Next-Gen Enzyme Replacement Therapy Receives FDA Priority Review with Expected Approval This Year; Novel Small Molecule for ALS Shows Promising Clinical Progress

Tividenofusp alfa (DNL310): Release of Phase 1/2 Clinical Trial Data

Denali Therapeutics Inc. announced the investigational therapy tividenofusp alfa for the treatment ofHunt SyndromeResults from the Phase 1/2 clinical trial in patients, published in The New England Journal of Medicine (NEJM).Tividenofusp alfa is a fusion protein drug that combines human iduronate-2-sulfatase (IDS) with Denali's Enzyme Transport Vehicle (ETV).Denali's transport carrier platform contains engineered Fc fragments that can bind to natural transport receptors. By binding to natural transport receptors expressed on the blood-brain barrier, it delivers large molecules to the brain through transcytosis, thereby alleviating the central nervous system symptoms of MPS II.ividenofusp alfaBLAObtainedPriority Review granted by the U.S. FDA, with a PDUFA date of April 5, 2026.

In a Phase 1/2 clinical trial involving 47 patients with MPS II, the therapy significantly reduced levels of key disease biomarkers in both the central and peripheral systems:Heparan sulfate (HS) in cerebrospinal fluid (CSF) decreased by an average of 91% from baseline at Week 24 and continued until Week 153, with 93% of subjects reaching the level of children without MPS II at Week 24.Urinary HS levels decreased by an average of 88% from baseline at Week 24 and remained sustained until Week 153; 58% of patients reached the level of children without MPS II at Week 24.Serum neurofilament light chain (NfL), a biomarker of neuronal damage, decreased by 76% at week 153, with 85% of patients reaching levels comparable to those without MPS II.In addition, the treatment also brought clinical benefits, including normalization of liver volume after 24 weeks, improvement in hearing thresholds within the tested frequency range, and progress in adaptive behavior and cognitive function in most patients. The most common treatment-related adverse events were infusion-related reactions, which decreased with continued use of the drug.

QRL-101: Announcement of Phase 1 Clinical Trial Data

QurAlis Corporation announced the Phase 1 Proof-of-Mechanism (PoM) clinical trial data for its investigational therapy QRL-101 in the treatment of amyotrophic lateral sclerosis.QRL-101 is a potential "best-in-class" selective Kv7.2/7.3 ion channel opener for the treatment of ALS patients with disease progression caused by neuronal hyperexcitability., a phenomenon that occurs in both sporadic and familial ALS, mostly due toKCNQ2The incorrect splicing of gene mRNA precursors leads to this condition. Kv7 channels are also clinically validated effective targets for modulating hyperexcitability in epilepsy. In vivo and in vitro studies have shown that, compared to the less selective first-generation Kv7.2/7.3 channel openers, QRL-101 exhibits higher potency and may cause fewer clinical adverse events.

The results announced this time show,Compared with placebo, QRL-101 treatment reduced motor neuron hyperexcitability, with more significant efficacy observed in patients with higher drug exposure.In addition, consistent and expected changes were observed across multiple evaluation metrics, including the Strength-Duration Time Constant (SDTC), Rheobase, and eight out of nine other parameters included in the Motor Neuron Excitability Threshold Tracking (mNETT) assessment. These results are generally consistent with the signals previously observed in healthy volunteers. The study also showed that the pharmacokinetic (PK) profile, safety, and tolerability of QRL-101 were consistent with findings reported in previous studies. No serious adverse events were reported in this study, and no subjects discontinued treatment due to adverse events.