How long were the pivotal tox studies for approved monoclonal antibodies?

“In a 52-week repeat dose toxicity study in sexually mature Cynomolgus monkeys, animals received 0.5, 1 or 9 mg concizumab/kg/day for 52 weeks.”

“In a 26-week repeat dose toxicology study in sexually mature Cynomolgus monkeys, animals were given 0, 3 or 9 mg concizumab/kg/day s.c. or 30 mg/kg/week i.v. with a 13-week recovery period.”

“The pivotal repeat dose toxicity studies consisted of a 26-week repeat-dose toxicity study and a 52-week immunotoxicity study, both performed in cynomolgus monkeys.”

“The animals were administered 10 and 100 mg/kg/week s.c. certolizumab pegol and 50 and 100 mg/kg/week s.c. in the 26- and 52- week study, respectively.”

“In 6/12-Month Repeated-dose Study in Monkeys (102090) denosumab was administrated at doses of 0, 1, 10, and 50 mg/kg.”

“SC injection, 0, 1, 10 and 50 mg/kg once/month for 6 or 12 months)”

“In repeat-dose toxicity studies in rabbits up to 14 weeks, and in adult and juvenile cynomolgus monkeys up to 40 weeks, a spectrum of effects related to the primary pharmacology of burosumab was observed.”

“In repeat-dose toxicity studies in rabbits up to 14 weeks, and in adult and juvenile cynomolgus monkeys up to 40 weeks, a spectrum of effects related to the primary pharmacology of burosumab was observed.”

“The Applicant submitted 5-week and 39-week GLP-compliant toxicity studies in cynomolgus monkeys.”

“In the 5-week study, ramucirumab was administered by intravenous infusion on Days 1, 15, 22, and 29 at dose levels of 0, 4, 12, and 40 mg/kg. In the 39-week study, ramucirumab was administered by intravenous infusion weekly at dose levels of 0, 5, 16, and 50 mg/kg.”

“Safety pharmacology parameters were included in the 6- and 39-week intravenous and/or 13-week subcutaneous repeat-dose toxicology studies in cynomolgus monkeys.”

“GLP-compliant repeat-dose studies of 6 weeks, 13 weeks and 9 months in duration were conducted in cynomolgus monkeys to evaluate the toxicity and TK of lebrikizumab.”

“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087).”

“The initial doses and subsequent weekly doses were 12 and 7.5 mg/kg for the low dose group, 38 and 24 mg/kg for the intermediate dose group, and 120 and 75 5 mg/kg for the high dose group.”

“In the pivotal 39-week toxicity study, cynomolgus monkeys (6/sex/group) received 0 (IV/SC), 10 (IV), 25 (IV), or 30 (SC) mg/kg benralizumab once every 2 weeks for a total of 20 doses.”

“In the pivotal 39-week toxicity study, cynomolgus monkeys (6/sex/group) received 0 (IV/SC), 10 (IV), 25 (IV), or 30 (SC) mg/kg benralizumab once every 2 weeks for a total of 20 doses.”

“Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed.”

“Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed.”

“Toxicity of tildrakizumab was evaluated in repeated dose studies of 3-months and 9 months treatment duration.”

“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”

“Olaratumab was evaluated in GLP-compliant repeat-dose toxicology studies in cynomolgus monkeys of up to 39 weeks in duration.”

“by i.v. infusion over 5, 13 and 39 weeks, followed by recovery periods of 7 or 8 weeks.”

“In the 39-week study (0, 15, 50, and 100 mg/kg/week) (with 2-week recovery)”

“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey”

“Repeat-dose toxicity of anifrolumab was evaluated in cynomolgus monkeys in 4-weeks and 39-weeks GLP toxicity studies with an additional recovery period of 7 or 12 weeks, respectively.”

“Repeat-dose toxicity of anifrolumab was evaluated in cynomolgus monkeys in 4-weeks and 39-weeks GLP toxicity studies with an additional recovery period of 7 or 12 weeks, respectively.”

“Once weekly subcutaneous injections of ixekizumab for 9 months in cynomolgus monkeys caused no adverse compound-related clinical signs at ≤5 mg/kg/week.”

“General toxicity studies used intravenous dosing for up to 8 weeks and subcutaneous dosing up to 39 weeks with recovery groups for high dose and controls.”

“Adult monkeys have been dosed for up to 39 weeks. Juvenile monkeys were tested in two separate studies (both 13 weeks).”

“Teprotumumab was administered at doses up to 75 mg/kg, with a frequency of 2x/wk in the initial 7-wk study, and 1x/wk in the longer 13-wk and 39-wk studies.”

“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”

“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”

“Toxicity studies of daclizumab were conducted in monkeys with up to 39 weeks duration.”

“The pivotal studies were 13- and 39-week studies and a 9-month study. All were conducted with DAC HYP, administered Q2W by subcutaneous injection, and included 3-month recovery periods.”

“populations of NK cells, which are central to immune surveillance, did not change during pivotal repeat dose studies of up to 7 months duration.”

“some safety pharmacology end points, such as cardiovascular and renal parameters and body temperature, were evaluated as part of the pivotal 4 week and 7 month repeat dose toxicity studies in cynomolgus monkeys.”

“Toxicity studies have shown tocilizumab to be well tolerated in cynomolgus monkeys, both as single intravenous (IV) doses up to 100 mg/kg and when given in multiple IV doses up to 50 mg/kg/day for 4 weeks or at IV doses up to 100 mg/kg/week for 6 months.”

“Toxicity studies have shown tocilizumab to be well tolerated in cynomolgus monkeys, both as single intravenous (IV) doses up to 100 mg/kg and when given in multiple IV doses up to 50 mg/kg/day for 4 weeks or at IV doses up to 100 mg/kg/week for 6 months.”

“26-Week Intravenous Injection Toxicity and Toxicokinetic Study (Seven Doses) with SelG1 in Cynomolgus Monkeys with a 4-Week Recovery Phase/8259995”

“Monkeys received crizanlizumab intravenously, once every 2-weeks up to 25.2 mg/kg in the 4-week study and once every 4-weeks up to 50 mg/kg in the 26-week study.”

“The no observed adverse effect level (NOAEL) for tralokinumab in cynomolgus monkeys was 90 mg/kg/week in the 13-week SC toxicology study and 100 mg/kg/week in the 26-week IV toxicology study.”

“The repeat dose toxicity studies included 4-, 13- and 26-weeks studies with weekly IV dosing at levels up to 100 mg/kg and weekly SC injections of up to 350 mg/injection for 4- and 13-weeks.”

“There were no clear drug-related adverse effects in the GLP 6-month study of ch12F6A (0, 10, 40, or 250 mg/kg/week IV) or aducanumab (250 mg/kg/week IV) in aged Tg2576 mice.”

“toxicity of the murine analog (ch12F6A) was tested in the Tg2576 mouse; shorter-duration toxicity studies were conducted in monkey (4-week) and Tg2576 mouse (13-week).”

“In the pivotal 3- and 6-month toxicity study with 15-week recovery period, SC doses of 0, 25, and 150 mg/kg were administered 2x per week (4/sex/group).”

“the pivotal (1- mo/acute IV + 4-month recovery; combined 3- and 6-month; enhanced pre- and postnatal development [ePPND]) studies were adequate by design and conduct”

“Repeat-dose toxicity studies with the duration of 1 month and 3 months were conducted both in rats and monkeys; the pivotal 26-week study was only conducted in monkeys.”

“The pivotal (GLP) toxicity studies were conducted in Sprague-Dawley rat (1- and 3-month) and cynomolgus monkey (1-, 3-, and 6-month).”

“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”

“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes. Immunogenicity in mice precluded conducting longer toxicology studies in this species.”

“Additionally, a 26-week iv with a 12-week recovery was conducted in adult cynomolgus monkeys.”

“Twice weekly iv administration of rhuMAbVEGF for 4 or 13 weeks were carried out in young adult to adult cynomolgus monkeys [91]. Additionally, a 26-week iv with a 12-week recovery was conducted in adult cynomolgus monkeys.”

“The toxicology of repeat IV administration of belimumab was assessed in two GLP toxicology studies in cynomolgus monkeys of 4 weeks and 6 months duration, respectively.”

“The toxicology of repeat IV administration of belimumab was assessed in two GLP toxicology studies in cynomolgus monkeys of 4 weeks and 6 months duration, respectively.”

“The Applicant has conducted repeat dose toxicity studies in cynomolgus monkeys with weekly doses administered by subcutaneous injection for up to 26 weeks, followed by a treatment-free recovery period of up to 21 weeks”

“The Applicant has conducted repeat dose toxicity studies in cynomolgus monkeys with weekly doses administered by subcutaneous injection for up to 26 weeks, followed by a treatment-free recovery period of up to 21 weeks”

“General toxicology studies of up to 26 weeks’ duration were conducted in cynomolgus monkeys.”

“The sponsor conducted 4-, 13-, and 26-week GLP intravenous toxicity studies in cynomolgus monkey.”

“In the pivotal 26-week repeat-dose toxicity study in Cynomolgus monkey Cmax- and AUC-levels were 1.5-1.7 times higher in males.”

“Repeat-dose toxicity studies were conducted with caplacizumab in guinea-pigs and Cynomolgus monkeys by i.v. or s.c. routes and designed to achieve continuous maximal target occupancy (target saturation)”

“In toxicology studies up to 6 months duration, no target organs of toxicity were identified in either mice or monkeys at an IV dose up to 25 mg/kg once every 4 weeks.”

“In toxicology studies up to 6 months duration, no target organs of toxicity were identified in either mice or monkeys at an IV dose up to 25 mg/kg once every 4 weeks.”

“In the pivotal cynomolgus monkey study, AIN457 derived from CHO cells was administered intravenously (15, 50, 150 mg/kg/week; 4/sex/group) for 26 weeks followed by a 13-week recovery period”

“In the pivotal cynomolgus monkey study, AIN457 derived from CHO cells was administered intravenously (15, 50, 150 mg/kg/week; 4/sex/group) for 26 weeks followed by a 13-week recovery period”

“Repeated dose studies of up to 26 weeks duration were conducted with REGN646 in cynomolgus monkeys.”

“The three pivotal repeat dose toxicity studies, including a 5-week intravenous infusion (IV), a 13-week subcutaneous (SC) and a 6-month IV and SC studies, were conducted with REGN646”

“The pivotal (GLP) subcutaneous (SC) toxicity studies (6-week + 9-week recovery, 3-month + 6-week recovery, and 6-month) were conducted in Sprague-Dawley rat and cynomolgus monkey.”

“The pivotal (GLP) subcutaneous (SC) toxicity studies (6-week + 9-week recovery, 3-month + 6-week recovery, and 6-month) were conducted in Sprague-Dawley rat and cynomolgus monkey.”

“A 26-week toxicity study was conducted in cynomolgus monkeys intravenously administered sutimlimab at 60 and 180 mg/kg/week.”

“Sutimlimab has been evaluated in repeat-dose studies in cynomolgus monkey for 5 (up to 100 mg/kg/week) and 26 weeks (up to 180 mg/kg/week) with 8 weeks of recovery.”

“In general toxicity studies in monkey, weekly subcutaneous doses of up to 50 mg/kg for 4 or 26 weeks resulted in no notable toxicity or effects on male (sperm analysis) and female (menstrual cycle) reproductive parameters and organs.”

“In general toxicity studies in monkey, weekly subcutaneous doses of up to 50 mg/kg for 4 or 26 weeks resulted in no notable toxicity or effects on male (sperm analysis) and female (menstrual cycle) reproductive parameters and organs.”

“repeated dose IV toxicology (14-day, 13-week, 26-week) in Cynomolgus monkeys and rabbits (3-month)”

“A 3-month IV toxicology study was conducted with MLN0002 in New Zealand white rabbits at 30 and 100 mg/kg and 3- and 6-month IV toxicology studies were conducted with MLN0002 in Cynomolgus monkeys at 10, 30 and 100 mg/kg administered once every two weeks.”

“Romosozumab has been evaluated in repeat-dose toxicity studies in rats (up to 26 weeks with 14 weeks recovery) and in monkeys (up to 26 weeks with 14 weeks recovery).”

“The program includes repeat-dose studies up to 26 weeks with 14 weeks recovery in rats and monkeys; reproductive toxicity studies in rats, a carcinogenicity study in rats”

“Evinacumab was administered once-weekly to sexually mature male and female cynomolgus monkeys (4 to 8 years old) for 26 weeks via SC injection at 10, 30, or 100 mg/kg/week or IV injection at 100 mg/kg/week, followed by a 13-week recovery.”

“All studies were previously reviewed, and the results of pivotal 13-week rat and 26-week monkey studies are summarized below.”

“A GLP-compliant repeat dose toxicity study in cynomolgus monkeys receiving depemokimab 10mg/kg and 100 mg/kg once every 3 months for 26 weeks has been performed.”

“In the 26-week toxicology study conducted in monkeys, doses of 10 (low dose [LD]) and 100 (high dose [HD]) mg/kg were administered to adult male and female monkeys (4/sex/group) once every 13 weeks for a total of 2 doses.”

“The route of application was IV (9, 13 and 26-weeks duration) and SC (4-week), thus reflecting the clinical route of administration in the pivotal 26-week study.”

“The route of application was IV (9, 13 and 26-weeks duration) and SC (4-week), thus reflecting the clinical route of administration in the pivotal 26-week study. A 37-week treatment free period was included after the 13 week and 26 week IV studies, respectively.”

“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”

“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”

“the toxicity and toxicokinetics of marstacimab were examined in male and female Crl:WI(Han) rats (n=15 per sex in vehicle and dosing groups, and n=3 (vehicle) and 4 (test-article) per sex in test-article TK satellite groups) via intravenous injections of 0, 60, 180, or 1000 mg/kg/week for 26 weeks.”

“Wistar Han rats and Cynomolgus monkeys in GLP-compliant repeat-dose studies of up to 3 months (monkeys) or 6 months (rats) in duration.”

“In the second study 26 weeks of treatment were followed by 6 weeks of recovery.”

“In two IV repeat-dose studies canakinumab was given twice a week at doses of 0, 10, 30 and 100 mg/kg. In the first study, a 4-week treatment period was followed by 8 weeks of recovery.”

“In the 26-week study, weekly 15-minute IV infusions of 0, 20, 100, or 300 mg/kg (3/sex/group, main; 2/sex/group, recovery) resulted in transient tremors and reddened skin.”

“Pivotal GLP-compliant repeat-dose studies consisted of 4- and 26-week studies in which”

“Following repeat administration at doses up to 50 mg/kg for either 1‐month (5 doses) or 6‐months (26 doses), signs comprised intermittent diarrhea”

“The toxicokinetics of tremelimumab was evaluated in cynomolgus monkeys following IV administrations of tremelimumab in a single‐dose (10, 30, and 100 mg/kg), 1 month (5, 15, and 50 mg/kg/week;) and 6 month (5, 15, and 50 mg/kg/week) toxicologic studies”

“Four monkeys/sex/group were sacrificed after the 26-week dosing period and the remaining 2 monkeys/sex/group were sacrificed after a 12-week recovery period.”

“The toxicity profile of sarilumab was evaluated in a number of GLP compliant repeat-dose toxicology studies in Cynomolgus monkeys by the intravenous (IV) route of administration for up to 6 months in duration and by the SC route for 3 months duration.”

“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”

“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”

“The Applicant evaluated the safety of cemiplimab in cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 26 weeks duration.”

“The toxicity of cemiplimab was evaluated in the repeat dose toxicity studies of 4, 13 and 26-weeks duration in monkeys. The 13-week study was dedicated to evaluation of fertility endpoints.”

“The FDA agrees that there were no toripalimab-related adverse effects up to doses of 100 mg/kg on male or female cynomolgus monkeys treated once weekly for 26 weeks.”

“In the 4-week GLP-compliant (Q2W) repeat- dose study (10, 30, 100 mg/kg) with a 7-week recovery period, toripalimab was well tolerated at doses up to 100 mg/kg.”

“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”

“Ranibizumab was administered bilaterally by 50 µl IVT injections every 2nd week at doses of up to 2.0 mg/eye.”

“Dose and frequency of dosing: 0 (vehicle), 1, 5, and 25 mg/kg, once every two weeks for 26 weeks (14 doses in total)”

“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”

“a GLP-compliant 13-week repeat-dose toxicity study with a 26-week recovery period in sexually mature cynomolgus monkeys, and a GLP-compliant, 26-week, repeat-dose toxicity study with an 8-week recovery in the cynomolgus monkey.”

“a GLP-compliant 13-week repeat-dose toxicity study with a 26-week recovery period in sexually mature cynomolgus monkeys, and a GLP-compliant, 26-week, repeat-dose toxicity study with an 8-week recovery in the cynomolgus monkey.”

“In toxicology studies up to 6 months duration, no target organs of toxicity were identified at a SC dose of 10 mg/kg or intravenous (IV) doses of 10-100 mg/kg administered once every 4 weeks for a total of 7 doses.”

“In a 6-month toxicology study, Cynomolgus monkeys received mepolizumab (SB240563) at a subcutaneous dose of 10 mg/kg or an intravenous dose of 10 or 100 mg/kg once every 4 weeks for a total of 7 doses”

“Two six-month toxicity studies were conducted in cynomolgus monkeys, one by IV (twice weekly) and the other by SC (once weekly) routes of administration.”

“The pivotal studies included a 4-week repeat dose toxicity study which used both subcutaneous and intravenous routes of administration, and two 6-month repeat dose toxicity studies, one using weekly subcutaneous injections and the second using twice weekly intravenous injections.”

“In a chronic (26-week) monkey study, garetosmab caused reversible, non-adverse minimal to moderate seminiferous tubule degeneration that did not impact sperm function.”

“Reproductive organs and fertility-related parameters were assessed in sexually mature cynomolgus monkeys in a 26-week study in which garetosmab was administered intravenously once weekly at doses up to 50 mg/kg”

“tolerability and the 6-month (Q weekly dosing x 26 weeks) repeat-dose toxicity studies in cynomolgus monkeys.”

“Study title: Twenty-six week intravenous toxicity and toxicokinetic study with pertuzumab in cynomolgus monkeys with an 8-week recovery period”

“A 6-Month Intermittent Subcutaneous or Intravenous Administration Toxicity Study of SKY59 (Crovalimab) in Mature Cynomolgus Monkeys Followed by a 6-Month Recovery Period (Study 1082669)”

“Crovalimab was administered SC at dose levels of 10, 40, and 100 mg/kg QW for 26 weeks after a single IV injection of 100 mg/kg on Day 1 of the study and was administered to an additional group IV at a dose level of 160 mg/kg.”

“In the 26-week study, monkeys were treated at dose levels of 0, 6, 19, or 60 mg/kg weekly for 26 weeks.”

“Monkeys were administered necitumumab weekly for 5 or 26 weeks to investigate the safety of the antibody.”

“Dose and frequency of dosing: 0, 2.5, 10, or 40 mg/kg; test article was administered once weekly for 26 weeks”

“In the 26-week study, mogamulizumab was administered IV at doses of 2.5, 10, or 40 mg/kg once weekly. Mogamulizumab was well-tolerated, and no adverse mogamulizumab-related changes were observed.”

“The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing.”

“The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing.”

“A 6 months toxicity study with an anti-mouse TNFα monoclonal antibody (chimeric V1q muG2a, which has functional characteristics similar to infliximab) was submitted in year 2001.”

“In this study, CD-1 mice were given 25 weekly i.v. doses of 10 or 40 mg/kg cV1q. No cV1q treatment-related mortality or clinical signs of toxicity were observed.”

“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection.”

“The primary nonclinical toxicity studies of evolocumab were conducted in hamsters for up to 3 months and monkeys for up to 6 months duration with once weekly subcutaneous dosing.”

“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”

“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”

“Cynomolgus monkeys dosed with 0, 10, 25 or 90 mg/kg/dose SC brodalumab weekly for six months were observed with mild skin changes and histopathology (MD and HD), increased neutrophil counts (HD) and decreased albumin/globulin ratios (MD and HD).”

“In the pivotal repeat dose cynomolgus monkey toxicity study, animals dosed with 0, 10, 25 or 90 mg/kg/dose SC brodalumab weekly for six months were observed with mild skin changes and histopathology (MD and HD)”

“In the 6-month subcutaneous study, using doses up to 50 mg/kg, no adverse effects due to golimumab treatment were seen on standard parameters.”

“following single or repeated dosing of cynomolgus monkeys via intravenous or subcutaneous administration at doses up to 50 mg/kg once or twice weekly for up to 6 months.”

“BI 655066: A 26-Week subcutaneous toxicity and toxicokinetics study in Cynomolgus monkeys with an 8-week recovery period”

“Repeat dose toxicity of risankizumab was evaluated in a four-week study after IV administration of up to 50 mg/kg/week and at 20 mg/kg/week after SC administration, and in a 26 week chronic study with subcutaneous doses of up to 50 mg/kg/week.”

“A twenty-six week study evaluated the toxicity of BB5.1 mAb.”

“Crl:CD-1®(ICR) BR mice received by IV route BB5.1 mAb at 0 mg/kg twice weekly, 30 mg/kg once weekly, or 30 mg/kg twice weekly (resulting in dose levels of 0, 30 and 60 mg/kg/week respectively).”

“BI 674304 was evaluated in a pivotal 26-week repeat-dose general toxicity study in CD-1 mice.”

“BI 674304 was evaluated in a pivotal 26-week repeat-dose general toxicity study in CD-1 mice. BI 674304 was administered via intravenous injection, twice weekly, at the doses of 0, 10, and 50 mg/kg.”

“CNTO 1275 (STELARA, ustekinumab) was dosed SC twice weekly to 3 dose groups of cynomolgus monkeys of 8/sex/group at doses of 22.5 or 45 mg/kg for 13 or 26 weeks.”

“Repeat-dose toxicity studies showed that CNTO 1275 (STELARA, ustekinumab) is generally well tolerated following IV doses up to 45 mg/kg/week for up to 1 month (Studies T-099-003 and T-099-004), and following twice-weekly SC doses up to 45 mg/kg for 6 months (Study T-2001-004).”

“Repeat dose toxicology studies of 3-months or 6-months duration with extended recovery periods were conducted using weekly IV infusion administration of 9.6 or 46 mg/kg/dose siltuximab alone or in combination with IL-2 administration.”

“Repeat dose toxicology studies of 3-months or 6-months duration with extended recovery periods were conducted using weekly IV infusion administration of 9.6 or 46 mg/kg/dose siltuximab alone or in combination with IL-2 administration.”

“The 27 lanadelumab doses administered in the 6-month study in juvenile to adolescent cynomolgus monkeys (2.7-3.3 years) receiving lanadelumab doses 5, 25 or 50 mg/kg/week were well-tolerated.”

“Studies up to 4 weeks duration (with 4-week recovery) and 6 months were performed in rats and monkey respectively.”

“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”

“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”

“A 6-month SC and IV study in cynomolgus monkeys (once weekly dosing) represented the pivotal toxicology study to support the marketing approval of tezepelumab.”

“The tezepelumab non-clinical safety package included 4 GLP cynomolgus monkey repeat-dose toxicology studies of up to 6 months in duration”

“Chronic toxicity studies of repeated doses of natalizumab over a 26-week period, followed by a 17 week dose-free period in cynomolgus monkeys”

“A six-month toxicity study with natalizumab as weekly intravenous infusion in juvenile cynomologus monkeys with a 17-week recovery period”

“The No Observed Adverse Effect Level (NOAEL) for BB5.1 mAb administered to CD‐1 mice via IV injection twice weekly for 26 weeks was determined to be 60 mg/kg/week, the highest dose tested.”

“In the 26‐week repeat‐dose study, mice were administered once or twice weekly by intravenous (IV) injection resulting in doses of 30 or 60 mg/kg/week.”

“Inebilizumab was administered to huCD19Tg mice (24/sex/group) by IV injection weekly for 26 weeks at dose levels of 0, 3, or 30 mg/kg.”

“General toxicology studies were conducted in huCD19Tg mouse with durations of 1, 3, and 6 months in which inebilizumab was administered weekly by IV injection at doses up to 30 mg/kg. (A second 3-month study was conducted using SC administration.)”

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

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

“Thirteen- and 26-week repeat-dose toxicity studies were conducted with pozelimab in cynomolgus monkeys.”

“Dose and frequency of dosing: IV: 5, 20, 100 mg/kg; SC: 100 mg/kg; once weekly”

“A 26-week IV study (25 to 100 mg/kg biweekly) showed no adverse effects at the highest dose of 100 mg/kg/dose.”

“A 26-week IV study (25 to 100 mg/kg biweekly) showed no adverse effects at the highest dose of 100 mg/kg/dose. A 26-week study with SC dosing (25 to 100.5 mg/kg biweekly) demonstrated a similar safety profile”

“The Division agreed that only a monkey chronic (6-month) study was needed (email correspondence, April 4, 2013).”

“In monkey, eptinezumab was tested in 28-day (0, 10, 30, and 100 mg/kg IV Q2W) and 6-month (0, 20, 50, and 150 mg/kg Q2W) studies.”

“Juvenile (8- to 10-month old) Cynomolgus monkeys received sc doses of 50 or 250 mg/kg omalizumab weekly for 26 weeks.”

“a 4-week iv/sc study with a 4-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg, and a 6- month iv/sc study with an 8-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg.”

“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”

“including safety pharmacology studies, repeat-dose toxicity studies in mice and monkeys for durations up to 4 and 26 weeks, respectively, reproductive toxicity studies in mice and rabbits”

“In a 6-month toxicity study in cynomolgus monkeys, ipilimumab in a dose of 10 mg/kg with monthly intervals (4 times over these 6 months) was not associated with adverse drug-related toxicity”

“ipilimumab generally did not result in adverse toxicities in any other monkeys when administered IV at doses up to 30 mg/kg for 1 week, 10 mg/kg administered weekly for 1 month, 1 mg/kg weekly for 10 weeks, or 10 mg/kg monthly for up to 6 months.”

“In the longest duration study (Study #04-0192-0134), monkeys received ocrelizumab every three weeks for 24 weeks (total of 8 total doses) at doses of 50 or 100 mg/kg IV.”

“In the pivotal chronic toxicity study (04-0192-0134), ocrelizumab was administered to cynomolgus monkeys (4/sex/group for main study; 2/sex C and HD for recovery) by IV bolus injection at doses of 0, 50, and 100 mg/kg every 3 weeks”

“Five-week SC and IV and 24-week SC toxicology studies were conducted in young adult to adult cynomolgus monkeys administered guselkumab SC at doses of 10 or 50 mg/kg, once per week for 5 or 24 weeks”

“Once weekly administration of guselkumab via the IV and SC route for 5 weeks (phase 1) or SC 24 weeks (phase 2) up to 50 mg/kg”

“The dosing period was approximately 5 months.”

“In the pivotal (GLP) studies, mE8c was administered to 12- to 15-month-old PDAPP mice weekly for 6 weeks (0, 10, 30, or 100 mg/kg SC) or 5 months (0, 30, or 100 mg/kg SC).”

“Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys.”

“Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing period.”

“Y-mAbs conducted a GLP-compliant 13-week toxicology study in nude rats.”

“Rats received intravenous naxitamab for 4 cycles of 3 treatment days per cycle (every other day on Days 1, 3, and 5) at doses of 0, 10, or 50 mg/kg.”

“In a 13-week study, monkeys received weekly intravenous (IV) doses up to 200 mg/kg.”

“No adverse effects on male or female reproductive organs were observed in the 8- or 13-week repeat-dose toxicity studies in cynomolgus monkeys.”

“Two GLP repeat-dose IV toxicity studies were conducted with durvalumab, a 4-week (Study VMM0008) and a 13-week (Study VMM0033) repeat-dose toxicity study.”

“in both studies a loading dose (double the maintenance dose) of 30, 60, or 200 mg/kg durvalumab was administered on Day 1, and followed by 4 or 13 weekly doses of 15, 30, or 100 mg/kg, respectively.”

“The Applicant evaluated the safety of dostarlimab in cynomolgus monkeys in GLP‐compliant repeat‐dose toxicity studies of up to 13 weeks duration.”

“The single dose and repeat dose studies of 4- and 13-week duration were all performed with similar dose levels of dostarlimab (10, 30 and 100 mg/kg).”

“Dose and frequency of dosing: 0, 15, 50, and 100 mg/kg/dose; once weekly for 13 consecutive weeks (13 doses)”

“The Applicant conducted GLP-compliant 6-week (doses up to 150 mg/kg/dose) and 13-week (doses up to 100 mg/kg/dose) repeat-dose toxicology studies of margetuximab in cynomolgus monkeys.”

“The safety of tafasitamab was evaluated in GLP-compliant 8- and 13-week general toxicology studies in cynomolgus monkeys.”

“once every two weeks at 2, 10 or 50 mg/kg in the 8-week study, or once every week at 0, 10, 30 or 100 mg/kg in the 13-week study.”

“In the 3-month toxicity study in cynomolgus monkeys, IV doses of nivolumab were administered 2QW (for a total of 27 doses) at dose levels of 0 (vehicle control), 10, or 50 mg/kg.”

“Pivotal 1- and 3-month IV repeat-dose toxicity studies of nivolumab alone were conducted in cynomolgus monkeys.”

“The Applicant evaluated the safety of penpulimab in cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”

“In 6-week repeat-dose toxicity study, no apparent toxicity was observed in cynomolgus monkeys following intravenous infusion of penpulimab at 4, 15, or 60 mg/kg once every two weeks for 6 weeks.”

“The Applicant performed a first repeat-dose toxicology study in monkeys (P14-057-CD), where 0/3/10/30 mg/kg tislelizumab was administered IV once biweekly for 13 weeks to 6 animals/sex/group followed by a 6-week recovery period”

“In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration for 13 weeks at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations)”

“Slow bolus intravenous injection via a saphenous vein once weekly for 13 weeks (14 doses) at a dose volume of 2 mL/kg.”

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

“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”

“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”

“The Applicant evaluated the toxicity of retifanlimab in a 13-week GLP-compliant repeat-dose toxicology study in cynomolgus monkeys.”

“Pivotal repeat-dose toxicity studies with retifanlimab in cynomolgus monkeys include a 4-week study (doses: 0, 10, 40, or 150 mg/kg) with a 10-week recovery period (T19-01-03) and a 13 week study (doses: 0, 5, 20, 100 mg/kg; T18 02-10).”

“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”

“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”

“The toxicology program for daratumumab consisted of a GLP 6-week repeat-dose toxicity study in chimpanzees”

“The nonclinical PK of daratumumab was evaluated in the 6-week repeat-dose toxicology study in chimpanzees administered weekly as an IV infusion, and followed by a 91 to 105-day recovery period.”

“Dose and frequency of dosing Weekly for 4 weeks (5 injections total)”

“In the 4-week toxicity study with a 25-week recovery period once weekly i.v. or i.m. administration (5 doses total) of nirsevimab of 0, 300 mg/kg/week i.v. or 0 and 300 mg/kg/week i.m (6 monkeys/sex/group) or 50 mg/kg/week i.v.”

“In a previous CHMP scientific advice, the 30-day toxicity testing was considered sufficient to cover the clinical schedule for alemtuzumab treatment, i.e. administration on 5 consecutive days followed by administration on 3 consecutive days after one year.”

“Two repeat dose studies were conducted in cynomolgus monkeys.”

“A 4-Week Intravenous Toxicity Study With an 8-Week Recovery Period in Rhesus Monkeys (Study #1016-1363):”

“A 4-Week Intravenous Toxicity Study With an 8-Week Recovery Period in Rhesus Monkeys (Study #1016-1363):”

“The nonclinical toxicology studies were designed to evaluate the potential toxicity of idarucizumab in rats and monkeys in GLP studies of up to 4- and 2-weeks of daily treatment, respectively.”

“The nonclinical toxicology studies were designed to evaluate the potential toxicity of idarucizumab in rats and monkeys in GLP studies of up to 4- and 2-weeks of daily treatment, respectively.”

“Pharmacokinetics of SDZ CIH 621 following single or multiple administration were studied in rhesus and cynomolgous monkeys in a 4-weeks intravenous toxicity studies.”

“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 safety of dinutuximab was evaluated in a 28-day repeat-dose toxicology study in rats.”

“Rats were administered dinutuximab at doses significantly higher than the clinically recommended dose for 4 weeks (4 days on, 3 days off/week) with a 6-week”

“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days”

“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.”

“Because an appropriate species for preclinical safety testing could not be identified, toxicology studies with isatuximab were limited to a repeat-dose (once weekly for 3 weeks) toxicity study in cynomolgus monkeys (preceded by a small exploratory study)”

“The weekly repeated intravenous administration of isatuximab for 3 weeks to cynomolgus monkeys at doses of 20, 50 or 100 mg/kg/week resulted in no isatuximab-related findings in any parameters and in any groups.”

“No findings of toxicological significance were observed in the single (4 weeks) or repeat-dose toxicity studies (2 or 3 weeks studies) performed with bezlotoxumab and/or actoxumab.”

“No findings of toxicological significance were observed in the single (4 weeks) or repeat-dose toxicity studies (2 or 3 weeks studies) performed with bezlotoxumab and/or actoxumab.”

“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”

“IV (Groups 2 to 5): 0, 30, 100, 300 mg/kg once every 3 days (Days 1, 4, 7, 10, 13) IM (Group 1 and 6): 0, 25 mg/kg on Days 1 & 13”

“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.”

“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.”

“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”

“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”

“Repeat-dose toxicity studies of elotuzumab were not conducted due to the lack of a relevant toxicology species or a valid transgenic mouse model.”

“A single dose of intravenously infused elotuzumab (0, 30, or 100 mg/kg) was well tolerated in rhesus monkeys with no clinical signs at any dose.”

“Studies on repeated dose toxicity, effects on the reproduction, embryo-foetal & perinatal toxicity, mutagenic potential, oncogenic/carcinogenic potential and ecotoxicity/environmental risk assessment were not considered necessary by the applicant and were not performed.”

“A single dose toxicity study of palivizumab administered to Sprague Dawley rats via intravenous injection including assessment of clinical signs, body weight changes, food consumption, ophthalmoscopy, haematology, clinical and anatomic pathology until 14 days post injection gave no indication of toxicity”

“3 GLP repeat-dose studies (Study N-10-104, Study N-12-042 and Study N-14-007) were conducted with the GMP material to determine the potential ocular toxicity, tolerability, and systemic exposure of brolucizumab in Cynomolgus monkeys after repeated IVT injections.”