After more than two decades of work on neurodegenerative diseases, Swiss biotech AC Immune claims it could have a game changer on its hands.
The company’s chief scientific officer, Madiha Derouazi, Ph.D., presented preclinical results from its brain-penetrant small molecule Morphomer platform at the Alzheimer’s Association International Conference on July 29. The idea is to combine these Morphomers with monoclonal antibodies from its SupraAntigen liposome platform to create a new class of neurodegenerative disease-fighting drug candidates called Morphomer antibody-drug conjugates (morADCs).
AC Immune hopes that these morADCs can target misfolded proteins, like amyloid beta and tau, which form the characteristic plaques and tangles in the brains of Alzheimer’s patients. The flexibility of the morADC model means they can even have a dual-targeting strategy—for example, by pairing an anti-amyloid beta antibody with an anti-tau small molecule.
It's a different setting for ADCs, which have made their name in oncology by homing in on specific tumor cells to kill.
The biotech has already conducted preclinical tests, which showed that morADCs penetrated the blood-brain barrier of mice at a rate three to six times higher than its monoclonal antibody alone.
“Somehow the small molecule helps to deliver the antibody to the brain,” AC Immune co-founder and CEO Andrea Pfeifer, Ph.D., told Fierce Biotech in an interview. “That was a totally unexpected result.”
Alzheimer’s therapeutics have primarily targeted amyloid beta, with mixed results. The first approved drug in this class, Biogen’s Aduhelm, is being discontinued by the biotech in favor of the newer Leqembi, which itself was recently spurned by the European Medicines Agency over safety concerns. Eli Lilly’s Kisunla was approved by the FDA earlier this month but has also attracted criticism for its modest benefits compared to the risk of serious side effects.
Pfeifer is supportive of these anti-amyloid drugs. “I'm almost now defending other people's programs, which is unusual,” she said.
“I do believe that the [Leqembi] and [Kisunla] approval in America is a great thing for the community,” the CEO added. But while targeting amyloid beta works for the early stages of Alzheimer’s, “very soon you need [to target] tau.”
Using morADCs, AC Immune was able to target both amyloid beta and tau, with the small molecule component binding to and deactivating the misfolded proteins. Pfeifer was surprised to find that the drug showed greater activity than the sum of its constituent parts, the monoclonal antibody and small molecule.
“It's not that one and one makes two, it's one and one makes maybe five,” Pfeifer said. The two parts of a morADC “both work together and can be against one target or two targets, but the effect together is a synergistic effect.”
How exactly morADCs work remains a mystery. “I can imagine this becomes now the prime focus for AC Immune, because it's an enormous opportunity,” Pfeifer said. “Nobody else has it.”
A promising asset like morADCs is likely welcome news for AC Immune after its monoclonal antibody crenezumab failed in a clinical trial of early-onset Alzheimer’s patients in 2022. Not that the biotech let that disappointment slow it down for long—the company sold an option to a phase 2 anti-amyloid beta active immunity drug to Takeda for $100 million upfront in May of this year.
Understanding the mechanism of morADCs, and whether the drugs are able to reach plaques that build up inside of neurons, too, remain key questions before moving into the clinic, which Pfeifer expects will take some time.
“I think we are a few years away from the clinic, but potential is pretty high,” she said. “It could be a landmark change in CNS.”