Z Factor crosses from idea to AATD gene treatment

Z Factor, the Cambridge-based drug development company created by European life sciences-oriented venture capital company Medicxi in partnership with the University of Cambridge in 2015, has dosed the first human volunteer with ZF874, its novel treatment for alpha-1-antitrypsin deficiency (AATD).

AATD, a genetic disorder, is the lack of a protein made by the liver that’s released into the bloodstream. The alpha-1 protein is designed to protect tissues in the body from being attacked by its own enzymes.

AATD affects around in one in 2,000 people in Western countries, where a single glitch in the DNA encoding the protein alpha-1-antitrypsin (A1AT) causes both liver and lung disease.

“Nearly all of the cases of AATD are caused by just a single mutation in the A1AT gene, known as the ‘Z mutation’,” says Jim Huntington, professor at the University of Cambridge and founder of Z Factor.

“The Z mutation causes most of the A1AT to misfold, forming polymers that stay in the liver instead of being secreted into the blood where it plays a key role in protecting the lungs and other organs from the damaging effects of inflammation.

“The low levels of correctly-folded A1AT in the lungs results in the development of emphysema in nearly all AATD sufferers. At the same time, accumulation of Z-A1AT polymers in the liver can cause liver disease, sometimes manifesting as liver failure in newborns and more commonly cirrhosis and liver cancer as carriers of this mutation age.”

ZF874 was developed with the help of a proprietary crystal structure solved by the Huntington lab. It is a novel compound that acts as a molecular ‘patch’ for the faulty protein, allowing it to fold correctly, thereby simultaneously relieving the liver burden of polymer accumulation and providing fully-functional Z-A1AT in the circulation to protect the lungs.

In mice genetically engineered to express human Z-A1AT in their livers, oral doses of ZF874 substantially increased the levels of correctly folded protein in the blood and completely eliminated accumulation of misfolded protein in the liver.

“We are excited to have dosed our first human volunteer with ZF874,” said Trevor Baglin, chief medical officer for Z Factor. “This trial is designed to allow us to determine how safe and effective it is at raising Z-A1AT levels in humans in a short period of time. We expect to have top-line results for this potentially disease-modifying treatment in subjects carrying the Z mutation by the end of this year.”

ZF874 has an excellent safety profile in preclinical toxicology studies and is suitable for oral dosing. It is “ideal for the long-term treatment of patients with AATD, and eventually in the two-three per cent of the population carrying a single copy of this mutant gene”.

Only one other programme targeting Z-A1AT folding is currently in the clinic, from the US pharmaceutical company Vertex, which expects to report data on a similar timeframe to Z Factor.

“The burden of disease caused by the Z-A1AT genetic defect has largely gone under the radar,” said David Grainger, the Cambridge-based venture capitalist, partner at Medicxi , and executive chairman at Z Factor.

“As many as a third of all emphysema and cirrhosis cases in Western countries, amounting to millions of patients, can trace the origins of their disease to this single error in their DNA.

“There is a huge unmet clinical need here.”