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Actemra | tocilizumab | IL-6R | Monoclonal antibodies | https://theatlas.bio/p/actemra | Cynomolgus monkey only | The cynomolgus monkey was chosen as the relevant responder species and a comprehensive toxicology program was conducted with single- and multiple-dose studies up to duration of 6 months to characterize the overall safety of tocilizumab. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=15 | Cross-reacts with monkey IL-6R in vitro and in vivo; no binding to rat, mouse or rabbit IL-6R | The cynomolgus monkey was chosen as the pharmacologically relevant species because tocilizumab cross-reacts with monkey IL-6R under in vitro and in vivo conditions. | EMA assessment report | 13 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=13 | Yes: rodent analogue MR16-1 (anti-mouse IL-6R), used for supportive mouse toxicology studies | Additionally supportive data from diverse studies conducted with the rodent analogue MR16-1 also were included in the assessment of the data. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=15 | 26 | 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. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=16 | Cynomolgus monkey IV studies: 4-week daily up to 50 mg/kg/day and 6-month weekly up to 100 mg/kg/week | 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. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=16 | IV | 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. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=16 | No special hazard in conventional genotoxicity studies | Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. | EMA assessment report | 17 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=17 | Not conducted; malignancy risk of IL-6 receptor blockade unknown | No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e5365ff-cb2a-4b16-b2c7-e35c6bf2de13 | Monkey EFD: no teratogenicity; increased abortion/embryo-fetal death at 10 and 50 mg/kg (1.25x MRHD and higher) | Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e5365ff-cb2a-4b16-b2c7-e35c6bf2de13 | Dedicated cardiovascular studies in cynomolgus monkeys; no effect on cardiac electrophysiology, cardiac tissue or pro-thrombotic activity up to 50 mg/kg IV | Tocilizumab showed no effect on the cardiac electrophysiological performance, cardiac tissue integrity or systemic pro-thrombotic activities IV at doses up to 50 mg/kg. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=14 | Not stated in public reviews | null | null | null | null | No major clinical pathology or histopathology findings; exposure 8- to 10-fold above maximum human exposure | 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 | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=16 | Immunogenic in monkeys with inverse dose relationship (ADA lower at high doses) | The observed anti-tocilizumab response showed a clear inverse dose relationship, an effect which is frequently observed with molecules of this type. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=16 | Placental transfer: monkey fetal plasma 39% and 60% of maternal at 10 and 50 mg/kg/day | In a segment II-embryo-foetal development study in cynomolgus monkeys foetal plasma concentrations of tocilizumab were 39% and 60% of the maternal plasma concentration after application of 10 and 50 mg/kg/day, resp. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=15 | Neutropenia from IL-6R blockade, without bone marrow changes in monkeys | A signal toward reduction of neutrophils was observed in the 2-week toxicity study with a clear pronounced manifestation in the 4-week daily treatment cynomolgus study with no manifestation in the bone marrow. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/roactemra-epar-public-assessment-report_en.pdf#page=16 |
Adakveo | crizanlizumab | P-selectin | Monoclonal antibodies | https://theatlas.bio/p/adakveo | Cynomolgus monkey only | The toxicity of crizanlizumab was evaluated in GLP-compliant 4- and 26-week toxicology studies in cynomolgus monkeys. | FDA multi-discipline review | 30 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=30 | Binds human and cynomolgus platelet P-selectin; no binding to dog or rat P-selectin | Crizanlizumab bound to human and cynomolgus monkey platelets expressing P-selectin, but did not bind to platelets expressing P-selectin from dog or rat. Thus, monkey is an appropriate toxicological animal model to study crizanlizumab. | FDA multi-discipline review | 34 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=34 | No surrogate; the clinical antibody (earlier SelG1 material and commercial SEG101) was tested in cynomolgus monkeys | The preclinical safety profile of crizanlizumab was mostly characterised using the previous CHO-K1-derived material (SelG1) in Cynomolgus monkeys. The current crizanlizumab SEG101 was tested in the enhanced pre- and postnatal developmental toxicity study. | EMA assessment report | 37 | https://www.ema.europa.eu/en/documents/assessment-report/adakveo-epar-public-assessment-report_en.pdf#page=37 | 26 | 26-Week Intravenous Injection Toxicity and Toxicokinetic Study (Seven Doses) with SelG1 in Cynomolgus Monkeys with a 4-Week Recovery Phase/8259995 | FDA multi-discipline review | 38 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=38 | GLP cynomolgus studies: 4-week IV every 2 weeks up to 25.2 mg/kg; 26-week IV every 4 weeks up to 50 mg/kg | 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. | FDA multi-discipline review | 30 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=30 | Intravenous (bolus) | Route of administration: Intravenous (bolus) injection | FDA multi-discipline review | 38 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=38 | Not conducted (ICH S6) | Genotoxicity studies are not considered relevant for a biological product in accordance with ICH S6. | FDA multi-discipline review | 42 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=42 | Not conducted; weight-of-evidence risk assessment concluded low carcinogenic risk | Instead, a comprehensive risk assessment including feasibility assessment of available animal models for carcinogenicity testing was performed. Based on the weight of evidence the risk of carcinogenicity can be considered low. | EMA assessment report | 38 | https://www.ema.europa.eu/en/documents/assessment-report/adakveo-epar-public-assessment-report_en.pdf#page=38 | Monkey ePPND (IV, organogenesis to delivery): non-dose-related increased fetal loss (abortions/stillbirths) at ~2.8x clinical exposure | In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at ... | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b2b7f8b4-fe9a-4a86-8129-9e43f99a20c6 | Incorporated into 4- and 26-week monkey studies; no cardiovascular, CNS or respiratory effects | No effects on cardiovascular, CNS or respiratory function were observed in Cynomolgus monkeys in the 26-week repeat-dose toxicity study. | EMA assessment report | 36 | https://www.ema.europa.eu/en/documents/assessment-report/adakveo-epar-public-assessment-report_en.pdf#page=36 | Not stated in public reviews | null | null | null | null | Well tolerated up to 25 mg/kg for 26 weeks; vascular inflammation in several tissues in two animals at 50 mg/kg | 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. | EMA assessment report | 42 | https://www.ema.europa.eu/en/documents/assessment-report/adakveo-epar-public-assessment-report_en.pdf#page=42 | ADA in 40% of treated monkeys in the 26-week study, with hypersensitivity reactions in some animals | Primate anti-human antibodies (ADAs) were detected in toxicological studies in Cynomolgus monkeys, accompanied by hypersensitivity reactions in some animals. Anti-human antibodies against SelG1 were detected in 40% of all treated animals at least once throughout the observation period in a 26-week repeat-dose toxicity ... | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/adakveo-epar-public-assessment-report_en.pdf#page=34 | TCR: binding to platelets (blood, spleen) and blood vessels in most human and cynomolgus tissues | Crizanlizumab binding was seen in platelets in the blood and spleen, and in blood vessels in the majority of tissues examined of both human and cynomolgus monkey. | FDA multi-discipline review | 30 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=30 | Fetal loss with placental infarcts (pharmacology or immunogenicity); vascular inflammation in monkeys | The cause for the fetal losses in monkeys is unknown but may be related in part due to the development of anti-drug antibodies against crizanlizumab-tmca. | FDA multi-discipline review | 31 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761128Orig1s000MultidisciplineR.pdf#page=31 |
Adbry | tralokinumab | IL-13 | Monoclonal antibodies | https://theatlas.bio/p/adbry | Cynomolgus monkey only | Therefore, cynomolgus monkey was selected as a single pharmacologically relevant species for use in nonclinical studies with tralokinumab. | FDA integrated review | 124 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=124 | 95% IL-13 sequence homology with cynomolgus monkey versus 55-62% in rodents; no mouse cross-reactivity | The IL-13 amino acid sequence homology between human and cynomolgus monkey is 95%, whereas that between human and rodent is 55% for mouse and 62% for rat. Tralokinumab did not cross-react with mouse IL-13. | FDA integrated review | 124 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=124 | No surrogate; the clinical antibody was tested in cynomolgus monkey | Therefore, cynomolgus monkey was selected as a single pharmacologically relevant species for use in nonclinical studies with tralokinumab. | FDA integrated review | 124 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=124 | 26 | 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. | FDA integrated review | 131 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=131 | Cynomolgus monkey 4-, 13- and 26-week weekly IV studies; 4- and 13-week weekly SC studies | 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. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/adtralza-epar-public-assessment-report_en.pdf#page=25 | IV and SC | Three IV and two SC repeat-dose toxicity studies were submitted. | FDA integrated review | 131 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=131 | Not conducted (ICH S6(R1)) | Genotoxicity No studies have been performed in accordance with ICH S6(R1). | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/adtralza-epar-public-assessment-report_en.pdf#page=26 | Not conducted; weight-of-evidence assessment found no concern for increased carcinogenic risk | In line with ICH S6 (R1), a weight of evidence approach has been provided which suggests that there are no identified concerns for increased carcinogenic risk with the use of tralokinumab. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/adtralza-epar-public-assessment-report_en.pdf#page=26 | Monkey fertility, EFD, PPND and ePPND studies; ePPND: no embryofetal toxicity, malformations or infant developmental effects to 6 months | No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth to 6 months of age. | FDA integrated review | 117 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=117 | Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or behavioral effects up to 100 mg/kg/week | Repeated administration of tralokinumab up to 100 mg/kg/week had no adverse effects on the evaluated parameters for cardiovascular, respiratory, and behavioral effects. | FDA integrated review | 124 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=124 | Not stated in public reviews | null | null | null | null | NOAEL 90 mg/kg/week (13-week SC) and 100 mg/kg/week (26-week IV); no adverse effects or target organs | 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. | FDA integrated review | 131 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000IntegratedR.pdf#page=131 | No significant modulation of CD4/CD8 T cells, NK cells or mature B cells in 26-week monkey study | In addition, the 26-week study included an immunophenotyping assessment which indicated that tralokinumab did not significantly modulate any of the immune cell populations investigated which including CD4 and CD8 T cells, NK cells and mature B cells. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/adtralza-epar-public-assessment-report_en.pdf#page=25 | Placental transfer in monkeys, neonate serum levels comparable to or above maternal | There was clear evidence of placental transfer in both studies with neonate serum levels measured comparable or even in excess of maternal levels. | EMA assessment report | 27 | https://www.ema.europa.eu/en/documents/assessment-report/adtralza-epar-public-assessment-report_en.pdf#page=27 | Low circulating IL-13 in naive monkeys may mask pharmacological effects, limiting predictivity | Whilst there were no apparent tralokinumab related effects in these studies, this could be explained by very low circulating IL-13 levels in naïve monkeys. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/adtralza-epar-public-assessment-report_en.pdf#page=25 |
Aduhelm | aducanumab | Aggregated amyloid-β | Monoclonal antibodies | https://theatlas.bio/p/aduhelm | Cynomolgus monkey and transgenic Tg2576 mouse (murine surrogate and aducanumab); rat for reproductive studies | The toxicology of aducanumab was adequately assessed in general toxicity studies in monkey and Tg2576 mouse. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=7 | Target is aggregated Aβ, absent in rodents and non-aged monkeys, so neither rat nor monkey is fully relevant | Neither rat nor monkey is a particularly relevant species for general toxicity because of the lack of aggregated amyloid in rodent or non-aged monkey. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=2 | Yes: murine chimeric analog ch12F6A, used for 13-week and 6-month toxicity studies in aged Tg2576 mice | In Tg2576 mouse, ch12F6A was administered for 13 weeks (0, 10, 70, or 500 mg/kg) or 6 months (0, 10, 40, or 250 mg/kg) weekly by intravenous injection; in each study, a separate group received aducanumab (500 or 250 mg/kg, respectively) according to the same regimen. | FDA pharmacology/toxicology review | 3 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=3 | 26 | 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. | FDA pharmacology/toxicology review | 48 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=48 | Chronic Tg2576 mouse study with murine analog ch12F6A; 4-week monkey and 13-week Tg2576 mouse studies | 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). | FDA pharmacology/toxicology review | 3 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=3 | IV (weekly slow bolus) | In Tg2576 mouse, ch12F6A was administered for 13 weeks (0, 10, 70, or 500 mg/kg) or 6 months (0, 10, 40, or 250 mg/kg) weekly by intravenous injection | FDA pharmacology/toxicology review | 3 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=3 | Not conducted; antibodies unable to interact with genetic material | No genotoxicity studies of aducanumab were conducted because antibodies are generally unable to interact with genetic material. | FDA pharmacology/toxicology review | 34 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=34 | Not conducted (target absent in wild-type rodents); no proliferative lesions in monkey or Tg2576 studies; FDA agreed | Carcinogenicity studies of aducanumab were not conducted because its target, aggregated Aβ, is not present in wild-type rodents. No increases in the incidence or severity of proliferative lesions were observed in the 4-week study in monkey or the 13- or 26-week studies in aged Tg2576 mouse. | FDA pharmacology/toxicology review | 34 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=34 | Rat fertility, embryo-fetal and pre/postnatal studies (up to 1000 mg/kg/week IV): no adverse effects; rat of limited relevance | There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=7 | Incorporated into monkey and Tg2576 toxicity studies; no ECG, CNS or pulmonary effects | Safety pharmacology was assessed in the pivotal toxicology studies of aducanumab in cynomolgus monkeys and of aducanumab and ch12F6A in aged Tg2576 mice. There were no adverse effects on ECG in the 4-week monkey study or on CNS- or pulmonary-related clinical signs in either species. | FDA pharmacology/toxicology review | 23 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=23 | Not stated in public reviews | null | null | null | null | 13-week transgenic mouse ch12F6A NOAEL 10 mg/kg/week; brain meningeal vascular inflammation and hemorrhage at 70 mg/kg/week | 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. | FDA pharmacology/toxicology review | 48 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=48 | No anti-drug antibodies in the 4-week monkey study | There were no ADA-positive samples. | FDA pharmacology/toxicology review | 26 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=26 | TCR: binding to amyloid plaques and cerebral vessel walls; other staining cytoplasmic and clinically irrelevant | All other staining was cytoplasmic, and, therefore, clinically irrelevant based on the inability of aducanumab to enter cells. | FDA pharmacology/toxicology review | 48 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=48 | ARIA-like risk: surrogate exacerbated cerebral amyloid angiopathy (vascular inflammation, thrombosis, hemorrhage) in aged transgenic mice | resulted in increased incidence and/or severity of meningeal and/or cerebral vascular inflammation, thrombosis, and/or hemorrhage at the mid and high doses consistent with slight exacerbation of the cerebral amyloid angiopathy that increases with aging in this mouse model. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000PharmR.pdf#page=7 |
Aimovig | erenumab | CGRP receptor | Monoclonal antibodies | https://theatlas.bio/p/aimovig | Cynomolgus monkey only | The pivotal, GLP-compliant toxicology studies were conducted in cynomolgus monkey, the only biologically relevant species | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=5 | High affinity for monkey and human CGRP-R; no affinity for rodent CGRP-R or related family members | Erenumab has high affinity for the monkey and human CGRP-R, but not for rodent CGRP-R or closely related CGRP-R family members. | FDA pharmacology/toxicology review | 14 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=14 | No surrogate; the clinical antibody was tested in monkeys (no pharmacological activity in other species) | General toxicology studies were conducted exclusively in monkeys, due to a lack of pharmacological activity in other species. | FDA pharmacology/toxicology review | 33 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=33 | 26 | 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). | FDA pharmacology/toxicology review | 33 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=33 | Monkey: 1-month IV with 4-month recovery; combined 3- and 6-month study; enhanced pre- and postnatal development study | 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 | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=5 | Subcutaneous and intravenous | SC doses of 0, 25, 75, 100, and 225 mg/kg were administered 2x per week or a single IV dose of 0 or 100 mg/kg was administered | FDA pharmacology/toxicology review | 33 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=33 | Not conducted (ICH S6(R1)) | no genotoxicity studies have been conducted, in accordance with ICH S6(R1). | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/aimovig-epar-public-assessment-report_en.pdf#page=30 | Not conducted; waived (no erenumab activity in rodents; no hyperplasia or neoplasia in toxicology studies) | Carcinogenicity studies were waived, based on the lack of erenumab activity in rodents, histopathological data from the submitted toxicology studies showing no carcinogenic risk factors (i.e. hyperplasia or neoplasia) | FDA pharmacology/toxicology review | 33 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=33 | Monkey ePPND study: unremarkable results; NOAEL 50 mg/kg | The results from the enhanced PPND study were unremarkable; therefore, the NOAEL was 50 mg/kg. | FDA pharmacology/toxicology review | 34 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=34 | Telemetry study in monkeys (0, 25 or 225 mg/kg SC): no adverse cardiovascular, pulmonary or neurobehavioral effects | In a safety pharmacology study, telemetry-instrumented conscious monkeys treated with 0, 25, or 225 mg/kg (SC) erenumab (6 males/group) showed no adverse cardiovascular, pulmonary, or neurobehavioral effects. | FDA pharmacology/toxicology review | 32 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=32 | Not stated in public reviews | null | null | null | null | NOAELs: 150 mg/kg twice weekly (3- and 6-month study) and 50 mg/kg Q2W (ePPND); AUC margins >100 and ~17 times human | 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 | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=5 | ADA in 3 low-dose monkeys reduced drug exposure (Cmax and AUC) | ADA was also observed in 3 LD animals, which resulted in reduced drug exposures (Cmax and AUC0-7d). | FDA pharmacology/toxicology review | 33 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=33 | Volume of distribution typical of a monoclonal antibody, suggesting limited extravascular distribution | Volume of distribution typical of a monoclonal antibody suggesting limited extravascular distribution. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/aimovig-epar-public-assessment-report_en.pdf#page=30 | Cardiovascular risk of chronic CGRP antagonism, as CGRP is a potent vasodilator | Because CGRP is known to be involved in regulation of the cardiovascular system and to be a potent vasodilator, concerns were raised regarding potential adverse effects of chronic CGRP antagonism in humans | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000PharmR.pdf#page=5 |
Ajovy | fremanezumab | CGRP | Monoclonal antibodies | https://theatlas.bio/p/ajovy | Rat and cynomolgus monkey (chronic study in monkey only) | Because the shorter duration studies in rat and monkey demonstrated no toxicity, the chronic study was conducted only in cynomolgus monkey. | FDA pharmacology/toxicology review | 71 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=71 | Pharmacologically active in rat, rabbit, monkey and human in binding and functional in vitro assays | Fremanezumab is pharmacologically active in rat, rabbit, monkey, and human, as characterized in a series of binding and functional in vitro assays. | FDA pharmacology/toxicology review | 4 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=4 | No surrogate; the clinical antibody was tested in rat and cynomolgus monkey | General toxicology studies were conducted in rat and cynomolgus monkeys. In general, fremanezumab was well tolerated, with no significant adverse effects in either species. | FDA pharmacology/toxicology review | 71 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=71 | 26 | 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. | EMA assessment report | 23 | https://www.ema.europa.eu/en/documents/assessment-report/ajovy-epar-public-assessment-report_en.pdf#page=23 | Sprague-Dawley rat 1- and 3-month; cynomolgus monkey 1-, 3- and 6-month | The pivotal (GLP) toxicity studies were conducted in Sprague-Dawley rat (1- and 3-month) and cynomolgus monkey (1-, 3-, and 6-month). | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=5 | IV and SC (weekly) | In the 3-month study in cynomolgus monkeys, animals received weekly IV or SC injection of fremanezumab at doses levels of up to 300 mg/kg. | FDA pharmacology/toxicology review | 71 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=71 | Not conducted (ICH S6(R1)) | Genotoxicity studies have not been conducted, in accordance with ICH S6(R1). | EMA assessment report | 24 | https://www.ema.europa.eu/en/documents/assessment-report/ajovy-epar-public-assessment-report_en.pdf#page=24 | Not conducted; weight-of-evidence (CGRP knockout data, CGRP biology, tox findings) judged studies unnecessary | Based on published studies in CGRP knockout animals and on the biological activity of CGRP (e.g., promotion of angiogenesis) and on the results from the sponsor’s studies of fremanezumab, it was concluded that standard carcinogenicity studies of fremanezumab were not needed. | FDA pharmacology/toxicology review | 6 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=6 | Rat fertility + EFD, rabbit EFD and rat PPND: no adverse effects on fertility or pregnancy outcome | Reproductive and developmental toxicity was assessed in a fertility + EFD study in rats, a EFD study in rabbits and a PPND study in rats. These studies have not revealed any adverse effects on fertility and pregnancy outcome. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/ajovy-epar-public-assessment-report_en.pdf#page=26 | Rat CNS/respiratory: no adverse effects; monkey IV cardiovascular assessment: minimal effects | No adverse effects on CNS or respiratory parameters were observed in rat following acute subcutaneous (SC) doses of fremanezumab (0, 100, and 300 mg/kg). Minimal cardiovascular effects were observed in monkey following intravenous (IV) bolus doses of 0 or 100 mg/kg | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=5 | Not stated in public reviews | null | null | null | null | Chronic monkey study, weekly SC up to 300 mg/kg: no adverse effects except injection-site inflammation | 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. | FDA pharmacology/toxicology review | 71 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=71 | Ciliary vessel inflammation with immune complex deposition in a monkey study (hypersensitivity-type); not reproduced in the 6-month study | The inflammation was accompanied by increased monocytes and deposition of immune complexes (C3 complement, IgG and/or IgM). These findings were not reproduced in the 6 month study. | EMA assessment report | 24 | https://www.ema.europa.eu/en/documents/assessment-report/ajovy-epar-public-assessment-report_en.pdf#page=24 | Low Vd (0.07-0.14 L/kg) across species; tissue distribution studies not conducted | Vd was low in all species (0.07-0.14 L/kg). Tissue distribution and metabolism studies were not requested or conducted. | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=5 | Cardiovascular risk of long-term CGRP antagonism (loss of vasodilation), especially with cardiovascular risk factors | Because of the potent vasodilatory properties of CGRP, concerns were raised regarding long-term antagonism of the CGRP in humans, particularly in patients with cardiovascular risk factors. | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761089Orig1s000PharmR.pdf#page=5 |
Alhemo | concizumab | TFPI | Monoclonal antibodies | https://theatlas.bio/p/alhemo | Cynomolgus monkey only (rabbit used for efficacy and PK/PD) | The rabbit was selected as efficacy species, the Cynomolgus monkey was selected as the nonrodent safety species and both species were used in pharmacokinetic/pharmacodynamic (PK/PD) assessment. | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=28 | Sub-nanomolar TFPI binding with similar constants in rabbit, monkey and human (KD 0.22, 0.06, 0.04 nM) | Characterisation of concizumab binding to TFPI showed high affinity, sub-nanomolar binding to rabbit, NHP and human TFPI with similar binding constants (KD of 0.22 nM, 0.06 nM and 0.04 nM for rabbit, Cynomolgus monkey and human, respectively). | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=29 | No surrogate; the clinical antibody was tested in cynomolgus monkeys | Toxicity studies of up to 52-week duration have been conducted in Cynomolgus monkeys with a normal coagulation system (non-haemophilic). | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=28 | 52 | 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. | EMA assessment report | 36 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=36 | Monkey studies up to 52 weeks; 26-week study: SC 3 or 9 mg/kg/day or IV 30 mg/kg/week, 13-week recovery | 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. | EMA assessment report | 36 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=36 | Subcutaneous (once daily) and intravenous (once weekly) | toxicity studies, concizumab was dosed i.v. once weekly or s.c. once daily. | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=28 | Not conducted (ICH S6(R1)) | According to ICH S6(R1), genotoxicity studies were not performed. | EMA assessment report | 37 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=37 | Not conducted; weight-of-evidence evaluation with up to 52-week monkey data suggests no carcinogenic potential | A thorough weight of evidence evaluation, in combination with data from the repeat dose toxicity studies, which included exposure to concizumab up to 52 weeks, does not suggest that concizumab has carcinogenic potential. | EMA assessment report | 37 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=37 | Fertility unaffected in 26-week monkey study up to 9 mg/kg/day SC (3400-fold human exposure) | In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC 0 to 24h ), concizumab-mtci did not affect fertility | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=156f6404-1f6f-417f-bcf8-f07a27a82cc1 | Incorporated into monkey DRF, 13-week and 52-week studies; no effects up to 200 mg/kg/week IV and 50 mg/kg/day SC | No effects of concizumab on safety pharmacology endpoints were observed in any of these studies at repeat doses up to 200 mg/kg/once weekly (i.v.) and 50 mg/kg/day (s.c.). | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=30 | Not stated in public reviews | null | null | null | null | 52-week NOAEL 0.5 mg/kg/day SC (~70x clinical exposure), based on thrombus formation | 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. | EMA assessment report | 37 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=37 | ADA induced in all monkey repeat-dose studies, causing loss of exposure without affecting study interpretation | Concizumab induced ADA in all repeat dose toxicity studies. ADA led to loss in exposure although this did not affect the overall interpretation of the studies. | EMA assessment report | 38 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=38 | TCR: binding to TFPI-expressing tissues; cytoplasmic off-target binding unlikely to be relevant in vivo | In a tissue cross reactivity study, concizumab showed anticipated binding to tissue in which TFPI is expressed. Off target binding was observed for cytoplasm but it is very unlikely that concizumab will be able to reach the cytoplasm in vivo. | EMA assessment report | 38 | https://www.ema.europa.eu/en/documents/assessment-report/alhemo-epar-public-assessment-report_en.pdf#page=38 | Thrombosis from exaggerated procoagulant pharmacology: thrombi at ≥10 (13-week), ≥3 (26-week) and ≥1 mg/kg/day (52-week) SC | Pharmacology mediated formation of thrombi manifested in cynomolgus monkeys dosed subcutaneously during toxicology studies of 13-weeks (≥ 10 mg/kg/day), 26-weeks (≥ 3 mg/kg/day) and 52-weeks (≥ 1 mg/kg/day) in duration | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=156f6404-1f6f-417f-bcf8-f07a27a82cc1 |
Andembry | garadacimab | Factor XIIa | Monoclonal antibodies | https://theatlas.bio/p/andembry | Mouse and cynomolgus monkey | 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. | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | Garadacimab cross-reacts with mouse, rabbit and cynomolgus βFXIIa | Garadacimab affinity is cross reactive with mouse, rabbit and cynomolgus βFXIIa (700pM, 400pM and 19nM respectively). | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/andembry-epar-public-assessment-report_en.pdf#page=29 | No surrogate; the clinical antibody was tested in mice, cynomolgus monkeys and rabbits | 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. | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | 26 | 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. | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | GLP 4-week CD-1 mouse and 26-week cynomolgus monkey studies, IV and SC; immunogenicity precluded longer mouse studies | 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. | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | Intravenous and subcutaneous | 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. | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | Not conducted (ICH S6(R1)) | Genotoxicity studies with biologics such as garadacimab are not required. | FDA integrated review | 127 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=127 | Not conducted; weight of evidence (26-week monkey study, literature) indicates low or negligible carcinogenic potential; rodent study not feasible | Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible. Further, there appears to be a low or negligible carcinogenic potential based on the results of the 26-week monkey study and review of the published literature regarding chronic inhi... | FDA integrated review | 127 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=127 | Rabbit PPND study: no effects on F1 survival, development, neurobehavior or reproductive performance | For the F1 generation, no garadacimab-related effects were observed on mortality, clinical signs, body weight, developmental signs, functional observation battery, eye-blink response, presence of motile sperm, reproductive performance, cesarean section parameters, or preweaning or postweaning macroscopic observations. | FDA integrated review | 103 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=103 | Incorporated into 26-week monkey study: no effects on ECG, blood pressure, respiration or pulse up to 100 mg/kg IV, 200 mg/kg SC | Safety pharmacology parameters were incorporated into the pivotal repeat-dose 26-week monkey toxicology study. With intravenous (IV) doses up to 100 mg/kg/week and subcutaneous (SC) doses up to 200 mg/kg/week, no treatment-related effects on electrocardiogram, blood pressure, respiration rate, or pulse rate were observ... | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | Not stated in public reviews | null | null | null | null | 26-week monkey NOAEL 30 mg/kg/week IV and 60 mg/kg/week SC, based on deaths at 100 mg/kg IV and 200 mg/kg SC | 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). | FDA integrated review | 118 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=118 | Mouse deaths and premature euthanasia, mainly at low IV dose, attributed to immunogenicity to the human protein | The deaths and/or premature euthanasia of the remaining animals, primarily in the LD IV group, were attributed to immunogenicity based upon observed adverse clinical signs, although there were no histopathological findings. | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | Monkey SC bioavailability ~66%; half-life 147-581 h (IV) and 206-424 h (SC) | The SC bioavailability of garadacimab (6 mg/kg) was ~66% in monkeys. Mean estimated t1/2 values for garadacimab in the single-dose PK study with monkeys ranged from 147 to 581 h (IV) and 206 to 424 h (SC). | FDA integrated review | 111 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=111 | FXIIa inhibition prolongs aPTT; no associated bleeding events in animals | Prolongation of aPTT was observed in all four studies with F0 male and female rabbits, but not associated with any bleeding events. | FDA integrated review | 103 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/761367Orig1s000IntegratedR.pdf#page=103 |
Anthim | obiltoxaximab | B. anthracis PA | Monoclonal antibodies | https://theatlas.bio/p/anthim | Rat and cynomolgus monkey | General toxicology studies were performed in rats and cynomolgus monkeys. | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=5 | Exogenous bacterial target; similar tissue cross-reactivity in human, rat and monkey supported both species as relevant models | The study and peer review pathologists stated that the data demonstrated that both the rat and cynomolgus monkey were appropriate and relevant models for toxicity testing of ETI-204. | FDA pharmacology/toxicology review | 92 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=92 | No surrogate; the clinical antibody was tested in rats, cynomolgus monkeys and rabbits | General toxicology studies were performed in rats and cynomolgus monkeys. | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=5 | 1 (dosing on Days 1, 4 and 7 in rats) | 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. | FDA pharmacology/toxicology review | 100 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=100 | Definitive GLP rat study: 3, 10, 30 mg/kg IV on Days 1, 4, 7; plus monkey IV infusion safety pharmacology/toxicology study | 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. | FDA pharmacology/toxicology review | 100 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=100 | IV (rats, monkeys); IM also tested in rats | was performed in 10-13 week old male Fischer 344 rats at repeated IV and IM doses up to 2.91 mg/rat | FDA pharmacology/toxicology review | 5 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=5 | Not conducted | Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39ad8799-00a4-4fc8-9852-c0536350c474 | Not conducted | Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39ad8799-00a4-4fc8-9852-c0536350c474 | Rabbit EFD: maternal and developmental NOEL 32 mg/kg (highest dose); fertility not studied | The No-Observed-Effect Level (NOEL) of ETI-204 for maternal and developmental toxicity was determined to be 32 mg/kg/dose, the highest dose tested | FDA pharmacology/toxicology review | 101 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=101 | Monkey cardiovascular telemetry studies: definitive study at 10 or 30 mg/kg IV showed no BP or QT effects (earlier study showed BP rise) | In the second study, following doses of 10 or 30 mg/kg IV, the changes in blood pressure were not seen; blood pressures were in the normal range for this species. No QT prolongation was reported. | FDA pharmacology/toxicology review | 100 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=100 | Single-dose clinical escalation supported by monkey AUC margin: 10 mg/kg AUC ~50,000 µg·hr/mL vs human AUC 10,000 at 114 mg | The 10 mg/kg dose to monkeys with an approximate AUC of 50,000 µg·hr/ml provides an appropriate margin of safety based upon the human AUC of 10,000 following a 114 mg dose of Anthim. | FDA pharmacology/toxicology review | 53 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=53 | NOAEL 30 mg/kg (highest dose) in definitive rat study; no test article-related toxicity; MTD not reached | The NOAEL was the high dose, 30 mg/kg, for both the Lonza and Baxter material | FDA pharmacology/toxicology review | 101 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=101 | Anti-drug antibodies in 8 of 12 monkeys (75%) after a single dose | Anti-product antibodies were detected in samples from 2 monkeys on Day 13 and an additional 6 monkeys on Day 26, for a total of 8 out of 12 monkeys, or 75%. | FDA pharmacology/toxicology review | 49 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=49 | TCR in human, rat and monkey tissues: cytoplasmic staining only (cytoskeletal elements), considered not relevant | Staining was reported to be cytoplasmic and was specifically localized to cytoplasmic granules and/or filaments, often associated with cell borders, suggestive of intracellular cytoskeletal elements, and therefore not relevant. | FDA pharmacology/toxicology review | 101 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/125509Orig1s000PharmR.pdf#page=101 | CNS inflammation and hemorrhage in infected non-survivors attributed to anthrax bacteria, not obiltoxaximab | Microscopic changes in the non-surviving animals that received obiltoxaximab were due to the presence of extravascular bacteria and not the effect of obiltoxaximab. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39ad8799-00a4-4fc8-9852-c0536350c474 |
Arzerra | ofatumumab | CD20 | Monoclonal antibodies | https://theatlas.bio/p/arzerra | Cynomolgus monkey only | Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog. | EMA assessment report | 10 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=10 | Cross-reactivity studies and cDNA analysis showed monkey (not mouse, rat or dog) is a suitable species | Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog. | EMA assessment report | 10 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=10 | No surrogate; the clinical antibody was tested in cynomolgus monkeys | Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog. | EMA assessment report | 10 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=10 | 30 (7 months) | populations of NK cells, which are central to immune surveillance, did not change during pivotal repeat dose studies of up to 7 months duration. | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=20 | Pivotal monkey IV infusion studies of 4 weeks and 7 months; a cycled IV study and a short SC study also run | 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. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=14 | IV infusion (pivotal); SC in a single study | The majority of studies were performed by the IV route (infusion over 30 minutes) as this is the clinical route of administration; however, the SC route of administration was also examined in a single study. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=14 | Not conducted (ICH S6) | The lack of genotoxicity studies is considered justified according to ICH S6 | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=20 | Not conducted; rodents not pharmacologically responsive and no evidence anti-CD20 B-cell depletion causes cancer | 2) ofatumumab is not pharmacologically active in rodents and so the standard carcinogenicity bioassays are unsuitable, 3) there is no scientific evidence to suggest that depletion of B cells by any other anti-CD20 therapeutics leads to cancer | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=20 | Monkey EFD: no malformations, fetal B-cell depletion. Fertility: no adverse effects. ePPND: high-dose infant deaths and impaired immune function | While the high dose was a no-effect dose for adverse developmental effects, a no-effect dose for mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose. | FDA review | 256 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/125326Orig1s070.pdf#page=256 | Incorporated into pivotal 4-week and 7-month monkey studies (cardiovascular, renal, body temperature endpoints); no heart rate or QT changes | 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. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=14 | Not stated in public reviews | null | null | null | null | Haemolytic anaemia (possibly ADA/immune-complex mediated) with unscheduled deaths; lymphoid germinal centre atrophy; infections | In repeat-dose toxicity studies, haemolytic anaemia developed in cynomolgus monkeys, leading to unscheduled deaths. | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=20 | Monkey complement activation and IL-6 rise suggesting mild cytokine release; ADA in all studies; reduced KLH antibody response | These results suggest that administration of ofatumumab may be associated with cytokine release syndrome. However, the severity of this syndrome in the monkeys was limited and clinical manifestations were not observed. | EMA assessment report | 19 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=19 | Placental transfer (detected in 17 of 20 fetal cord blood samples); no off-target binding in human TCR | Ofatumumab was present in maternal plasma up to Gestation Day 100 and was also detectable in 17 of 20 umbilical cord blood samples from the foetuses, confirming exposure to ofatumumab during late pregnancy (GD100). | EMA assessment report | 18 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=18 | Infections from B-cell depletion and haemolytic anaemia led to monkey deaths; fetal B-cell depletion | The reasons for animal withdrawal can be categorised into those which had a probable Campylobacter jejuni (C. jejuni) infection and those which showed signs of haemolytic anaemia. | EMA assessment report | 17 | https://www.ema.europa.eu/en/documents/assessment-report/arzerra-epar-public-assessment-report_en.pdf#page=17 |
Avastin | bevacizumab | VEGF-A | Monoclonal antibodies | https://theatlas.bio/p/avastin | Cynomolgus monkey and rabbit | Toxicology studies were performed in cynomolgus monkeys and rabbits. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=15 | Cyno VEGF predicted identical to human; binds rabbit VEGF with lower affinity (Kd 8.0 vs 1.1 nM) | Cynomolgus monkey VEGF is predicted to have a protein sequence identical to that of human VEGF [41]. According to the applicant, bevacizumab also binds rabbit VEGF, although with a lower affinity than for human VEGF; the dissociation constant (Kd) is 8.0 nM for rabbit VEGF compared with 1.1 nM for human VEGF. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=15 | No surrogate in toxicology; murine parent A4.6.1 used for pharmacology; clinical antibody tested in monkey and rabbit | Most submitted pharmacological studies are performed with A4.6.1 but equivalence between bevacizumab and A4.6.1 has been adequately documented with regard to VEGF affinity and anti-proliferative effect. | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=20 | 26 | Additionally, a 26-week iv with a 12-week recovery was conducted in adult cynomolgus monkeys. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=15 | Cynomolgus monkey IV 4- and 13-week (twice weekly) and 26-week studies with 12-week recovery | 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. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=15 | Intravenous | The toxicology program was designed to support IV administration of bevacizumab. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=15 | Not conducted | No genotoxicity studies were performed. | EMA assessment report | 17 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=17 | Not conducted | No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=939b5d1f-9fb2-4499-80ef-0607aa6b114e | Rabbit EFD: maternal NOAEL 10 mg/kg, fetal NOAEL <10 mg/kg; reduced fetal weight and ossification, malformations | The maternal NOAEL was 10 mg/kg. The foetal NOAEL was less than 10 mg/kg, since all treatment doses reduced foetal weights and number of ossification sites, whereas the two higher treatment doses produced a statistically significant increase in multiple malformations. | EMA assessment report | 18 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=18 | No dedicated studies; assessed in monkey toxicology studies with no effects on respiration, blood pressure, ECG or temperature | Safety pharmacology endpoints were evaluated as part of the toxicology studies (see Toxicology). No treatment-related effects on physical examinations, including respiration rate, blood pressure, ECG, rectal body temperature and urinalysis, were observed | EMA assessment report | 12 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=12 | Not stated in public reviews | null | null | null | null | No NOAEL stated; physeal dysplasia from about 2 mg/kg (males) and 10 mg/kg (females) in monkeys | Physeal dysplasia occurred in males at about 2 mg/kg and in females at 10 mg/kg. | EMA assessment report | 21 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=21 | Rabbits developed anti-drug antibodies 8-11 days after start of dosing, limiting rabbit study duration | Antibodies developed between 8 and 11 days after the initiation of dosing. | EMA assessment report | 18 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=18 | Crossed the rabbit placenta; fetal serum concentrations mostly exceeded maternal (median ratio 1.87) | In most cases, foetal serum concentrations were greater than maternal serum concentrations with a median ratio of foetal serum:maternal serum concentrations of 1.87. | EMA assessment report | 17 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=17 | VEGF inhibition: dose-dependent physeal dysplasia from blocked vessel formation in growth plates | The toxicity included a dose-dependent occurrence of physeal dysplasia secondary to the inhibition of blood vessel formation in long bone growth plates. | EMA assessment report | 21 | https://www.ema.europa.eu/en/documents/scientific-discussion/avastin-epar-scientific-discussion_en.pdf#page=21 |
Bavencio | avelumab | PD-L1 | Monoclonal antibodies | https://theatlas.bio/p/bavencio | Cynomolgus monkey only | Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys. | FDA multi-discipline review | 40 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=40 | Similar binding affinity to monkey and human PD-L1 and comparable tissue cross-reactivity | The cynomolgus monkey was, however, a pharmacologically relevant species for toxicity testing based on a similar avelumab binding affinity to cynomolgus monkey and human PD-L1 and the comparable cross-reactivity of avelumab across cynomolgus monkey and human tissues. | FDA multi-discipline review | 40 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=40 | No surrogate; avelumab itself binds mouse and cynomolgus PD-L1 | Avelumab shows similar binding affinity for human, mouse and cynomolgus PD-L1. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/bavencio-epar-public-assessment-report_en.pdf#page=29 | 13 | Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys. | FDA multi-discipline review | 40 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=40 | 13-week cynomolgus monkey IV study, once weekly 20, 60 or 140 mg/kg, 2-month recovery; plus 1-month monkey study | 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. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/bavencio-epar-public-assessment-report_en.pdf#page=30 | IV infusion (over 90 minutes) | Route of administration: IV infusion over 90 minutes | FDA multi-discipline review | 50 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=50 | Not conducted (ICH S6) | Not conducted per ICH S6. | FDA multi-discipline review | 51 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=51 | Not conducted (ICH S6, S1 and S9) | Not conducted per ICH S6, ICH S1, and ICH S9. | FDA multi-discipline review | 51 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=51 | Not conducted; literature-based assessment of reproductive risk submitted instead | 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. | FDA multi-discipline review | 51 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=51 | Incorporated into 4- and 13-week monkey studies; heart rate, ECG, blood pressure, respiration, CNS and temperature unaffected at 140 mg/kg | In both studies the heart rate, electrocardiogram, arterial blood pressure, respiratory rate, CNS parameters, and body temperature were unaffected by treatment with avelumab at the high dose level of 140 mg/kg weekly. | EMA assessment report | 22 | https://www.ema.europa.eu/en/documents/assessment-report/bavencio-epar-public-assessment-report_en.pdf#page=22 | Not stated in public reviews | null | null | null | null | No NOAEL in 13-week monkey study: perivascular mononuclear infiltrates in brain and spinal cord at all doses; LOAEL 1.5-fold human 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. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/bavencio-epar-public-assessment-report_en.pdf#page=29 | Human PBMC cytokine release limited to a 5-7 fold TNFα increase at 24 hours | The results were limited to a 5-7 fold increase in TNFα following 24 hours of exposure to avelumab at concentrations ≥ 14.4 ng/mL. | FDA multi-discipline review | 52 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=52 | Human and monkey tissue staining generally comparable | Overall, except for these differences, avelumab staining of normal human and cynomolgus tissues was generally comparable. | FDA multi-discipline review | 52 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf#page=52 | Immune-related toxicity from loss of PD-L1-mediated self-tolerance | Avelumab’s mode of action removes the suppressive effects of PD-L1 on T cells, which may lead to decreases in self-tolerance and immune-related effects. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/bavencio-epar-public-assessment-report_en.pdf#page=30 |
Benlysta | belimumab | BLyS (BAFF) | Monoclonal antibodies | https://theatlas.bio/p/benlysta | Cynomolgus monkey only | The non-clinical toxicology program supporting belimumab development has been performed exclusively in the cynomolgus monkey (Macaca fascicularis) based on the following reasons: | EMA assessment report | 17 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=17 | Monkey and human BLyS share 96.4% (full-length) and 98% (soluble) identity | The cynomolgus monkey was considered as the most relevant species in nonclinical studies since the monkey and human BLyS share 96.4% amino acid identity across the full length protein and 98% amino acid identity in the cleaved soluble portion of BLyS | EMA assessment report | 23 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=23 | No surrogate; the clinical antibody was tested in cynomolgus monkeys | The non-clinical toxicology program supporting belimumab development has been performed exclusively in the cynomolgus monkey (Macaca fascicularis) based on the following reasons: | EMA assessment report | 17 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=17 | 26 | 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. | EMA assessment report | 18 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=18 | GLP IV cynomolgus monkey studies of 4 weeks and 6 months | 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. | EMA assessment report | 18 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=18 | IV (plus SC local tolerance and immunogenicity studies) | A local tolerance study of subcutaneously administered belimumab in cynomolgus monkey was conducted to support clinical studies evaluating the SC route of administration of belimumab. | EMA assessment report | 21 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=21 | Not conducted; not required for a monoclonal antibody | No genotoxicity studies were conducted. Belimumab is a monoclonal antibody and is not expected to interact directly with DNA or other chromosomal material. | EMA assessment report | 19 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=19 | Not conducted; malignancy risk to be evaluated clinically in a post-marketing safety study | CHMP concurred with the Applicant’s argumentation that the potential risk for malignancy with belimumab can only be evaluated in a clinical setting; the proposal for a clinical post-marketing safety study was supported. | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=20 | Monkey combined EFD/PPND: no maternal toxicity, embryofetal/infant survival effects or malformations at 9-fold MRHD exposure | There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately 9 times the MRHD of 10 mg/kg intravenously or 20 times the MRHD of 200 mg subcutaneously | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2fa3c528-1777-4628-8a55-a69dae2381a3 | Incorporated into three GLP monkey studies; no abnormalities attributable to belimumab | In accordance with the Guideline CHMP/ICH/539/00, the Applicant included safety pharmacology assessments in three GLP studies in cynomolgus monkeys. In each of these studies, belimumab was generally safe and well tolerated and no abnormalities were attributable to belimumab. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=16 | Not stated in public reviews | null | null | null | null | Few noteworthy findings beyond pharmacological B-cell effects; low potential for toxicity | 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. | EMA assessment report | 19 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=19 | ADA in 12 of 124 monkeys (6 with reduced exposure) | In summary, across all studies, detectable, treatment emergent anti-belimumab antibodies have been identified in 12 out of 124 monkeys. Of these, 6 monkeys had reduced belimumab serum concentrations. | EMA assessment report | 22 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=22 | No specific binding in human tissue cross-reactivity study | No specific staining of the human tissues by the belimumab antibody was identified at any concentration. | EMA assessment report | 22 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=22 | Infection and malignancy risk from B-cell suppression; not increased in long-term monkey studies | Long-term toxicology studies in cynomolgus monkeys do not indicate an increased risk of infection or malignancy with belimumab. | EMA assessment report | 19 | https://www.ema.europa.eu/en/documents/assessment-report/benlysta-epar-public-assessment-report_en.pdf#page=19 |
Beovu | brolucizumab | VEGF-A | Monoclonal antibodies | https://theatlas.bio/p/beovu | Cynomolgus monkey only | Cynomolgus monkeys were chosen as they are the only species in which brolucizumab is both pharmacologically active and possessing a similar ocular anatomy to humans. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | Only species in which brolucizumab is pharmacologically active and has human-like ocular anatomy | Cynomolgus monkeys were chosen as they are the only species in which brolucizumab is both pharmacologically active and possessing a similar ocular anatomy to humans. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | No surrogate; the clinical antibody fragment was tested in cynomolgus monkeys and rabbits | The non-clinical safety of up to 6 mg brolucizumab was established for intravitreal IVT in cynomolgus monkeys and rabbits | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | Not stated in public reviews | null | null | null | null | Three GLP repeat-dose intravitreal studies in cynomolgus monkeys (N-10-104, N-12-042, N-14-007) | 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. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | Intravitreal | The non-clinical safety of up to 6 mg brolucizumab was established for intravitreal IVT in cynomolgus monkeys and rabbits | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | Not conducted (ICH S6(R1)) | No genotoxicity studies have been conducted. Since brolucizumab is an antibody fragment, the lack of genotoxicity studies is in accordance with the available guideline ICH S6 (R1) and this point is accepted. | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=34 | Not conducted (ICH S6(R1)) | Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals. | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=34 | Monkey ePPND (IVT, every 4 weeks): no effects on embryo-fetal development, pregnancy, parturition or offspring at 6 mg/eye; no fertility studies | There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis). | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5d1dc1fa-a2d3-46ed-9e9a-c1a036590d3d | Incorporated into repeat-dose toxicity studies; no respiratory, cardiovascular or CNS effects | No effect on respiratory function or cardiovascular function, and no effects on the central nervous system were detected in toxicological studies. | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=28 | Not stated in public reviews | null | null | null | null | NOAEL 6 mg/eye (highest dose tested); well tolerated, no systemic toxicity | 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. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | Weakly immunogenic; ADA in all groups (including pre-existing) without effect on exposure | ADA response was assessed in the in vivo studies. Although antibodies were detected in all the studied groups, no effects were detected in brolucizumab exposure. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=30 | Serum exposure after IVT >7000-fold (monkey) and >20000-fold (rabbit) lower than vitreous | Following IVT administration, systemic (serum) exposure of free brolucizumab in rabbits and cynomolgus monkeys was found to be >20000-fold and >7000-fold lower than in vitreous humor. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=29 | Systemic VEGF inhibition: potential impairment of fertility and embryo-fetal development | Based on its mechanism of action (VEGF inhibitor), brolucizumab has the potential to impair fertility and embryo-foetal development in relation to the degree of systemic VEGF-inhibition. | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf#page=34 |
Beyfortus | nirsevimab | RSV F protein | Monoclonal antibodies | https://theatlas.bio/p/beyfortus | Cynomolgus monkey only | The non-clinical safety programme consisted of a 1-month repeat-dose toxicity study in cynomolgus monkeys and tissue cross-reactivity studies in human tissues | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=32 | Exogenous viral target; monkey chosen for comparable human/cynomolgus FcRn affinity, as YTE substitution decreases exposure in rodents | Therefore, use of cynomolgus monkeys as the relevant animal species for the non-clinical in vivo program of nirsevimab is endorsed based on the comparable affinity of nirsevimab to human and cynomolgus FcRn and the fact that the YTE substitution decreases antibody exposure in rodents. | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=32 | No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkeys (non-YTE parent antibody used only in cotton rat pharmacology) | A repeat-dose toxicology study was conducted in cynomolgus monkeys to evaluate the potential toxicity of nirsevimab (study No 1468-038). | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=32 | 4 | Dose and frequency of dosing Weekly for 4 weeks (5 injections total) | FDA integrated review | 157 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761328Orig1s000IntegratedR.pdf#page=157 | GLP 4-week cynomolgus monkey study, weekly IV (50 or 300 mg/kg) or IM (300 mg), 5 doses, with recovery period | 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. | EMA assessment report | 33 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=33 | IV and IM | Route of administration Either intravenous or intramuscular | FDA integrated review | 157 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761328Orig1s000IntegratedR.pdf#page=157 | Not conducted (ICH S6(R1)) | Genotoxicity studies have not been conducted with nirsevimab. In accordance with ICH S6(R1), genotoxicity studies are not required for biologics as they are not anticipated to interact with DNA or other genetic material. | FDA integrated review | 162 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761328Orig1s000IntegratedR.pdf#page=162 | Not conducted; weight-of-evidence assessment revealed no specific carcinogenic risk | Carcinogenicity studies have not been conducted with nirsevimab. A weight of evidence approach was conducted in accordance with the FDA’s recommendations and applicable ICH guidelines for establishing the carcinogenic potential of nirsevimab and did not reveal any specific carcinogenic risk. | FDA integrated review | 162 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761328Orig1s000IntegratedR.pdf#page=162 | Not conducted (ICH S6(R1)): exogenous viral target, infant population; no reproductive tissue effects or placental binding | In accordance with ICH guideline S6(R1), no dedicated studies have been conducted to evaluate the effects of nirsevimab on fertility, embryo-foetal, and prenatal and postnatal development. | EMA assessment report | 33 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=33 | Incorporated into 4-week monkey study: no ECG, CNS or respiratory effects | Safety pharmacology of nirsevimab was assessed as a component of the GLP 4-week repeat dose toxicology study in cynomolgus monkeys (Study #1468-038). | FDA integrated review | 155 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761328Orig1s000IntegratedR.pdf#page=155 | Not stated in public reviews | null | null | null | null | NOAEL 300 mg/kg IV or IM (highest dose); minor nonadverse APTT, globulin, total protein increases and splenic macrophage hypertrophy | 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). | FDA integrated review | 121 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761328Orig1s000IntegratedR.pdf#page=121 | No ADA during dosing; ADA in 4 (22.2%) recovery monkeys; no evidence of immunotoxicity | None of the animals in the control or treated groups tested positive for ADA at any time point during the treatment phase. ADAs to nirsevimab was only observed in the recovery period and in a limited number of animals (four (22.2%) of the recovery animals). | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=34 | No tissue cross-reactivity in human juvenile, neonatal and fetal tissue panels | Results revealed no staining with nirsevimab, and therefore, no tissue cross-reactivity was identified against a panel of normal human juvenile, neonatal and foetal tissues. | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=34 | Antibody-dependent enhancement of RSV disease; low risk on weight of evidence (no viral enhancement in cotton rats) | the overall weight of evidence presented by the Applicant indicates a low risk of ADE of disease for nirsevimab. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/beyfortus-epar-public-assessment-report_en.pdf#page=30 |
Bimzelx | bimekizumab | IL-17A/IL-17F | Monoclonal antibodies | https://theatlas.bio/p/bimzelx | Cynomolgus monkey only | The only relevant species for nonclinical testing is the nonhuman primate. | FDA multi-discipline review | 205 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=205 | No or very low affinity for mouse IL-17A, IL-17F or IL-17AF; binds cynomolgus IL-17A/F | The non-clinical evaluation has been conducted in the Cynomolgus monkey only since bimekizumab has no or very low affinity for mouse IL-17A, IL-17F or IL-17AF. | EMA assessment report | 22 | https://www.ema.europa.eu/en/documents/assessment-report/bimzelx-epar-public-assessment-report_en.pdf#page=22 | No surrogate; the clinical antibody was tested in cynomolgus monkeys (no anti-rodent IL-17A/F surrogate available) | Bimekizumab is not pharmacologically active in rodents and no anti-rodent IL-17 A/F surrogate is available. | FDA multi-discipline review | 208 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=208 | 26 | 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 | FDA multi-discipline review | 205 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=205 | Cynomolgus monkey weekly SC repeat-dose studies up to 26 weeks with up to 21-week recovery | 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 | FDA multi-discipline review | 205 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=205 | Subcutaneous and intravenous | Intravenous and subcutaneous routes of administration were explored. | EMA assessment report | 22 | https://www.ema.europa.eu/en/documents/assessment-report/bimzelx-epar-public-assessment-report_en.pdf#page=22 | Not conducted (ICH S6(R1)) | No genotoxicity studies have been conducted with bimekizumab in line with ICH S6 (R1) guideline. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/bimzelx-epar-public-assessment-report_en.pdf#page=26 | Not conducted; literature weight-of-evidence shows no clear carcinogenicity concern from IL-17A/F inhibition | In conclusion, the literature does not suggest a clear concern that inhibition of IL-17A and IL-17F would lead to carcinogenicity or tumor development. | FDA multi-discipline review | 208 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=208 | Monkey ePPND: NOAEL 50 mg/kg/week for maternal and developmental toxicity (38x MRHD) | The no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was identified as 50 mg/kg/week which is 38 times (based on mg/kg comparison) the maximum recommended human dose | FDA multi-discipline review | 209 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=209 | Incorporated into monkey repeat-dose studies; no CNS, respiratory, ECG or blood pressure effects up to 200 mg/kg/week | Clinical observations from the repeat-dose toxicity studies conducted in cynomolgus monkeys indicate bimekizumab does not induce central nervous system or respiratory effects. No ECG or blood pressure effects were observed in cynomolgus monkeys treated subcutaneously for 26 weeks with up to 200 mg/kg/week bimekizumab. | FDA multi-discipline review | 206 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=206 | Not stated in public reviews | null | null | null | null | NOAEL was highest dose in 8-week studies (200 and 20 mg/kg/week); none in 26-week study (skin findings, GI infection deaths) | 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 c... | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/bimzelx-epar-public-assessment-report_en.pdf#page=25 | Increased infection risk from reduced muco-epidermal immunity in single and repeat-dose monkey studies | The main finding in single and repeat dose studies was the increased risk of infection due to reduced muco-epidermal immunity. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/bimzelx-epar-public-assessment-report_en.pdf#page=25 | No cross-reactive binding in any human or cynomolgus monkey tissue | No cross-reactive binding of bimekizumab conjugated to fluorescein isothiocyanate was observed in any human or monkey tissue at any concentration tested | FDA multi-discipline review | 206 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=206 | Infections from exaggerated IL-17A/F pharmacology reducing muco-epidermal immunity | Bimekizumab specifically inhibits IL-17A and IL-17F and as such muco-epidermal infections are considered to be related to exaggerated pharmacology, leading to decreased muco-epidermal immunity. | FDA multi-discipline review | 208 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761151Orig1s000MultidisciplineR.pdf#page=208 |
Briumvi | ublituximab | CD20 | Monoclonal antibodies | https://theatlas.bio/p/briumvi | Cynomolgus monkey only | Therefore, cynomolgus monkey was determined to be the single relevant species for nonclinical evaluations. | FDA pharmacology/toxicology review | 11 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=11 | High-affinity (low nM) binding to CD20 on human and cynomolgus B cells; no binding to rodent CD20 | Ublituximab binds with high affinity (low nM range) to CD20 on B cells from human and cynomolgus monkey. The product does not bind to rodent CD20. | FDA pharmacology/toxicology review | 11 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=11 | Yes: human CD20 transgenic mice, used for an embryo-fetal development study with ublituximab | In a subsequent study conducted in pregnant CD20 (huCD20) transgenic mice, a pharmacologically relevant animal model, intravenous administration of ublituximab-xiiy (0, 5, 20, or 50 mg/kg) during organogenesis (gestation day 6 and 12) resulted in no adverse effects on embryofetal development. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3a77cd8c-811b-407c-9140-d0c5c26435c2 | 26 | General toxicology studies of up to 26 weeks’ duration were conducted in cynomolgus monkeys. | FDA pharmacology/toxicology review | 50 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=50 | GLP 4-, 13- and 26-week intravenous toxicity studies in cynomolgus monkeys | The sponsor conducted 4-, 13-, and 26-week GLP intravenous toxicity studies in cynomolgus monkey. | FDA pharmacology/toxicology review | 3 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=3 | Intravenous (short infusion of 3 or 15 min, or slow bolus) | For these studies, ublituximab was administered intravenously, either by short infusion (3 or 15 min) or slow bolus. | FDA pharmacology/toxicology review | 3 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=3 | Not recommended for biologics; an Ames assay was conducted and was negative | Genotoxicity assays are not recommended for biological therapeutics. An Ames assay was conducted, and results were negative. | FDA pharmacology/toxicology review | 28 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=28 | Not conducted; not feasible because ublituximab is not active in rodents | Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=2 | Monkey ePPND (0 or 30 mg/kg weekly by trimester): severe immunogenic response causing maternal morbidity, death and embryofetal loss | Weekly intravenous administration of ublituximab-xiiy (0 or 30 mg/kg) to pregnant monkeys during the first, second, or third trimester of pregnancy produced a severe immunogenic response in dams, resulting in maternal morbidity and death and embryofetal loss. | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3a77cd8c-811b-407c-9140-d0c5c26435c2 | Assessed in general toxicology studies; no cardiac, respiratory or CNS findings | There were no observed clinical findings concerning cardiac, respiratory, or CNS safety pharmacology in the general toxicology studies. | EMA assessment report | 33 | https://www.ema.europa.eu/en/documents/assessment-report/briumvi-epar-public-assessment-report_en.pdf#page=33 | Not stated in public reviews | null | null | null | null | No NOAEL identified in the 26-week study, as only one dose level was tested | Since only one dose level of ublituximab was administered, no NOAEL was identified. | FDA pharmacology/toxicology review | 51 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=51 | No significant changes in serum IL-6, IL-8, IFN-γ or TNF-α in monkeys after repeated dosing | Levels of four inflammatory cytokines (IL-6, IL-8, IFN-γ, and TNF-α) were evaluated after repeated dosing of ublituximab and no significant changes were observed. | FDA pharmacology/toxicology review | 15 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=15 | Tissue cross-reactivity in human and monkey tissues: specific binding in lymphoid tissues and CD20+ areas; no off-target binding | In addition, tissue cross reactivity studies in human and cynomolgus monkey tissue showed specific binding in lymphoid tissues and areas known to be positive for CD20+ cells, and no off-target or unexpected binding was observed. | FDA pharmacology/toxicology review | 50 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=50 | Effects of in-utero exposure on immune function, not assessable in monkeys because of maternal immunogenicity | Potential adverse effects of ublituximab exposure during organogenesis on immune function could not be adequately assessed because of the immunogenic effects in dams. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761238Orig1s000PharmR.pdf#page=7 |
Cablivi | caplacizumab | von Willebrand factor (A1 domain) | Monoclonal antibodies | https://theatlas.bio/p/cablivi | Guinea pig and cynomolgus monkey | The toxicology of caplacizumab was evaluated in single and repeat-dose toxicity studies in both rodent (guinea pig) and non-rodent species (Cynomolgus monkey). | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=25 | Cross-reactive with cynomolgus monkey and guinea pig vWF; no pharmacological activity in rats, mice or dogs | Caplacizumab is cross-reactive to vWF in Cynomolgus monkey and guinea pig, but displays no pharmacological activity in rats, mice and dog. | EMA assessment report | 31 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=31 | No surrogate; the clinical Nanobody was tested in guinea pig and cynomolgus monkey | This shows that caplacizumab is pharmacologically active in both species used for toxicity testing and that the animals were sufficiently exposed | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=25 | 26 | 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. | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=28 | GLP repeat-dose studies in guinea pigs and cynomolgus monkeys (IV or SC) designed for continuous target saturation | 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) | EMA assessment report | 27 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=27 | Intravenous and subcutaneous | Toxicokinetic investigations were performed in the repeat-dose toxicity studies in guinea pig and Cynomolgus monkey after both intravenous (i.v.) and subcutaneous (s.c.) administration. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=25 | Not conducted (ICH S6(R1)) | In line with ICH S6(R1), genotoxicity studies are not considered relevant for proteins and were not performed with caplacizumab. | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=28 | Not conducted (ICH S6(R1)); no carcinogenic risk identified from mode of action and 26-week monkey data | In line with ICH S6(R1), no carcinogenicity studies have been performed. No carcinogenic risk was identified based on the pharmacological mode of action, results from chronic dosing toxicity studies in Cynomolgus monkey (up to 26 weeks) | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=28 | Guinea pig placental transfer study: fetal exposure shown, no effects on fetal development | The placental transfer study with caplacizumab in pregnant guinea pigs qualitatively demonstrated foetal exposure to caplacizumab but exact concentrations could not be measured in the foetuses. Exposure of the dams had no effects on foetal development. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=29 | Incorporated into repeat-dose monkey and guinea pig studies; no adverse cardiovascular effects besides bleeding | Overall, the safety pharmacology studies in vivo indicate that, besides bleeding, there are no adverse cardiovascular effects (ECG, blood pressure and heart rate) | EMA assessment report | 23 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=23 | Not stated in public reviews | null | null | null | null | 26-week monkey NOAEL 4 mg/kg/day, based on high-dose (40 mg/kg/day) male sacrificed with persistent anaemia | 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 | EMA assessment report | 28 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=28 | Anti-drug antibodies observed but did not affect exposure except in one 26-week monkey | Anti-drug antibodies were observed but did not affect drug exposure, with the exception of one animal in the 26-week Cynomolgus monkey study, which consequently was excluded from the study interpretation. | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=32 | Mouse radiolabel study: free drug eliminated via kidneys, vWF-complexed drug targets and is likely catabolized in liver | data from the biodistribution study in mice using 125I-radiolabeled caplacizumab suggest that free caplacizumab is eliminated via the kidneys, while vWF-complexed caplacizumab appears to target and possibly be catabolized in the liver. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=25 | Bleeding from exaggerated pharmacology (vWF neutralization) | Excessive pharmacology in the form of increased bleeding was identified as the only relevant safety risk. | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/cablivi-epar-public-assessment-report_en.pdf#page=32 |
Campath | alemtuzumab | CD52 | Monoclonal antibodies | https://theatlas.bio/p/campath | Cynomolgus monkey (general toxicity); huCD52 transgenic mouse (reproductive toxicity) | Single and repeated dose toxicity studies were investigated in cynomolgus monkeys. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=26 | Pharmacologically active in monkey but of limited relevance due to CD52 amino acid sequence differences | With respect to cynomolgus monkeys, the CHMP considered that although alemtuzumab was pharmacologically active in the species, the relevance of this species was limited due to species differences in the amino acid sequence for the CD52 antigen. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=25 | Yes: human CD52 transgenic mouse model, used for fertility, embryo-fetal and pre/postnatal studies | Reproductive and developmental toxicity studies were conducted in the huCD52 transgenic mouse model. This model was characterised in a series of pharmacodynamic studies. | EMA assessment report | 27 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=27 | 4 | 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. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=26 | Two cynomolgus monkey repeat-dose studies: daily dose escalation over a month and a dose-ranging tolerability pilot | Two repeat dose studies were conducted in cynomolgus monkeys. | EMA assessment report | 21 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=21 | IV and SC | Alemtuzumab was investigated in 3 single dose toxicity studies in cynomolgus monkeys, using both i.v. and s.c. administrations of alemtuzumab at dose levels ranging from 0.1 to 30 mg/kg. | EMA assessment report | 21 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=21 | Not conducted (ICH S6) | The lack of genotoxicity testing was considered acceptable, as in accordance with the ICH S6 guideline, the range and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=26 | Not conducted: no appropriate animal model; established indirect tumorigenicity risk from prolonged immunosuppression | The CHMP also considered acceptable that no carcinogenicity testing was performed, taking into account the lack of an appropriate animal model, the well-established risk of indirect tumorigenicity caused by prolonged immunosuppression | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=26 | huCD52 mice: no teratogenic effects; embryolethality with dosing in organogenesis | When alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6–10 or GD 11–15) at intravenous doses of 3 or 10 mg/kg, no teratogenic effects were observed. However, there was an increase in embryolethality | US prescribing information | null | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f5f7255-7abc-4328-bd1a-ceaf139ef3e0 | No dedicated studies; CV and respiratory effects assessed in monkey toxicity studies; not clinically relevant | No dedicated safety pharmacology studies were conducted by the applicant. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=25 | Not stated in public reviews | null | null | null | null | No NOAEL defined; dose-limiting infections or hypersensitivity causing deaths; reduced CD52 affinity in monkey limits model | 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). | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=26 | IL-6, IL-10, MCP-1 and TNF-α elevated 2-4 hours after dosing in huCD52 transgenic mice | The levels of the cytokines IL-6, IL-10, MCP-1 and TNF-α were significantly elevated especially at 2-4 hours post-dosing. | EMA assessment report | 18 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=18 | Placental transfer to fetuses in huCD52 transgenic mice | Alemtuzumab was detected in foetuses of dams treated with alemtuzumab during gestation which confirmed transfer across the placental barrier. | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=20 | Immunosuppression and severe infections from lymphocyte depletion limited achievable exposure margins | evaluating doses corresponding to a 10-fold exposure margin when compared to the exposure in the MS patients would not be feasible due to immunosuppression and severe infections. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/lemtrada-epar-public-assessment-report_en.pdf#page=26 |
Cimzia | certolizumab pegol | TNF-α | Monoclonal antibodies | https://theatlas.bio/p/cimzia | Cynomolgus monkey (main species) | Based on the species specificity of target binding, the cynomolgus monkey has been selected as the main species for toxicity testing. | EMA assessment report | 10 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=10 | No binding to rodent, rabbit, guinea pig or dog TNFα; inhibits non-human primate TNFα, though with at least 1000-fold lower activity | Certolizumab pegol did not bind TNFα from rodents, rabbit, guinea pigs and dog, but it inhibited TNFα from non-human primates, with at least a 1000-fold lower activity than against hTNFα. | EMA assessment report | 10 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=10 | Yes: cTN3 PF, a chimeric PEGylated anti-rat TNFα Fab' fragment, used for rat fertility, embryo-fetal and pre/postnatal studies | Instead, the homologous agent cTN3 PF, which is a chimeric Fab' fragment conjugated to 40 kDa PEG, was tested in the reproductive and developmental toxicity studies. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=15 | 52 | 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. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=14 | Cynomolgus monkey 26-week SC (10, 100 mg/kg/week) and 52-week SC immunotoxicity study (50, 100 mg/kg/week) | 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. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=14 | Subcutaneous (weekly); intravenous in 4-week monkey and rat studies | 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. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=14 | Conducted: negative in Ames, human lymphocyte chromosomal aberration and mouse micronucleus assays | Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay. | FDA review | 32 | https://www.accessdata.fda.gov/drugsatfda_docs/bla/2009/125160Orig1s080.pdf#page=32 | Not conducted; acceptable given nature of compound and lack of pharmacological activity in species normally used | No conventional carcinogenicity testing was performed with certolizumab pegol, which was acceptable considering the nature of the compound and the lack of pharmacological activity and immunogenicity of certolizumab pegol in species normally used for such testing. | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=14 | Rat surrogate studies over the full reproductive cycle: no effects on female fertility, reproductive function or offspring development; reduced sperm motility in males | In female rat studies covering dosing throughout the complete reproductive cycle, there were no effects on fertility, reproductive function or developmental effects on offspring. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=15 | No in vivo safety pharmacology studies; monitoring incorporated into repeat-dose monkey studies with no effects | No in vivo safety pharmacology studies have been conducted with certolizumab pegol, however monitoring of potential undesirable pharmacological activity was incorporated in both the repeat dose toxicity studies and single dose Phase 1 clinical studies. | EMA assessment report | 11 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=11 | Not stated in public reviews | null | null | null | null | Cellular vacuolation, mainly in macrophages, in multiple organs including choroid plexus of the brain | 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). | EMA assessment report | 14 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=14 | Anti-drug antibody incidence 10-20% in main monkey toxicity studies | The antibody incidence in the main monkey toxicity studies were 10-20%. | EMA assessment report | 16 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=16 | Rat study: highest PEG level in liver (7% of dose); no TNF-associated tissue uptake of PEG | The highest level of PEG was detected in the liver (7% of the dose administered). There was no indication of tissue uptake of PEG, associated with binding to membrane bound TNF alpha. | EMA assessment report | 12 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=12 | Lymphoma/malignancy risk from long-term TNF-α inhibition | the possible risk for the development of lymphomas or other malignancies in patients treated with TNF antagonists is reflected in the SPC and PL, and warrants post marketing surveillance. | EMA assessment report | 15 | https://www.ema.europa.eu/en/documents/assessment-report/cimzia-epar-public-assessment-report_en.pdf#page=15 |
Cinqair | reslizumab | IL-5 | Monoclonal antibodies | https://theatlas.bio/p/cinqair | Mouse and cynomolgus monkey | Pivotal nonclinical studies were conducted in CD-1 mice and Cynomolgus monkeys; both were identified as relevant species in a series of pharmacology studies. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=2 | Similar binding affinity to human, monkey and mouse IL-5 (KD 24, 20 and 31 pM) | Reslizumab binds with similar affinity to human, monkey, and mouse IL-5 (KD = 24, 20, and 31 pM; respectively, as determined by BIAcore biosensor assays). | FDA pharmacology/toxicology review | 30 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=30 | No surrogate; the clinical antibody was tested in mice, rabbits and cynomolgus monkeys | The nonclinical program for reslizumab included studies conducted in mice, rabbits, and monkeys, which were all considered pharmacologically relevant species based on data from in vivo eosinophilia models in sensitized animals | FDA pharmacology/toxicology review | 30 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=30 | 26 | 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. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=2 | 6-month IV studies in mice and cynomolgus monkeys, 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. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=2 | IV | Repeat-dose GLP toxicology studies were conducted in CD-1 mice, CByB6F1- Tg(HRAS)2Jic mice, and cynomolgus monkeys using the IV route of administration. | FDA pharmacology/toxicology review | 48 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=48 | Not applicable for a protein; Ames and in vitro chromosomal aberration assays negative | Genetic toxicity studies were not applicable for this therapeutic biologic protein though reslizumab was negative in two in vitro assays. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=2 | Tg.rasH2 transgenic mouse study up to 500 mg/kg IV every two weeks: no drug-related neoplasms | A transgenic mouse (Tg.rasH2) carcinogenicity study was conducted with dose concurrence by the Executive Carcinogenicity Assessment Committee (ECAC). No drug-related neoplasms were found after dosing up to 500 mg/kg IV once every two weeks. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=2 | No effects on fertility or development up to 50 mg/kg IV; about 6-fold exposure margin in mouse studies | No effects on fertility or development parameters were identified at doses up to 50 mg/kg IV; exposure margins of approximately 6-fold were available in the mouse studies. | FDA pharmacology/toxicology review | 3 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=3 | Rat and monkey studies at 100 and 25 mg/kg: no cardiovascular, CNS or gastrointestinal effects | Reslizumab administered iv at a dose of 100 mg/kg (600 mg/m2) to rats (DS-2014-080) and 25 mg/kg (300 mg/m2) to monkeys (SN96333) did not elicit effects on the most important parameters related to organ functions (cardiovascular, CNS, or gastrointestinal). | EMA assessment report | 20 | https://www.ema.europa.eu/en/documents/assessment-report/cinqaero-epar-public-assessment-report_en.pdf#page=20 | Phase 1 single-dose escalation in severe asthma at 0.03 to 1.0 mg/kg; derivation of starting dose not described | This product has been used in Europe in an initial phase 1 single dose, dose escalation trial for treatment of 32 subjects with severe asthma (I96-350). Doses ranged from 0.03 mg/kg to 1.0 mg/kg. | FDA pharmacology/toxicology review | 125 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=125 | NOAEL 25 mg/kg (highest dose) in mice and monkeys; no target organs; about 3-fold exposure margin | 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. | FDA pharmacology/toxicology review | 2 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=2 | ADA in 3 monkeys in pivotal study; one at 25 mg/kg had repeated hypersensitivity-type infusion reactions | Immunogenicity noted in 3 animals in the pivotal toxicity study (1 at 5 mg/kg, 2 at 25 mg/kg); 1 of the 25 mg/kg animals had repeated infusion reactions c/w hypersensitivity | FDA pharmacology/toxicology review | 126 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=126 | Human TCR binding only in spinal cord, brain and optic nerve; no binding in other tissues | In human tissue, binding was observed in spinal cord, brain and optic nerve. No binding was seen to peripheral nerves, or any other human tissue examined. | EMA assessment report | 19 | https://www.ema.europa.eu/en/documents/assessment-report/cinqaero-epar-public-assessment-report_en.pdf#page=19 | Lack of eosinophil recovery, parasitic infection risk, CNS toxicity from tissue binding, hypersensitivity | Lack of recovery of eosinophils, increased risk of parasitic infections, nonspecific CNS toxicity due to potential tissue binding, hypersensitivity responses. | FDA pharmacology/toxicology review | 125 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761033Orig1s000PharmR.pdf#page=125 |
Cosentyx | secukinumab | IL-17A | Monoclonal antibodies | https://theatlas.bio/p/cosentyx | Cynomolgus monkey only | Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=7 | Cross-reacts with cynomolgus, rhesus and marmoset IL-17A but not rodent IL-17A | Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=7 | Yes: murine anti-mouse IL-17A antibody BZN035, used for mouse fertility/early embryonic and peri-/postnatal development studies | A murine surrogate antibody against mouse IL-17A (BZN035) was developed and used for fertility and early embryonic development and peri- and postnatal development studies in mice. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=7 | 26 | 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 | FDA pharmacology/toxicology review | 22 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=22 | Cynomolgus 26-week IV study (15, 50, 150 mg/kg/week) followed by 13-week recovery | 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 | FDA pharmacology/toxicology review | 22 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=22 | Intravenous and subcutaneous | In a 13-week toxicology study (study # 0770712-01), AIN457 derived from CHO cells was administered by the subcutaneous route to cynomolgus monkeys at 15, 50, and 150 mg/kg/week | FDA pharmacology/toxicology review | 22 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=22 | Not conducted (ICH S6(R1)) | Based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1) 2011), genotoxicity studies have not been conducted for secukinumab which is acceptable to CHMP. | EMA assessment report | 33 | https://www.ema.europa.eu/en/documents/assessment-report/cosentyx-epar-public-assessment-report_en.pdf#page=33 | Not conducted (species-specific binding precludes rodent study); malignancy monitored clinically via risk management plan | Since secukinumab cannot be tested in a traditional 2-year rodent study to evaluate carcinogenic potential due to its species specific binding, the sponsor will monitor malignancy in psoriasis patients administered secukinumab as a part of a comprehensive Risk Management Plan. | FDA pharmacology/toxicology review | 27 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=27 | Monkey EFD: maternal NOAEL 150 mg/kg/week; fetal NOAEL 50 mg/kg/week (dose-related tail vertebra misalignment) | Therefore, the NOAEL for maternal toxicity was determined to be 150 mg/kg/week but for fetal toxicity the NOAEL was 50 mg/kg/week. | FDA pharmacology/toxicology review | 28 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=28 | Stand-alone monkey safety pharmacology study: no significant CNS, respiratory or cardiovascular effects up to 100 mg/kg IV (NOAEL) | A safety Pharmacology study conducted in cynomolgus monkeys revealed no significant adverse treatment related effects on CNS, respiratory and cardiovascular functions after i.v. administration of secukinumab up to 100 mg/kg dose (NOAEL = 100 mg/kg). | EMA assessment report | 38 | https://www.ema.europa.eu/en/documents/assessment-report/cosentyx-epar-public-assessment-report_en.pdf#page=38 | Not stated in public reviews | null | null | null | null | NOAEL 50 mg/kg/week in monkey repeat-dose studies, based on clinical chemistry effects and immunotoxicity (lymphocyte, B- and T-cell decreases) at high dose | 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. | FDA pharmacology/toxicology review | 7 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=7 | Immunotoxicity in one high-dose female: skin lesions, splenic lymphocytic atrophy, decreased NK cell activity and TDAR | Immunotoxicity was observed in one high-dose female (#451) that developed skin lesions (treated with antibiotics), splenic lymphocytic atrophy, decreased NK cell activity, and decreased T-cell dependent antigen response (TDAR; see below). | FDA pharmacology/toxicology review | 22 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=22 | Placental transfer in cynomolgus and marmoset monkeys; fetal exposure about 2% of maternal serum concentration | Serum analysis revealed that that secukinumab is transferred across the placenta during the pregnancy in cynomolgus monkeys and in marmosets, and that the fetuses are exposed to secukinumab at the level corresponding approximately 2% of the mean maternal serum concentration. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/cosentyx-epar-public-assessment-report_en.pdf#page=29 | Increased infection susceptibility from neutralizing IL-17A, a mediator of innate and adaptive immunity | Secukinumab therapy is designed to neutralize critical mediators of innate and adaptive immunity. Thus it may carry the risk of an increased susceptibility to infection. | FDA pharmacology/toxicology review | 31 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125504Orig1s000PharmR.pdf#page=31 |
Crysvita | burosumab | FGF23 | Monoclonal antibodies | https://theatlas.bio/p/crysvita | Rabbit and cynomolgus monkey | Hence, rabbits and cynomolgus monkeys were used in the in vivo nonclinical studies. | FDA multi-discipline review | 44 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761068Orig1s000MultidisciplineR.pdf#page=44 | Similar high affinity (KD ~10-11 M) for human, cynomolgus and rabbit FGF23; no binding to mouse, rat or dog FGF23 | it was shown to bind with similar binding affinity (KD~10-11 M) to human, cynomolgus monkey and rabbit FGF23. KRN23 shows no binding to mouse, rat or dog FGF23. | EMA assessment report | 23 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=23 | Yes: murine anti-FGF23 antibody, used for a 2-week toxicity study in wild-type and Hyp mice | A murine anti-FGF23 antibody at doses of 0, 3, 10 and 30 mg/kg was administered by SC injection twice a week for 2 weeks, or as a single dose, to male wild-type (WT) mice (C57BL/6J) and male hypophosphatemic (Hyp) mice (B6.Cg-PhexHyp/J). | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=32 | 40 | 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. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=26 | Rabbit repeat-dose up to 14 weeks; adult and juvenile cynomolgus monkey studies up to 40 weeks | 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. | EMA assessment report | 26 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=26 | Intravenous (rabbit and monkey) and subcutaneous (monkey) | The toxicological profile of burosumab (KRN23) was characterized in rabbits and cynomolgus monkeys via single-dose IV (rabbit) injection, and via repeat-dose IV (both species) injection/infusion and SC (cynomolgus) injection. | EMA assessment report | 25 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=25 | Not conducted (not appropriate for monoclonal antibodies) | Genotoxicity and carcinogenicity studies are generally not appropriate for biotechnology-derived monoclonal antibodies such as burosumab. No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=30 | Not conducted; weight-of-evidence risk assessment concluded carcinogenicity risk appears low | Overall, it is agreed that the carcinogenicity risk of burosumab appears to be low. | EMA assessment report | 30 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=30 | Monkey ePPND: no teratogenicity up to 30 mg/kg; pre-/postnatal developmental NOAEL 3 mg/kg | The Applicant’s proposed NOAEL at 3 mg/kg for pre- and postnatal development in fetuses and offspring is agreed with. It is also agreed that burosumab did not induce teratogenicity in monkeys up to a dose of 30 mg/kg. | EMA assessment report | 32 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=32 | No separate studies; respiratory, ECG, blood pressure and cardiac function assessed in 14- and 40-week monkey studies | Safety pharmacology studies were not performed in separate studies, but safety pharmacology parameters (respiratory rate, ECG, blood pressure and cardiac function) were assessed in 14- and 40- week repeat-dose toxicity studies in adult and juvenile cynomolgus monkeys | EMA assessment report | 24 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=24 | Not stated in public reviews | null | null | null | null | Adult monkey NOAEL 0.3 mg/kg (0.9x adult human AUC) in both repeat-dose studies | The NOAEL was 0.3 mg/kg (0.9x adult human AUC) in both | FDA multi-discipline review | 45 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761068Orig1s000MultidisciplineR.pdf#page=45 | ADA in some monkeys reduced burosumab exposure and attenuated phosphate and vitamin D increases | In all monkeys with ADA, serum concentrations of burosumab were diminished and increases in serum inorganic phosphate and 1,25-dihydroxy vitamin D were also attenuated. | EMA assessment report | 29 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=29 | Crossed the placenta: detected in fetal serum at all dose levels in monkey ePPND | Burosumab was detected in serum from fetuses at all dose levels, indicating transport across the placenta. | EMA assessment report | 31 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=31 | Hyperphosphataemia-driven ectopic mineralization (kidney, heart, vessels) from exaggerated FGF23 inhibition | The main toxicological effect observed in the non-clinical studies was ectopic mineralization. | EMA assessment report | 34 | https://www.ema.europa.eu/en/documents/assessment-report/crysvita-epar-public-assessment-report_en.pdf#page=34 |
End of preview. Expand in Data Studio
Atlas: Nonclinical Precedents from FDA & EMA Reviews
🌐 Search it free at theatlas.bio
Not predictions. Precedent. Atlas records what FDA and EMA accepted in the nonclinical (toxicology) packages of approved drugs. Each value comes with a verbatim quote from the FDA review, EMA assessment report (EPAR) or US label, its page number and a link to the source document.
- Website: https://theatlas.bio
- Methodology: https://theatlas.bio/methodology
- Founder: Nikolaus Becker, PhD (LinkedIn)
- Data updated: 13 Oct 2026
Coverage
437 approved products across 7 modalities:
| Modality | Products |
|---|---|
| Small molecules | 211 |
| Monoclonal antibodies | 117 |
| Cell therapy | 27 |
| Gene therapy | 26 |
| Oligonucleotides | 24 |
| Bispecific antibodies | 18 |
| Antibody-drug conjugates | 14 |
Browse on Atlas
Every product has its own page on Atlas (column Atlas page in the CSVs, field page in nested).
| Modality | Board | Species | Study length | Skipped studies | First dose | Risks |
|---|---|---|---|---|---|---|
| Monoclonal antibodies | board | species | study-length | skipped-studies | first-dose | risks |
| Bispecific antibodies | board | species | study-length | skipped-studies | first-dose | risks |
| Antibody-drug conjugates | board | species | study-length | skipped-studies | first-dose | risks |
| Oligonucleotides | board | species | study-length | skipped-studies | first-dose | risks |
| Gene therapy (AAV) | board | species | study-length | skipped-studies | first-dose | risks |
| Cell therapy | board | species | study-length | skipped-studies | first-dose | risks |
| Small molecules | board | species | study-length | skipped-studies | first-dose | risks |
Guides: Check your nonclinical plan · IND readiness · How first-in-human doses were set · IND clinical holds · Worked examples · Methodology
Files
| Config / file | Rows | What it is |
|---|---|---|
all_products — data/atlas_all_products.csv |
437 | Flat table, one row per product. Columns: Product, INN, Target, Modality, Atlas page, then for each of 15 questions: value, quote, source, page, link (80 columns). |
monoclonal_antibodies — data/atlas_monoclonal_antibodies.csv |
117 | Same columns, monoclonal antibodies only. |
nested — data/atlas_nested.parquet (also data/atlas_nested.jsonl) |
437 | One JSON object per product: slug, brand, inn, targets, modality, page, and fields with {value, source, page, link} per question. Page and value are stored as strings. |
raw/atlas.json |
– | Original JSON export from theatlas.bio (with field and modality dictionaries). |
raw/atlas-llms-full.txt |
– | Full plain-text/Markdown version of every product, built for LLM retrieval. |
A source-attribution footer line in the original CSV exports was removed from the tables.
The 15 questions: Species · Why that species · Surrogate molecule · Longest pivotal study · Pivotal GLP studies · Route in tox · Genotoxicity · Carcinogenicity · Reproductive & developmental · Safety pharmacology · First-in-human starting dose · NOAEL / key findings · Immune & cytokine safety · Biodistribution & persistence · Modality-specific risk.
"Not stated in public reviews" means the public documents do not report the value (for the first-in-human dose, the rationale is usually in the confidential IND).
Use
from datasets import load_dataset
ds = load_dataset("AtlasBio/atlas-nonclinical-precedents", "all_products", split="train")
Intended for IND/CTA planning research, regulatory and toxicology review, and grounding or evaluating LLM answers with citable sources. Not regulatory advice: precedent for one product does not predict what a regulator will accept for another. Always read the cited page.
Sources and licensing
- FDA documents: works of the U.S. federal government are generally not subject to U.S. copyright (17 U.S.C. §105).
- EMA documents: reproduction is permitted for non-commercial and commercial purposes provided EMA is acknowledged as the source (EMA legal notice). Every value names its source and links to it.
- US labels: short quoted excerpts with citation.
- The Atlas compilation (selection, structure, summaries) is released under CC BY 4.0. Cite Atlas and the linked source document and page.
Limitations
Values are extracted from public documents and each quote is checked against the page it cites, but errors are possible. Report them at theatlas.bio.
Citation
@misc{atlas_nonclinical_2026,
title = {Atlas: Nonclinical Precedents from FDA and EMA Reviews},
author = {Becker, Nikolaus},
year = {2026},
url = {https://theatlas.bio},
note = {Hugging Face dataset AtlasBio/atlas-nonclinical-precedents, data updated 2026-10-13}
}
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