Studies of DNL747 Paused, Work Shifts to Possibly Better Treatment

Inês Martins, PhD avatar

by Inês Martins, PhD |

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RIPK1 protein inhibitor studies

Denali Therapeutics and Sanofi announced a pause in clinical testing of their small molecule inhibitor DNL747 in favor of work on a possibly more effective compound, DNL788, for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, and multiple sclerosis.

DNL747 was seen to be safe and well tolerated in two clinical studies in ALS and Alzheimer’s patients, but a higher dose would be needed for desired effectiveness — and that is not feasible due to chronic toxicity.

The alternative compound, DNL788, appears to have a superior profile, being better able to block its target at similar doses, potentially avoiding the side effects seen at high doses of DNL747. Plans are to start clinical testing of DNL788 next year.

“Together with our partner Sanofi, we have decided to pause clinical studies with DNL747 and focus our efforts on accelerating development of DNL788, which we believe has superior drug properties and a more rapid path toward proof-of-concept clinical studies in patients in multiple neurological indications,” Ryan Watts, PhD, CEO at Denali, said in a press release.

“We’d like to thank all patients who took part in these studies. Your participation is critical in the ultimate success of developing medicines for these terrible diseases,” Watts added.

DNL747 and DNL788 are two small molecule inhibitors of the RIPK1 protein that are able to cross the protective blood-brain-barrier and reach the brain. When overactive, this protein is involved in excess inflammation and cell death in the brain, contributing to neurodegeneration in diseases that include ALS.

DNL747 was investigated against placebo in two Phase 1b trials, one in ALS (NCT03757351) and one in Alzheimer’s (NCT03757325). In total, 31 patients received the active treatment for 29 days; one group in each study started on a placebo for 29 days before crossing over to DNL747 for the same length of time, an exact opposite “crossover” mix was given the other group.

Each trial’s main goal was DNL747’s safety, as assessed by the number of patients experiencing treatment-emergent adverse events and serious adverse events, and those with abnormalities in neurological exams or in laboratory tests.

The trials both met their primary goal, with the treatment being safe and well tolerated at the dose tested. But researchers noted that when the therapy reached its lowest concentration in the blood before the next dose — called trough level — only 80% of the RIPK1 protein was targeted. Higher doses would be needed to improve efficacy.

However, chronic toxicity studies in cynomolgus monkeys showed that higher doses were likely to cause significant adverse events, as the treatment had dose- and duration-dependent adverse findings at doses higher than those tested in the trials.

This risk of side effects would require studying the safety and tolerability of higher DNL747 doses over time, significantly delaying the potential therapy’s clinical development should safety again be established.

DNL758, in contrast, has shown greater effectiveness in preclinical studies, meaning that the dose used may be enough to reach full target inhibition without the risk of side effects at higher doses.

“Due to emerging evidence that higher levels of target inhibition may be required for maximizing efficacy, and challenges to achieving higher doses imposed by molecule-specific toxicity findings with DNL747, we are pausing additional studies with this molecule,” said Carole Ho, MD, chief medical officer at Denali.

“Our experience and learnings with DNL747 should allow us to progress quickly with clinical studies for DNL788. Importantly, DNL788 appears to have a superior preclinical therapeutic window compared to DNL747, facilitating development in multiple indications, including Alzheimer’s disease, ALS and multiple sclerosis,” Ho added.

Denali is also developing a RIPK1 inhibitor, DNL758, that does not enter the brain, working instead to prevent inflammation and cell death elsewhere. This treatment was seen to be safe and well tolerated across all doses tested in a Phase 1 trial in healthy volunteers.

Under a 2018 agreement, clinical development of DNL758 is being led by Sanofi, which is now planning to advance it into clinical studies of systemic inflammatory diseases, such as rheumatoid arthritis and psoriasis.