Z Factor Ltd, a Cambridge-based drug development company spun out of the University of Cambridge, announced that the first human volunteer was dosed today with ZF874, its novel treatment for alpha-1-antitrypsin deficiency (AATD). AATD is a common genetic disorder, affecting around in 1 in 2000 people in Western countries, where a single mistake 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’. 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” explained Jim Huntington, Professor at the University of Cambridge and Founder of Z Factor (pictured). “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 were able to substantially increase levels of correctly folded protein in the blood and to completely eliminate 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, ideal for the long-term treatment of patients with AATD, and eventually in the 2-3% of the population carrying a single copy of this mutant gene, who are also at increased risk of both liver and lung disease. Only one other program targeting Z-A1AT folding is currently in the clinic, from the US pharmaceutical company Vertex (NASDAQ: $VRTX), who expect to report data on a similar time-frame to Z Factor. “The burden of disease caused by the Z-A1AT genetic defect has largely gone under the radar”, said David Grainger, 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.” Z Factor was founded in 2015, as a spin-out from the University of Cambridge, armed with the world’s first detailed structure of the Z-A1AT polymer from the Huntington laboratory. Cambridge Enterprise, the commercialisation arm of the University of Cambridge, licensed the technology into Z Factor. Cambridge Enterprise also participated in both the seed round and the Series A round, which was led by Medicxi, with Cambridge Innovation Capital participating. The funding allowed the team to leverage this window onto the folding defect caused by the Z mutation, working in collaboration with the local out-sourced discovery platform company, RxCelerate, to create ZF874. Entry into the clinic marks a significant step in the development pathway for a drug from concept to approval. “We are one important step closer to delivering a drug that will not only treat the diseases associated with AATD, but that, given prophylactically, may ensure carriers of the Z mutation never develop these diseases in the first place” said Huntington.