Zanidatamab

Zanidatamab is a dual HER2-targeted bispecific antibody that simultaneously binds extracellular domains 2 and 4 on separate HER2 monomers (binding in trans). Binding of zanidatamab with HER2 results in internalization leading to a reduction of the receptor on the cell surface. Zanidatamab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumour growth inhibition and tumour cell death.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with incidence of ADA in other studies.

ADA were rarely detected. Zanidatamab is categorised as a low-risk molecule to elicit an immune response on the basis of assessment of the immunogenicity risk factors and the low incidence of ADAs observed to date across the clinical studies (1.6% [3 of 183 evaluable participants] and 1.2% [1 of 85 evaluable participants] in Study 101 and Study 203, respectively). No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.

Cardiac electrophysiology

The relationship between time-matched zanidatamab serum concentrations and ΔQTcF measurements was evaluated based on data obtained during treatment with zanidatamab from participants in Study 101. The C-QT analysis dataset included measurements of QTcF from 179 out of the 192 participants enrolled in Study 101. Zanidatamab has no effect on QTc interval and there was no relationship between zanidatamab exposure and change in QTc interval.

Zanidatamab PK exhibited non-linear kinetics with more rapid clearance (CL) at low doses ranging from 5 to 30 mg/kg. Following the first dose, the geometric mean zanidatamab C_max was dose proportional with increasing doses, while total systemic exposure (AUC_0-∞) was greater than dose proportional with increasing doses. The geometric mean accumulation indices based on Ctrough at steady state was approximately 2.7 for the 20 mg/kg once every 2 weeks zanidatamab dose level. The observed zanidatamab exposure and PK parameters following the first administration in the first cycle and steady state, based on the available sampling scheme, are described in the table below.

The pharmacokinetics of zanidatamab following intravenous infusion in participants with HER2 expressing cancers was evaluated in a population pharmacokinetic model analysis from 279 participants. From the PopPK analysis, participants with BTC were predicted to have a typical CL of 0.0115 L/h, a typical Vc of 3.51 L, a typical Vp of 3.95 L, and an estimated t_1/2 of approximately 21 days. Based on the estimated t_1/2, it would take approximately 3.5 months (i.e., 5 half-lives) to reach steady state following multiple dose administration of zanidatamab.

Study 203: Pharmacokinetic parameters (geometric mean [percent coefficient of variation]) of zanidatamab following the first administration of zanidatamab at 20 mg/kg Q2W in cycle 1 and steady-state in BTC patients:

Abbreviations: AUC_0-tau = area under the curve during the dosing interval; C_max = maximum concentration; C_trough = trough concentration; Q2W = once every 2 weeks
Note: Cycle 1 and Cycle 4 are referred to as “first dose” and “steady-state”, respectively; these terms are interchangeable.

Absorption

Zanidatamab is administered as an intravenous infusion.

Distribution

Following intravenous dosing, zanidatamab undergoes biphasic elimination from the circulation. Based on population pharmacokinetic analysis, participants with HER2 amplified BTC were predicted to have a typical Vc of 3.51 L and a typical Vp of 3.95 L.

Elimination

Based on population pharmacokinetic analysis, participants with BTC were predicted to have a typical CL of 0.0115 L/h and an estimated t_½ of approximately 21 days for zanidatamab administered at 20 mg/kg every 2 weeks at steady-state.

Specific populations

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on age (24 to 88 years), sex, race (White, Black, Asian), and body weight (35.4 kg to 128 kg).

Renal impairment

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD-EPI). The pharmacokinetics of zanidatamab in patients with severe renal impairment and end-stage renal disease with or without hemodialysis is unknown. However, as IgG monoclonal antibodies are not primarily cleared via renal pathways, a change in renal function is not expected to influence zanidatamab exposure.

Hepatic impairment

Based on population pharmacokinetics analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST). The pharmacokinetics of zanidatamab in patients with moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe hepatic impairment (total bilirubin > 3 ULN and any AST) is unknown. However, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence zanidatamab exposure.

Carcinogenicity

Studies have not been conducted to evaluate the carcinogenic potential of zanidatamab.

Genotoxicity

Studies have not been conducted to evaluate the mutagenic potential of zanidatamab.

Repeat-dose toxicity

Zanidatamab was generally well tolerated in a 13-week repeat dose toxicity study in cynomolgus monkeys dosed once weekly (intravenous) at dose levels resulting in exposure margins up to at least 10 times the exposure in human patients. Non-severe, transient, non-dose dependent treatment-related soft or watery faeces was observed at clinically relevant exposure. In some, but not all animals, soft or watery faeces correlated with non-severe changes in blood urea nitrogen and blood albumin levels. From day 22, BUN was generally increased (up to 45%) and albumin levels tended to be decreased (up to 12%) throughout the dosing phase. However, these values were not dosed-related and remained within historical control ranges.

Developmental and reproductive toxicity

Reproductive and developmental toxicity studies have not been conducted with zanidatamab. However, antibodies that bind to HER2 have been observed to cause severe embryo-foetal toxicity. Fertility studies have not been performed with zanidatamab. In a 13-week repeat-dose toxicity study in cynomolgus monkeys dosed once weekly (intravenous) at dose levels resulting in exposure margins up to at least 10-times the exposure in human patients, zanidatamab had no effect on male and female reproductive organs when evaluated by organ weights and histopathology.