Centessa showed positive early results from its Phase I Part B study on a potential drug that could direct mutation activity in patients with a particular gene that can cause liver and lung diseases.
Centessa Pharmaceuticals has expressed excitement over positive early results from its Phase I Part B study on a potential drug that could direct mutation activity in patients with a particular gene that can cause liver and lung diseases.
The clinical trial of ZF874 on individuals with at least one Z-mutated alpha-1-antitrypsin allele (PixZ) demonstrated proof-of-concept data in the first three subjects. Conducted with subsidiary firm Z Factor Limited, this is the first-ever indication that a pharmacological chaperone can provide sufficient functional Z-AIAT increases to reach more than 11 micromolar levels in patients with the PiZZ gene.
The study, labeled ZF-0101, is evaluating ZF874, a drug chaperone designed to rescue the folding of the Z variant of alpha-1-antitrypsin (A1AT) to treat alpha-1 antitrypsin deficiency (AATD), which is a disorder caused by missense mutations in A1AT. Patients diagnosed with AATD typically suffer from liver disease and/or chronic obstructive pulmonary disease.
Part A of the trial involved seven healthy participants, while Part B was designed for 14 PixZ patients observed over 28 days for tolerability, safety, pharmacokinetics and an increase in serum A1AT levels. Subjects who were given 15 mg/kg of ZF874 twice a day saw their A1AT levels rise to equivalents of 3.5 to 6 micromolar in patients with one Z-gene copy and 12 to 17 micromolar in patients with two Z-gene copies. The results were consistent with findings in mouse models during the pre-clinical trial. Liver function tests, such as ALP, GGT, and bilirubin, also remained within normal levels.
The trial is small, but the findings are highly significant given that this is the first time this proof-of-action has been observed. Centessa and Z Factor also decided to unblind the study before the Part B enrollment process was completed as one participant was seen to have elevated liver enzymes. Overall, however, adverse events linked to the drug were mostly mild.
“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,” said Dr. Saurabh Saha, M.D., Ph.D., the chief executive officer of Centessa, in a statement.
Centessa, which was launched early this year, is reportedly seeking to accelerate the enrollment and dose exploration of more trial participants, particularly those who carry PiXZ. It is also considering opening more clinical locations in the UK and other parts of the EU.
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