AC Immune Moves Closer to Clinical Studies of Anti-TDP-43 Antibody

AC Immune is planning to advance its investigational anti-TDP-43 antibody into clinical testing for neurodegenerative diseases in which TPD-43 protein aggregates play a major role in brain damage, including diseases such as Alzheimer’s, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration with TDP-43 pathology.

The company began preclinical studies that, if successful, would pave the way for an investigational new drug (IND) application to the U.S. Food and Drug Administration seeking permission to begin the first in-human studies.

“This milestone reinforces AC Immune’s position as a leader in developing novel therapies against neurodegenerative diseases, with our anti-TDP-43 antibody on track to become the first in the world to reach clinical development,” said Andrea Pfeifer, PhD, CEO of AC Immune, in a press release.

TDP-43 has emerged as a potential therapeutic target for certain neurodegenerative diseases. This protein is normally found within the cell nucleus where it stabilizes RNA — DNA ‘blueprints’ that serve as intermediaries in the production of proteins.

However, evidence has shown that specific mutations can cause TDP-43 to become abnormally shaped and accumulate in the cytoplasm, instead of the nucleus, leading to its accumulation and clumping within nerve cells.

In fact, approximately 50% of Alzheimer’s patients show signs of TDP-43 aggregation, which is thought to contribute to symptom severity.

Researchers at AC Immune have used the company’s proprietary SupraAntigen platform to generate antibodies that can specifically target TDP-43 and block its ability to form aggregates.

Recently, the company shared data at the virtual Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting, showing that its antibody mitigated brain damage in a mouse model of TDP-43-associated neurodegeneration.

The antibody is the first to show efficacy in living organisms, the company stated, and may become the first anti-TDP-43 antibody in the world reaching clinical development.

By launching the latest round of preclinical experiments, AC Immune hopes to further the development of this antibody to treat Alzheimer’s and other neurological orphan (rare) diseases.

“Aggregation of pathological forms of TDP-43 is an increasingly validated therapeutic target and a well-established hallmark of neurodegeneration,” said Pfeifer. “Initiation of IND-enabling studies for our first-in-class lead anti-TDP-43 antibody is a major step toward addressing pressing unmet need in NeuroOrphan indications.”

AC Immune has used its SupraAntigen platform to generate antibodies against two other proteins that contribute to neurodegenerative disease, including the semorinemab antibody against the tau protein and the crenezumab antibody against amyloid beta (Abeta).

Both antibodies are currently in Phase 2 clinical trials, including studies of semorinemab in patients with prodromal (very early form) to mild Alzheimer’s (NCT03289143) and in patients with moderate Alzheimer’s (NCT03828747, currently recruiting), and a study of crenezumab in patients with moderate Alzheimer’s (NCT01998841).

“The Company’s success is driven in part by our proprietary SupraAntigen platform, which has already produced therapeutic monoclonal antibody candidates targeting Abeta and Tau that were successfully out-licensed to leading pharmaceutical companies and are currently advancing in multiple Phase 2 clinical studies,” said Pfeifer.

As neurodegenerative disorders such as Alzheimer’s have a complex pathology, a combinatorial approach with multiple molecular targets may prove beneficial for patients, according to the company.

As such, AC Immune used its proprietary Morphomer platform to develop a tracer for TDP-43 toxic protein clumps, which could enable physicians to locate and measure the amount of these protein aggregates in nerve cells during imaging exams, and to measure responses to treatment.

“Advancement of the anti-TDP-43 antibody further validates the continuing productivity of this [SupraAntigen] platform, which, together with our Morphomer platform for small molecule development, are responsible for discovery and development of our maturing pipeline of first-in-class or best-in-class therapeutic and diagnostic candidates,” Pfeifer said.