Zynlonta

“No pharmacologically relevant nonclinical species for safety evaluation—as defined in ICH S6(R1)—exists for loncastuximab tesirine, due its antibody component being selective for human CD19.”

“The monoclonal antibody (mAb) component of loncastuximab tesirine, RB4v1.2, is selective for human CD19 and not cross‐reactive with CD19 from any nonclinical species.”

“Importantly, on‐target (ie, CD19‐mediated) toxicity cannot be evaluated in this or any other nonclinical species; however, a considerable body of data on the nonclinical and clinical safety of CD19‐ and CD20‐specific B‐cell‐depleting agents exists.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199 given the genotoxic mode of action of SG3199 (covalent DNA crosslinking/ alkylating agent) and the intended clinical use in patients with advanced cancer.”

“Importantly, on‐target (ie, CD19‐mediated) toxicity cannot be evaluated in this or any other nonclinical species; however, a considerable body of data on the nonclinical and clinical safety of CD19‐ and CD20‐specific B‐cell‐depleting agents exists.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“All in vivo studies with ADCT-402 or SG3199 used the IV route of administration, the intended clinical route of administration”

“No genotoxicity studies were conducted with ADCT-402. SG3199 was genotoxic in GLP in vitro studies (in vitro micronucleus assay and the chromosome aberration assay in human lymphocytes from whole blood).”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199”

“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”

“Consistent with International Council for Harmonization (ICH) S6(R1), no stand‐alone safety pharmacology studies were conducted with loncastuximab tesirine, and safety pharmacology endpoints were evaluated as part of the GLP‐compliant 4‐ and/or 13‐week repeat‐dose toxicity studies in cynomolgus monkeys.”

“A GLP bacterial reverse mutation assay (Ames test) was also conducted; however, mutagenicity could not be assessed due to cytotoxicity at all concentrations tested.”

“The payload, SG3199, was genotoxic in GLP in vitro studies (in vitro micronucleus assay and the chromosome aberration assay in human lymphocytes from whole blood).”

“Genotoxicity of SG3199 was evaluated in two in vitro assays in human lymphocytes, a micronucleus assay, and a chromosome aberration assay.”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199 given the genotoxic mode of action of SG3199 (covalent DNA crosslinking/ alkylating agent) and the intended clinical use in patients with advanced cancer.”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A, no carcinogenicity studies were conducted with loncastuximab tesirine or SG3199 given the genotoxic mode of action of SG3199 (see Section 5.5.2) and the intended clinical use in patients with advanced cancer.”

“No evaluation for hERG inhibition was submitted for the ADC or SG3199. There was large variability in the individual ECG data in monkeys, but overall any observed changes in cardiovascular parameters assessed as part of the GLP toxicology studies in monkeys were not considered adverse or ADC‐related.”

“The cynomolgus monkey was selected as nonclinical species for safety evaluation of loncastuximab tesirine, given the greater predictive value of PK data generated in this species for humans, potential for reduced impact of antidrug antibody (ADA) formation on drug exposure, and the proven utility of 1/6th highest non‐severely toxic dose (HNSTD) for setting clinical starting doses with ADCs.”

“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”

“Treatment of monkeys with loncastuximab tesirine resulted in pro‐inflammatory responses as indicated by increases in the white blood cells (WBCs) and/or differentials, increased fibrinogen, and histopathology observations (multi‐organ inflammation, particularly the lung, kidney, or injection site).”

“There was no apparent distribution of SG3199 to melanin‐ containing tissues or the brain or spinal cord.”

“In repeat‐dose toxicity studies in cynomolgus monkeys, loncastuximab tesirine exhibited a safety profile consistent with SG3199‐mediated effects on the skin (epidermal hyperpigmentation with hyperplasia/hyperkeratosis), bone marrow (hypocellularity associated with regenerative anemia)”

“Note: 5 of the 7 confirmed positive titers were taken from pretest (Day ‐6) samples and 2 of the 7 were from animals on Day 85 (one female each at 0.075 and 0.15 mg/kg). The exposure to conjugated ADCT‐402 was notably lower compared to the profiles of other animals in the respective dosing groups”

“In LOTIS-2, 0 of 134 patients tested positive for antibodies against loncastuximab tesirine-lpyl after treatment.”

“The cynomolgus monkey was selected as nonclinical species for safety evaluation of loncastuximab tesirine, given the greater predictive value of PK data generated in this species for humans, potential for reduced impact of antidrug antibody (ADA) formation on drug exposure, and the proven utility of 1/6th highest non‐severely toxic dose (HNSTD) for setting clinical starting doses with ADCs.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”

“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”

“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199 given the genotoxic mode of action of SG3199 (covalent DNA crosslinking/ alkylating agent) and the intended clinical use in patients with advanced cancer.”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199 given the genotoxic mode of action of SG3199 (covalent DNA crosslinking/ alkylating agent) and the intended clinical use in patients with advanced cancer.”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A, no carcinogenicity studies were conducted with loncastuximab tesirine or SG3199 given the genotoxic mode of action of SG3199 (see Section 5.5.2) and the intended clinical use in patients with advanced cancer.”

“The dose of 0.3 mg/kg in animals results in an exposure (AUC) that is approximately 3 times the exposure at the maximum recommended human recommended dose [MRHD] of 0.15 mg/kg.”

“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”

“The in vivo activity of ADCT‐402 was evaluated in immunodeficient mice subcutaneously (SC) xenografted with the CD19 positive human Ramos or Daudi Burkitt’s lymphoma cell lines or with the CD19 positive human DLBCL cell line, WSU‐DLCL2 (Study No. ADCT‐402_R_007_R).”

“The monoclonal antibody (mAb) component of loncastuximab tesirine, RB4v1.2, is selective for human CD19 and not cross‐reactive with CD19 from any nonclinical species.”

“The nonclinical studies conducted with ADCT-402 using a panel of cell lines derived from lymphoma and leukaemia patients have supported the clinical testing of loncastuximab tesirine in patients. Findings from these nonclinical studies support the use of cancer cell lines for nonclinical studies with ADCs.”