Excitement and confidence at Dewpoint in TDP-43 condensate modulator development candidate

Dewpoint Therapeutics, a US biotech developing condensate-modulating therapeutics, has announced the selection of a development candidate (DC) for its TDP-43 program.

The DC is a small molecule designed to correct disease-associated TDP-43 condensates, restoring normal TDP-43 function and addressing the core molecular pathology that drives neurodegeneration in ALS and related diseases.

Pathogenic condensation and dysfunction of TDP-43 is observed in more than 97% of ALS cases and across multiple related neurodegenerative diseases.

Drugging the undruggable 

However, despite decades of trying, no disease-modifying treatments exist for ALS and TDP-43 has remained largely undruggable using traditional therapeutic approaches. Dewpoint’s condensate biology platform enabled a fundamentally new strategy to directly modulate TDP-43 by targeting the aberrant condensate state that underlies its loss of function in disease.

The TDP-43 DC was selected based on a comprehensive preclinical data package demonstrating restoration of TDP-43 function in relevant cellular systems, robust activity in TDP-43 driven in vivo models of neurodegeneration including neurofilament light chain (NfL) reductions, clear evidence of on-mechanism activity, and pharmacologic properties supportive of advancement into IND-enabling studies. The molecule also shows applicability across a broader spectrum of TDP-43–associated neurodegenerative disorders, including frontotemporal dementia and traumatic brain injury.

Isaac Klein, chief scientific officer of Dewpoint, said: “ALS remains one of the most devastating diseases, and pathologic TDP-43 condensates are the central driver for the vast majority of patients.

“This development candidate represents the first time anyone has achieved full restoration of TDP-43 function in preclinical models by directly correcting the pathologic condensates that underlie ALS. We believe this approach has the potential to deliver disease-modifying outcomes for patients.”

Validates approach

Chief executive Ameet Nathwani added: “This announcement reflects more than a single program milestone, it validates an emerging therapeutic approach and modality we are pursuing at Dewpoint.

“Our condensate biology platform has enabled what has not been possible before: direct, mechanistic restoration of TDP-43 function, one of the most important and historically inaccessible targets in neurodegeneration. Advancing this program underscores our conviction that condensate-modulating therapeutics can redefine what is achievable in neurology.”

Dewpoint plans to begin IND-enabling studies while continuing to talk closely with the ALS community to inform clinical development strategy and trial design.

Dr Klein said that the work to get to this point started even long before the founding of the company in 2018.

“This program represents nearly 15 years of work on the fundamental science of condensates and ALS, by the founding scientists of Dewpoint, as well as the global academic community. Our molecule emerged from this science, and the data we have seen from this molecule in preclinical studies over the last several months has convinced us this could be a game-changer for ALS patients,” he said.

Milestone in ALS and beyond

“Building on the scientific principles to reach the stage of having a candidate ready to begin IND-enabling studies has been a remarkable journey”, said Jesse Lai, Dewpoint’s ALS program lead.

“From a biology perspective, this candidate was discovered through iterations on the Dewpoint platform, using patient-derived induced pluripotent stem cell motor neurons, which is basically the closest thing that we can get to a patient in the lab,” he explained. “Then we backed that up with the most cutting-edge in vivo models to capture all aspects of the disease and the broadest patient population.”

Dewpoint is now very confident that it has a molecule that can reverse, rescue, and prevent multiple facets of ALS pathology. The company’s confidence comes from its capacity to restore TDP-43 function, the hallmark of ALS pathology, excellent blood-brain barrier penetration, and an attractive safety profile.

Ann Boija SVP, Head of Research added “What gives us confidence in this program is the convergence of mechanistic restoration across disease-relevant systems. We consistently see correction of pathogenic TDP-43 condensates, restoration of normal TDP-43 function, and alignment with biomarker and neurodegenerative outcomes across multiple models.

“That level of coherence between mechanism, biology, and disease readouts is exactly what you would expect from a truly disease-modifying approach, and it’s what makes this development candidate particularly compelling.”

Another exciting consideration is that TDP-43 dysfunction not only underlies ALS, but also many other neurodegenerative diseases, from chronic traumatic encephalopathy to frontotemporal dementia.

Dr Klein said: “I think ALS is a clear one that we want to go to first, but either at the same time or shortly thereafter, we want to see how broad the impact can be across other diseases.”

‘Huge sense of achievement’

Even so, having the opportunity to go forward in ALS marks a massive moment for the company, providing a convergence of the clinical opportunity that its science can present and a manifestation of one of the first insights that condensate science gave into disease.

“Taking this concept from the inception of the field to the clinic is a huge sense of achievement,” Dr Klein added. “ALS patients are in dire need of a therapeutic breakthrough; we are excited to bring our molecule to them quickly.”