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Denali Therapeutics Announces Fast Track Designation Granted by the U.S. FDA to ETV:IDS (DNL310) for the Treatment of Patients with Hunter Syndrome (MPS II)

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SOUTH SAN FRANCISCO, Calif., March 11, 2021 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ:DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to ETV:IDS (DNL310) for the treatment of patients with Hunter syndrome (MPS II). DNL310, Denali's lead investigational brain-penetrant enzyme replacement therapy, is under evaluation in a Phase 1/2 study in patients with Hunter syndrome as a potential treatment for both central nervous system (CNS) and peripheral manifestations of the disease.

"Hunter syndrome is a devastating disease for which current approved treatments fail to effectively cross the blood-brain barrier and therefore do not address CNS symptoms," said Carole Ho, M.D., Denali's Chief Medical Officer. "Using Denali's Transport Vehicle technology, we have designed DNL310 to treat both body and brain in Hunter syndrome after intravenous administration. Receiving Fast Track designation is an important milestone in the DNL310 development program, and we look forward to our continued collaboration with the FDA to bring safe and effective treatments to patients with Hunter syndrome." 

Fast Track is an FDA process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Denali expects that Fast Track designation may allow for early and frequent communication with the FDA regarding the development of DNL310 for the treatment of Hunter syndrome. This designation also enables rolling review, and potentially priority review, of the marketing application.      

About the DNL310 Development Program for the Potential Treatment of Hunter Syndrome (MPS II)
Hunter syndrome (MPS II) is a rare neurodegenerative lysosomal storage disorder caused by a mutation in the gene that encodes for the enzyme iduronate-2-sulfatase (IDS). The resultant reduction or loss of IDS enzyme activity leads to accumulation of glycosaminoglycans (GAGs), which causes lysosomal dysfunction and neurodegeneration as well as progressive damage to multiple organs including bone, cartilage, heart and lung. Current standard of care enzyme replacement treatment does not address neuronopathic manifestations of the disease as it does not sufficiently cross the BBB. DNL310 is a fusion protein composed of IDS fused to Denali's proprietary Enzyme Transport Vehicle (ETV), which is engineered to cross the BBB via receptor-mediated transcytosis into the brain. Denali previously announced human biomarker proof-of-concept for its TV technology from Cohort A (n=5) of an ongoing Phase 1/2 study of DNL310 in patients with Hunter syndrome (ClinicalTrials.gov Identifier: NCT04251026). The study is currently enrolling Cohort B, and a Cohort C is planned to further explore clinical endpoints. DNL310 is an investigational drug and is not approved by any health authority.

About Denali's TV Platform 
The BBB is essential in maintaining the brain's microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB has posed significant challenges to drug development for CNS diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali's TV platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration. The TV technology is based on engineered Fc fragments that bind to specific natural transport receptors, such as transferrin receptor, which are expressed at the BBB and deliver TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the TV technology demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates. ETV:IDS (DNL310) is Denali's lead TV-enabled program in Phase 1/2 development for the potential treatment of Hunter syndrome (MPS II).  

About Denali Therapeutics 
Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com.  

Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding Denali's progress and business plans; plans, timelines and expectations related to DNL310, timing and frequency of interactions with the FDA about, and its review of applications for, the DNL310 development program for Hunter syndrome, Denali's TV technology platform, and the ongoing Phase 1/2 study, and planned future studies, of DNL310; the therapeutic potential of DNL310 and Denali's TV platform; and statements made by Denali's Chief Medical Officer. 

Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: any and all risks to Denali's business and operations caused directly or indirectly by the evolving COVID-19 pandemic; risk of the occurrence of any event, change or other circumstance that could give rise to the termination of Denali's agreements with its partners; Denali's early stages of clinical drug development; Denali's and its partners' ability to complete the development and, if approved, commercialization of its product candidates; Denali's and its partners' ability to enroll patients in its ongoing and future clinical trials; Denali's reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali's dependence on successful development of its blood-brain barrier platform technology and TV-enabled product candidates; Denali's and its partners' ability to conduct or complete clinical trials on expected timelines; the potential for clinical trial results of DNL310 to differ from preclinical, preliminary or expected results, whether DNL310 will cause any serious adverse events, whether DNL310 will impact downstream biomarkers of neurodegeneration, and that DNL310 may not receive regulatory approval as a treatment of Hunter syndrome necessary to be commercialized; Denali's ability to obtain, maintain, or protect intellectual property rights related to its product candidates; implementation of Denali's strategic plans for its business, product candidates and blood-brain barrier platform technology; and other risks. In light of these risks, uncertainties and assumptions, the forward-looking statements in this press release are inherently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali's Annual and Quarterly Reports filed on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 26, 2021, and Denali's future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results or to make changes in Denali's expectations, except as required by law. 

Investor Relations Contact: 
  
Laura Hansen, Ph.D. 
Vice President, Investor Relations 
(650) 452-2747 
hansen@dnli.com

Media Contacts: 
  
Lizzie Hyland 
(646) 495-2706 
lhyland@gpg.com
  
or 
  
Morgan Warners 
(202) 295-0124 
mwarners@gpg.com


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