Phase 1b/2a Open‑Label Study Assessing Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous DNL952 in Adults with Late‑Onset Pompe Disease
- Trial ID
- 2025-524082-25-00
- Protocol
- DNLI-J-0001
- Sponsor
- Denali Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to evaluate the safety and tolerability of DNL952 in adult participants with late‑onset Pompe disease, generating data on adverse event frequency and severity to support clinical risk assessment.
Secondary objectives include:
- Characterization of DNL952 serum pharmacokinetics following single and multiple intravenous infusions.
- Assessment of DNL952 serum immunogenicity.
Participants
The trial enrolled 26 participants diagnosed with Late-Onset Pompe Disease, comprising both female and male individuals aged 18 to 75 years at screening. All participants were required to have a body weight of at least 40 kg, an upright forced vital capacity of 30 % or greater of the predicted normal value, and the ability to ambulate a minimum of 40 meters on the six‑minute walk test, with use of assistive devices permitted. Enrollment included cohorts of participants who were either receiving enzyme replacement therapy (avalglucosidase alfa or cipaglucosidase alfa) for at least 12 months without dosing gaps exceeding eight weeks, or who were enzyme‑replacement‑naïve with no therapy in the preceding 12 months and limited prior exposure. Additional selection criteria required a confirmed genetic diagnosis based on two pathogenic GAA variants, absence of significant cardiac hypertrophy in early life, and compliance with contraception requirements for individuals of childbearing potential. The population represented patients meeting these clinical and genetic parameters, reflecting a range of functional abilities and treatment histories within the specified age and gender distribution.
Plans and Procedures
The study is a multicenter, open‑label, non‑randomized Phase 1b/2a trial evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL952 administered by intravenous infusion in adult participants with Late-Onset Pompe Disease. Eligible adults (18–75 years) who meet disease‑specific genetic and respiratory criteria and who are either receiving stable enzyme replacement therapy (ERT) or are ERT‑naive according to cohort specifications are enrolled. Following a screening visit to confirm eligibility, participants attend a baseline visit for the first infusion and collection of baseline safety and laboratory data. Subsequent visits are scheduled at regular intervals—typically monthly—during the treatment phase to monitor adverse events, infusion‑related reactions, laboratory parameters, and to obtain blood samples for PK/PD assessments; the study concludes with an end‑of‑study visit after the final dose to evaluate overall safety and immunogenicity. Participant involvement therefore extends from screening through the final follow‑up, encompassing the entire treatment period and a post‑treatment observation window, with the total duration expected to span several months. Early termination may occur for safety reasons (e.g., serious adverse events or intolerable infusion reactions), protocol non‑compliance, or voluntary withdrawal, after which a termination visit is performed to document outcomes.
Treatment
The investigational product, DNL952, is supplied as a sterile solution for infusion and is administered by intravenous infusion. The specific dose, concentration, and infusion rate are defined in the study protocol, and the medication is delivered in a clinical setting under direct supervision of study personnel. Dosing frequency follows the protocol‑specified schedule, which may include single or multiple administrations depending on the cohort.
No placebo, active comparator, or additional experimental agents are administered in this trial. Participants receive only the investigational infusion; any concomitant therapies are limited to standard supportive care that is not considered part of the study intervention.
Administration procedures include verification of product identity, documentation of infusion start and end times, and continuous monitoring of vital signs during the infusion. Compliance is assessed through infusion logs and electronic case report forms, ensuring that each dose is delivered according to the predefined schedule. The trial enrolls adult participants with Late-Onset Pompe Disease to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of the study drug.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Are aged 18 to 75 years, inclusive, at screening
- Have a body weight ≥ 40 kg
- Are willing and able to give informed consent for study participation
- Are able to communicate with the investigator and staff
- Are willing and able to comply with the requirements of the study, including scheduled visits, study restrictions, laboratory tests, and all other study procedures
- 6a. Female participants of childbearing potential are permitted in the study and, if sexually active with a male partner, must use an acceptable highly effective method of contraception (Table 12) from at least 30 days prior to the core study period, throughout the core and extension study periods, and for 90 days after the final administration of study intervention 6b. Female participants of non-childbearing potential are permitted in the study and include female participants who have been surgically sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; proper documentation required) at least 3 months prior to dosing, and female participants who are postmenopausal
- For male participants: When engaging in sex with a female participant of childbearing potential, the male participant and female partner must use two forms of birth control—a male barrier method such as a latex or polyurethane condom and an acceptable highly effective method (Table 12)—from the start of dosing, throughout the core and extension study periods, and for 90 days after the final administration of study intervention. 7a. Male participants must not donate sperm at any time from the start of dosing, throughout the clinical study period, and for 90 days after the final administration of study intervention.
- Have a diagnosis of LOPD, defined as meeting both of the following criteria: a. Two pathogenic or likely pathogenic variants (excluding pseudodeficiency alleles) in the GAA gene (based on historical records available for review by investigator or Sponsor, or genetic testing at screening) b. No known history of clinically significant Pompe-related cardiac hypertrophy in the first year of life
- Have an upright FVC ≥ 30% of predicted normal value at screening. Patients may be rescreened if their clinical condition changes. Patients who failed screening because their FVC % predicted was below the cutoffs above due to intercurrent illness may rescreen after the illness resolves.
- Are able to ambulate ≥ 40 meters on the 6MWT at screening. Use of assistive ambulatory devices (eg, cane or walker) is acceptable.
- For Cohorts A1, A2, and, if opened, A3, and A4 (all enrolling ERT-experienced participants with LOPD): Must currently be receiving avalglucosidase alfa or cipaglucosidase alfa at a dose of 20 mg/kg Q2W and must have been treated for at least 12 months prior to screening with no gaps between doses of longer than 8 weeks and no missed doses in the 8 weeks prior to screening or during screening.
- For Cohorts B1 and B2, if opened (all enrolling ERT-naïve participants with LOPD): Must not have received any ERT for Pompe disease in the 12 months prior to screening and have received no more than four total doses of ERT for Pompe disease at any time.
Exclusion Criteria
- Have any ongoing, clinically significant, unstable, or poorly controlled neurological, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematological, immunological, allergic not related to Pompe disease, or other major disorders. Well-controlled conditions are permitted if investigator and Sponsor agree.
- Have had suicidal ideation, as assessed by the C-SSRS at screening, in the prior 6 months (a “yes” response to questions 1 and/or 2 on the Suicidal Ideation section with Intensity of Ideation scores ≤ 2 may be allowed pending investigator and Sponsor medical monitor agreement) or a lifetime suicide attempt (as defined by a “yes” response to lifetime actual, interrupted, or aborted attempt on the Suicidal Behavior section; a lifetime suicide attempt > 5 years before screening may be allowed pending investigator and Sponsor medical monitor agreement)
- Have a history of alcohol or substance use disorder, as defined by the DSM-5 criteria for moderate to severe substance use disorder, in the 12 months prior to screening
- Have used any smoked or inhaled tobacco, marijuana, or related products, including vaping, within 3 months before screening
- Have a positive drug screen (not including cannabinoids) with positive confirmatory drug test at screening
- Have renal impairment, as indicated by an estimated glomerular filtration rate < 90 mL/min/1.73 m2 at screening, ( as estimated with the CKD-EPI cystatin C equation) or urine albumin-to-creatinine ratio > 300 mg/g, or history of immune complex–mediated nephropathy
- Have other clinical laboratory test values outside of the normal range at screening, unless assessed by the investigator as clinically nonsignificant values. Clinically significant elevations in creatine kinase related to Pompe disease, in the opinion of the investigator, are permitted.
- Have positive serology for HIV, HBV (positive anti-HBc with negative hepatitis B DNA is acceptable), or HCV (treated/resolved HCV infection with negative PCR RNA is allowed)
- Have a supine SBP < 90 or > 160 mmHg, pulse rate < 40 or > 110 bpm, or elevated body temperature (≥ 100.4°F [38°C]) at screening Note: Blood pressure, heart rate, and temperature measurements may be repeated up to three times during the screening period if initial measurements are considered to be atypical for the participant.
- Are wheelchair-dependent
- Have a history or presence of a clinically significant ECG abnormality, including, but not limited to, complete left bundle branch block, type 2 second- or third-degree heart block, or other abnormalities that, in the investigator’s opinion, put the participant at risk and/or preclude accurate interpretation of cardiac intervals (eg, PR, QT, QRS)
- ECG abnormalities due to right bundle branch block in the absence of other significant cardiac disease or due to pacemaker may be acceptable pending investigator and Sponsor medical monitor agreement.
- Have received an experimental gene therapy at any time or participation in any other investigational drug trial or use of investigational drug within 60 days or 5 half-lives, whichever is longer, before screening and thereafter
- Have donated or lost more than 500 mL whole blood within 30 days before screening
- Have been hospitalization due to acute illness during the 4 weeks prior to screening. Brief stays for monitoring or minor elective procedures may be permitted with agreement of the investigator and Sponsor.
- Are an employee of the Sponsor or research site personnel directly affiliated with this study or their immediate family members, defined as a spouse, parent, child, or sibling, whether biological or legally adopted
- Have any other issue that, in the opinion of the investigator, would make the participant ineligible for study participation due to a potential risk to the participant’s safety or ability to comply with study procedures.
- Require noninvasive ventilation for an average of more than 6 hours per day while awake or any invasive ventilation. Use of noninvasive ventilation during sleep is acceptable.
- Have a positive serum pregnancy test or currently lactating or breastfeeding
- Are currently receiving systemic treatment(s) for malignancy, or have a history of malignancy within 5 years before screening, except fully resected basal cell carcinoma or other treated malignancies at low risk of recurrence, depending on investigator and medical monitor agreement.
- Have a history of severe hypersensitivity reaction or anaphylaxis to any ERT for Pompe disease, or history of severe allergy or hypersensitivity to any of the excipients contained within the DNL952 study drug product
- Have used any of the following prohibited medications within 7 days of screening or intend to use any during the study: miglitol, acarbose, and voglibose
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 30 Jul 2026 | 4 |
 The Netherlands | Not Yet Recruiting | 30 Jul 2026 | — |
| Netherlands | — | — | 2 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DNL952 | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | — | — | PRD13133502 |