Anakinra in Sanfilippo syndrome: a phase 1/2 trial

Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a severe childhood-onset neurodegenerative disorder characterized by developmental regression, loss of speech, disordered sleep and movement, pain, and escalating neurobehavioral symptoms (hyperactivity, agitation, aggression, distress, social disengagement). Onset typically occurs at ages 3–5 years with relentless progression leading to death in the second or third decade. The disease results from lysosomal enzyme deficiencies causing glycosaminoglycan (GAG) accumulation and downstream pathological cascades, including neuroinflammation, which likely contributes to neurobehavioral and functional symptoms. No approved therapies exist for any MPS III subtype, and while enzyme-restorative approaches are under development, the Sanfilippo community prioritizes relief of pain, sleep disturbance, movement disorder, and neurobehavioral challenges. Anakinra, an FDA-approved recombinant human IL-1 receptor antagonist that crosses the blood–brain barrier and treats neuroinflammatory conditions, was hypothesized to palliate Sanfilippo symptoms by reducing central and peripheral inflammation triggered by GAG accumulation. This phase 1/2 study evaluated safety, tolerability, and effects of anakinra on neurobehavioral, functional, and quality-of-life outcomes.

Preclinical studies in MPS III models implicate neuroinflammation as a key driver of CNS disease; reducing IL-1 signaling (for example, increasing IL-1Ra or knocking out IL-1 receptor) ameliorated CNS pathology and behavior in mice. Broader literature highlights innate and adaptive immune activation in MPS III brains and benefits of anti-inflammatory strategies in related lysosomal disorders. Caregiver- and patient-focused publications emphasize that pain, sleep disturbance, movement abnormalities, and neurobehavioral symptoms are high-priority treatment targets, beyond traditional neurocognitive endpoints. Anakinra has established safety and efficacy in multiple inflammatory and neuroinflammatory conditions (CAPS, NOMID, DIRA, rheumatoid arthritis, and others), supporting its repurposing for MPS III. Consensus guidelines for MPS III trial design recommend inclusion of meaningful, patient-centered outcomes and composite measures to capture heterogeneous treatment effects, informing the MDRI and ICR approaches used here.

Design and oversight: Single-site, phase 1/2, open-label study consisting of an 8-week treatment period followed by a 28-week open-label extension (total on-treatment 36 weeks), each preceded and followed by 8-week observational periods. Conducted January 2020–March 2023; registered NCT04018755. Independent data and safety monitoring; ethics approval by the John F. Wolf, M.D. Human Subjects Committee (Lundquist Institute). Caregivers provided informed consent; participants were unable to assent due to severe cognitive impairment. Participants: 24 screened (ages 6–26 years), 23 enrolled (12 female, 11 male?; overall 12 female/12 male at screening); majority White (88%) and non-Hispanic (88%); MPS IIIA (83%), IIIB (13%), IIIC (4%). Inclusion required genetically confirmed MPS III, age ≥4 years, stable concomitant therapies (for example, genistein, sleep medications), and predefined clinical criteria (sleep disturbance, SBRS elevation, CNS impairment/behavioral disturbance, pain score, seizure disorder due to MPS III, or movement disorder) or prior involvement/exclusion in restorative trials or Vineland functional age ≤0.5 of chronological age. Key exclusions: concurrent therapeutic trial; prior IL‑1 inhibitors. Intervention and dosing: Anakinra 100 mg subcutaneous (SC) once daily starting day 1; dose escalated to 200 mg SC daily at week 8 or week 16 if neither of the two caregiver-selected ‘most bothersome’ outcomes improved by ≥ minimal clinically important difference (MCID). Maximum dose limited to 8 mg/kg/day. Dose reduction by 50 mg permitted for persistent neutropenia (<1,200/µL, threshold lowered from 1,500/µL during study), thrombocytopenia, mild/moderate hypersensitivity, or grade 3 AE; discontinuation if unresolved within 2 weeks; potential re-challenge at half-dose. Outcomes: Primary (phase 1): safety/tolerability via AEs/SAEs. Primary (phase 2): percent requiring dose increase from 100 to 200 mg at week 8 or 16. Secondary efficacy: a Multi-Domain Responder Index (MDRI) capturing patient-level heterogeneity across six measures—Sanfilippo Behavior Rating Scale (SBRS), Children’s Sleep Habits Questionnaire (CSHQ), PROMIS Fatigue—Parent Proxy Custom Short Form, Non-Communicating Children’s Pain Checklist—Revised (NCCPC-R), Autism Parenting Stress Index (APSI), and a 7-day disordered movement log (duration/severity). Improvement/no change/worsening defined by measure-specific MCIDs (from literature or derived from pre-treatment observation for movement log). Additional secondary outcomes: mean change over time in each MDRI component and an Individual Clinical Response (ICR) (caregiver-selected five most impactful items rated longitudinally). Immunophenotyping: Whole blood flow cytometry to quantify monocytes (CD14+ CD16+), neutrophils (bright CD16+ SSC high), T cells (CD3+ with CD4+ and CD8+ subsets), and B cells (CD19+), performed at each visit; correlations with MDRI response explored post hoc. Statistics: Safety set included all who received ≥1 dose. Efficacy analyzed by intent-to-treat with mixed models for repeated measures (unstructured covariance) providing least-squares means and 95% CIs; sensitivity analyses with last observation carried forward imputation and non-parametric Wilcoxon signed-rank tests. Spearman correlations assessed associations between immunophenotype and MDRI improvements/worsenings. Two-sided tests; P<0.05 considered significant; no multiplicity adjustment. Sample size determined by feasibility for this rare disease.

Enrollment and disposition: 24 screened, 23 enrolled (ages 6–26). One excluded for persistent neutropenia during screening. Twenty continued treatment to week 8; 21 rolled over to extension (20 received extension drug). Seven discontinued treatment during the extension (intolerability of daily injections n=3, lost to follow-up n=2, persistent ANC <1,500 n=2); one grade 3 agitation led to early cessation before week 8 but continued assessments. Primary dosing endpoint: 15 of 20 (75%) participants who continued to week 8 required dose escalation to 200 mg at week 8 or week 16 (12 at week 8; 3 at week 16). No baseline demographic or efficacy differences between escalators and non-escalators. Efficacy (MDRI/ICR): Improvement in at least one MDRI domain occurred in 18/21 (86%) at week 8 and 15/16 (94%) at week 36. After 8 weeks, the most frequent MCID-level improvements were in parenting stress (APSI; 48%) and pain (NCCPC-R; 48%). After 36 weeks, improvements were most common in parenting stress (69%), followed by behavioral symptoms (SBRS total averaged score; 56%) and pain (44%). ICR least-squares mean change improved from day 1 to week 8 (-2.0; 95% CI -3.4, -0.6), week 16 (-2.8; 95% CI -4.9, -0.8), and week 36 (-2.7; 95% CI -4.3, -1.0). Across SBRS clusters/domains, significant improvements were observed during treatment in Movements, Social/Emotional Dysfunction, Orality, and Mood/Anger/Aggression; no significant effects in Lack of Fear or Executive Dysfunction. Symptom rebound off treatment (week 36–44) suggested on-treatment improvements were not due to natural history. Safety: Mean treatment duration 187 ± 92 days; mean missed doses 5.2 ± 6.6. AEs occurred in 22/23 (96%), predominantly mild injection-site reactions (erythema 74%, swelling 43%). Three SAEs (viral pneumonia, muscle laceration injury during treatment; upper GI hemorrhage post-treatment) were not related to anakinra. No unexpected AEs were observed. Immunophenotype post hoc: Higher CD4+ T-cell counts correlated with a greater number of improved MDRI outcomes; trends suggested fewer improvements with more pro-inflammatory profiles (higher CD8+ T cells/monocytes), though not all reached significance.

Targeting neuroinflammation with anakinra in MPS III was safe and associated with clinically meaningful improvements in caregiver-prioritized outcomes, including parenting stress, behavior, and pain. The MDRI and ICR captured heterogeneous, individualized benefits consistent with consensus recommendations and patient-focused guidance. The observed rebound of symptoms after stopping anakinra supports a treatment effect rather than natural disease fluctuation. Post hoc correlations between a less pro-inflammatory immunophenotype (increased CD4+ T cells) and better MDRI responses align biologically with the anti–IL-1 hypothesis. Practical challenges—particularly daily SC injection burden in a population with significant behavioral dysregulation—affected adherence and led to discontinuations, highlighting a need for more feasible administration strategies. Findings suggest that anti-inflammatory strategies may be symptom-modifying in Sanfilippo syndrome, with potential applicability to other mucopolysaccharidoses.

This phase 1/2 open-label study indicates that anakinra is safe and associated with improvements across neurobehavioral and quality-of-life measures in Sanfilippo syndrome. The results support further controlled studies to confirm efficacy, optimize dosing, and evaluate durability. Future research should prioritize randomized, placebo-controlled designs where feasible, explore delivery methods that reduce injection burden, incorporate qualitative caregiver interviews, and assess broader applicability to other MPS types.

Open-label design without placebo control increases risk of bias and effect size inflation, particularly with caregiver-reported outcomes. Small sample size and rare-disease feasibility constraints limit generalizability. Heterogeneity of disease stage and subtypes may confound response interpretation. Daily SC injection burden led to discontinuations, potentially biasing outcomes toward those able to tolerate treatment. Multiple comparisons were not adjusted, so P values and CIs should be interpreted cautiously.