restore rhNAGLU enzyme activity in the central nervous system following intracerebroventricular injection. rhNAGLU typically lacks the mannose-6-phosphate 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 mannose-6-phosphate 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. Twenty-two individuals with MPS IIIB have been administered TA-ERT therapy. TA-ERT has demonstrated an adequate safety profile based on integrated five years of 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. To learn more, visit www.sprucebio.com and follow us on X , LinkedIn , Facebook and YouTube . SOURCE: Spruce Biosciences

Clinical Result

100 Deals associated with Tralesinidase alfa

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Indication	Highest Phase	Country/Location	Organization	Date
Mucopolysaccharidosis III	Phase 3	United States	Allievex Corp.	18 Oct 2022
Mucopolysaccharidosis III	Phase 3	Colombia	Allievex Corp.	18 Oct 2022
Mucopolysaccharidosis III	Phase 3	Germany	Allievex Corp.	18 Oct 2022
Mucopolysaccharidosis III	Phase 3	Turkey	Allievex Corp.	18 Oct 2022
Mucopolysaccharidosis III	Phase 3	United Kingdom	Allievex Corp.	18 Oct 2022
Mucopolysaccharidoses	Phase 2	Spain	Allievex Corp.	19 Feb 2018
Mucopolysaccharidoses	Phase 2	Taiwan Province	Allievex Corp.	19 Feb 2018

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02754076 \| NCT03784287 \| NCT05492799 (Company_Website) Manual	Not Applicable	Mucopolysaccharidoses	22	TA-ERT	fuggqrghgh(ooyqtszcsk): Difference = 10.67 (95.0% CI, 3.23 - 18.11), P-Value = 0.005 View more	Positive	14 Aug 2025
	Not Applicable	Mucopolysaccharidoses	22	untreated		Positive	14 Aug 2025
NCT02754076 (Pubmed) Manual	Phase 1/2	Mucopolysaccharidosis III	22	Tralesinidase alfa	raprzstikn(ieavlkcfjc) = Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. xszpwxifch (tjmvkunyao ) View more	Positive	22 Nov 2022

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