Denali gains on Parkinson’s results as it looks to select a Phase II candidate

Denali reported data Tuesday from pair of Phase I trials that will inform the company’s selection of a Parkinson’s disease candidate to advance to Phase II.

Denali Therapeutics Inc. (NASDAQ:DNLI) gained $5.16 (29%) to $22.74 after presenting safety and biomarker data for its two small molecule LRRK2 inhibitors for PD at the J.P. Morgan Healthcare Conference in San Francisco.

In PD, lysosomal dysfunction is linked to inflammation and neuronal loss. Denali said DNL201 ameliorated lysosomal dysfunction, as measured by urine levels of the phospholipid bis-monoacylglycero-phosphate (BMP), in PD patients in a Phase Ib study. The low dose of the first-in-class compound reduced BMP levels by 20% with no or mild treatment-related adverse events (AEs). The high dose led to a 60% decrease in BMP levels, with most patients experiencing mild to moderate AEs; one severe AE of headache led to dose reduction and one patient withdrew from the study due to headache and nausea.

The company also reported interim data from healthy volunteers in a dose-escalation Phase I trial of backup LRRK2 inhibitor DNL151, which lowered BMP levels by up to 50%. DNL151 was well tolerated at all doses with no severe AEs. The company said that the trial and ongoing Phase Ib testing of DNL151 in PD patients will be expanded to include higher doses.

DNL201 is dosed twice a day, compared with once daily for DNL151. CMO and Head of Development Carole Ho said at the conference that twice-daily dosing is not viewed as a big barrier for PD patients.

Denali will select one of the LRRK2 inhibitors to advance into Phase II/III testing based on safety, target engagement and biomarker improvement in mid-2020, when final data are expected from DNL151’s Phase Ib study.

Denali gained exclusive, worldwide rights to its LRRK2 inhibitors in 2016 from the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY).

At least one other LRRK2 inhibitor has progressed to Phase I for PD: the LRRK2-targeting antisense oligonucleotide ION859 from Ionis Pharmaceuticals Inc. (NASDAQ:IONS) and Biogen Inc. (NASDAQ:BIIB).

Also on Tuesday, Denali announced it had submitted an IND for DNL310, a recombinant IDS enzyme replacement therapy to treat neuropathic and systemic Hunter Syndrome. It will be the first clinical test of the neurodegeneration company’s Transport Vehicle technology, which uses a transferrin receptor-binding motif to promote blood-brain-barrier penetration. Six of its other preclinical programs incorporate the technology, and the company plans IND-enabling studies in late 2020.

Targets: IDS - Iduronate 2-sulfatase; LRRK2 - leucine-rich repeat kinase 2

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