Tremelimumab

Cytotoxic T lymphocyte-associated antigen (CTLA-4) is primarily expressed on the surface of T lymphocytes. Interaction of CTLA-4 with its ligands, CD80 and CD86, limits effector T-cell activation, through a number of potential mechanisms, but primarily by limiting co-stimulatory signalling through CD28.

Tremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity and enhanced antitumour activity.

The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor results in improved anti-tumour responses in metastatic non-small cell lung cancer In murine syngeneic tumour models, dual blockade of PD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.

The pharmacokinetics (PK) of tremelimumab was assessed for tremelimumab as monotherapy and in combination with durvalumab.

The PK of tremelimumab was studied in patients with doses ranging from 75 mg to 750 mg or 10 mg/kg administered intravenously once every 4 or 12 weeks as monotherapy, or at a single dose of 300 mg. PK exposure increased dose proportionally (linear PK) at doses ≥75 mg. Steady state was achieved at approximately 12 weeks. Based on population PK analysis that included patients who received tremelimumab monotherapy or in combination with other medicinal products in the dose range of ≥75 mg (or 1 mg/kg) every 3 or 4 weeks, the estimated tremelimumab clearance (CL) and volume of distribution (Vd) were 0.309 l/day and 6.33 l, respectively. The terminal half-life was approximately 14.2 days.

Special populations

Age (18–87 years), body weight (34-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, tumour type, race or ECOG/WHO status had no clinically significant effect on the PK of tremelimumab.

Patients with renal impairment

Mild (creatinine clearance (CrCL) 60 to 89 ml/min) and moderate renal impairment (creatinine clearance (CrCL) 30 to 59 ml/min) had no clinically significant effect on the PK of tremelimumab. The effect of severe renal impairment (CrCL 15 to 29 ml/min) on the PK of tremelimumab is unknown.

Patients with hepatic impairment

Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1.0 to 1.5 × ULN and any AST) and moderate hepatic impairment (bilirubin >1.5 to 3 x ULN and any AST) had no clinically significant effect on the PK of tremelimumab. The effect of severe hepatic impairment (bilirubin >3.0 x ULN and any AST) on the PK of tremelimumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence tremelimumab exposure.

Animal toxicology

In the chronic 6-month study in cynomolgus monkeys, treatment with tremelimumab was associated with dose-related incidence in persistent diarrhoea and skin rash, scabs and open sores, which were dose-limiting. These clinical signs were also associated with decreased appetite and body weight and swollen peripheral lymph nodes. Histopathological findings correlating with the observed clinical signs included reversible chronic inflammation in the cecum and colon, mononuclear cell infiltration in the skin and hyperplasia in lymphoid tissues.

A dose-dependent increase in the incidence and severity of mononuclear cell infiltration with or without mononuclear cell inflammation was observed in the salivary gland, pancreas (acinar), thyroid, parathyroid, adrenal, heart, esophagus, tongue, periportal liver area, skeletal muscle, prostate, uterus, pituitary, eye (conjunctiva, extra ocular muscles), and choroid plexus of the brain. No NOAEL was found in this study with animals treated with the lowest dose of 5 mg/kg/week, however the intermediate dose of 15 mg/kg week was considered the highest non-severely toxic dose (HNSTD). This dose provided an exposure-based safety margin of 1.77 to clinical relevant exposure.

Carcinogenicity and mutagenicity

The carcinogenic and genotoxic potential of tremelimumab has not been evaluated.

Reproductive toxicology

Animal fertility studies have not been conducted with tremelimumab. Mononuclear cell infiltration in prostate and uterus was observed in repeat dose toxicity studies. Since animal fertility studies have not been conducted with tremelimumab, the clinical relevance of these findings for fertility is unknown. In reproduction studies, administration of tremelimumab to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or effects pregnancy losses, foetal weights, or external, visceral, skeletal abnormalities or weights of selected foetal organs.