- Interim results from Part A in healthy volunteers demonstrated dose-dependent increases in CSF progranulin levels, consistent with robust brain delivery of DNL593
- Single doses of DNL593 were generally well tolerated
- Data support progression to enrolling participants with FTD-GRN in Part B of the Phase 1/2 study
SOUTH SAN FRANCISCO, CA, USA I November 01, 2022 I Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage disorders, today announced interim results from Part A of a Phase 1/2 study evaluating TAK-594/DNL593 (PTV:PGRN) in healthy subjects. Progranulin (PGRN) levels measured in cerebrospinal fluid (CSF) increased in a dose-dependent manner compared to baseline and placebo, consistent with brain delivery of DNL593 and exceeding levels believed to be necessary to rescue deficits associated with progranulin deficiency, based on preclinical models.1 Single doses of DNL593 were generally well tolerated, based on blinded safety analysis. These data support dosing in participants with frontotemporal dementia and a mutation in the granulin gene (FTD-GRN) in Part B of the study. DNL593 is an investigational, brain-penetrant progranulin replacement therapy being co-developed by Denali and Takeda. These data were presented at the FTD Prevention Initiative meeting in Paris, France. A copy of the presentation is available on Denali’s website on the Investor & Media Relations section under the Events page.
“These data show that single doses of DNL593 result in substantial increases in CSF progranulin levels suggesting brain delivery of DNL593 was achieved and has the potential to address progranulin deficiency, which drives disease progression in people living with FTD-GRN,” said Carole Ho, M.D., Chief Medical Officer at Denali. “Together with the safety profile to date, these results support initiation of dosing in participants with FTD-GRN and underscore the potential of our Protein Transport Vehicle (PTV) platform to deliver biotherapeutics across the blood-brain barrier. As the study progresses, we look forward to learning more about how DNL593 may impact patients with this devastating neurogenerative disease who have no approved treatment options.”
As previously announced, this Phase 1/2 study is a multicenter, randomized, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of DNL593. The study is divided into three parts: In Part A, 35 participants in five cohorts received either single ascending doses of DNL593 or placebo; Part B will evaluate participants with FTD-GRN over 25 weeks; Part C is an optional 18-month open-label extension period available for all participants who complete part B. More information about the study (NCT05262023) is available here.
About FTD
FTD is the most common form of dementia in people under 60 years of age. While the progression of symptoms varies by individual, FTD brings an inevitable decline in function together with changes in personality and social behaviors, and sometimes language and/or motor dysfunction. Mutations in the granulin (GRN) gene, which encodes the progranulin (PGRN) protein, generally result in reduced levels of PGRN and are amongst the most common genetic causes of FTD. There are currently no approved medicines to stop or slow the progression of FTD or FTD-GRN.
About TAK-594/DNL593 (PTV:PGRN)
TAK-594/DNL593 is an investigational, intravenously administered, brain-penetrant progranulin (PGRN) replacement therapy enabled by Denali’s Protein Transport Vehicle (PTV) technology. PGRN is known to promote lysosomal function, in addition to having neurotrophic and anti-inflammatory effects. Data from in vitro and in vivo models providing preclinical proof of concept for DNL593 were published in the September 2, 2021, issue of the scientific journal Cell.1 The studies demonstrated that DNL593 enhanced brain uptake of peripherally administered PGRN by multiple cell types in the brain, including neurons and microglia, and improved lysosomal function. In addition, DNL593 rescued both neurodegeneration and microglial dysfunction in PGRN-deficient mice. These preclinical data support the potential for DNL593 to increase PGRN levels in the brain and impact disease progression in individuals with FTD-GRN.
Denali and Takeda are collaborating to co-develop and co-commercialize DNL593. Denali may receive future milestone payments from Takeda upon achievement of certain clinical and regulatory milestone events as well as certain sales-based milestones. Subject to the terms of the collaboration agreement, Denali will share the development and commercialization costs equally with Takeda, and, if applicable, profits on a worldwide basis.
DNL593 is an investigational therapeutic that has not been approved by any regulatory authority for any commercial use.
About Denali’s Transport Vehicle Platform
The blood-brain barrier is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the blood-brain barrier has posed significant challenges to drug development for central nervous system diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the blood-brain barrier after intravenous administration. The Transport Vehicle technology is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptor, which are expressed at the blood-brain barrier and are designed to deliver the Transport Vehicle and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the Transport Vehicle 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.
About Denali Therapeutics
Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier 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.
Reference:
1. Logan T. et al. “Rescue of lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic” Cell 2021 Sep 2;184(18):4651-4688.
SOURCE: Denali Therapeutics
Post Views: 76
- Interim results from Part A in healthy volunteers demonstrated dose-dependent increases in CSF progranulin levels, consistent with robust brain delivery of DNL593
- Single doses of DNL593 were generally well tolerated
- Data support progression to enrolling participants with FTD-GRN in Part B of the Phase 1/2 study
SOUTH SAN FRANCISCO, CA, USA I November 01, 2022 I Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage disorders, today announced interim results from Part A of a Phase 1/2 study evaluating TAK-594/DNL593 (PTV:PGRN) in healthy subjects. Progranulin (PGRN) levels measured in cerebrospinal fluid (CSF) increased in a dose-dependent manner compared to baseline and placebo, consistent with brain delivery of DNL593 and exceeding levels believed to be necessary to rescue deficits associated with progranulin deficiency, based on preclinical models.1 Single doses of DNL593 were generally well tolerated, based on blinded safety analysis. These data support dosing in participants with frontotemporal dementia and a mutation in the granulin gene (FTD-GRN) in Part B of the study. DNL593 is an investigational, brain-penetrant progranulin replacement therapy being co-developed by Denali and Takeda. These data were presented at the FTD Prevention Initiative meeting in Paris, France. A copy of the presentation is available on Denali’s website on the Investor & Media Relations section under the Events page.
“These data show that single doses of DNL593 result in substantial increases in CSF progranulin levels suggesting brain delivery of DNL593 was achieved and has the potential to address progranulin deficiency, which drives disease progression in people living with FTD-GRN,” said Carole Ho, M.D., Chief Medical Officer at Denali. “Together with the safety profile to date, these results support initiation of dosing in participants with FTD-GRN and underscore the potential of our Protein Transport Vehicle (PTV) platform to deliver biotherapeutics across the blood-brain barrier. As the study progresses, we look forward to learning more about how DNL593 may impact patients with this devastating neurogenerative disease who have no approved treatment options.”
As previously announced, this Phase 1/2 study is a multicenter, randomized, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of DNL593. The study is divided into three parts: In Part A, 35 participants in five cohorts received either single ascending doses of DNL593 or placebo; Part B will evaluate participants with FTD-GRN over 25 weeks; Part C is an optional 18-month open-label extension period available for all participants who complete part B. More information about the study (NCT05262023) is available here.
About FTD
FTD is the most common form of dementia in people under 60 years of age. While the progression of symptoms varies by individual, FTD brings an inevitable decline in function together with changes in personality and social behaviors, and sometimes language and/or motor dysfunction. Mutations in the granulin (GRN) gene, which encodes the progranulin (PGRN) protein, generally result in reduced levels of PGRN and are amongst the most common genetic causes of FTD. There are currently no approved medicines to stop or slow the progression of FTD or FTD-GRN.
About TAK-594/DNL593 (PTV:PGRN)
TAK-594/DNL593 is an investigational, intravenously administered, brain-penetrant progranulin (PGRN) replacement therapy enabled by Denali’s Protein Transport Vehicle (PTV) technology. PGRN is known to promote lysosomal function, in addition to having neurotrophic and anti-inflammatory effects. Data from in vitro and in vivo models providing preclinical proof of concept for DNL593 were published in the September 2, 2021, issue of the scientific journal Cell.1 The studies demonstrated that DNL593 enhanced brain uptake of peripherally administered PGRN by multiple cell types in the brain, including neurons and microglia, and improved lysosomal function. In addition, DNL593 rescued both neurodegeneration and microglial dysfunction in PGRN-deficient mice. These preclinical data support the potential for DNL593 to increase PGRN levels in the brain and impact disease progression in individuals with FTD-GRN.
Denali and Takeda are collaborating to co-develop and co-commercialize DNL593. Denali may receive future milestone payments from Takeda upon achievement of certain clinical and regulatory milestone events as well as certain sales-based milestones. Subject to the terms of the collaboration agreement, Denali will share the development and commercialization costs equally with Takeda, and, if applicable, profits on a worldwide basis.
DNL593 is an investigational therapeutic that has not been approved by any regulatory authority for any commercial use.
About Denali’s Transport Vehicle Platform
The blood-brain barrier is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the blood-brain barrier has posed significant challenges to drug development for central nervous system diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the blood-brain barrier after intravenous administration. The Transport Vehicle technology is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptor, which are expressed at the blood-brain barrier and are designed to deliver the Transport Vehicle and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the Transport Vehicle 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.
About Denali Therapeutics
Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier 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.
Reference:
1. Logan T. et al. “Rescue of lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic” Cell 2021 Sep 2;184(18):4651-4688.
SOURCE: Denali Therapeutics
Post Views: 76
