Centessa Pharmaceuticals Plc (NASDAQ: CNTA) and its subsidiary Z Factor Limited have announced proof-of-mechanism results from the first three participants dosed in the current repeat dose first Phase Part B ZF874 study in people with at least one Z-mutated alpha-1-antitrypsin allele.
Pharmacological chaperone offers enough functional Z-AIAT increase in PiZZ
This will be the first proof that a pharmacological chaperone can give enough functional Z-A1AT elevations in PiZZ genotype individuals to achieve levels larger than 11 micromolar potentially. ZF-0101 is a Phase 1 trial investigating ZF874, a new, catalytically active pharmacological chaperone designed to rescue the Z version of alpha-1-antitrypsin (“A1AT”) folding in order to treat Alpha-1 Antitrypsin Deficiency (“AATD”). A1AT misfolding causes AATD, an autosomal recessive condition caused by missense mutations in the A1AT gene. Chronic obstructive pulmonary disease and/or hepatic disease are common in people with AATD.
The observed rise in functional A1AT in both PiMZ subjects dosed with 15 mg/kg BID with ZF874 was between 3.5 and 6 micromolar for both subjects having one Z-gene copy. During the penultimate week of dosage, the A1AT levels began to rise quickly. In people with two Z- gene copies, the level of A1AT was similar to 12 to 17 micromolar after only 28 days of therapy (PiZZ). A1AT levels continue to rise after 28 days in preclinical Piz mouse models treated with ZF874. The present A1AT augmentation medications were approved based on A1AT plasma levels of 11 micromolar. The levels of A1AT in the placebo-treated subjects did not vary appreciably.
Centessa established XF874 proof of mechanism
CEO Saurabh Saha said, “With only two subjects of data, we have established proof of mechanism for ZF874 and show, for the first time, the promise of a catalytic small molecule corrector to restore A1AT to clinically significant levels. This now becomes a drug development exercise as we refine a dose and regimen for our planned global six-month Phase 2 study.”
