What tox package did approved monoclonal antibodies have, from first-in-human to approval?

“EMR100070-001 Conducted in US, Belgium, Czech Republic, France, Germany, Hungary, Korea, Poland, Taiwan, Republic of China, and UK Phase I, open-label, 2-phase (dose escalation and treatment expansions) in solid tumors”

“MSB0010718 (Anti-PD-L1): 13-Week Toxicity Study in Cynomolgus Monkeys by Intravenous Infusion Followed by an 8-Week Recovery Period”

“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”

“Genotoxicity and carcinogenicity studies are generally not required for biotechnology-derived monoclonal antibodies such as avelumab (ICH S9).”

“JGDC (IMCL CP15-0601) is a phase 1 multicentre open-label dose escalation study of olaratumab single agent in advanced solid tumours and lymphomas, conducted in 2 US centres between December 2006 and March 2009.”

“Weekly I.V. infusion of olaratumab for 39 weeks induced an increase in the incidence and/or severity of lymphocyte infiltration in numerous tissues, which often persisted or developed during the 8-week recovery period.”

“Prenatal and Postnatal Development Not conducted and not required to support the approval of a pharmaceutical intended for the treatment of patients with advanced cancer.”

“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICHS9).”

“The pharmacokinetic profile of toripalimab was assessed preliminarily in three Phase 1 studies, conducted in China, in patients with a variety of tumor types.”

“26-week toxicity with 66-day recovery period IV, cynomolgus monkey (1348RD2)”

“no reproductive and development toxicity studies have been conducted as there is public information indicating that antibodies targeting PD-1 may cause fetal harm when administered to a pregnant woman, obviating the need for reproductive studies.”

““Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer”.”

“Multicenter, first-in-human, dose-escalation, open-label study”

“13-3278 3/sex (main) 2/sex (recovery) IV: 0, 5, 15, 50 26 weeks Q1W”

“The Applicant did not conduct reproductive and developmental toxicology studies with atezolizumab.”

“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”

“Study title: 26-week subcutaneous injection chronic toxicity and toxicokinetic study with once-weekly dosing of LBR-101 in cynomolgus monkeys with a 16- week recovery phase”

“Pre- and postnatal development was evaluated in rat.”

“Carcinogenicity assessments were not conducted for fremanezumab. The sponsor submitted a request for waiver of the carcinogenicity assessment. which was granted.”

“In the definitive study, 8 rats/sex/group were administered vehicle (saline), 3, 10, or 30 mg/kg by IV injection on Days 1, 4, and 7.”

“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”

“Number/Sex/Group: 3/sex/group for 39-week study; 3 females/group for 12-week study; no recovery groups”

“Genotoxicity, carcinogenicity, developmental or reproductive toxicology studies were not conducted with ramucirumab in line with available guidance [ICH S9 (EMEA/CHMP/ICH/646107/2008)] as ramucirumab is indicated for the treatment of patients with advanced gastric cancer.”

“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”

“MK-1654 (clesrovimab) nonclinical safety studies included a good laboratory practice (GLP) 2- week IV/IM repeat-dose toxicology study in Wistar Han rats with a 4-week recovery period”

“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets.”

“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”

“Cynomolgus monkeys were administered a solution of tremelimumab in vehicle intravenously at doses of 5, 15, and 50 mg/kg/week for 6 months (the same dose levels as in the 1-month study). Six monkeys/sex were assigned to the 0 (control) and 50 mg/kg/week groups (with 4 monkeys/sex designated as main study monkeys and 2 monkeys/sex designated as recovery-phase monkeys).”

“Pre- and postnatal development studies were not performed, and this is acceptable and in line with ICH S9.”

“Carcinogenic potential of tremelimumab was not evaluated, and this is acceptable given the indication sought in the treatment of unresectable hepatocellular carcinoma (uHCC).”

“A 3-month intravenous toxicity study of MDX-1106 With a 28-day recovery period in cynomolgus monkeys”

“The Applicant evaluated potential nivolumab-associated effects on reproduction in an expanded pre- and postnatal development study (EPPND) in the cynomolgus monkey.”

“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”

“In the 26-week study, mogamulizumab was administered IV at doses of 2.5, 10, or 40 mg/kg once weekly.”

“Fertility/early embryonic development and pre/postnatal development studies were not conducted as these studies are not required to support a marketing application for products intended to treat patients with advanced cancer.”

“No carcinogenicity studies were conducted or are required to support a marketing application for the current indication.”

“Table 8: Study design for a 26-week intravenous and subcutaneous toxicity study with alirocumab in cynomolgus monkeys with a 13-week recovery period”

“Reproductive toxicity assessments were conducted in rats during the period of embryofetal development at up to 24-fold and in monkeys in an enhanced pre/postnatal development toxicity study at up to 81-fold the 150 mg Q2W human dose, based on plasma exposure.”

“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”

“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.”

“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14.”

“No additional nonclinical studies are recommended.”

“Repeated dose toxicity study has been performed in monkeys (4 weeks intravenous in the rhesus monkey with an 8 week treatment, doses at 0.5 to 4.5 mg/kg every 4th day).”

“The mutagenic/oncogenic potential has not been investigated which is acceptable for a monoclonal antibody.”

“Serum analysis indicated that the extent of mean % haemolysis decreased from pre-treatment levels of 70-80 % to below 20 % in treated mice at weeks 12 and 25. Although results were similar for both treated mice groups, the mean % haemolysis was slightly less for the 60 mg/kg/week mice in most instances. Following a four-week recovery period, the mean % haemolysis approximated pre-study values for both treatment groups.”

“Female Crl:CD-1®(ICR) BR mice received BB5.1 mAb at 30 mg/kg/dose once or twice weekly (groups 2 and 3, low and high dose, respectively) or vehicle.”

“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”

“CK-301: Once Weekly Intravenous Slow Bolus Injection Toxicity and Toxicokinetic Study in Cynomolgus Monkeys for 13 Weeks with a 10-Week Recovery Phase”

“A literature-based risk assessment of developmental and reproductive risk was conducted in lieu of performing developmental and reproductive toxicology studies.”

“Per ICH S9, no carcinogenicity study or carcinogenicity risk assessment was performed.”

“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”

“No pre- and post-natal development animal studies have been conducted with panitumumab.”

“No carcinogenicity studies have been conducted.”

“To investigate reversibility after a 4-week treatment-free period, an additional 5 males and 5 females were assigned to the control and 300 mg/kg groups”

“In line with ICH S9, only embryofoetal development was assessed; omission of studies on fertility and early embryonic development and on pre-/post-natal development is acceptable.”

“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”

“A Repeat-Dose Toxicity and Toxicokinetic Study in Cynomolgus Monkeys Administered OMS721 by Subcutaneous and/or Intravenous Injection Once Weekly for 26 Weeks with a 10-Week Recovery”

“NARSOPLIMAB: A Developmental and Perinatal/Postnatal Reproduction Study by Subcutaneous and Intravenous Injection in the Mouse, Including a Postnatal Behavioral/Functional Evaluation”

“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”