What flexibility did FDA and EMA accept for approved monoclonal antibodies?

“In the 26-week study (0 or 30 mg/kg QW), only one dose level was tested, based on the development of antidrug antibodies, resulting in loss of pharmacological activity, at the low and mid doses in the 13-week study.”

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

“In accordance with ICH Guideline S6(R1), conventional carcinogenicity studies (i.e., rodent bioassays) have not been conducted with MLN0002 to assess its carcinogenic potential as it lacks pharmacological activity in mice and rats.”

“Toxicology studies in juvenile animals have not been conducted. The Applicant argued that α4β7 integrin does not play a role in mammalian growth and development (literature references have been provided) and that the developmental effects of inhibiting the α4β7 integrin can be studied sufficiently in mice with genetic ablation of the β7 integrin gene (Itgb7)”

“Reproductive and developmental toxicity No reproductive and developmental toxicity studies were performed.”

“The dosage was based on the human therapeutic starting dose of 400 mg/m2 and subsequent weekly doses of 250 mg/m2 , which translates to 12 and 7.5 mg/kg for a human ofbody surface area of 1.8 m2 and 60 kg body weight.”

“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.”

“In summary, no safety margin was established for the reductions in TDAR observed in infants in the ePPND study.”

“No dedicated fertility studies have been conducted however assessment of specific fertility endpoints (menstrual cycle lengths, testicular volume/size, sperm analysis for sperm count, morphology and motility and analysis of reproductive hormones), in addition to the reproductive organ weights and histopathology analysis at necropsy, were carried out in the 39-week repeat dose toxicity study, in which all monkeys were sexually mature.”

“Even though ICH M3(S2) specifies that in the EU/EEA 6-months studies in rodents and non-rodents are required, ICH S6(R1) specifies that there might also be derivations from this principle when scientifically justified. Justification on this aspect was provided in the scientific advice procedure EMA/H/SA/3363/1/2016/I, 21 July 2016.”

“Nipocalimab is a mAb which does not cross-react with rodent FcRn, precluding the conduct of traditional carcinogenicity studies. In line with ICH guideline S6(R1) and based on a WoE approach it was concluded that nipocalimab does not pose an increased carcinogenic risk.”

“Donanemab is not pharmacologically active in normal rodent or nonrodent; therefore, toxicity studies were conducted in cynomolgus monkey (6-week IV donanemab) to assess for any off-target toxicity, and in the PDAPP transgenic mouse model (6-week and 6- month SC mE8c, a murine surrogate) to assess for relevant on-target effects (toxicity and pharmacology).”

“A small number of chimpanzees, the only relevant species identified for safety testing, were given single or up to 5 once daily repeated doses of infliximab.”

“Stand-alone safety pharmacology studies were not conducted. Safety pharmacology studies were not embedded in the repeat-dose toxicity studies. However, no treatment-related organ toxicities or clinical signs indicative of respiratory or neurobehavioral effects were observed in mice”

“(A chronic toxicity study in a second species (rat) and rodent carcinogenicity studies were not required, primarily because of data demonstrating development of anti-drug antibodies in rat that precluded conduct of meaningful long-term studies.)”

“vascular (Studies ALD403-003-TOX, ALD403-015-TOX, and ALD403-055-TOX), and respiratory (ALD403-015-TOX) endpoints were evaluated in single and repeat dose toxicology studies, although an FOB, or equivalent was not conducted and only respiratory rate evaluated.”

“Plasma exposure data at 150 mg/kg (collected in the pivotal EFD studies) were limited to mean concentrations at 5 min postdose: 4473 and 4116 µg/mL in rat and rabbit, respectively. Therefore, safety margins for labeling must rely on interspecies comparisons based on dose (mg/kg).”

“Lack of dedicated safety pharmacology studies was justified by the incorporation of safety pharmacology endpoints in repeat-dose toxicity studies, and the human systemic exposure being below levels where any meaningful effect of a VEGF-related activity is expected.”

“No dedicated studies, including tissue cross-reactivity, have been conducted with brolucizumab. The justification for the absence of the aforementioned studies relies on the nature of the product (a humanized antibody fragment) and the route of administration (IVT), resulting in specific target engagement and lower systemic concentrations after treatment, respectively.”

“EmbryoǦFetal Development Separate EFD studies were not performed. However, an ePPND study was conducted in cynomolgus monkeys.”

“However, a deficiency of this study is the lack of toxicokinetic data.”

“A formal fertility study with teprotumumab has not been performed, since mating studies are not practical for NHPs.”

“For juveniles, the low-dose (3 mg/kg/week IV) is the lowest adverse effect level (LOAEL), and no NOAEL was identified.”

“Reproductive and developmental toxicity studies have not been conducted with tislelizumab. In line with ICH S9, omission of fertility/early embryonic development studies and of pre-/post-natal development studies is accepted.”

“Therefore, a comparative study with Nivolumab and Pembrolizumab in an animal model to determine the lack of antibody effector function in vivo would have been supportive of the non-clinical proof of concept of tislelizumab.”

“Lack of cross-reactivity with other species than human, gorilla, chimpanzee and gibbon was confirmed in silico, and it is therefore agreed that, in addition to chimpanzee, no relevant species for further non-clinical testing of teplizumab are available.”

“Carcinogenicity The absence of carcinogenicity studies is justified by the weight of evidence approach in line with the ICH S1B (R1) and ICH S6 (R1) guidelines.”

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

“Formal pharmacokinetic studies with ch14.18 have not been conducted, and instead data has been obtained and summarized from the public literature.”

“Therefore, rat does not appear to be a pharmacologically relevant species. Reproductive and developmental toxicity studies are generally not required by FDA for products indicated for the treatment of patients with dementia of the Alzheimer’s type because of the age of the intended population.”

“The respiratory assessment was inadequate because the assessment of respiratory rate was not supported by other measures of respiratory function, such as tidal volume or hemoglobin oxygen saturation.”

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

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

“Reproductive studies with certolizumab pegol have not been undertaken due to the lack of recognition of rodent TNF and immunogenicity in rats. 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.”

“No carcinogenicity studies were conducted. However, an assessment of the carcinogenic potential of dupilumab was made based on literature data on the role of the IL-4/IL-13 pathway in tumour development and on non-clinical data for both REGN646 and REGN1103.”

“In some studies, rodent versions of the humanized antibody AMG785 (rat 13c7 (r13c7) and mouse 13c7 (m13c7)) were used because AMG785 causes anti-drug antibody (ADA) formation in those species.”

“100 mg/kg/week in both species by the SC route (0.4 and 3-fold the MRHD in rats and monkeys, respectively, based on AUC).”

“While fertility studies were not submitted, no notable effects on the male and female reproductive organs were observed in monkeys in the 1 month and 3 month repeat dose toxicology studies; however, these results may not be representative at all of the potential clinical risk because of the immaturity of the reproductive system of animals used in the studies.”

“A weight-of-evidence assessment of carcinogenicity risk was conducted considering this possibility afforded by ICH S6 and S1 guidelines instead of conducting 2-years carcinogenicity study in rodents and 6-month Tg Ras study to support long-term human use of lecanemab. The whole approach is supported.”

“The lack of an adequate TDAR evaluation in the pre- and postnatal development (PPND) study precluded an evaluation of potential adverse effects on immune function.”

“Of note, humoral immune suppression was observed in infant monkeys exposed in utero to another drug in this class (alirocumab); effects on humoral immunity were not evaluated in the developmental studies for the evolocumab program.”

“Only Cmax data are available suggesting that the exposure levels in the toxicity studies were similar to those attained in humans.”

“The cynomolgus monkey was chosen as the most relevant non-clinical species, since golimumab showed little or no neutralization of dog, rabbit, mouse or rat TNFα. For the studies in mice, an analogous anti-mouse TNFα monoclonal antibody designated cV1q, developed during the non-clinical testing of another TNFα inhibitor, infliximab (Remicade), was used.”

“No development toxicity studies with tezepelumab were conducted to evaluate early embryonic development to implantation as it is not practical to do mating studies in cynomolgus monkeys.”

“The carcinogenic potential of ALXN1210 in animals is unknown. However, in the 26‐week repeat dose toxicology study in mice with BB5.1, multiple hematopoietic neoplasms (lymphoma/lung/salivary glands/thymus) occurred in 1 high dose female (60 mg/kg/week), lymphoid or lymphoreticular hyperplasia in mandibular lymph node and thymus occurred in another high dose female.”

“There was no evidence of late gestational maternal or offspring toxicity. However, further dosing and evaluation of the offspring were not performed, for example with regard to immunotoxicity.”

“In a 26 week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinical exposure based on Cmax and AUC at steady state after weekly administration of 5, 25, and 50 mg/kg).”

“The validations of the bioanalysis methods used for quantification of obinutuzumab in Cynomolgus monkey serum were not performed according to GLP.”

“According to ICH guidance M3(R2), the results of these studies are considered appropriate to address acute toxicity aspects. Therefore, the lack of dedicated single-dose toxicity studies was considered acceptable.”

“Reviewer’s comment: This assay did not include a set of experiments using immobilized antibodies. By not doing, the assay may not adequately mimic the in vivo conditions that may give rise to cytokine release.”

“Dedicated reproductive and developmental toxicology studies were not conducted as concizumab is primarily indicated for use in male patients with hemophilia and the clinical development program was conducted exclusively in males.”

“Dedicated juvenile animal studies have not been conducted with concizumab as studies in neonatal and infant monkeys are technically challenging and are unlikely to identify potential reactions that were not identified from studies in fully developed (adult) animals.”

“The reversibility of the findings in cynomolgus monkeys was not assessed and the NOAEL (0.5 mg/kg/day, 1660 µg.hr/mL AUC0-24, Week 52) represents a 74x exposure margin to the anticipated clinical dose (0.20 mg/kg, 22.4 µg.hr/mL AUC0-24).”

“No specific studies on the effects of belimumab on fertility and early embryonic development were conducted. The reproductive organ/tissues were assessed in the 6 months repeat dose toxicology study and there were no indications that belimumab had an adverse effect on reproductive organs.”

“Your embryo-fetal development/postnatal development study does not appear to have functional characterization of the impact of your product on the developing immune system. Exposure to this product during development can alter the offspring's immune system.”

“No specific safety pharmacology studies were conducted due to the high specificity of belimumab for its target. In accordance with the Guideline CHMP/ICH/539/00, the Applicant included safety pharmacology assessments in three GLP studies in cynomolgus monkeys.”

“Daratumumab binds to human and chimpanzee CD38, but not to CD38 of species typically used for nonclinical toxicology testing, ie, mouse, rat, rabbit, pig, and cynomolgus and rhesus monkey. Therefore, another anti-CD38 mAb, HuMab-CD38, that binds human and cynomolgus monkey CD38 was also characterized and used in some exploratory studies.”

“No chronic toxicity testing has been conducted with daratumumab.”

“A NOAEL was not established in this study.”

“In order to investigate the potential effects of incomplete blockade of EGFR signaling with an antibody, the Applicant was able to provide surrogate data by right of reference to the reproductive toxicology study conducted as a post-marketing requirement for the anti-EGFR antibody cetuximab.”

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

“While the purpose of tissue-cross-reactivity studies is typically to demonstrate comparability of binding between nonclinical and clinical species, and to potentially identify patterns of drug-related toxicity, in this study, the Applicant chose to evaluate each tissue in only one species, and therefore, it is not possible to conclude that the binding pattern was similar between the two species”

“No carcinogenicity studies were conducted in accordance with available regulatory guidance. Ovariectomized monkey treated for up to 16 months with denosumab showed no evidence of pre neoplastic lesions.”

“The relevance of using these models instead of denosumab in studies on immunomodulatory effects is uncertain and considering the mechanism of action of denosumab, potential effects on immunomodulation and immunosuppression cannot be ruled out.”

“However, this study only assessed fetal toxicity during the first trimester, and fetal lymph nodes were not examined.”

“Therefore, the species selected for nonclinical testing was the human CD19 transgenic mouse model (huCD19 Tg), which was considered the only relevant species.”

“Carcinogenicity In accordance with the weight of evidence approach outlined in ICH S6 (R1), the applicant has presented argumentation for waiving of carcinogenicity studies.”

“A no-effect dose for adverse effects on fertility was not identified.”

“Safety pharmacology studies, including cardiovascular safety studies in the cynomolgus monkey, conducted during preclinical development were not done under formal GLP requirements.”

“Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning).”

“For both assays several concerns were raised regarding the design and the validation of the methods, especially since the presence of ofatumumab seems to interfere with the detection of anti-ofatumumab antibodies even at low concentrations. The applicant did not provide adequate answers to these concerns.”

“The lack of single-dose toxicity studies is acceptable in accordance with the concept paper on single dose/acute toxicity (EMEA/CHMP/SWP/302413/2008).”

“The initial clinical trials investigating the activity and dosing of naxitamab were conducted on the basis of previous clinical data with the murine parent antibody rather than supported by toxicology data with the clinical candidate.”

“In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”

“Due to the lack of species-specific cross-reactivity, no relevant animal species or valid transgenic mouse models were identified in which to conduct the nonclinical toxicology studies.”

“Safety pharmacology, repeat dose toxicity, and reproductive and developmental toxicity studies were not conducted due to the lack of a pharmacologically-relevant animal species. The Applicant submitted a risk assessment for the potential for reproductive and developmental toxicity for elotuzumab based on the tissue distribution of SLAMF7 and published literature.”

“Canakinumab does not bind to IL-1β from mouse, rat, rabbit, or cynomolgus monkey. The only nonhuman species specifically recognized by canakinumab is the marmoset monkey.”

“However, given that transfer of IgG across the placenta starts late during gestation, it is unlikely that the fetus was exposed to canakinumab during the period of organogenesis. In addition a full panel of reproductive toxicity studies was performed with the surrogate mAb 01BSUR in mice.”

“The used species for toxicity testing, cynomolgous monkey, was not regarded a pharmacological relevant species as the antibody does not recognise the target in this species.”

“The FDA's Assessment: Due to the lack of an appropriate pharmacologically relevant animal species, the evaluation of embryofetal development of isatuximab is based on a weight of evidence (WOE) assessment in lieu of conducting studies in animals.”

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

“For the current application the relevance of this study, and other cited anti-tumour studies using homologous mouse tumour models is limited because in all these studies the (blocking) CTLA-4 antibody was administered at the time or shortly after tumour inoculation”

“This is acceptable as there is no species in which target-mediated toxicity can be investigated.”

““A short-term safety study in one species can be considered; no additional toxicity studies, including reproductive toxicity studies, are appropriate.” Therefore animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab.”

“The sponsor has generated a mouse IgG1/k monoclonal antibody (BZN035) with appropriate neutralizing activity and specificity for mouse IL-17A for use as a murine surrogate for AIN457.”

“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”

“The applicant’s claim that the weight-of-evidence assessment of carcinogenic potential was done in line with the ICH S6 (R1) and that it showed a low cancerogenic risk of sutimlimab is accepted.”

“Extrapolation of these results to humans is compromised by the fact that the animals used do not express human p185HER2 on normal tissues.”

“Pivotal nonclinical studies of sarilumab were conducted in Cynomolgus monkeys by intravenous and SC dosing since only monkeys were identified as a relevant species for sarilumab in a series of pharmacology studies. Fertility and juvenile toxicity studies were also conducted in mice with an analogous monoclonal antibody (REGN844).”

“Due to these differences, results from mouse xenograft models with human tumor cells may be limited in evaluating the anti-tumor effects of the modified Fc domain of margetuximab (Study RND MGAH22-09-1013).”

“A comparison with rituximab was provided, which is considered acceptable due to the similar mode of action to deplete B-cells via ADCC and ADCP. Based on available rituximab data, no increased risk for SPMs induced by tafasitamab was expected.”

“While the ePPND study, where Non-Human Primates (NHPs) are generally selected by ultrasound scanning at GD 18–20 to start on study, gives no information regarding effects of exposure during implantation and earliest stages of embryogenesis, an ePPND study can be conducted instead of an EFD study in accordance with ICH S5.”

“No dedicated standalone male or female fertility studies were conducted and are generally not practical in monkeys; however, garetosmab may potentially reduce fertility.”

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

“A pharmacology study in an animal model of PNH was not conducted; however, the Applicant assessed complement inhibition in a pharmacokinetics/pharmacodynamics study and in repeat-dose toxicology studies in monkeys as well as in patients with PNH.”

“In line with ICH S6(R1) a carcinogenicity risk assessment has been provided, discussing the relevance and need for in vivo carcinogenicity studies.”

“The applicant stated in the preclinical expert report that since the product is indicated only for use in infants there is no need to evaluate the potential toxicity of palivizumab on the reproduction.”

“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article. Two in vitro and three in vivo studies were performed to study the effects the natalizumab on human α 4 expressing tumour cell lines in vitro and in vivo (as transplants into SCID and nude mice).”

“Because DAC HYP is pharmacologically active only in monkey, carcinogenicity studies are not feasible; therefore, the carcinogenic potential of DAC HYP was not assessed.”

“Embryo-fetal developmental toxicology studies were not conducted with retifanlimab. Rather, consistent with the alternative approach to providing information on the potential for reproductive toxicity described in ICH S6(R1) and ICH S9, the Applicant provided a weight-of-evidence assessment of the potential reproductive toxicity of retifanlimab.”