Animal model or human cells: efficacy evidence for approved small molecules

“Difamilast inhibits the activity of PDE-4 in in vitro studies, e.g., increasing intracellular cAMP levels in inflammatory cells and inhibiting/suppressing the productions of various cytokines and chemokines. Difamilast showed efficacy in a mouse model of chronic contact dermatitis.”

“In vivo proof-of-concept studies were conducted in mdx mice, which harbor a nonsense point mutation in exon 23 that results in production of a truncated and nonfunctional dystrophin protein.”

“The topical administration of delgocitinib ointment for three weeks in the ears of rat skin inflammation model (DNCB-induced dermatitis) showed dose-dependent suppression of ear swelling (male rats).”

“The supportive nonclinical mechanistic data that contributed to CE include in vitro and in vivo data in (1) wildtype and NPC1-deficient Chinese hamster ovary (CHO) (Npc1-/- CHO) cells; (2) fibroblasts derived from patients with NPC; and (3) Npc1-/- mice”

“Overall, the studies support the activity of artesunate and DHA in severe malaria animal models that include rodents infected with the erythrocytic stage parasites of P. berghei, immunocompromised chimeric mice infected with P. falciparum, nonhuman primates infected with P. coatneyi, P. cynomolgi, P. falciparum or P. knowlesi.”

“Cell lines such as NIH/3T3 cells, a murine fibroblast cell line, or Ba/F3 cells, a murine pro-B cell line, were engineered to express ROS1 mutants/fusion proteins for xenograft studies.”

“In LGSOC patient-derived xenograft (PDX) models in vivo, the combination of avutometinib with the FAK inhibitor surrogate VS-4718 induced tumor regressions with a delay in tumor progression relative to avutometinib or VS-4718 alone”

“Avapritinib also exhibited anti-tumor activity in a mouse mastocytoma tumor model with an activating KIT exon 17 mutation and in an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/exon17 mutations.”

“Although inhibition of PDGFRα exon 18 mutants by avapritinib at low nM concentrations has been demonstrated, the effect of avapritinib in PDGFRα driven in vivo animal tumour models have not been examined.”

“In vivo, erdafitinib demonstrated antitumor activity in immune-deficient rodents bearing tumors derived from multiple human cancer cell lines with FGFR1, 2 and 3 alterations (fusion or amplification) including the bladder, lung, GI and liver.”

“Studies conducted in ferrets have shown that amisulpride inhibits emesis caused by apomorphine, with an estimated ED 50 of less than 1 mcg/kg, subcutaneously; and inhibits cisplatin-induced emesis at 2 mg/kg and morphine-induced emesis at 3 to 6 mg/kg, when given intravenously.”

“The in vivo anti-tumor activity of sonrotoclax was evaluated in the MAVER-1 MCL subcutaneous xenograft model in immunocompromised mice with oral administration.”

“The Applicant conducted several nonclinical PK-PD studies examining the effect of gepotidacin on Enterobacterales and Staphylococcus aureus in vivo (neutropenic murine thigh infection models) and Escherichia coli in vitro (1-compartment “chemostat” models).”

“In diabetic mouse (db/db) and rat (ZDF) models, bexagliflozin 0.1 mg/kg to 3 mg/kg dose-dependently reduced HbA1c after four weeks of oral treatment at exposures equivalent to the clinical dose (Figure 3).”

“The in vivo activity of BGB-3111 was evaluated in a subcutaneous xenograft model of MCL, using the REC-1 cell line.”

“A4250 (odevixibat) reduced liver/body weight ratios and serum markers of liver damage and cholestasis in Mdr2-/- mice, a mouse model of cholestasis.”

“Transgenic mice with mutations in troponin T resulting in pathogenic HCM phenotypes which displayed marked diastolic dysfunction with minimal fibrosis, were administered 0.83 mg/kg/day for 6 months. Mavacamten improved diastolic function while preserving fractional shortening.”

“Lumateperone displayed in vivo functional activity in several rodent models of antipsychotic activity including 5-HT2 receptor agonist-induced head twitch in rats and mice (study Nos. ITI DPI001 & ITI-007 INT IC200131, Inhibition of DOI-Induced Head Twitch), conditioned avoidance response (study No. ITI DPI002), and inhibition of amphetamine-induced hyperlocomotion in rats”

“Abrocitinib treatment resulted in a dose dependent inhibition of paw swelling (disease severity) in the rats after seven days of treatment which was significant for the dose levels between 5-50 mg/kg.”

“Xanomeline exhibited antipsychotic-like effects in several animal models of schizophrenia, including conditioned avoidance responding in rodents, psychostimulant-induced hyperactivity in rodents, and scheduled-controlled behavior in rodents and monkeys.”

“The sponsor conducted numerous in vitro and in vivo pharmacology studies to investigate both intended protection from chemotherapy-induced myelosuppression as well as unintended tumor cell protection from chemotherapy-induced cytotoxicity.”

“The pharmacology of trofinetide was characterized in in vitro and in vivo studies, including one in vivo study in an animal model of Rett syndrome (MeCP2 knockout mouse). In that study, trofinetide (0 or 20 mg/kg) was administered by intraperitoneal injection daily for 5 or 20 weeks.”

“The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. The pharmacology of trofinetide was characterized in in vitro and in vivo studies, including one in vivo study in an animal model of Rett syndrome (MeCP2 knockout mouse).”

“were compared in wildtype mice and in very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) or KO mice”

“Studies were conducted in the C57BL/10ScSn-Dmdmdx/J (i.e., B10.mdx) and D2.B10-Dmdmdx/J (i.e., D2.mdx) mice which were intended to model the IAAM (mild) and VTTT (severe) haplotypes, respectively, in DMD.”

“The activity of TCBZ was reported in animals experimentally infected with F. hepatica or F. gigantica”

“Female nude mice injected subcutaneously with H3122 lung cancer cells harboring EML4-ALK E13/A20 received 0 or 25 mg/kg of ensartinib QD or 25 mg/kg BID for 3 weeks via oral gavage.”

“The in vivo activity of RIS was investigated in 2 different SMA mouse models (SMNΔ7 and C/C), which both carry the human SMN2 transgene”

“The intended pharmacological target, the SMN2 gene, exists only in humans, and thus a pharmacological responder species as requested by existing guidelines does not exist unless studies are conducted in transgenic mouse models.”

“dose-fractionation studies in hollow fiber and neutropenic murine thigh infection models identified %fT >2 µg/mL (i.e., the percentage of time that unbound drug concentrations exceed the threshold concentration of 2 µg/mL) as the PK-PD index that best correlates with enmetazobactam’s activity.”

“The Applicant investigated the in vivo anti-tumor activity of mobocertinib in immunocompromised mice (10/group) implanted subcutaneously (SC) with patient-derived NSCLC LU0387 tumor fragments expressing an EGFR exon 20 NPH insertion mutation”

“Cefiderocol with ascending doses (0.3-30 mg/kg q3h) was tested in murine thigh and lung infection models for each tested strain to determine the effective dose and %fT > MIC required to achieve static effect and 1-log10 reduction in the number of viable cells compared to the mean of untreated baseline control group.”

“The activity of fexinidazole was measured in acute and chronic murine infection models of HAT.”

“Although the route of infection in mice is intraperitoneal, several aspects of the disease in T. brucei-infected animal models mimic human disease.”

“The test article has demonstrated efficacy in 2 rodent models of IgAN (also known as Berger’s disease) - the grouped Deutschland, Denken, and Yoken (gddY) mouse model and an engineered immune complex (EIC)-induced “passive IgAN” mouse model - and in a model of mesangial proliferative glomerular nephritis - the anti-Thymocyte (Thy-1) rat (ATS) model.”

“In vivo pharmacodynamic studies in mice and rats bearing human or murine xenograft tumors demonstrated that tivozanib inhibited tumor growth at a dose of 0.2 mg/kg in rats, via inhibition of angiogenesis and vascular permeability.”

“Efficacy was demonstrated in cynomolgus monkeys and in Glp1rS33W rats (a model of humanized GLP-1 receptor), the latter of which are genetically modified to be sensitive to orforglipron.”

“Wild-type rodents lack pharmacological responsiveness to orforglipron because their GLP-1 receptor contains serine (S) at position 33 instead of tryptophan (W), which is present in humans and monkeys and is required for orforglipron binding.”

“Fruquintinib demonstrated dose-dependent and reproducible tumour growth inhibition for the following human xenograft models in BALB/c nude mice: BGC-823, HT-29, Caki-1, and NCI-H460.”

“Pralsetinib exhibited in vivo anti-tumor activity in mice bearing subcutaneously (SC)-implanted tumor xenografts bearing RET activating mutations, including the cabozantinib resistant mutation V804L, or patient-derived NSCLC and colorectal cancer (CRC) xenografts expressing KIF5B-RET and CCDC6-RET, respectively.”

“The functional studies utilised a model for bladder overactivity where acetic acid is administered to induce a hyperactive state of the bladder.”

“β3 AR is the dominant receptor in bladder smooth muscle in humans and monkeys. β3 and β2 receptor subtypes are expressed in rats. β2 receptors only are expressed in mice and rabbits.”

“Mirdametinib was administrated to a genetically engineered mouse model of the NF1 neurofibroma disease (Nf1fl/fl;Dhh-Cre mouse model).”

“Treosulfan showed in vivo myeloablative and immunosuppressive activity in a murine allogeneic bone marrow transplant model.”

“In one model, mice implanted with patient-derived lung cancer cells (ST-3107) expressing HER2 exon 20-YVMA demonstrated dose-dependent tumor growth inhibition (TGI) of ≥119% following twice daily oral administration of ≥30 mg/kg zongertinib.”

“In vivo, sevabertinib exhibited antitumor activity against NSCLC patient-derived xenograft (PDX) models harboring the HER2 exon 20 insertion YVMA.”

“In a stress-induced IBS-C model of rat, and a mouse model of opioid-induced constipation, tenapanor showed a significant improvement of GI function following oral doses of up to 50 mg/kg. Oral administration of tenapanor (0.5 mg/kg) to a rat model of IBS-like syndrome (intracolonic infusion of 0.5% acetic acid) resulted in reductions in colonic hypersensitivity”

“Evaluation of antitumor activity was conducted in subcutaneous xenograft mouse models using Ba/F3 cells expressing ROS1 mutants/fusion proteins CD74-ROS1 and CD74-ROS1G2032R or NSCLC cells harboring the CD74-ROS1 gene fusion.”

“Imlunestrant was well tolerated and induced significant tumor growth inhibition and tumor regressions in multiple ER+ breast cancer xenograft models, including an ESR1-Y537S mutant PDX model.”

“In conclusion, chronic treatment with sotagliflozin in a metabolic rat model of HFpEF improved strong in vivo surrogate markers of diastolic dysfunction including left ventricular end-diastolic pressure, left atrial remodeling, and isovolumetric relaxation time.”

“The in vivo effect of cedazuridine on the antitumor activity of orally administered decitabine was assessed in the L1210 and KG-1 disseminated leukemia mouse models.”

“In vivo studies in mouse models of JAK2V617F-driven myeloproliferative disease showed that twice daily oral doses of fedratinib at 60 or 120 mg/kg blocked phosphorylation of STAT3/5, increased survival to 100% at the highest dose after 42 days of treatment, and improved disease-associated symptoms, including reduction of white blood cells, hematocrit, splenomegaly, and fibrosis.”

“Due to the absence of an animal model that adequately mimics the pathophysiology of human primary biliary cholangitis (PBC), the pharmacological effects of elafibranor have been studied in rodent models of NASH (characterized by liver inflammation and fibrosis, relevant to PBC) and chemically induced liver fibrosis.”

“Due to the absence of an animal model that adequately mimics the pathophysiology of human primary biliary cholangitis (PBC), the pharmacological effects of elafibranor have been studied in rodent models of NASH (characterized by liver inflammation and fibrosis, relevant to PBC) and chemically induced liver fibrosis.”

“Inavolisib showed anti-tumor effects in xenograft mouse models of human breast cancer using KPL-4, HCC1954X1, and MCF7 cell lines.”

“In the in vivo bleomycin model of lung fibrosis, nerandomilast was associated with reversal of bleomycin-induced changes in pulmonary remodelling, lung function in mice at 12.5 mg/kg bid and rats at 2.5 mg/kg bid.”

“Pirtobrutinib had anti-tumor activities in vitro against the human lymphoma cell lines tested (Ramos RA1 and TMD8), and in vivo in mouse xenograft models of lymphoma containing WT BTK or C481S mutant BTK.”

“In vivo, zidesamtinib demonstrated anti-tumor activity in patient-derived xenograft (PDX) murine models bearing subcutaneous NSCLC tumors expressing SDC4-ROS1 or CD74-ROS1G2032R following twice daily oral treatment at ≥0.2 mg/kg (SDC4-ROS1) or ≥1 mg/kg (CD74-ROS1G2032R).”

“Leniolisib was evaluated in two mechanistic and one relevant disease model of PI3Kδ activation.”

“Currently, there is no validated APDS disease model in animals. The Sponsor explored antibody response to sheep red blood cells (SRBC) in rats and ozone-induced neutrophil infiltration in mouse bronchoalveolar lavage (BAL).”

“In vitro and in vivo studies indicate that BAY 94-8862 is a potent and selective mineralocorticoid receptor (MR) antagonist with protective effects on the heart and/or kidney in animal models of heart failure and chronic kidney disease.”

“The in vivo anti-tumor activity of ziftomenib was evaluated in xenograft models using the human AML cell lines MV4-11 and MOLM-13 and patient-derived cells in immunocompromised rats and mice with oral administration and a variety of treatment durations.”

“In vivo, selumetinib reduced proximal nerve root sizes as well as the number and size of tumors in a Nf1fl/fl;DhhCre, a mouse model which allows for targeted knockout of NF1 and recapitulates the development of endogenous neurofibromas.”

“In a panel of KRAS G12C-mutant and KRAS G12C-negative tumor xenograft models, adagrasib had anti-tumor activity in 14 of 17 KRAS G12C-mutant lung xenograft models. In contrast, adagrasib did not exhibit anti-tumor activity in KRAS G12C-negative tumor models.”

“In vivo pharmacology studies were conducted in mice as human xenografts growing in immunodeficient mice are a well-established and useful model in studying human tumour biology.”

“Primary pharmacodynamics A total of five non-GLP primary pharmacodynamic studies, including three literature studies, were conducted using wild-type (WT), Tk2KO, and Tk2KI mouse models to evaluate the effects of nucleoside and nucleotide therapies on TK2 deficiency (TK2d).”

“Both models exhibit mitochondrial dysfunction and respiratory chain defects, mimicking the severe mitochondrial DNA (mtDNA) depletion caused by thymidine kinase 2 deficiency, which closely resembles human infantile encephalomyopathy.”

“Several studies reported the activity of nifurtimox in acute and/or chronic infection models of T. cruzi. Approximately 62 strains/isolates were tested in several animal species that include mice, rats, hamsters, guinea pigs, rabbits and dogs.”

“The lesions and characteristic chronic pathology, in general, are similar to those observed in human disease, and include diffuse myocarditis and signs of heart failure.”

“Further, oral administration of lazertinib inhibited both SC and intracranial tumor growth and extended survival in a dual implantation NSCLC EGFR L858R/T790M mutant xenograft model in nude mice, suggesting lazertinib may have activity against brain metastases.”

“Antitumor activity was evaluated for relacorilant in combination with paclitaxel or paclitaxel alone in mouse xenograft studies with human ovarian (SK-OV-3), human endometrial (MFE-280, Ishikawa), and human cervical (HeLa) cancer cells.”

“Intravenously administered ritlecitinib at 30mg/kg prevented the onset of AA by effectively reducing AA-associated skin inflammation (e.g. supported by data from immunofluorescence and flow cytrometric analysis) and avoiding hair loss in C3H/HeJ skin grafted mice.”

“the applicant justified that exposure data of ritlecitinib after oral administration (the proposed route of administration in human) in AA mice and data on symptoms, markers of neuroinflammation and molecular data upon ritlecitinib withdrawal were not available as the study in AA mice was performed solely with the intention to demonstrate that JAK3 inhibition would improve symptoms of AA.”

“The effect of seladelpar in a carbon tetrachloride (CCl4) model of liver fibrosis in mice was investigated.”

“In the rat partial bile duct ligation (pBDL) model of cholestasis, maralixibat alone at oral doses of 0.3, 1, and 10 mg/kg/day or the combination of maralixibat (1 mg/kg/day) and UDCA (1 mg/kg/day) reduced serum bile acids (sBA), ALP, AST, ALT, GGT, and total bilirubin after 14 days of treatment.”

“ALGS is a cholestatic liver disease for which no animal model has been established. Therefore, the Applicant evaluated the potential effectiveness of maralixibat in a rat cholestasis model that involved partial bile duct ligation (pBDL), to simulate the reduced bile flow in Patients with ALGS and other cholestatic liver diseases.”

“In vivo pharmacodynamics effects on HCMV were analysed in different animal models (transplanted human tissue or surrogate animal viral strains) in comparison to ganciclovir a two other benzimidazole nucleosides.”

“Of note, the strict species specificity of HCMV makes studying this virus in an animal model challenging. No animal model perfectly duplicates the human infection.”

“In vivo, sotorasib induced dose-dependent inhibition of ERK1/2 phosphorylation and tumor growth in mice bearing subcutaneously (SC)-implanted human tumor cell lines (including NSCLC) expressing KRASG12C but not KRASG12V or KRASG12D mutations”

“The pharmacological activity of voclosporin has been demonstrated both in vitro and in vivo using calcineurin inhibition and lymphocyte proliferation as markers of pharmacological effect and using different animal models for autoimmune uveitis, arthritis and organ transplants.”

“SAM was also able to mitigate OLZ-induced metabolic dysfunction, including weight gain and adiposity, in rats and nonhuman primates (NHP), however it did not prevent OLZ-induced liver insulin resistance in rats or have any effects on HbA1c levels or glucose tolerance.”

“Futibatinib had antitumor activity and inhibited FGFR2 phosphorylation and downstream AKT and ERK signaling in a human endometrial carcinoma mice model with an FGFR2 mutation. Antitumor activity was also observed in a nude rat model with human gastric carcinoma SNU‐16 xenograft tumors (FGFR2 gene amplification).”

“In animal models of experimental autoimmune encephalomyelitis (EAE), oral and ICV administration of siponimod resulted in reduce adverse clinical signs.”

“Arimoclomol was shown to increase NPC1 protein expression in fibroblast cell lines from NPC patients in vitro at considerably higher concentrations than those achieved clinically, and reduced hepatic GSL accumulation and improved neurological motor ability deficit in NPC -/- mutant mice in one in vivo non-GLP study and one publication.”

“In mice bearing orthotopic intracranial (brainstem inoculated) tumors, the in vivo antitumor activity of dordaviprone was assessed by evaluating survival and pharmacodynamic endpoints.”

“Prospect of clinical benefit was shown using heterozygous transgenic MYH7 R403Q mice with HCM, and a cat model of hereditary oHCM (A31P MYBPC3 mutation), using aficamten doses comparable to those used in toxicology studies.”

“Both species are considered pharmacologically relevant given the high conservation of the cardiac myosin motor between species and based on in vitro and single-dose in vivo pharmacology studies.”

“In a study in male Beagle dogs, a single oral dose of tradipitant at 0.3, 1.0, or 3.0 mg/kg (less than the clinical dose of tradipitant of 170 mg/day, based on human equivalent dose [HED]) administered 2 hours prior to challenge with the pro-emetogenic drug, apomorphine, resulted in significantly decreased incidence of emesis compared to no treatment.”

“Long-term treatment (160 days) with bempedoic acid at 120 and 240 mg/kg resulted in significant decreases in LDL-C levels (54% to 63%) in LDLR+/- pigs; modest decreases (27% to 29%) in LDL-C were noted in LDLR-/- pigs as compared to vehicle control.”

“From the pharmacokinetic point of view, the rats and monkeys were the most relevant species for non-clinical efficacy and safety studies.”

“Istradefylline potentiated apomorphine’s effects in a 6-OHDA-lesioned rat model of Parkinson’s disease. In the MPTP-treated primate model of Parkinson’s disease, the symptoms improved and no increase in dyskinesias was found.”

“Istradefylline showed similar high affinity for the A2A receptor with Ki values of 12.4 nmol/L in human, 11 nmol/L in marmosets, 8.18 nmol/L in rats but higher affinity in the mouse (Ki of 2.2 nmol/L) and lower affinity in the dog (Ki of 65 nmol/L).”

“In vivo, darolutamide administration inhibited tumor growth in mouse xenograft models of human prostate cancer and suppressed the relative increase in serum PSA when compared to control group.”

“animal data from a knockout mouse model of MoCD Type A showing a reduction of plasma and brain SSC and improved mortality in treated mice compared to controls.”

“The MoCo synthesis pathway is highly conserved, and cPMP is considered identical between species.”

“Overall, in vivo, tovorafenib distributed to different tumour types xenografts (WM-266-4 B-Raf mutant melanoma model, Calu-6 B-Raf wild-type lung cancer model, and BxPC-3 B-Raf wild-type pancreatic cancer model) and resulted in TGI or even regression”

“In vivo pharmacological activity of momelotinib has been confirmed in a mouse model of myeloproliferative neoplasms (MPN) and a rat model of anemia of chronic disease (ACD).”

“In mice and rats, oliceridine elicits antinociception in multiple models of spinal reflexive and supraspinal affective nociceptive pain (potency reported to be 3 to 10 times that of morphine) with less respiratory depression and constipation in rodents compared to “equianalgesic” doses of morphine.”

“Topical ocular omidenepag isopropyl decreased IOP in ocular normotensive rabbits and monkeys, and in a monkey model of ocular hypertension.”

“In MPTP-lesioned cynomolgus monkeys with stable Parkinsonian-like symptoms, BIA 9-1067 was found to augment the effects of L-DOPA/benserazide (a DDI) on motor activity.”

“PK/PD index and target determination for sulopenem were previously conducted using neutropenic and immune-competent murine thigh infection models.”

“For uUTI, there is no established nonclinical model to reliably determine PK/PD targets relevant to the site of infection.”

“In in vivo ER+/PR+/HER2- xenograft and ER+ patient derived xenograft (PDX) breast cancer models, elacestrant led to ≥96% tumor growth inhibition (TGI) at ≥30 mg/kg/day.”

“The effect of oveporexton on wakefulness during the sleep phase was also demonstrated in OX/ataxin-3 transgenic mice (a NT1 mouse model in which the transgene selectively eliminates orexin producing neurons in the hypothalamus) and their non-transgenic WT littermates.”

“Because mice are nocturnal animals with a polyphasic sleep/wake structure, studies were also conducted in cynomolgus monkeys which are diurnal and have a monophasic sleep/wake structure more analogous to humans.”

“All voxelotor-treated SS mice exhibited an increase in Hb-O2 affinity and a decrease in the ex vivo RBC sickling, the effect was dose dependent”

“PF-07321332 showed antiviral activity in mouse models with mouse-adapted (MA) SARS-CoV-2 infection in BALB/c and 129 mouse strains (studies 105036 and 022652).”

“SARS-CoV-2 MA exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which expresses human ACE2, and thus SARS-CoV-2 MA is used by numerous investigators in the SARS-CoV-2 field.”

“Pemigatinib exhibited in vivo anti-tumor activity in mice bearing subcutaneous (SC) human xenografts with FGFR1, FGFR2, or FGFR3 activation, including patient-derived cholangiocarcinoma xenografts expressing a FGFR2 TRA2B fusion and FGFR2-amplified human gastric cancer xenografts.”

“These data were confirmed when alpelisib was administered to mice bearing a diverse range of breast cancer tumor xenografts, including the ER-positive breast cancer mouse models with PIK3CA mutations as well as additional breast cancer patient-derived xenograft (PDX) models (Fritsch et al 2014).”

“The therapeutic efficacy of ACT-128800 was investigated in a murine Experimental Autoimmune Encephalomyelitis (EAE) model (Study #B-08.460), in which mice were immunised with a peptide derived from myelin oligodendrocyte glycoprotein (MOG)”

“In vivo activity of pretomanid was evaluated in acute, chronic and latent TB murine models as monotherapy and in combination with a variety of first- and second-line TB drugs, including the compounds in clinical development.”

“Evaluation of drug monotherapies in TB clinical trials is not ethical nor feasible. The evidence for the contribution of the individual components to the BPaL regimen comes from the studies in the murine models of pulmonary tuberculosis,”

“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”

“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”

“In vivo inhibition of KIT was associated with inhibition of tumour growth in a variety of tumour xenograft models including exon 11 mutant KIT GIST T1 xenografts and an imatinib-resistant exon 17 mutant KIT GIST patient-derived xenograft.”

“The results in halothane-epinephrine, electrical stimulation, and aconitine-induced-arrhythmia and tachycardia models indicated that ONO-1101 has a potential to improve experimental tachycardic atrial flutter and fibrillation and increased sympathetic nerve activity.”

“In vivo cell-line derived xenograft (CDX) mouse models using mutant KRAS G12X pancreatic ductal adenocarcinoma (PDAC) cell lines demonstrated tumor regression with 25 mg/kg daraxonrasib administered daily via oral route of administration with mean tumor regressions of 53%–93%.”

“Several animal models of infection in neutropenic mice were utilized for determining the in vivo efficacy of REL co-administered with IMI.”

“An in vivo primary pharmacology study was conducted in the SOD1 G93A transgenic mouse model of ALS in which oral BID doses of 100/200 mg/kg PB/TUDCA were administered for 50 days. There was no effect on lifespan or markers of disease progression that would suggest any therapeutic potential for AMX0035.”

“Using these cell lines in in vivo studies, investigators observed selpercatinib dose-dependent reduction in tumor growth in mice implanted with TT human thyroid medullary carcinoma and human LC-2/ad human lung adenocarcinoma.”

“inhibited tumor cell growth in human patient-derived xenograft (PDX) ER+ breast tumors with or without PIK3CA and PTEN mutations. In the MCF7 orthotopic mouse xenograft model of PIK3CA-mutant breast cancer, the combination of gedatolisib with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or doublet combinations.”

“The anti-tumor activity of revumenib was evaluated using the human AML cell lines MV4;11 and MOLM-13 in rats or immunocompromised mice and with various routes of administration and treatment durations.”

“In rodent efficacy models, lasmiditan inhibited trigeminovascular protein extravasation (neuroinflammatory response), induction of c-fos, dural-evoked nociception transmission, α-CGRP release, and vasodilation.”

“In vivo studies focused on trigeminal ganglia nociceptive neurotransmission because it is implicated as the origin of migraine pain and expresses 5-HT1F receptors.”

“Decreases in liver weight and severity of liver vacuolation were observed in mice fed an admixture of resmetirom (RO4923659) and high-fat diet (HFD) for 25 weeks compared to placebo+HFD admixture-fed control animals.”

“The dataset did not include any in vivo models that produced all the histological features of NASH (i.e., steatosis, inflammation, hepatocyte ballooning, and fibrosis).”

“In vivo studies in cGVHD mouse models demonstrated treatment with belumosudil resulted in improvement in cGVHD-related safety endpoints in the lung and skin. In addition, belumosudil reduced pulmonary fibrosis (one of the clinical manifestations of GVHD) and inflammation in a murine model of pulmonary fibrosis.”

“The Applicant conducted several studies examining the nonclinical PK-PD of REZ in a neutropenic candidiasis murine model with C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, or C. dubliniensis.”

“In vivo, remibrutinib showed a response in two animal models relevant to CSU, a mouse reverse passive Arthus model and a mouse passive cutaneous anaphylaxis model.”

“An Adjuvant-induced arthritis (AIA) model in rats was also used to determine the efficacy of UPA on the development of paw swelling inhibition, bone erosion, and ankle histology.”

“entrectinib demonstrated response towards 9 TRK1,3-driven and 3 ROS1-driven tumour models (both cell-based and patient-derived xenografts of which only 1 orthotopic model for glioma)”

“it is understood that it is not possible to reflect with non-clinical models the wide clinical pattern in terms of tissue environment and pathophysiological context including gene fusion events.”

“The same treatment schedule of asciminib (3-30 mg/kg) resulted in dose-dependent inhibition of tumor growth in mice with a KCL-22 xenograft harboring a T315I mutant.”

“The potential effectiveness of sepiapterin was evaluated in three in vitro studies using COS-7 cells expressing different PAH protein variants and an in vivo single dose non-GLP study with a Pah-R261Q mouse model of human PKU disease.”

“Proof of concept in vivo studies with palovarotene were conducted in various injury-induced heterotopic ossification (HO) and FOP mice models, including BMP-2 implant, transgenic mice expressing constitutively active ALK2Q207D mutant and the human relevant ALK2R206H mutation (Shimono et al. 2011; Chakkalakal et al. 2012; Chakkalakal et al. 2016).”

“BMS-986165 was evaluated for efficacy against the IL-23-induced acanthosis model of psoriasis in mice, murine anti-CD40 induced colitis, T-cell transfer colitis, and lupus nephritis in lupus-prone NZB/W mice.”

“In a proof of concept study in hypocretin/ataxin-3 transgenic mice (mouse model of narcolepsy), solriamfetol dose-dependently induced continuous wakefulness during the resting (light) and active (dark) phase.”

“Capmatinib demonstrated anti-tumor activity against patient-derived human lung cancer xenografts with either MET exon 14-associated skipping mutations or MET amplifications implanted into nude mice.”

“In the ANCA disease model in hC5aR KI mice, avacopan caused dose-dependent and significant reductions in the incidence of glomerular crescent formation and necrosis relative to vehicle-treated mice”

“As avacopan retains little, if any, potency for C5aR expressed by mice or rats, the applicant generated a human C5aR knock-in (hC5aR KI) mouse strain in which the mouse C5aR gene was replaced with the human C5aR gene.”

“using several patient-derived synovial sarcoma xenograft lines bearing SS18 fusions that lead to INI impairment.”

“In mice implanted with human tumor cell lines harboring METex14 skipping alterations with and without gene amplification, maximal anti-tumor activity occurred at doses as low as 6 mg/kg once daily, leading to complete tumor regression in 100% of mice bearing tumors with both the METex14 skipping alteration and gene amplification.”

“Capivasertib demonstrated anti-tumor activity in vivo in human cancer xenograft models including estrogen receptor positive (ER+) breast cancer models with mutations or alterations in PIK3CA, AKT1, and PTEN.”

“Infigratinib exhibited anti‐tumor activity in mouse and rat xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including patient‐derived xenograft models of cholangiocarcinoma with FGFR2‐fusions.”

“Aprocitentan showed acute antihypertensive effects, including decreased mean arterial pressure (MAP), in salt-sensitive and volume-dependent hypertensive (i.e., deoxycorticosterone acetate [DOCA]-salt rat and Dahl-S rat) or spontaneously hypertensive (SHR) rat models.”

“In vivo, single agent tucatinib showed anti-tumor activity and inhibition of HER2 phosphorylation in mouse xenograft models of HER2 expressing tumor cells.”

“The in vivo antitumor activity of umbralisib was evaluated in a MOLT-4 xenograft model. MOLT-4 tumor-bearing mice were dosed orally with umbralisib at 150 mg/kg/day for 25 days, with the measurement of tumor growth continuing until 41 days after dosing initiation.”

“In vivo nonclinical infection model studies summarized below evaluated the bactericidal effects of tebipenem using clinically relevant dosing regimens in neutropenic mouse and immunocompetent rat pyelonephritis models.”

“Using the MV4-11 cell line, quizartinib also displayed in vivo anti-tumor activity in a mouse tumor xenograft model and increased the lifespan of animals.”

“In a spontaneous IgAN mouse model (grouped-ddY mouse strain), treatment with atrasentan at doses of 10, 20, or 30 mg/kg/day for 5 days reduced albuminuria from baseline by 28, 62, and 63%, respectively.”

“In vivo efficacy of RDV was assessed via mouse models of SARS-CoV and MERS-CoV infection and non-human primate models of SARS-CoV-2 and MERS-CoV infection.”

“As primary pharmacology animal model the applicant chose a model employing adoptive transfer of CD4+CD45RBhigh T cells from WT mice to severe combined immunodeficiency (SCID) mice, which showed among other effects that 3 mg/kg bw of etrasimod significantly reduced the expression of the T cell and monocyte markers in isolated colonic tissue.”

“In vivo pharmacology studies demonstrated fezolinetant attenuated hot flash-like symptoms in ovariectomized (OVX) rats (a nonclinical model of postmenopause).”

“In the ER+ ESR1 WT MCF7 xenograft model, 30 mg/kg/day of vepdegestrant led to tumor shrinkage (124% TGI on Day 28) and reduced ER levels by >94% in tumor tissue, and both ER degradation and TGI were significantly better following vepdegestrant treatment compared to fulvestrant in this model.”

“in vivo pharmacodynamic studies were conducted in healthy rats and dogs, spontaneous hypertensive rats (SHR), a hypertension and heart failure model (renin-transgenic rats), a dog and minipig model of pulmonary arterial hypertension (PAH), and a dog model of pulmonary hypertension secondary to left ventricular dysfunction (PH-LVD).”

“The activity of oteseconazole was evaluated in two studies using an estrogen-dependent murine model of vaginal candidiasis.”

“Two proof-of-concept studies were conducted in murine models of myelofibrosis whose pathology is driven by excessive JAK2 activity, recapitulating the dysregulated JAK/STAT pathway described in human myelofibrosis.”

“Oral administration of vonoprazan inhibited aspirin and indomethacin-induced gastric lesions in rats. Vonoprazan also inhibited experimental reflux esophagitis in rats.”

“In mouse xenograft studies using a subcutaneous U87 IDH2R140Q glioma model and an orthotopic TS603 IDH1R132H glioma model, vorasidenib had a liner dose-PK relationship, tumor to plasma ratios greater than 1, and dose-dependent decrease in 2-HG levels in the tumor tissue.”

“In animal models, the anti-inflammatory activity of tapinarof has been demonstrated in the imiquimod mouse model of psoriasis. It led to reductions in epidermal thickness and mRNA expression of key pro-inflammatory cytokines (IL-17a, IL-17f, IL-19, IL-1β, and IL-23a).”

“In addition to enhanced wakefulness, pitolisant decreased the number of narcoleptic attacks and a reduced the total duration of narcolepsy when administered in the narcolepsy mouse model (Orexin-/-).”

“In a murine model for ITP, rilzabrutinib pretreated animals were stressed with an intraperitoneal injection of an anti-CD41 antibody to induce thrombocytopenia (DVR0288).”

“This is because mouse, rat, dog, and rabbit BTK are nearly identical to the human version of the protein (approximately 99% homologous amino acid sequence), with no differences in the sites where rilzabrutinib binds.”

“The anti-tumour activity of belzutifan was evaluated in a VHL-deficient tumour xenograft model derived from the human ccRCC cell line 786-O implanted in SCID/Beige mice.”

“In vivo, its efficacy was shown in the hamster flank organ model, where topical application reduced testosterone-induced enlargement without systemic effects.”

“The Golden Syrian Hamster animal model has been extensively used to evaluate anti-seborrheic mechanisms through modulation of sebum production and sebocyte proliferation; this animal model closely replicates the pathogenic mechanism involved in acne.”

“The Applicant conducted several studies examining the nonclinical pharmacokinetics (PK)/ pharmacodynamics (PD) of sulbactam-durlobactam in murine thigh and pneumonia models of MDR ABC infection.”

“Cenobamate, administered IP and/or PO, produced antiepileptic effects in mice and rats at doses between 0.3 and 30 mg/kg.”

“CBM was shown to be active in various standard animal models of epilepsy thought to be predictive of efficacy against generalized and partial seizures.”

“The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio has been shown to be the best Pharmacokinetic-Pharmacodynamic (PK-PD) index for the antibacterial activity of lefamulin in animal infection models of Streptococcus pneumoniae and Staphylococcus aureus pneumonia.”

“The in vivo antitumor activity of selinexor was evaluated alone and in combination with dexamethasone in mouse xenograft models of multiple myeloma.”

“The activity of cefepime/zidebactam was evaluated using three models: neutropenic lung, neutropenic thigh, and cUTI mouse models.”

“The Applicant investigated the in vivo anti-tumor activity of sunvozertinib in nude mice (6-9/group) implanted subcutaneously (SC) with a human squamous cell carcinoma cell line expressing WT EGFR (A431) or patient-derived NSCLC xenograft models carrying EGFR exon20ins mutations (LU0387 and LU3075).”

“In vivo, iberdomide also demonstrated anti-tumor activity MM tumor xenograft models, including in models of lenalidomide resistance.”

“Consistent with the impact of ozanimod and its metabolites on circulating lymphocytes, efficacy in the mouse (C57BL/6) experimental autoimmune encephalomyelitis model and cuprizone demyelination model were demonstrated.”

“exhibited antitumor activity (decrease in the tumour volume or an increase in the survival time) against different experimental models of either subcutaneously or orthotopically xenografted human cell-derived (CDX) and patient-derived (PDX) tumours such as lung, breast, prostate, bladder, kidney, ovary, pancreas and sarcoma.”

“In summary, ceftobiprole was shown to be active against MSSA and MRSA in the murine septicemia model and rat and rabbit endocarditis and osteomyelitis models. Ceftobiprole was active against S. pneumoniae, including penicillin resistant strains in the murine septicemia and the murine acute pneumonia models.”

“which shows how lonafarnib in a mouse model of Hutchinson-Gilford Progeria Syndrome (homozygous LmnaG609G/G609G mice) prolonged survival”

“GNX (IP or oral) was active in several traditional rodent seizure models (eg, chemically-induced convulsions, corneal kindling). GNX was not tested for activity in a Cdkl5 disease model.”

“While Cdkl5 knockout mouse models have been generated, these do not exhibit overt seizures.”

“CuHis administered alone did not provide a survival benefit in a mouse model of MD.”

“Some possibilities include: 1) the study designs did not mimic clinical administration of the drug; 2) gene therapy may have superseded any benefit of CuHis; 3) subcutaneous CuHis may not be readily distributed in mice compared to humans;”

“Studies with radiolabeled iron in rats, confirmed in dogs and humans, demonstrate that intact ferric maltol is found in the gastrointestinal tract, but not in the blood.”

“The scientific literature includes an exhaustive characterization of the presence and pharmacological effects of iron in the human body.”

“The in vivo pharmacodynamics of acoramidis were assessed by correlating its circulating levels in serum samples from dogs and monkeys with its ability to stabilise TTR.”

“Animal models of amyloidosis that can recapitulate the human phenotype of ATTR are not available. Therefore, no in vivo proof of concept studies of the efficacy of acoramidis were conducted.”

“Sodium-Depleted Telemetry Studies: To evaluate pharmacodynamic effects under conditions of maximal RAAS activation, telemetered cynomolgus monkeys were maintained on a low-sodium diet and treated with the diuretic furosemide, which models a common clinical scenario.”

“The cynomolgus monkey renin-angiotensin system closely resembles the human system, making it a relevant species for assessing pharmacodynamic efficacy and toxicity.”

“There are no established models for NCFB. Therefore, the Applicant has evaluated the activity of brensocatib in a lipopolysaccharide (LPS)-induced acute lung injury model.”

“There is no in vivo animal model of bronchiectasis that provides direct evidence of the non-clinical efficacy of brensocatib.”

“Flumazenil prevents or inhibits the sedative effects of remimazolam. Onset of sedation and recovery from sedation was rapid in all species tested compared to midazolam.”

“However, the Applicant demonstrated etripamil pharmacological effects in isolated rabbit hearts (ex vivo), and in spontaneously hypertensive rats (SHRs) and normotensive rabbits.”

“There are no dedicated animal models of PSVT. The Applicant did not directly assess the effect of etripamil in alternative arrhythmia animal models.”

“These studies demonstrated that crinecerfont inhibits CRF1 receptors and antagonizes CRF-induced cyclic adenosine monophosphate (cAMP) synthesis and ACTH secretion from pituitary, and blocks stress-induced increases in ACTH in rats (Table 99).”

“In animal studies, including rats, dogs, and minipigs, cipepofol produced anesthesia at a similar depth as propofol, but with a 6-fold higher anesthetic potency.”

“Oral administration of lemborexant to mice and rats significantly increased total sleep time, without an effect on the REM sleep ratio, with an ED50 of 1 mg/kg and 4.4 mg/kg, respectively.”

“No HAE-disease animal model has been established. Therefore, a carrageenan-induced paw edema study in Sprague-Dawley rats (a non-HAE disease model of acute inflammation) was used to evaluate the in vivo anti-inflammatory activity of sebetralstat.”

“Since there is no established animal model of HAE, the CPE model was selected as a surrogate for tissue swelling in HAE attacks.”

“Neurological effects: Gepirone was active in animal models that are predictive of antidepressant and anxiolytic activity in humans.”

“Using a different experimental design including higher doses (up to 10000 ug/kg), Weldon et al showed that osilodrostat inhibited ACTH stimulated cortisol synthesis in monkeys with an EC50 of 1500 nM being approximately 300-fold higher than EC50 for aldosterone synthesis.”

“Daprodustat treatment resulted in dose-related increases in RBC parameters (up to 18%, 22%, and 26% of RBC, hemoglobin, and hematocrit, respectively) that were evident by Day 8 and further increased on Day 22.”

“The Applicant therefore evaluated the ability of linerixibat to decrease serum bile acids and increase fecal excretion of bile acids (resulting from inhibition of enterohepatic recirculation) in healthy mice and dogs and in a rat model of necrotizing enterocolitis (NEC).”

“PBC is a cholestatic liver disease for which animal models have not been established.”

“In a Mongolian gerbil foot tapping model, elinzanetant at intracerebroventricular doses of 1, 3 and 10 mg/kg reduced GR-73632 (NK-1 receptor agonist) induced foot tapping, a behaviour associated with NK-1 receptor agonists.”

“Two (2) in vivo non-GLP rabbit studies showed after four times daily ocular instillations of F6H8 into the right eye of NZW rabbits for 7 days, a trend with an increase of TFBUT (tear film breakup time) 15 minutes after the last administration of F6H8”

“In New Zealand White rabbits, E4 inhibited ovulation and implantation with respective oral ED50s of 0.7 mg/kg bid and 0.06 mg/kg bid.”

“Rimegepant effectively antagonised the hCGRP-induced increases in marmoset facial blood flow showing 75% to 80% inhibition at plasma levels of ~700 nM (or 374 ng/mL).”

“Comparing activity across species, rimegepant exhibits similar receptor affinities at both human (Ki of 33 pM) and nonhuman primate (marmoset (92 pM) and cynomolgus monkey (60 pM)) CGRP receptors, with more than 1,300-fold less activity at dog (43 nM), rat (209 nM) and mouse (104 nM) CGRP receptors as compared to human.”

“However, the Applicant did not conduct any in vivo pharmacology studies using COPD animal models. The in vivo pharmacology studies were primarily for allergic conditions as well as asthma.”

“While there are no animal models that fully recapitulate all aspects of COPD, the most frequently employed animal models use cigarette smoke, lipopolysaccharide, and elastase to induce various features of COPD.”

“In vivo, administration of relugolix suppressed the pituitary-gonadal axis, causing a decrease in plasma luteinizing hormone in castrated monkeys after a single dose and reduction of serum testosterone levels in human GnRH receptor knock-in male mice after repeat dosing.”

“In contrast, a 19,000x and 24,000x reduction in binding affinity was noted to rat GnRH receptor (IC50 = 2900 nM) compared to monkey and human receptors, respectively.”

“Paltusotine orally administered to rats (≥3 mg/kg) significantly and dose-dependently suppressed rat GH elevation induced by growth hormone-releasing hormone (GHRH), with a plasma EC50 of 11 ng/mL.”

“In pharmacology studies in rats, following oral administration, lactitol increased the weight of the contents of the small intestine and fermentation was not necessary for lactitol-induced osmotic effects in the small intestine.”

“In vivo administration of viloxazine to the rat increased brain norepinephrine levels, as well as serotonin (5-HT) and dopamine (DA) levels.”

“A specific animal model for the evaluation of prophylactic effects of atogepant on migraine was not provided by the applicant. As a surrogate pharmacological parameter for clinical efficacy of atogepant in the prophylaxis of migraine, inhibition of capsaicin-induced dermal vasodilatation (CIDV), an effect considered to be mediated largely by release of CGRP, was used by the applicant.”

“Proof-of-concept for the indication was sufficiently demonstrated in in vivo primary pharmacology studies using as usually naive rats and dogs as models.”

“Rats and dogs are pharmacologically species relevant for daridorexant, as the orexin system is highly conserved across mammalian species, and as activity on sleep parameters had been clearly demonstrated.”

“The in vivo activity of olutasidenib was assessed by measuring 2-HG in xenograft models of cell lines engineered to express mutated IDH1.”

“The models employed in the in vivo primary PD studies are CSF1R-dependent but not TGCT models.”

“Oral centanafadine dose-dependently increased NE, DA, and 5-HT levels in the prefrontal cortex as well as DA and 5-HT levels in the ventral striatum.”

“The ability of omaveloxolone to induce expression of Nrf2 target genes in vivo was demonstrated using tissues collected from healthy omaveloxolone-treated mice, rats and monkeys.”

“Because well-established animal models of FA are not commercially available, omaveloxolone was tested in several rodent models of neurological disease.”

“In comparison with a concurrent ethanol control group, a single topical application of sofpironium bromide gel at a 20% concentration statistically significantly inhibited perspiration induced by subcutaneous injection of the muscarinic receptor agonist pilocarpine.”

“A single topical ocular dose of acoltremon (10 µL/eye/OU at 0, 10, 50, or 200µM acoltremon into the lower conjunctival sac) increased blink rate in guinea pigs (measured over 5 minutes) and in parallel, a slight but not statistically significant increase in tear rate was measured compared to vehicle, with an EC50 of 9.1µM.”

“In an in vivo model in which injection of CSFR1 signaling-dependent cells results in splenomegaly, pexidartinib inhibited splenomegaly by 79%, compared to the vehicle control.”

“In efficacy models, ubrogepant inhibited relaxation of capsaicin-induced dermal vasodilation (a CGRP mediated response) in the rat (EC50=3 nM), rabbit (EC60 20 µM), and monkey (EC50=3 pM), and inhibited of CGRP-induced relaxation of human cranial arteries dose dependently (up to ~25% at 1 µM).”

“Vadadustat was evaluated in exploratory studies of healthy, normoxic mice and rats but not in any animal model of anemia.”

“In an efficacy study (Study #21-130-0009), pupil response was measured in New Zealand White rabbits following a single topical administration of aceclidine 1.75% with or without”

“In serum derived from cynomolgus monkeys administered single oral or multiple oral doses of danicopan, an ex vivo analysis revealed that significant (80% to 90%, at concentrations greater than or equal to 258nM) and concentration-dependent inhibition of AP activity was achieved in monkeys.”

“Based on the pharmacology data (and the lack of cross reactivity to rodent species), the cynomolgus monkey, beagle dog, and New Zealand white (NZW) rabbit were selected as the nonclinical efficacy species.”

“An in vivo pharmacology study indicated suppression of CGRP-induced facial blood flow in monkeys without vasoconstrictive effects on coronary or cerebral arteries (as measured by laser doppler).”

“In vitro primary pharmacology studies indicated similar affinity of BHV-3500 for human and cynomolgus monkey CGRP receptors; however, affinity was approximately 10,000-fold lower for dog, rabbit, and rat CGRP.”

“In general animal behavioral studies, brexanolone produces dose-dependent depressant effects such as sedation and muscle relaxation in rats and dogs and decreased locomotion in mice.”

“PD target engagement was also studied in rodent models of anticonvulsant, electroencephalographic, anxiolytic-like, and sedative activity consistent with the GABAA receptor PAM mechanism.”

“TEZ+D-IVA+VNZ treatment results in increased processing and trafficking of the F508del-CFTR protein in CF-HBE cells with the F508del/F508del and F508del/MF genotype.”

“As there is no validated animal model for CF that fully mimics the human multi organ affected disease, the use of in vitro systems to study the pharmacology can be accepted.”

“RPV had antiviral activity against wild-type laboratory strain HIV-1IIIB in the MT4 T-cell line with a median EC50 value of 0.73nM and against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01nM”

“In vitro assays using erythrocytes from patients with PNH showed that iptacopan inhibited both hemolysis and C3 deposition, suggesting that iptacopan may prevent both IVH and EVH features of PNH.”

“This active form inhibits HIV-1 replication, and the parent drug exhibited an IC50 of 0.21 nM in human PBMCs.”

“SUZ inhibited action potential firing in primary human DRG in current-clamp manual patch electrophysiology.”

“SUZ was at least 80-fold less potent in rodent NaV1.8 (IC50: 56nM) than in human NaV1.8. Therefore, in vivo primary pharmacology studies were not conducted in rodents.”

“In vitro, the concentration of tirbanibulin at which proliferation of cultured keratinocytes is reduced by 50% is 40 nM.”

“Nirogacestat also demonstrated growth inhibition in various Notch expressing patient‐derived desmoid tumor cell lines in vitro with IC50s of 4‐160 µM. Nirogacestat exhibited anti‐tumor activity in numerous Notch‐driven tumor xenograft models in mice but did not induce tumor growth inhibition in a non‐Notch‐driven tumor xenograft model.”

“Finally, BCX7353 was shown to inhibit kallikrein activity ex-vivo from subjects with HAE, with a range of EC50s slightly higher than in normal human plasma, ranging from 11.7 to 20.0 nM, and a mean EC50 of 15.9 ± 0.57 nM (Study BR-7353-006-REV-01).”

“Temsavir IC50 value ranged from 0.01 to >2000 nM against clinical isolates of subtypes A, B, B', C, D, F, G and CRF01_AE in PBMCs.”

“In MT-4 cells, LEN demonstrated antiviral activity with an EC50 value of 0.19nM and a selectivity index (CC50 value/EC50 value) of 140,000.”

“Alone and in combination with tezacaftor and ivacaftor, elexacaftor facilitates processing and trafficking of CFTR leading to increased chloride transport in HBE cells collected from CF patients.”

“There is no validated animal model for CF that fully mimics the human multi organ affected disease. Furthermore, the proposed treatment is specific for mutated CFTR proteins.”

“The compound inhibited CXCL12 binding to CXCR4 with an IC50 of 6.1 nM in K562 lymphoblast cells stably overexpressing wild type (WT) CXCR4 and IC50 ranging between 3.2 and 11 nM in cells overexpressing different WHIM mutant variants.”

“No studies in WHIM syndrome animal models were conducted with mavorixafor.”

“In a primary pharmacology in vitro radioligand receptor binding assay (Study No. AB54825); SDX at concentrations from 0.03 to 10 µM did not show significant binding to the human dopamine transporter (DAT), norepinephrine transporter (NET), or serotonin transporter”

“KP415 is a combination of a new molecular entity (NME), serdexmethylphenidate (SDX), and a previously approved product, dexmethylphenidate (d-MPH). SDX is a prodrug of d-MPH.”

“Ibrexafungerp demonstrated activity with MIC90 values ranging from 0.015 – 4 μg/mL against C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. lusitaniae, C. guillermondii, C. orthopsilosis, C. pelliculosa, C. kefyr, and C. auris.”

“The Applicant has demonstrated in vitro activity of taurolidine against the following microorganisms. This list will be included in the Microbiology section of labeling.”

“Deuruxolitinib exhibited similar pharmacology properties compared with ruxolitinib, including the selectivity and potency of JAK inhibition and the inhibition of interleukin-6 (IL-6)-stimulated STAT3 activation.”

“Dose ranging and dose fractionation studies in HFIM showed that single doses ranging from 2 g to 8 g successfully eradicated N. gonorrhoeae reference strains WHO-F and WHO-X.”

“Neisseria gonorrhoeae is a human specific pathogen that grows poorly in nonhumans. As such, animal models (mouse, rabbit, guinea pig, hamster, chimpanzees etc.) are unreliable models of N. gonorrhoeae infection.”

“The pharmacologic activity of tafamidis was demonstrated only in vitro, through its binding to TTR at the thyroxine binding sites and stabilisation of the TTR tetramer under non-physiologic (acid and urea denaturation conditions) and physiologic conditions.”

“The CHMP considered that at the time of the preclinical development of tafamidis, an animal model of ATTR-PN that would reflect the clinical disease or resemble the pathology was not available, and that none of the transgenic animals described in the literature reproduce the pathology seen in ATTR patients.”

“The ovicidal activity of the to-be-marketed formulation, abametapir lotion 0.74%, was investigated using three different developmental stages of a permethrin-and-DDT-resistant strain of head lice eggs”

“Proof of concept studies were not conducted for the indication of Demodex blepharitis.”

“Lotilaner has been shown to be effective against Demodex mites in dogs (Snyder 2017) and has been developed and approved as a veterinary drug for the eradication of skin parasites such as ticks and fleas.”