(M1030-10-65) Clinical Correlation of Conventional Allometric Scaling Approach for PK Predictions of FcRn Enhanced and Protease Resistant Long-Acting mAbs, TAVO101 and TAVO103

Purpose: TAVO101, anti-TSLP, and TAVO103, anti-IL-1b, are long-acting monoclonal antibodies under the clinical development for allergic and inflammatory diseases. These two molecules were engineered to have an effective extension of their half-life by enhancing FcRn binding at lower pH and increasing protease resistance. Allometric scaling is used to project human PK from relevant cynomolgus monkey data. Clinical data are available only for a handful of mAbs with extended half-life for the evaluation of human PK prediction by allometric scaling; yet limited data sets had revealed potential pitfalls of this conventional approach when applied to half-life extended molecules. Human PK predictions from monkey PK results of TAVO101 and TAVO103 were performed by allometric scaling, and the results were evaluated against clinical data.

Methods: Animal PK studies were conducted in cynomolgus monkeys. TAVO101 at 4 mg/kg and TAVO103 at 10, 50 or 100 mg/kg were administered by corresponding single intravenous injections. Serum samples were collected for PK analyses. Serum drug concentrations were analyzed using ELISA assays. The clinical trials of TAVO101 and TAVO103 were conducted in Australia and the US, respectively, as first-in-human, double blinded, single dose escalation Phase 1 studies in healthy volunteers to assess both the safety and PK profiles. Clinical serum samples were collected and analyzed using validated specific ELISA assays. The PK profiles obtained from the animal and humans were analyzed using non- and two-compartmental models. Models employing allometric scaling with different exponent values were performed for the predictions of human PK.

Results: In monkeys, TAVO101 and TAVO103 showed half-lives of 26 and 19 days, clearances of 1.88 and 3.36 mL/kg/day, and Vds of 71 and 91 mL/kg, respectively. Preliminary clinical data demonstrated excellent safety profiles for TAVO101 and TAVO103. Preliminarily available PK data exhibited an estimated half-life of 61 and 60-day with much lower clearance for TAVO101 and TAVO103, respectively. The extended long half-life was a result from the Fc engineering of enhanced FcRn binding and increased protease resistance. Projected human clearance based on an exponent of 0.85 for the clearance and of 1.0 for the volume of distribution overestimated human clearance and underestimated half-life although provided a reasonable estimation of the Cmax. The full clinical data packages are used to evaluate the predictions and to propose more relevant allometric scaling approaches.

Conclusion: Conventional allometric scaling from monkey PK data for monoclonal antibodies with extended half-life, e.g., TAVO101 with a 61-day and TAVO103 with a 60-day clinical half-life, using exponents of 0.75-0.9 resulted in an overestimation of human clearance and underestimation of half-life. The projection still provided a reasonable estimation of the Cmax possibly addressing drug concentrations-related safety concerns. With the evaluations of additional clinical data sets, a better approach is to be explored, defined, and proposed for future studies.