What safety margins were accepted for approved monoclonal antibodies?

“Based on weekly dose, this effect occurred at dose levels slightly below (>0.8-fold) the proposed clinical dose, and exposure levels were approximately 1.5- to 2.0-fold below the expected human clinical exposure, based on average serum concentrations.”

“Physeal dysplasia occurred in males at about 2 mg/kg and in females at 10 mg/kg.”

“The dosage was based on the human therapeutic starting dose of 400 mg/m2 and subsequent weekly doses of 250 mg/m2 , which translates to 12 and 7.5 mg/kg for a human ofbody surface area of 1.8 m2”

“Clinical and necropsy findings indicated that the skin was the primary target organ, with dose-dependent effects observed at all dose levels. Severe skin reactions and 5 intercurrent deaths were observed in the high dose group.”

“In the 5-week study, exposure at the NOAEL dose level (40 mg/kg) was approximately the same as the median exposure expected at the maximum clinical dose level”

“A no-observed-adverse-effect level (NOAEL) was not established in the 26-week toxicity study due to adverse skin effects at all dose levels.”

“The major concerns were the low level of exposure in Cynomolgus as compared to human level of exposure (1:1) and the lack of long-term animal studies, since B-cell recovery was not complete 90 days post dose.”

“No effect other than the expected pharmacological depletion of B–cells in peripheral blood as well as in lymphatic tissues was observed in toxicity studies.”

“The toxicity studies provide no margin to the exposure at the proposed clinical dose of atezolizumab.”

“Atezolizumab-related findings in the repeated dose toxicity studies were sciatic neuropathy in C57BL/6 mice and arteritis/periarteritis in Cynomolgus monkeys. Both findings may be due to enhancement of an autoreactive immune-response in pre-disposed animals.”

“Based on Cmax values, the exposures were significantly below those observed in the clinical setting, following administration of the recommended therapeutic dose. Higher exposure margins were established by the applicant based on AUC values obtained in a PK study. The use of these AUC data yielded exposure margins of 0.6- to 4.4-fold.”

“dose-limiting toxicity (increased susceptibility to infections or hypersensitivity leading to lethality/early sacrifice) and limitation of the animal model (decreased affinity of alemtuzumab for CD52 in the cynomolgus monkey).”

“mean maternal AUC inf (3220 mcg•day/mL) were approximately 3 times and 0.62 times the respective values for C max and AUC reported in clinical trial subjects at the maximum recommended adult dose of 16 mg/kg.”

“The NOAEL was the high dose, 30 mg/kg, for both the Lonza and Baxter material”

“Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.”

“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.”

“The NOAEL was 0.3 mg/kg (0.9x adult human AUC) in both”

“The NOAEL was 0.3 mg/kg (0.9x adult human AUC) in both”

“Rat 0, 20, 250 20 213 7x 29900 1x Unexplained death in 2 HD males General Toxicology Monkey 0, 2, 100 100 4490 143x 579500 21x”

“The NOAEL in the 6-month rat study was the LD, because a drug-related cause of death could not be ruled out in the 2 HDM. In the 6-month monkey study, the NOAEL was the HD, because the injection site irritation was not considered adverse.”

“The NOAELs for chronic administration of evinacumab in rats and monkeys were 100 mg/kg/week IV for both species, or ~1 and 4-fold, respectively, the maximum recommended human dose (MRHD) of 15 mg/kg IV every 4 weeks based on AUC)”

“The NOAELs for chronic administration of evinacumab in rats and monkeys were 100 mg/kg/week IV for both species”

“No NOAEL was found in this study with animals treated with the lowest dose of 5 mg/kg/week requiring supportive care. This dose provided an exposure-based safety margin of 1-2 to clinically relevant exposure (taking species difference in potency into account).”

“A dose of 5 mg/kg was considered to be the no‐observed effect level (NOAEL) following 1‐month of dosing and following 6‐months of dosing a NOAEL was not established but 15 mg/kg was considered to be the maximum tolerated dose.”

“In the vitreous, only the lowest dose tested (1.0-fold the clinical 0.5 mg dose on a mg/ml vitreous basis) in the 13-week study gave an inflammatory response that subsided to levels comparable to those observed in vehicle-injected animals while the animals were still on treatment.”

“The NOEL or NOAEL were not identified in any of the studies, since all doses tested (0.25-2 mg) resulted in an ocular inflammation.”

“Plasma exposure (AUC) achieved in the repeat-dose toxicity studies in monkeys exceeded the human therapeutic exposure by 10- to 15-fold. Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”

“Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”

“A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.”

“Repopulation of B cells was demonstrated at all dose levels. NOAEL is100 mg/kg.”

“Exposure multiples (based on Cmax) varied from 2.3-43 for i.v. administrations and from 2.2-227 for s.c. administrations.”

“Monkeys were dosed weekly via SC injection at dose levels of up to 300 mg/kg for 25 weeks, followed by a 16-week recovery period. No adverse effects except injection site inflammation were observed at any dose.”

“The mean maternal plasma exposure corresponds to 2.4-fold the clinical exposure following administration of 2 gram ofatumumab.”

“In repeat-dose toxicity studies, haemolytic anaemia developed in cynomolgus monkeys, leading to unscheduled deaths.”

“The NOAEL for crovalimab in cynomolgus monkeys is associated with a maximum plasma concentration (Cmax) of 996 μg/mL and area under the concentration-time curve (AUC) from 0 to 7 days of 5750 μg·d/mL that corresponds to 3.3- and 2.6-times the exposure observed in patients with PNH at the maximum recommended human dose for male and female animals, respectively.”

“The no observed adverse effect level (NOAEL) for crovalimab in cynomolgus monkeys after 6 months of SC intermittent dosing is defined at the low dose of 10 mg/kg/week based on the occurrence of arteritis/periarteritis in multiple organs at higher doses tested”

“This NOAEL also provides adequate safety margin (3-fold on an AUC basis) for the proposed clinical dose of 3 mg/kg IV q4 weeks.”

“The NOAELs of 25 mg/kg provided a safety margin of approximately 3-fold compared to the recommended clinical dose based on systemic exposure comparisons.”

“Sutimlimab was tolerated up to the highest dose of 180 mg/kg (exposure approximately 3- or 5-fold greater than that at 6.5 g or 7.5 g clinical dose, based on AUC) with no adverse effects on the health of the animals.”

“The no observed adverse effect level (NOAEL) in the repeat-dose toxicity study was 180 mg/kg weekly in male and female monkeys.”

“In summary, the NOAEL in rhesus monkeys treated with idarucizumab in the absence or presence of dabigatran for 2 days or 2 weeks was 500 mg/kg/day. The resulting exposure multiples, taking into account different human populations (healthy, elderly, with renal impairment) were approx. 5-7x based on Cmax and 3-6x based on AUC0-24.”

“In summary, the NOAEL in rhesus monkeys treated with idarucizumab in the absence or presence of dabigatran for 2 days or 2 weeks was 500 mg/kg/day. The resulting exposure multiples, taking into account different human populations (healthy, elderly, with renal impairment) were approx. 5-7x based on Cmax and 3-6x based on AUC0-24.”

“Cmax values in rabbits after dosing with 120 mg/kg were 3629 mcg/mL and 4337 mcg/mL after the first and second dose of raxibacumab respectively; these are more than 3 and 4 times the mean Cmax values in humans.”

“Anthrax infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of CNS lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared to dead placebo control animals”

“Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of SOLIRIS had no adverse effects on mating or fertility.”

“Treatment did not affect any of the toxicity parameters examined.”

“At the NOAEL ibalizumab exposure in cynomolgus monkeys without an anti-ibalizumab response was approximately 4 fold exposure at the MRHD.”

“Multifocal glomerulopathy was observed together with reduced albumin levels, which can be an indication for protein loss through the kidney. As these effects were observed only in animals with a strong antibody response against ibalizumab, its relevance for humans is limited.”

“mg/kg, approximately 4x the total human dose administered in a cycle of treatment based on body surface area (BSA).”

“The NOAEL was <0.3 mg/kg based on severe hypersensitivity reactions.”

“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), no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.”

“no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.”

“there were no notable effects on male and female reproductive organs up to the highest dose tested of 60 mg/kg (approximately ≥4.7 times the human exposure based on AUC at the 200 mg clinical dose)”

“Histological findings included increased cellularity and erythrophagocytosis in the inguinal, mandibular, and mesenteric lymph nodes. • The NOAEL was 60 mg/kg.”

“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg). At this dose level, the AUC0-168h was 74,500 μg•h/mL, corresponding to approximately 6 and 5 times the clinical exposure at 500 mg Q3W andQ6W.”

“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg).”

“A no observed adverse effect level was established at 50 mg/kg (the highest dose tested, approximately five￾times the maximum clinical exposure by AUC) for both sexes.”

“A no observed adverse effect level was established at 50 mg/kg (the highest dose tested, approximately five-times the maximum clinical exposure by AUC) for both sexes.”

“There was no evidence of maternal toxicity, embryotoxicity, or teratogenicity when omalizumab was administered throughout the period of organogenesis at doses that produced exposures approximately 5 times the MRHD (on a mg/kg basis with maternal subcutaneous doses up to 75 mg/kg/week).”

“Chronic administration of omalizumab was well tolerated in non-human primates, with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals.”

“The no-observed-adverse-effect-level (NOAEL) for bezlotoxumab alone or in combination with actoxumab was ≥125 mg/kg/dose. This is up to 5 fold over the exposure in humans at the clinically recommended dose (10mg/Kg).”

“The no-observed-adverse-effect-level (NOAEL) for bezlotoxumab alone or in combination with actoxumab was ≥125 mg/kg/dose. This is up to 5 fold over the exposure in humans at the clinically recommended dose (10mg/Kg).”

“at doses up to the high dose level of 50 mg/kg (approximately 5.5 to 25.5 times the human exposure by AUC at the human dose of 350 mg once every 3 weeks).”

“The NOAEL was considered to be 50 mg/kg/week in all repeat-dose toxicity studies in monkeys, the highest dose administered. However, while setting this dose as the NOAEL any adverse reactions as a consequence of high immunogenicity was excluded. Given that in 26-week toxicity study in monkeys two animals died (one in 10 and 50 mg/kg dose groups in each) due to immune complex deposition and associated tissue damage.”

“Nonclinical safety data provides a 2-fold ocular margin of safety for the recommended human dose and a 12- and 6-fold systemic margin of safety, based on Cmax and AUC respectively (NOAEL corresponds to the highest tested dose in Alcon study N-12-042 i.e. 6 mg/eye).”

“Overall, results of the different studies revealed that brolucizumab was well tolerated with a NOAEL value of 6 mg/eye corresponding to the highest tested dose and no systemic toxicity was observed.”

“No off-target toxicity was observed in Cynomolgus monkeys following IV and SC administration of obinutuzumab at AUC exposures up to 6-fold those observed in humans following administration of the maximum recommended dose of 1000 mg.”

“Hypersensitivity reactions were noted at all doses (≥5 mg/kg) in the 26-week study and were attributed to cross-species reactivity to a foreign protein.”

“There were no mortalities following intravenous (I.V.) administration of the antibody at dose levels up to 75 mg/kg once weekly for up to 39 weeks. This dose resulted in exposures approximately 9.5- and 6-fold higher based on AUC0-t and AUC0-168, respectively, than the steady-state AUCtau seen on Day 8 at the recommended human dose”

“In this study, monkey serum Cmin was 1164 μg/mL at the no observed adverse effect level (NOAEL) of 75 mg/kg”

“Serum AUC at the NOAEL was at 11-12-fold based on clinical data, and 6–7-fold based on the new Pop-PK model.”

“No adverse findings were observed in mice. In the 4-week monkey study, vomiting was observed in one male each from the 10 mg/kg and 30 mg/kg dose groups on Day 8 (second administration).”

“39-Week repeat-dose toxicity study 50 mg/kg LOAEL 5 mg/kg NOAEL 144c 15.3d 61x 6.5x”

“Based on the injection site reactions requiring dose suspension, the NOAEL for this 9-month study was 5 mg/kg/week.”

“In the 13-week study, mean Cmax fold differences at the 100 mg/kg/dose after the 13th dose were 8.6× and 6.6× in males and females, respectively.”

“or 6 weekly doses of 0, 15, 50 or 150 mg/kg/dose (Report UOK00019). These data support a no-observed-adverse-effect level (NOAEL) of 150 mg/kg/dose.”

“the mean ± SD AUC0-t in monkeys (20264.11 ± 4435.72 μg·day/mL) was approximately 7-fold higher than the mean ± SD AUC0-t value (2800.9 ± 1086.2 μg·day/mL) in cancer patients.”

“No significant toxicities were observed in the 3- or 6-month toxicology studies with siltuximab and the toxicokinetic (TK) results indicated that anti-siltuximab antibodies did not interfere with exposure or study results.”

“it appears that the low dose used in these studies (10 mg/kg) was the NOAEL for microglial aggregates. This dose produced exposures in monkeys approximately 7 times the exposure in humans at the recommended dose.”

“In the 39-week and 9-month studies, the NOAEL for microglial aggregates was 10 mg/kg administered biweekly”

“NOAEL =500 mg/kg/dose (AUClast =222664 µg.day/mL at Day 22, gender-averaged) Exposure multiple =7.6”

“NOAEL =500 mg/kg/dose (AUClast =222664 µg.day/mL at Day 22, gender-averaged) Exposure multiple =7.6”

“The systemic steady state exposure to tocilizumab in these monkey studies was 8-to10-fold above the maximum human exposure comparing trough levels in the animals with the maximum level measured in clinical trials.”

“No major abnormal findings were observed in either the clinical pathology investigations or in the histopathological evaluation of tissues. The systemic steady state exposure to tocilizumab in these monkey studies was 8-to10-fold above the maximum human exposure”

“Based on the NOAEL of 300 mg/week i.m. calculated safety margins for a dose of 50 mg i.m. for infants weighing <5 kg and 100 mg i.m. for those weighing ≥5 kg entering their first RSV season was 44-fold based on Cmax and 8-fold based on AUC.”

“No adverse, drug-related findings were observed in the GLP 4-week toxicology study in cynomolgus monkeys up to the highest doses tested (no observed adverse effect level (NOAEL) =300 mg/kg IM or IV).”

“The cynomolgus AUC values were normalised to account for the difference in dosing schedule and provide a sufficient margin (approx. 8x) to the human exposure.”

“For adults, the low-dose (3 mg/kg/week IV) is the lowest adverse effect level (LOAEL), and a no observed adverse effect level (NOAEL) was not identified.”

“The NOAEL in the 26week repeat dose toxicity was considered by the Rapporteur to be 10 mg/kg instead of 100 mg/kg due to the increase in QTc at 100 mg/kg in 4/6 animals at 100 mg/kg, which is considered to be an adverse effect. The exposure margin is 8.48 or 9.65 when based on AUC and 10.9 or 12.0 when based on Cmax (for patients with asthma or CRSwNP, respectively).”

“The NOAEL in the 26week repeat dose toxicity was considered by the Rapporteur to be 10 mg/kg instead of 100 mg/kg due to the increase in QTc at 100 mg/kg in 4/6 animals at 100 mg/kg, which is considered to be an adverse effect.”

“In HD monkeys, plasma exposures (Day 22 AUC0-168 hrs) were 9-fold greater than the expected AUCTAU,SS in humans at the maximum proposed clinical dose of 10 mg/kg IV aducanumab. Adjusting for the differences in dosing frequency (QW in monkey vs. Q4W in human), estimated AUC exposure margins were ~35-fold.”

“Based on the meningeal vascular inflammation and acute hemorrhage in brain at the MD of 70 mg/kg/week, the NOAEL was the LD of 10 mg/kg/week IV ch12F6A.”

“In the 13-week repeat-dose general toxicity study in cynomolgus monkeys, no adverse effects on male and female reproductive organs were observed up to the highest dose tested, 100 mg/kg/week (approximately 9 times the human exposure based on AUC at the clinical dose of 12 mg/kg/week).”

“In general, tafasitamab was well tolerated in single-dose studies up to 10 mg/kg and in repeat-dose studies up to 100 mg/kg, supporting the NOAEL of 100 mg/kg determined based on the 13-week”

“The NOAEL for maternal and developmental toxicity was 100 mg/kg/week based on the results of this study, which is 10 times the maximum recommended human dose (MRHD) on a mg/kg basis.”

“In summary, no adverse effects were observed in the repeat-dose studies. In all studies, the NOAEL was the highest dose administered”

“maximum proposed clinical dose of 1400 mg/month IV donanemab. Adjusting for the differences in dosing frequency (weekly in monkey vs. every 4 weeks in human), the estimated AUC exposure margin was ~10-fold.”

“In summary, there were no drug-related adverse effects in aged PDAPP mice administered mE8c at 100 mg/kg/week SC for 5 months, or in cynomolgus monkeys administered donanemab for 6 weeks at 100 mg/kg/week IV.”

“Based on the AUC exposures at the highest doses tested in monkeys with IV and SC dosing for 6 months, these studies established 13-fold and 10-fold safety margins, respectively, for clinical exposures at the MRHD of 400 mg (Table 42).”

“The no-observed-adverse-effect level (NOAEL) was established at the high dose of 100 mg/kg/2-week”

“the NOAEL should be lowered to 100 mg/kg providing safety margins of 10.8 and 6.7 based on AUC0-last and Cmax, respectively.”

“As nipocalimab cannot be ruled out as involved in the mechanism of systemic lymphoproliferation in the euthanised monkey in the 26-week study, the NOAEL should be lowered to 100 mg/kg providing safety margins of 10.8 and 6.7 based on AUC0-last and Cmax, respectively.”

“In an embryo-fetal development study, pregnant marmoset monkeys received canakinumab from gestation days 25 to 109 at doses that produced exposures approximately 11 times that achieved with MRHD and greater (on a plasma area under the curve [AUC] basis with maternal subcutaneous doses of 15, 50, or 150 mg/kg twice weekly).”

“In all the studies, NOEL or NOAEL was the highest dose administered (100 mg/kg/dose IV or 150 mg/kg/dose SC). No signals were identified for general toxicity and for reproductive toxicity.”

“No significant adverse findings were observed at the doses tested which achieved exposure multiples up to 11-fold in rats and 103-fold in monkeys compared to the maximum recommended human dose of 150 mg alirocumab administered subcutaneously once every two weeks.”

“Alirocumab was subcutaneously administered for 6 months to rats at up to 50 mg/kg/week and to monkeys at up to 75 mg/kg/week; no evidence of dose-limiting test item-related toxicity was observed”

“The highest dose used in the 4 week study provided an exposure margin of 5 with regard to Cmax and 12 with regard to AUC.”

“Aside from effects associated with the pharmacological activity of belimumab, there were few noteworthy findings in the toxicology studies indicating a low potential for toxicity.”

“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks). Clinical safety margins are 12-15 relative to the predicted drug exposure following the proposed IV loading dose and subsequent weekly weight-based dosing regimen.”

“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks). Clinical safety margins are 12-15 relative to the predicted drug exposure”

“Exposure achieved in the monkeys at the 100 mg/kg dose level on Day 92 was 13 to 23-fold higher than the AUC in patients receiving either 240 mg flat dose once every 3 weeks (34,212 ug*hr/mL after Dose 6) or 3 mg/kg once every 2 weeks (19,674 ug*hr/mL after Dose 7) on Day 85.”

“Therefore, the NOAEL was considered 100 mg/kg for this study.”

“Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg).”

“In 6/12-Month Repeated-dose Study in Monkeys (102090) denosumab was administrated at doses of 0, 1, 10, and 50 mg/kg. Overall, no effects on organ weights or macroscopic or microscopic evidence of target organ toxicity were noted.”

“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”

“the results of several repeated dose toxicity studies in Rhesus monkeys indicated no toxic effects up to the maximum dose of 5mg/kg.”

“Crizanlizumab exposure levels at 50 mg/kg was AUC0-504h 274500 μg*h/mL, resulting in approximately 13.5-fold higher exposure than in humans receiving the 5 mg/kg dose of crizanlizumab (AUCtau 20400 μg*h/mL).”

“Toxicity data suggests that crizanlizumab is well tolerated up to 25 mg/kg once per week intravenous administration up to 26 weeks. An inflammatory reaction in the blood vessels of several tissues was observed in two animals of the high dose of 50 mg/kg group.”

“No effects on fertility parameters such as reproductive organs, reproductive hormones or menstrual cycle length were observed in sexually mature female cynomolgus monkeys that were administered intravenous doses of lebrikizumab-lbkz up to 25 mg/kg/week for 37 weeks, which was associated with plasma exposure (C avg,ss ) approximately 15 times the human exposure at the MRHD.”

“The NOAEL for lebrikizumab in cynomolgus monkeys was the highest dose tested in all three studies, i.e., 22.7 mg/kg/week in the 6-week intravenous toxicology study and 25 mg/kg/week in the 9-month intravenous toxicology study and 13-week subcutaneous toxicology study.”

“The NOAEL of 100 mg/kg/week in the 26-week IV toxicology study is 10 times the MRHD based on a mg/kg of 10 mg/kg/week. The mean AUC0-168h values associated with the NOAEL are 694,805 and 677,731 µg hr/mL for males and females, respectively, which are 18 times the MRHD based on AUC comparison for males and females.”

“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 exposure (AUC) at the NOAEL dose of 100 mg/kg in monkeys is approximately 18 times higher than the mean AUC at the recommended human dose of 300 mg.”

“The exposure (AUC) at the NOAEL dose of 100 mg/kg in monkeys is approximately 18 times higher than the mean AUC at the recommended human dose of 300 mg.”

“Exposures at the highest dose levels in monkeys after repeat dosing (34900 μg.day/mL) exceeded (19.6 X) the estimated AUC0-14 day of 1773.2 µg*day/mL in humans at the clinically recommended dose of 10 mg/kg every two weeks.”

“The selection of the high dose in all three studies is therefore also accepted as NOAEL (200/100 mg/kg) in the pivotal toxicity studies.”

“Cmax and AUC0-2 wk values at the NOAEL dose in the 6-month SC cynomolgus monkey study exceed the clinical values at the maximum recommended human dose of 300 mg by 21-fold and 23-fold respectively.”

“The target organs of toxicity were SC injection sites, although these findings were considered monitorable in a clinical setting. The mean AUClast at the no observed adverse effect level (NOAEL) of 50 mg/kg was 110,500 µg*hr/ml.”

“No adverse effects on male or female reproductive organs were observed at the only dose level evaluated (30 mg/kg) in a 26-week intravenous toxicity study in monkeys, which was associated with plasma exposures (C ave ) approximately 24 times that in humans at the maximum recommended human dose (450 mg).”

“Since only one dose level of ublituximab was administered, no NOAEL was identified.”

“Exposures achieved in rats at the 50 mg/kg dose level were 32 (males) and 25 (females) times higher than the AUC in patients (2386 µg*h/mL) at the once every 3 days per cycle clinical dose of 9 mg/kg.”

“In the 13-week study, adverse findings in histopathology evaluations of the stomach resulted in the NOAEL to be established at 10 mg/kg/day (30 mg/kg per cycle) in male rats only”

“A fertility study was conducted in female Cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.”

“In all three studies there was a minimal toxic response, with the only noteworthy observations concerning injection-site trauma in the rhesus monkey.”

“As illustrated in Table 2 below, predicted satralizumab plasma exposures (AUC) in humans at steady-state during treatment with the proposed clinical dose were 26-fold lower than those observed at the maternal NOAEL in the ePPND study and at the HD (NOAEL) in the pivotal 26-week study.”

“The NOAEL was the high dose of 50 mg/kg/week.”

“Across the studies, animals were given weekly doses ranging between 1 and 150 mg/kg (150 mg/kg corresponds to 26-fold the proposed MRHD exposure) administered via IV infusion.”

“Following administration for 13 weeks, the NOAEL was considered to be 100 mg/kg per dose, the highest dose evaluated (sex combined mean Cmax of 4.88 mg/mL and AUC of 237 h•mg/mL).”

“The safety margin to the anticipated clinical exposure was 27-fold (based on AUC).”

“The no-observed adverse effect level (NOAEL) was the highest dose tested in the 8-week studies (200mg/kg/week and 20mg/kg/week, respectively, for Study NCD2260 and Study NCD2384). Due to the severity of skin findings in some high-dose animals and mortalities in the low dose group consecutive to GI infection, no NOAEL could be determined in the 26-week study.”

“Once weekly dosing resulted in safety margin levels of 27/14-fold (AUC/Cmax)”

“In the 39-week intermittent intravenous dose toxicity study with 13-week recovery period, NOAEL (be 100 mg/kg, once a week) corresponded to mean AUC(0-384h) for males and females of”

“In an embryo-fetal development study pregnant cynomolgus monkeys were administered mogamulizumab IV once weekly at 40 mg/kg (approximately 27 times the exposure in patients at the recommended dose, based on AUC) from the start of organogenesis until late 3rd trimester.”

“The NOAEL of mogamulizumab was judged to be 40 mg/kg or greater since no toxicologically significant changes were observed in any examination.”

“No adverse effects were observed in monkeys at doses up to 30 times the MRHD (300 mg Q4W IV), based on AUC comparison.”

“The NOAEL was 100 mg/kg/dose • Findings were limited to changes in hematology parameters which included mildly to moderately decreased red blood cell indices for one female monkey at 300 mg/kg/dose on day 180.”

“Finally, model derived human exposure was used to calculate margins of safety, when compared with non-compartmentally derived exposure of free rozanolixizumab in monkeys in the toxicology studies. Margin of safety is in the range of 36-228 and therefore fully acceptable.”

“No adverse effects were seen in male and female cynomolgus monkeys administered subcutaneous (SC) doses of up to 150 mg/kg UCB7665 every 3 days for 4, 13, and 26 weeks.”

“The AUC0- 30days at the monkey SC NOAEL is approximately 37-fold higher than the clinical AUC at the recommended human dose of 200 mg once monthly.”

“NOAELs were identified as the mid doses (MDs) of 30 mg/kg/week (IV) and 60 mg/kg/week (SC) based upon deaths observed at 100 mg/kg/week (IV) and 200 mg/kg/week (SC).”

“No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 37 and 90 times, respectively, the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison)”

“No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 37 and 90 times, respectively, the systemic exposure observed in humans”

“The no observed adverse effect level (NOAEL) identified in the 26-week monkey study was 300 mg/kg/week by the SC route (38-fold the maximum recommended human dose (MRHD))”

“The no observed adverse effect level (NOAEL) identified in the 26-week monkey study was 300 mg/kg/week by the SC route (38-fold the maximum recommended human dose (MRHD)), while the NOAEL for the IV route was not established due to irreversible changes in protein and albumin levels at 150 mg/kg”

“For the NOAEL of 300 mg/kg, a safety margin of >40-fold based on AUC0-72h and Cmax were obtained for the two age groups in the clinical studies, which is considered sufficient.”

“No adverse, product-related findings were observed in the GLP 2-week toxicology study in Wistar Han rats up to the highest doses tested (no-observed-adverse-effect level [NOAEL] =300 mg/kg [IV] and 25 mg/kg [IM]).”

“Though exposures in the monkey studies were up to 42-fold higher than the clinical AUC of 25500 µg*hr/mL determined when nivolumab was administered at the recommended dose of 3 mg/kg on a once every two week schedule, no evidence of autoimmune disease was observed in the monkey toxicology studies.”

“Nivolumab was evaluated in 4- and 13-week repeat dose studies in the cynomolgus monkey and was well-tolerated at doses of up to 50 mg/kg.”

“However, there were no proliferative changes in cynomolgus monkeys administered weekly subcutaneous doses of brodalumab at 90 mg/kg for 6 months (AUC exposure 47-fold higher than in human patients receiving Kyntheum 210 mg every 2 weeks).”

“These changes were at least partially reversible during the six month recovery period. The NOAEL for this study was determined to be 90 mg/kg/dose.”

“Exposure multiples for safety in humans at dose levels that produce maximal neutralising effect of IL-17A were significant; for the AUC 48-108 fold and for the Cmax 53-100 fold.”

“Due to clinical chemistry effects and immunotoxicity (decreases in total lymphocytes, B cells and T cells) observed at the high dose, the NOAEL appears to be 50 mg/kg/week.”

“The exposure margin for the mean AUCDay 161-168 value (5411.67 µg.day/mL) in monkeys was approximately 49.9-fold higher than the mean AUCinf value in psoriasis patients following a single 100 mg/kg SC dose of guselkumab (108.48 µg.day/mL).”

“The no observed adverse effect level (NOAEL) was 50 mg/kg/week for 5-week IV administration and for 24-week SC administration in cynomolgus monkeys”

“Despite the increase in total lymphocytes, it is agreed by the assessor that a NOAEL can be set to 50 mg/kg, which gives a margin to maximum human exposure of approximately 600 (mean for male/female animals), based on Cmax values and 50 based on AUC values.”

“Despite the increase in total lymphocytes, it is agreed by the assessor that a NOAEL can be set to 50 mg/kg, which gives a margin to maximum human exposure of approximately 600 (mean for male/female animals), based on Cmax values and 50 based on AUC values.”

“No effects on fertility parameters as reproductive organ morphology, menstrual cycle length, or sperm/testicular analysis were observed in male or female sexually mature cynomolgus monkeys that were administered nemolizumab-ilto at subcutaneous doses up to 25 mg/kg once every two weeks for 6 months (53 times the MRHD for PN and 72 times for AD, based on AUC comparison).”

“No significant toxicity was noted in this study. The NOAEL was identified as the high dose, 25 mg/kg once every two weeks.”

“A HED-based safety margin of 6.9-fold and an exposure-based safety margin of 55-fold was calculated by comparing doses and exposures at the NOAEL of 30 mg/kg/week over a 6-month treatment period in huCD19 Tg mice in the 09-2153 study and human patients.”

“A HED-based safety margin of 6.9-fold and an exposure-based safety margin of 55-fold was calculated by comparing doses and exposures at the NOAEL of 30 mg/kg/week over a 6-month treatment period in huCD19 Tg mice in the 09-2153 study and human patients.”

“The plasma exposures of anifrolumab at the no-observed-adverse-effect levels (NOAELs) for general toxicity and reproductive and developmental toxicity are >59- and 28-fold higher than the human exposure (AUC) at the MRHD.”

“Based on the arterial inflammation observed, the NOAEL for males is less than 5 mg/kg IV and 15 mg/kg SC. If the observed arteritis is not factored into the NOAEL determination, the NOAEL of anifrolumab for males is at least 50 mg/kg IV and 60 mg/kg SC, the highest doses tested.”

“The NOAEL in this study was the highest dose tested (50 mg/kg/week) with an exposure level at Week 26 being 69-fold greater than the highest exposure in human subjects (a mean corresponding AUC0–168hr of 86 mg•hr/mL)”

“The NOAEL was 50 mg/kg/week, the highest dose tested, with exposure levels that were significantly above the recommended clinical dose in psoriasis patients (150 mg SC on Weeks 0 and 4, then every 12 weeks), providing a margin of exposure of approximately 70.”

“the NOAEL (0.5 mg/kg/day, 1660 µg.hr/mL AUC0-24, Week 52) represents a 74x exposure margin to the anticipated clinical dose (0.20 mg/kg, 22.4 µg.hr/mL AUC0-24).”

“The NOAEL for this study was 0.5 mg/kg/day based on thrombus formation. The exposure at the NOAEL was approximately 70-times that of the intended clinical exposure.”

“The NOAEL of 50 mg/kg/week from the 6-month study provided a safety margin of > 80-fold compared to the recommended clinical doses based on systemic exposure comparisons.”

“The NOAEL was identified at the high dose of 50 mg/kg/week based upon no findings of dose-limiting toxicity or target organs of toxicity. Exposure at the NOAEL provided a safety margin >80 times the exposures at proposed clinical doses.”

“The NOAEL of 100 mg/kg q4 weeks provides adequate safety margin (greater than 90-fold on an AUC basis) for the proposed clinical dose of 100 mg SC q4 weeks.”

“The NOAEL was the high IV dose of 100 mg/kg q4 weeks or the SC dose of 10 mg/kg q4 weeks; the NOAEL for IV dosing provided a safety margin of approximately 70-fold compared to the maximum recommended clinical dose based on systemic exposure comparisons.”

“The highest subcutaneous doses tested in the combined 3- and 6-month toxicity (150 mg/kg twice weekly) and the ePPND (50 mg/kg Q2W) studies (both NOAELs) provided serum exposure (AUC) margins >100 and ~17 times that anticipated in humans at the maximum recommended dose of 140 mg QM.”

“The highest subcutaneous doses tested in the combined 3- and 6-month toxicity (150 mg/kg twice weekly) and the ePPND (50 mg/kg Q2W) studies (both NOAELs) provided serum exposure (AUC) margins >100 and ~17 times”

“In the chronic toxicity study, exposure in the high-dose group was > 100x greater than the maximum clinical exposure.”

“No adverse effects of IV eptinezumab were observed in either the rat 4-week or monkey 6-month general toxicology studies; the NOAELs were determined to be 100 mg/kg/week and 150 mg/kg every 2 weeks, respectively.”

“The mean steady-state Cmax value following a 45 mg/kg twice-weekly SC dose in monkeys was approximately 116-fold higher than the median Cmax value following 4 weekly 90 mg SC doses in subjects with psoriasis.”

“ustekinumab was generally well tolerated under a regimen of twice weekly subcutaneous dosing at 45 mg/kg for 6 months in cynomolgus monkeys and adequate margins of exposure over the human clinical exposure were demonstrated. No target organs were identified and there was no delayed toxicity after dosing had stopped.”

“No effects on fertility parameters were observed in male or female cynomolgus monkeys that were administered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once every two weeks for 3 months (133 or 155 times the MRHD, respectively, based on AUC comparison).”

“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.”

“Based on plasma exposures measured in toxicity studies in hamsters, the safety margins for the 140 mg Q2W, 420 mg QM, and 420 mg Q2W doses are 112, 48 and 20X, respectively. In monkeys, the safety margins are 744, 300, and 134X the recommended human doses of 140 mg Q2W, 420 mg QM, and 420 mg Q2W, respectively.”

“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection. Two monkeys/sex/group were allowed a 25-week treatment-free recovery period. The NOAEL is considered to be 300 mg/kg/week, the highest dose tested.”

“These nonclinical safety data provide adequate margins of exposure between the observed 6-month repeat-dose study SC NOAEL (300 mg/kg) and the maximum recommended human dose (MRHD) of 210 mg SC every 4 weeks (approximately 134 times the MRHD on an AUC at steady state basis, and 128 times the MRHD on a Cmax at steady state basis).”

“The NOAEL was the highest dose tested for each route of administration in each repeat-dose study. Serum cholesterol was minimally to mildly decreased at the 300 mg/kg dose level in most repeat-dose studies.”

“The NOAEL doses were associated with systemic exposures (AUC) that provided 153- to 271-fold exposure margins compared to the recommended clinical dose.”

“NOAELs of 10 mg/kg IV and 30 mg/kg SC were identified. The primary finding at a dose of 25 mg/kg IV was a post-dose reaction in one high-dose female that included bruising in the areas of the eyes, face, chest and lower abdomen, a decrease in platelet counts, and abnormal erythrocytes after the fourth dose.”

“The no observed adverse effect level (NOAEL) was 400 mg/kg.. The maximal exposure attained was approximately 200-fold higher than that observed at the maximal recommended human dose (approximately 50 µg/ml)”

“In rats and monkeys histopathology revealed cellular vacuolation, present mainly in macrophages, in a number of organs (lymph nodes; injection sites, spleen; adrenal; uterine, cervix; choroid plexus of the brain, and in the epithelial cells of the choroid plexus).”

“Thus, the top weekly intravenous dose of 1000 mg/kg/dose in rats and 500 mg/kg/dose in monkeys were regarded as the no observed adverse effect level (NOAEL) doses, with AUC exposures approximately 200-times greater than clinical exposure at the maximum recommended human dose (Table 55).”

“Thus, the top weekly intravenous dose of 1000 mg/kg/dose in rats and 500 mg/kg/dose in monkeys were regarded as the no observed adverse effect level (NOAEL) doses, with AUC exposures approximately 200-times greater than clinical exposure at the maximum recommended human dose”

“In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week).”

“In the 39 weeks study, most of these changes were reversible within the 20-week recovery period. In this study, the NOAEL was 32 mg/kg, with an AUC of 304 800 µg*h/ml.”

“Increased bleeding (dose dependent and reversible) was observed at all doses tested and a NOAEL and exposure margin to the clinic is therefore not possible to define.”

“In this study, the NOAEL was set to 4 mg/kg/day based on a premature sacrifice of one male in the high dose-group administered 13.5 mg/kg 3 times/day (40 mg/kg/day) on day 85 due to persistent signs of anaemia”

“At the end of the 39-week study in monkeys, exposure to ramucirumab ranged from approximately 0.2-5.6 times the exposure after multiple doses in humans at the recommended dose of 8 mg/kg.”

“The target organs identified in repeated dose Cynomolgus monkey toxicity studies were kidney (glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphyseal growth plate) and female reproductive organs (decreased weight of ovaries and uterus)”

“The primary toxicities identified in chimpanzees were infusion related reactions, thrombocytopenia, anemia, leukopenia, in addition to elevated AST values.”

“Single IV administration of elotuzumab at dose levels of 30 or 100 mg/kg (≤ AUC[INF] range of 335 to 447 mg•h/mL) were well tolerated.”

“NI-0501 was tolerated in monkeys up to 30 mg/kg/week, the highest dose tested.”

“In addition, in both monkey studies, exposure of pembrolizumab at all dose levels tested exceeded that measured in humans at the intended clinical dose and schedule of 2 mg/kg once every 3 weeks.”

“Overall, pembrolizumab was well tolerated and the NOAEL in both studies was the highest dose tested.”

“Axatilimab-related microscopic findings included dose-dependent accumulation of basophilic material within numerous organs/tissues and alterations in femoral bone thickening of the growth plate and metaphysis and degeneration of the growth plate at all dose levels.”

“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”

“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”

“However, ophthalmic examinations revealed a dose-related increase of bilateral crystalline deposits in the lens capsule of treated male mice. The relevance of this finding for humans is not known.”

“Therefore, under these study conditions, the dose of 100 mg/kg/week was considered to be the no-observed adverse effect level (NOAEL)”

“As no margins to clinical exposure has been calculated for the surrogate antibody, Cmax at NOAEL in the 4-week study was compared to the IC90 of NF-kB inhibition in primary mouse dermal fibroblasts.”

“The NOAEL for the 6-month toxicity study was the highest dose 50 mg/kg/dose.”

“gave no indication of toxicity or statistically significant deviations from normal caused by the test article for the described parameters.”

“Common and reproducible effects of natalizumab in cynomolgus monkeys were: • dose related, significantly increased counts of WBC even at the end of recovery periods • elevated reticulocyte counts • severe increases in spleen weights”

“The CHMP notes that a NOAEL has not been identified for the 28-day study in the rat.”

“(NOAEL) for males and females was lower than 5 mg/kg/day based on the liver-related changes, the slight decrease in erythrocyte parameters, and changes related to hematopoiesis”

“No-Observed-Adverse-Effect-Level: 100 mg/kg, once per week”

“There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).”

“Toxicity to skin and diarrhoea was the primary toxicity of panitumumab in monkeys. These effects were severe enough to cause a significant number of unscheduled deaths.”

“The most notable concern identified during non-clinical testing was a low incidence of serious irAEs, manifested as colitis or dermatitis, for which no safety margin could be determined.”

“Fatal colitis and persistent dermatitis/rash observed in two animals along the toxicology programme were considered by the Applicant as immune-related adverse event (irAEs) linked with the intended pharmacologic basis of CTLA-4 blockade.”