New molecule seen as potent at stabilizing TTR protein, treating FAP

PITB effectively and safely prevents toxic clumping in early studies

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A newly developed second-generation transthyretin (TTR) protein stabilizer may be more effective at treating forms of TTR amyloidosis (ATTR), including familial amyloid polyneuropathy (FAP), than one already tested in patients, scientists in Spain announced.

Called PITB, the molecule was seen to be better than tolcapone — a TTR stabilizer in clinical development for ATTR — at stabilizing the resulting TTR protein of the most common FAP-causing mutation, preventing its toxic clumping.

Findings were detailed in two recent studies published in the Journal of Medicinal Chemistry and the European Journal of Medicinal Chemistry.

“PITB has all the desired characteristics to be one of the most effective drugs in the fight against ATTR, and at a more affordable price than any current alternative,” Salvador Ventura, PhD, the senior author of both studies with the Institut de Biotecnologia i Biomedicina at the Universitat Autònoma de Barcelona (IBB-UAB), said in a university press release.

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In all forms of ATTR, an abnormal, misfolded version of TTR clumps up and toxically accumulates in tissues. FAP is a hereditary form wherein mutations in the TTR gene cause the resulting TTR protein to aggregate mostly in the peripheral nerves that transmit signals between the brain and the rest of the body.

Another common form is ATTR with cardiomyopathy (ATTR-CM), wherein TTR accumulates mainly in the heart and may or may not be due to TTR mutations.

The TTR protein normally is made up of four identical subunits, or monomers, that create a stable protein, called a tetramer. ATTR-causing TTR mutations affect the protein’s stability, increasing the likelihood of its dissociation into individual monomers that are prone to clumping.

Therefore, a therapeutic strategy for ATTR is to identify molecules that can bind to and stabilize TTR, allowing it to keep a normal structure that’s not likely to clump.

One such TTR stabilizer is tafamidis (sold under the brand name Vyndaqel and Vyndamax), an oral therapy approved in Europe for FAP and for all forms of ATTR-CM. In the U.S., it is approved only to treat ATTR-CM.

A few years ago, Ventura and colleagues at IBB-UAB identified tolcapone, a molecule approved to treat Parkinson’s disease under the brand name Tasmar, as a potent TTR stabilizer.

In a Phase 1/2 clinical trial (NCT02191826), tolcapone was shown to effectively stabilize TTR without adverse effects in a group of hereditary ATTR patients, including those carrying V30M, the most common FAP-causing mutation.

The same research team now described the design of a second-generation TTR stabilizer, called Pharmacokinetically Improved TTR Binder or PITB, that may be more potent than tolcapone.

In their first recent study, “Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis ,and Evaluation,” the scientists worked with the known structure of tolcapone to develop a number of spinoff molecules, identifying one called M-23 with a particularly high ability to bind to TTR.

M-23 was better than both tafamidis and tolcapone at binding to two sites believed to be particularly important for TTR stabilization, positioning it as “one of the strongest TTR [binding molecules] described so far,” the researchers wrote.

It also was found to enhance TTR stability and prevent aggregation in lab studies, without showing signs of toxicity.

When M-23 was given to mice, however, it lacked pharmacological properties in the bloodstream that would favor its use, particularly regarding its absorption and likely duration or half-life. The researchers then used M-23’s structure to design a related molecule addressing these limitations.

PITB prevents TTR clumping in samples from FAP patients with V30M mutation

In the study, “PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties,” the scientists showed that PITB also strongly binds to TTR, stabilizes it, and prevents its clumping without toxicity to lab-grown human cells, generally outperforming tolcapone across measures.

Importantly, PITB stabilized and prevented the aggregation of TTR forms resulting from the two most clinically relevant TTR mutations, V30M and V122I, which is commonly linked to hereditary ATTR-CM.

Similar effects were observed for TTR proteins in blood samples from patients carrying the V30M mutation and from healthy people.

These findings “support the potential of PITB to become a drug candidate for the treatment of both hereditary and non-hereditary forms of ATTR,” the researchers wrote.

The new molecule also showed favorable pharmacological properties when administered to mice either orally or directly into the bloodstream. The oral route of PITB was found to result in greater drug exposure and to last longer in the body than tolcapone.

“Considering that tolcapone has already demonstrated efficacy … and given that PITB outperforms this drug in nearly every analyzed aspect, our results provide compelling support for further preclinical and clinical development of PITB,” the researchers wrote.

“All in all, the findings presented here underscore the strong potential of PITB as a therapeutic agent for ATTR, particularly in cases of FAP caused by V30M-TTR — the most prevalent mutation in hereditary ATTR cases,” they added.

These scientists are pursuing funding sources to continue testing PITB’s safety and efficacy in animal models. They’re also considering creating a spinoff company to advance the molecule toward early trials, likely to take place at two hospitals in Barcelona.