Denali halts extension of DNL343 arm in HEALEY ALS trial
Oral candidate failed to reduce nerve cell damage biomarker levels
Denali Therapeutics‘ oral candidate DNL343 has failed to reduce levels of an established biomarker of nerve cell damage in adults with amyotrophic lateral sclerosis (ALS).
That’s according to new data from the DNL343 arm of the HEALEY ALS platform trial (NCT04297683), where patients who received the experimental therapy for six months showed no differences in neurofilament light (NfL) levels over the placebo group. There were also no NfL benefits in a subset of patients who entered the study’s extension part and received DNL343 for seven months.
The therapy also earlier failed to meet the main goal of slowing disease progression after six months and also didn’t improve secondary measures of muscle strength and respiratory function compared with a placebo.
Given these results, Denali has announced in a Securities and Exchange Commission (SEC) filing that it will discontinue the extension part of DNL343’s arm in HEALEY. The company said DNL343 was found to be safe and well tolerated, and it “intends to assess potential future development opportunities for DNL343.”
DNL343 is a once-daily oral therapy that activates eIF2B, a protein complex that regulates protein production and is essential for nerve cell health and function. When nerve cells are under stress, eIF2B activity is suppressed and protein production slowed as part of a defense mechanism called the integrated stress response (ISR), which tries to protect the cell from harm.
In ALS, continuous activation of the ISR in nerve cells is believed to contribute to their damage by promoting the formation of stress granules, or dense, membrane-less clusters of proteins and RNA molecules. These granules are thought to be a precursor of the abnormal TDP-43 protein clumps observed in nearly all cases 0f the disease.
By activating eIF2B, DNL343 is intended to put the brakes on the ISR pathway, restoring normal protein production and helping cells clear out the toxic clumps. This was expected to slow disease progression and improve survival in ALS patients.
After demonstrating the ability to inhibit the ISR in mouse models, and being deemed safe and well tolerated in early clinical trials, DNL343 was selected for testing in a Phase 2/3 arm of the HEALEY trial.
Main, secondary goals not met
HEALEY is a multi-center study that’s set up to test a number of potential ALS treatments at the same time. To speed up the search for treatments, the approach tests different therapies in separate arms against a shared placebo group. This is possible because all the trial participants share the same inclusion criteria.
The DNL343 arm (NCT05842941) included 249 adults with ALS who were randomly assigned to receive the experimental therapy (186 patients) or a placebo (63 patients) for 24 weeks, or about six months. Then, all the participants could enter the arm’s extension part and receive DNL343 for 28 weeks, or seven months, to study its longer-term effects.
Results from the placebo-controlled part showed DNL343 failed to meet the main goal of slowing disease progression, as measured by changes in the ALS Functional Rating Scale-Revised, over a placebo. The placebo group included the 63 patients given a placebo in DNL343’s arm and 76 patients who received a placebo in another trial arm.
Key secondary goals, including muscle strength and lung function, were also not met.
Despite the disappointing results, Denali said it was still gathering data from biomarker analyses, along with data from participants who’d moved on to the extension part, which would provide additional insights.
Some of these results have now been shared in an SEC filing, where the company said DNL343 “did not demonstrate a treatment effect on neurofilament light (NfL), a biomarker of neuronal damage, over the 24-week, double-blind period and in a subset of participants that completed an additional 28 weeks in the open-label active treatment extension.” As a result, Denali said the extension portion was discontinued and the company plans to share data from the DNL343 arm at an upcoming medical meeting.
To date, DNL343 is the fifth drug that failed to demonstrate efficacy in the HEALEY trial, alongside zilucoplan, verdiperstat, SLS-005, and more recently fosigotifator. Only CNM-Au8 and pridopidine have shown promise in the platform trial and are progressing toward Phase 3 clinical testing.
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