DNL343 for ALS

Overseen By Healey Center for ALS at Massachusetts General Hospital

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Merit E. Cudkowicz, MD

Must not be taking: Cytochrome P450 inducers

Disqualifiers: Epilepsy, Seizure, Hypersensitivity, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, DNL343, to evaluate its safety and effectiveness in treating ALS, a condition affecting nerve cells in the brain and spinal cord. Researchers aim to determine if DNL343 can help manage symptoms or slow disease progression. Participants will receive either the actual drug or a placebo (a substance with no active medicine) to compare outcomes. People with ALS who have not had a seizure or epilepsy diagnosis in the past six months and do not have allergies to the drug might be suitable for the trial. As a Phase 2 trial, this study measures how well DNL343 works in an initial, smaller group, offering participants a chance to contribute to important ALS research.

Do I need to stop taking my current medications for the trial?

You may need to stop taking some medications if they interact with the study drug. Specifically, you cannot take medications that affect certain enzymes or drug transporters. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that DNL343 has been tested for safety in both healthy individuals and those with ALS (Amyotrophic Lateral Sclerosis). Trials found that most participants tolerated the drug well. Some side effects occurred, but they were usually mild or moderate.

In earlier studies, DNL343 did not cause serious health problems for participants. However, the drug did not achieve the main goals in some trials, indicating that its effectiveness is still under investigation. This offers some reassurance about its safety.

For those considering joining a study with DNL343, it's important to know that while the drug has been tested and is considered safe for trial use, ongoing research helps ensure any risks are understood and managed. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for ALS?

Most treatments for ALS, like Riluzole and Edaravone, aim to slow disease progression or reduce symptoms. But DNL343 works differently, targeting stress granules in nerve cells to potentially halt the disease at a molecular level. Researchers are excited about DNL343 because it represents a novel approach that addresses a root cause of ALS, offering hope for a more effective intervention. This unique mechanism could lead to better outcomes and an improved quality of life for patients.

What evidence suggests that DNL343 might be an effective treatment for ALS?

Research has shown that DNL343, which participants in this trial may receive, is safe and generally well-tolerated, but it did not meet the primary goals of improving function or survival in people with ALS. Early studies found that the drug reached the brain and spinal fluid and worked at a cellular level by blocking the integrated stress response (ISR). However, these effects did not significantly slow the disease compared to a placebo. Despite this, the treatment showed potential in affecting important biological markers, which could guide future research. ^{4 5 6 7 8}

Who Is on the Research Team?

Merit Cudkowicz, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for people with ALS, also known as Lou Gehrig's disease. Participants must not have had a seizure in the last 6 months and cannot be taking certain medications that affect liver enzymes or drug transporters.

Inclusion Criteria

No additional inclusion criteria beyond the inclusion criteria specified in the Master Protocol (NCT NCT04297683).

Exclusion Criteria

I am not taking any medications that affect certain enzymes or drug transporters.

You are allergic to DNL343 or any of the ingredients in the DNL343 drug.

I have been diagnosed with epilepsy or had a seizure in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants complete a baseline assessment before randomization

1 week

1 visit (in-person)

Treatment

Participants receive either active DNL343 or matching placebo

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DNL343
• Matching Placebo

Trial Overview The HEALEY ALS Platform Trial - Regimen G is testing DNL343 against a placebo to see if it's safe and effective for treating ALS. Patients will either receive the actual drug or a dummy pill without knowing which one they're getting.

How Is the Trial Designed?

Group I: DNL343 Experimental Treatment 1 Intervention

Group II: Matching Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Merit E. Cudkowicz, MD

Lead Sponsor

Trials

8

Recruited

2,900+

Denali Therapeutics Inc.

Industry Sponsor

Trials

24

Recruited

1,900+

Citations

1. massgeneral.org massgeneral.org/assets/MGH/pdf/neurology/als/community-qa-may-22-2025.pdf

Results from Regimen G in the Healey Platform Trial DNL343 in Amyotrophic Lateral Sclerosis: Results from Regimen G in the Healey Platform Trial. Danna Jennings, MD. Denali Therapeutics. Page 2. Denali ...

2. neurologylive.com neurologylive.com/view/dnl343-falls-short-primary-end-point-phase-2-3-healey-als-platform-trial

DNL343 Falls Short of Primary End Point in Phase 2/3 ... DNL343 did not meet primary endpoints for function and survival in ALS patients but was safe and well-tolerated. Further analyses, including ...

3. targetals.org targetals.org/2025/07/22/denali-therapeutics-learning-from-the-dnl343-trial-in-als/

Denali Therapeutics: Learning from the DNL343 Trial in ALS Initial studies showed encouraging signs; DNL343 reached the brain and spinal fluid, inhibited the ISR in patient cells, and reduced a key blood ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05842941

HEALEY ALS Platform Trial - Regimen G DNL343 Regimen G will evaluate the safety and efficacy of a single study drug, DNL343, in participants with ALS. ... The Amyotrophic Lateral Sclerosis Functional Rating ...

5. firstwordpharma.com firstwordpharma.com/story/5940349

Denali halts ALS extension study after biomarker results ... The topline Regimen G results, shared in January, showed that DNL343 did not significantly slow disease progression over placebo, as measured by ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05006352

NCT05006352 | A Study to Determine the Safety, ... Also called a data safety ... A Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL343 in Participants With Amyotrophic Lateral Sclerosis.

7. nature.com nature.com/articles/s41467-025-63031-y

Investigational eIF2B activator DNL343 modulates the ... The investigational drug DNL343 was advanced into Phase 1 and Phase 1b randomized, double-blind, placebo-controlled trials in healthy and ALS ...

8. denalitherapeutics.com denalitherapeutics.com/patient-community/amyotrophic-lateral-sclerosis-als

Amyotrophic Lateral Sclerosis (ALS) Clinical Program - Denali DNL343 is being studied to determine if it may slow or stop the progression of neurodegeneration in ALS. Denali is studying the effects and safety of DNL343 ...