Can targeting fibrin combat Alzheimer’s and age-related disease?

Therini Bio CEO on overcoming the challenges of targeting fibrin to develop immunotherapies for Alzheimer’s and beyond.

The excitement around the FDA’s approval of Alzheimer’s drug lecanemab has been tempered by experts’ doubts around whether its risks outweigh its benefits. These concerns highlight how much work is still necessary before significant progress is made against this devastating disease. While a step in the right direction, drugs like lecanemab – antibodies designed to clear amyloid beta from the brain – haven’t yet delivered the kind of results that the world is waiting for.

But it’s important to remember there are many companies out there working on different approaches to treating Alzheimer’s. One such company is Therini Bio, which recently closed a sizeable $36 million funding round and has just dosed its first patients in a Phase 1 trial of its fibrin-targeting therapeutic candidate for Alzheimer’s disease.

Longevity.Technology: The insoluble protein fibrin has long been implicated as a driver of chronic inflammation in many diseases, including Alzheimer’s. However, fibrin plays an important role in helping our bodies stop bleeding, and no one has yet found a way to target its inflammatory aspects without impairing its positive effects. Therini believes it has overcome these challenges and is developing therapies that block inflammation in diseased tissues, without any impact on the beneficial functions of fibrin. To learn more, we caught up with Therini’s CEO Dr Michael Quigley.

Therini’s approach is built on the work of its founder, Dr Katerina Akassoglou, Professor of Neurology at UCSF, to solve the key issues associated with fibrin in order to develop fibrin-targeting immunotherapies.

Can targeting fibrin combat Alzheimer’s and age-related disease?
Therini Bio CEO Dr Michael Quigley

“The problem to date has been the inability to separate the very important role of fibrin in clotting and coagulation from this disease-driving inflammatory process,” says Quigley. “In the 70s and 80s, there were attempts to use anticoagulants, fibrolytics, to break down the fibrin. But in the patient populations being looked at, long-term treatment with anticoagulants presented too much impact in terms of bleeding risk.”

“At Therini we have for the first time, to our knowledge, developed the ability to specifically target the inflammatory component of fibrin, while completely sparing any impact on clotting and coagulation – based on all our preclinical data to date, at least.”

Clinical data expected in 2024

Therini’s new funding carries it through its current Phase 1 trial, which is being conducted in healthy volunteers, even though the company has not seen any impact on clotting and coagulation in its preclinical work.

“It’s important for us, but also the onus is on us in the context of the regulators, to make sure we completely discharge that risk,” says Quigley.

Key safety and proof of mechanism clinical data is expected by the end of 2024. Assuming all goes well, Therini aims to take a “precision medicine-type approach”, which will see the company target the patients most likely to benefit from its therapy.

“Our goal is to enrich biologically for patients that we believe have their disease driven in large part by this fibrin mechanism,” says Quigley. “This smoldering, toxic inflammation, which we believe we can alleviate.”

One of the Alzheimer’s patient groups that Therini predicts could benefit from its approach are those with the APOE4 gene.

“Carriers of APOE4 are known to be more prevalent in the Alzheimer’s population and are also known to have a leakier or more exposed blood brain barrier,” says Quigley. “As we and others have seen, those patients have quite a bit of fibrin deposited in their brain. And so that’s how we view our early clinical development: enriching for a patient population that we believe to have fibrinpathic dementia.”

Fibrin and amyloid beta

While Therini is not targeting amyloid plaque directly, Quigley points out that there is a strong link between fibrin and amyloid beta.

Can targeting fibrin combat Alzheimer’s and age-related disease?
(Top) Retina from a patient with diabetic macular edema. The bright red band denotes a layer of fibrin.
(Bottom) Normal retina.

“It turns out that fibrin binds amyloid beta in particular and, when it does, it makes fibrin five to 10-fold more resistant to degradation,” he explains. “We quite readily see fibrin and amyloid co-located in postmortem tissue of Alzheimer’s patients and in the broader dementia landscape.”

“I think a paradigm shift will occur as amyloid clearing therapies become standard of care – akin to the oncology space – where combination therapies are going to be needed that are complementary to an amyloid clearing therapy.”

For example, Quigley says that Therini is generating preclinical data which shows that its lead compound may have the potential to reduce the incidence of ARIA, the cerebral microhemorrhages that can occur as a result of amyloid clearing therapies.

“We think that we’re quite well positioned to perhaps bring additional benefit to those patients that will continue to be treated by the amyloid clearing therapies.”

Looking beyond Alzheimer’s

In addition to its work in dementia, Therini is working on a “dual development path” that also includes diabetic macular edema, which Quigley says “harbors all the same biology in the context of that disease.” But the future potential of the approach extends into many other areas of human health.

“From the datasets that we’ve generated we clearly see broad applicability of fibrin deposition in a wide range of diseases,” he adds. “We see it in the inflamed synovium of rheumatoid arthritis patient tissue, we see it in the gut of IBD patients, we see it in certain proportions of kidney disease.”

“There’s clearly a broad biology here, and we believe that the value of the Phase 1 study in healthy volunteers is that it also enables a breadth of downstream development. But, from a small company perspective, with our precision medicine lens, we think that the validity of the data we’ve generated points us clearly towards the brain and the eye.”