Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 121

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 121
---
ofusp alfa resulted in a substantial reduction from baseline in CSF and urine heparan sulfate levels by Week 24 with the majority of participants below the upper limit of the normal range; this effect was maintained through Week 153, or nearly three years, of treatment (Figure 8). 

Figure 8: CNS and peripheral heparan sulfate. a Heparan sulfate was measured as a sum of the disaccharides D0A0, D0A6, D0S0, and D2S6 by mass spectrometry after enzymatic digestion. bBased on MMRM model with fixed effects for visit week, age group at tividenofusp alfa initiation, genotype, and baseline CSF or urine HS (urine HS was also adjusted for prior enzyme replacement therapy ("ERT") status group); only protocol planned visits consistent across all cohorts and with ≥ 5 observations were included in the model. cCFB for timepoints with collection for limited dose escalation cohorts: W5 (cohort A only), range: –24.9%, –93.1%; W7 (cohort B only), range: –67.3, –92.7%; W9 (cohort A only), range –36.1%, –92.5%. BL, baseline; CFB, change from baseline; CI, confidence interval; CNS, central nervous system; CSF, cerebrospinal fluid; MMRM, mixed model for repeated measures; ULN, upper limit of normal; W, week.

15

Robust reduction from baseline in serum NfL, a marker of neuronal damage, was observed with long-term dosing with the majority of participants below the upper limit of the normal range at Week 104 (Figure 9).

Figure 9: Robust reduction of serum NfL, a marker of neuronal damage, was observed with long-term dosing.

Mean hearing thresholds improved from baseline in all tested frequencies (500, 1000, 2000, 4000 Hz) and reductions were statistically significant from week 24 onward (Figure 10).

Figure 10: Hearing Thresholds. Mean change from baseline in pure tone average by ABR (eHL) and audiometry (HL). Pure tone average is defined as the average across the four tested frequencies (500, 1000, 2000, and 4000 Hz). Pure tone average is only calculated if the numeric values of all individual frequencies are available. ABR