Table S1: Approvals for Cardiovascular Drugs 2012-2016

Additional file 1

Table S1: Approvals for cardiovascular drugs 2012-2016

Drug Description Companion Animal models for diagnostic efficacy 2012 apixaban factor Xa inhibitor no Effects of apixaban anticoagulant were evaluated in indicated to reduce anesthetized rats, the risk of stroke and rabbits, and dogs. systemic embolism in The models patients with included arterial- nonvalvular atrial venous shunt fibrillation, and for thrombosis, tissue the prophylaxis of factor-stasis venous deep vein thrombosis thrombosis, in patients who have FeCl2-induced vena undergone hip or cava thrombosis, knee replacement FeCl2-induced carotid surgery artery thrombosis, electrically induced carotid arterial thrombosis and deep vein thrombosis. Hemostasis was assessed in models of cuticle bleeding time, renal cortex bleeding time, and mesenteric bleeding time. (ten models) (Pharmacology Review, Application Nr: 202155Orig1s000, FDA) lomitapide microsomal Yes, homozygous The cholesterol triglyceride transfer familial hyper- lowering activity of protein inhibitor cholesterolemia can lomitapide was indicated for the be diagnosed by shown in Sprague- treatment of patients testing LDLc levels, Dawley rats, Golden with homozygous a definitive diagnosis Syrian hamsters, and familial can be made by gene cynomolgous hypercholesterolemia or receptor analysis. monkeys. (3 models) (Pharmacology Reviews, Application number:203858Orig1 s000, FDA) icosapent ethyl ethyl ester of no In rats fed with high eicosapentaenoic acid cholesterol diet ethyl

1 (EPA) indicated as an EPA a significant adjunct to diet to reduction of reduce triglyceride cholesterol and TG (TG) levels in adult levels was detected. patients with severe (one model) hypertriglyceridemia (Pharmacology Reviews, Application Nr: 202057Orig1s000, FDA) 2013 riociguat oral soluble no Normotensive rats, guanylate cyclase spontaneously stimulator for the hypertensive rats, and treatment of normal dogs were pulmonary used to demonstrate hypertension riociguats hemodynamic effects of decreased mean arterial pressure, increased coronary blood flow and oxygen saturation. Also three models of induced pulmonary hypertension were used (mice, rabbits, rats). (six models) (Pharmacology Reviews, Application Nr: 204819Orig1s000, FDA) mipomersen sodium oligonucleotide Yes, homozygous No animal models inhibitor of familial hyper- were reviewed. apolipoprotein B-100 cholesterolemia can (Pharmacology synthesis indicated be diagnosed by Reviews, Application for the treatment of testing LDLc levels, Nr. patients with a definitive diagnosis 203568Orig1s000, homozygous familial can be made by gene FDA) hypercholesterolemia or receptor analysis. nimodipine calcium channel no No animal models blocker indicated to were reviewed. improve neurological (Pharmacology outcome following Reviews, Application subarachnoid Nr. hemorrhage 203340Orig1s000, FDA) macitentan dual endothelin no Pharmacodynamic receptor antagonist effects of macitentan for the treatment of have been

2 patients with investigated in pulmonary arterial normal rats and in rat hypertension disease models in which endothelin receptor plays a pathological role. (three models) (Pharmacology Reviews Application Nr: 204410Orig1s000, FDA) polidocanol sclerosing agent no New Zealand rabbits injectable foam indicated for the were used to model treatment of varicose the situation where veins the vein is occluded, and to investigate the effect of polidocanol on vein endothelium. (four models, thereof one negative) (Pharmacology Reviews, application Nr: 205098Orig1s00, FDA) 2014 omega-3-carboxyclic fish oil-derived no The lipid lowering acids mixture of free fatty effects of EPA have acids for the been observed in treatment of patients rodent, rabbits and with severe primates. hypertriglyceridemia (3 models) (Pharmacology Reviews, Application Nr: 205060Orig1s000, FDA) vorapaxar protease-activated no No animal models receptor-1 antagonist reviewed. for the prevention of Only non-human cardiovascular events primates or humans in high risk patients can be used to demonstrate efficacy and anti- thrombotic activity of an antagonist specific to human PAR-1, as they express PAR-1 and PAR-4 on their

3 platelets. (Pharmacology Reviews, Application Nr: 204886Orig1s000, FDA) 2015 ivabradine hyperpolarization- no Bradycardic effect activated cyclic was shown in nucleotide-gated conscious channel blocker normotensive rat indicated for the after single, treatment of chronic intravenous or oral heart failure administration. Cardiac and regional haemodynamic effects were evaluated in conscious Long Evans rats. Hemodynamic and electrocardiographic effects were evaluated in anesthetized pigs. Improvement of angiogenesis and vascular protection by ivabradine was shown in a rat model of left ventricular dysfunction and chronic heart failure. The effect of chronic administration of ivabradine on left ventricular contractile properties in a rat model of chronic heart failure was evaluated. The effect of long- term therapy with ivabradine on LV function and remodelling in dogs with chronic heart failure was evaluated. The effect of chronic administration on

4 survival and on the development of heart failure in 132-AR transgenic mice was evaluated. Further the effects of subchronic administration of ivabradine on pressure overload- induced heart failure in rats was examined. (eight models, thereof two negative) (Pharmacology Reviews, Application number: 206143Orig1s000, FDA) sacubitril and neprilysin inhibitor no Effects on the valsartan and angiotensin II cardiovascular receptor blocker system have been combination indicated evaluated in three to reduce the risk of different rodent death and disease models. hospitalization in (three models) patients with chronic (Pharmacology heart failure Reviews, Application Number: 207620Orig1s000, FDA) sebelipase alfa enzyme replacement Yes, test for Administration therapy for the biallelic pathogenic resulted in the treatment of lysosomal variants in LIPA or restoration of LAL acid lipase (LAL) deficient LAL enzymatic activity deficiency enzyme activity in and reversal of the peripheral blood associated leukocytes, pathophysiology of fibroblasts or dried LAL-/- rats. (one blood spots needed. model) (Pharmacology Reviews, Application Nr: 125561Orig1s000, FDA) cangrelor intravenous P2Y12 no In anaesthetized platelet inhibitor mongrel dog model indicated for use in of stenosed femoral patients undergoing artery induced by percutaneous coronary clamping for five intervention to reduce minutes, cangrelor

5 the risk of exhibited dose- periprocedural related inhibition of thrombotic events thrombosis as measured by inhibition of cyclic blood flow, with increase in prolongation of bleeding time. In conscious beagle dogs infused continuously with cangrelor for 7 days, platelet aggregation in response to ADP was abolished. In the dog model of occlusive thrombus and stenosis in the left circumflex coronary artery induced by electrical stimulation cangrelor reduced re-occlusion and cyclic blood flow in the coronary artery and reduced myocardial infarct size. (three models) (Pharmacology Reviews, Application Nr. 204958Orig1s000, FDA) alirocumab proprotein convertase Yes, familial hyper- No animal models subtilisin/kexin type 9 cholesterolemia can reviewed. inhibitor monoclonal be diagnosed by (Pharmacology antibody for the testing LDLc levels, Reviews, Application treatment of a definitive Nr. heterozygous familial diagnosis can be 125559Orig1s000, hypercholesterolemia, made by gene or FDA) or patients with receptor analysis. atherosclerotic heart disease who require additional lowering of LDL-cholesterol evolocumab monoclonal antibody Yes, homozygous In vivo administration targeting proprotein familial hyper- of evolocumab in convertase cholesterolemia can hamsters resulted in subtilisin/kexin type 9 be diagnosed by increased hepatic (PCSK9) indicated for testing LDLc levels, LDLR protein,

6 the treatment of a definitive decreased serum non- patients with diagnosis can be HDL-C, and heterozygous familial made by gene or total cholesterol. In hypercholesterolemia, receptor analysis. vivo administration of homozygous familial evolocumab in male hypercholesterolemia , cynomolgous or patients with monkeys resulted in atherosclerotic heart decreased total disease who require cholesterol and serum additional lowering of LDL-C. LDL-cholesterol (two models) (Pharmacology Reviews, Application Nr. 125522Orig1s000, FDA) edoxaban oral, once-daily factor no An anti-thrombotic Xa inhibitor effect was shown in a anticoagulant indicated rat arteriovenous for the prevention of shunt model, in a rat stroke and systemic venous stasis model, embolism in patients a rat venous with nonvalvular atrial thrombosis model, fibrillation, and for the and a rat tissue factor treatment of deep vein induced disseminated thrombosis, and intravascular pulmonary embolism coagulation model. (four models) (Pharmacology Reviews, Application Nr. 206316Orig1Orig2s0 00, FDA) selexipag oral prostacyclin no No animal models receptor agonist reviewed. indicated for the (Pharmacology treatment of Reviews, Application pulmonary arterial Nr. hypertension 207947Orig1s000, FDA) 2016

Table S2: Approvals in oncology 2012-2016

Drug 2012 cabozantinib

vismodegib

7 axitinib

pertuzumab ingenol mebutate

regorafenib enzalutamide ziv-aflibercept bosutinib ponatinib carfilzomib vincristine sulfate LIPOSOME injection omacetaxine mepesuccinate

2013 afatinib ado-trastuzumab emtansine trametinib dabrafenib radium Ra 223 dichloride obinutuzumab ibrutinib pomalidomide

8 mechlorethamine

2014 ramucirumab pembrolizumab olaparib nivolumab ceritinib belinostat blinatumomab idelalisib

2015 alectinib cobimetinib palbociclib talimogene laherparevec lenvatinib trifluridine and tipiracil

sonidegib

irinotecan liposome injection necitumumab osimertinib

9 dinutuximab trabectedin daratumumab elotuzumab panobinostat ixazomib

2016 cabozantinib olaratumab atezolizumab rucaparib venetoclax

Table S3: Approvals for psychiatric drugs 2012-2016

Drug Description Companion Animal models for diagnostic efficacy 2012 2013 vortioxetine multimodal no Vortioxetine had an antidepressant for antidepressant-like the treatment of effect in the forced major depressive swim test in mice, but disorder not in the chronic mild stress model of depression. It had an anxiolytic-like effect in the mouse marble burying test, the rat social interaction test, and in conditioned fear-

10 induced vocalization model in rats (seven models, thereof three negative) (Pharmacology Reviews, Application Nr: 204447Orig1s000, FDA) levomilnacipran serotonin and no The anxiolytic-like norepinephrine effect of reuptake inhibitor levomilnacipran was indicated for the evaluated in male treatment of major Sprague-Dawley depressive disorder rats in two studies by testing the ability of the drug to attenuate conditioned stress- induced ultrasonic vocalizations. The efficacy of levomilnacipran was also evaluated for its anxiolytic-like effects in several other animal models such as Vogel Conflict test and Elevated Plus-Maze test in male Han Wistar rats and Four Plates test and Marble burying test in male NMRI mice. The results of single- dose and chronic doses studies showed no anxiolytic-like effects by levomilnacipran in any of the animal models at any of the dose levels tested in the learned helplessness model of depression in male Wistar rats. Sub- chronic administration of levomilnacipran failed to produce improvements in the escape performance in the active avoidance task demonstrating the lack of antidepressant-like

11 effects. Forced swim test was positive (eleven models, thereof five negative) (Pharmacology Reviews, Application Nr: 204168Orig1s000, FDA) 2014 2015 brexpiprazole serotonin-dopamine no Correlation was found activity modulator in different animal for the treatment of models, effect was schizophrenia and higher in combination the adjunctive therapy with fluoxetine, treatment of major paroxetine or sertraline depressive disorder (five models) (Pharmacology reviews, Application Nr. 205422Orig1s000, 205422Orig2s000, FDA cariprazine dopamine D3/D2 no Correlation with receptor partial different animal models agonist atypical for antipsychotic like antipsychotic for the activity, antimanic acute treatment of potential and manic or mixed antidepressive like episodes associated effects were reviewed. with bipolar I (17 models, thereof four disorder and for the negative) treatment of (Pharmacology schizophrenia Reviews, Application Nr: 204370Orig1Orig2s000, FDA) 2016 pimavanserin non-dopaminergic, no Pimavanserin selective serotonin pretreatment of rats inverse agonist for significantly reversed the treatment of the number of head psychosis associated twitches that were with Parkinson’s induced with 6- disease hydroxydopamine lesions, significantly reduced the amount of amphetamine-induced hyperactivity, and significantly disrupted prepulse inhibition induced by the 6- hydroxydopamine

12 lesions (eight models) (Pharmacology Reviews, Application Nr: 207318Orig1s000, FDA

Table S4: Approvals for anti-viral drugs 2012-2016

Drug Description Companion Animal models for diagnostic efficacy 2012 elvitegravir, complete once-daily Yes, indicated for No animal models used cobicistat, single tablet regimen patients, who are for efficacy, this is not emtricitabine, for HIV-1 infection antiretroviral requested by the FDA. tenofovir disoproxil for treatment-naive treatment-naive (Microbiology fumarate adults and have no known Reviews; Application substitutions Nr: 203100Orig1s000, associated with FDA) resistance to the individual components of the regimen. 2013 simeprevir protease inhibitor for Yes, screening of No animal models were the treatment of patients with HCV reported, this is not chronic hepatitis C genotype 1a requested by the FDA. virus infection infection for the (Microbiology presence of virus Reviews; Application with the NS3 Q80K Nr: 205123Orig1s000, polymorphism at FDA) baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. sofosbuvir once-daily oral Yes, therapy scheme No animal models were nucleotide analogue depends on the used, this is not for the treatment of genotype of virus requested by the FDA. chronic hepatitis C and patient group. (Microbiology virus infection Reviews; Application Nr: 204671 Orig1s000, FDA) dolutegravir integrase inhibitor Yes, testing for No animal models indicated for use in different resistances: used,this is not combination with Poor virologic requested by the FDA.

13 other antiretroviral response was (Microbiology agents for the observed in subjects Reviews; Application treatment of HIV-1 with an INSTI- Nr: 204790 Orig1s000, resistance Q148 FDA) substitution plus 2 or more additional INSTI-resistance substitutions including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R. 2014 ledipasvir and once-daily NS5A Yes, genotyping is No animal models sofosbuvir inhibitor and needed. Drug is reported, this is not nucleotide analog indicated for patients requested by the FDA. polymerase inhibitor with chronic (Microbiology fixed-dose hepatitis C with Reviews; Application combination for the genotype 1 Nr: 205834 Orig1s000, treatment of chronic FDA hepatitis C virus genotype 1 peramivir injection influenza virus Prescribers should Peramivir is active in neuraminidase consider mouse, ferret and inhibitor indicated available cynomolgus monkey for the treatment of information from the models of influenza acute uncomplicated CDC on influenza virus infections. (three influenza in adults virus models) drug susceptibility (Microbiology/Virology patterns and reviews, Application treatment Nr: 206426Orig1s000, effects when FDA) deciding whether to use RAPIVAB, but no obligatory testing. ombitasvir, NS5A inhibitor, Yes, genotyping is No animal studies were paritaprevir, NS3/4A protease required, as the drug reported, this is not ritonavir and inhibitor and is indicated requested by the FDA. dasabuvir CYP3A inhibitor for the treatment of (Microbiology/Virology combination co- patients with Reviews, Application packaged with a genotype 1 chronic Nr. 206619Orig1s000, non-nucleoside hepatitis C virus FDA) NS5B palm (HCV) infection polymerase inhibitor including for the treatment of those with patients with compensated genotype 1 chronic cirrhosis. hepatitis C virus

14 infection 2015 daclatasvir NS5A inhibitor Yes, genotype No animal models were indicated for use in determination used, this is not combination with needed (drug is requested by the FDA. sofosbuvir for the indicated for (Microbiology/Virology treatment of chronic genotype 3). Reviews, Application hepatitis C virus Nr. 206843Orig1s000, genotype 1 or FDA) genotype 3 infection elvitegravir, antiretroviral Yes, resistance No animal models used, cobicistat, combination for the testing, indicated for this is not requested by emtricitabine, and treatment of HIV patients twelve years the FDA. tenofovir infection of age and older who (Microbiology/Virology alafenamide have no Reviews, Application antiretroviral Nr. 207561Orig1s000, treatment history or FDA) to replace the current antiretroviral regimen in those who are virologically- suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of the drug. 2016 sofosbuvir and nucleotide analog Yes, as treatment No animal models used, velpatasvir polymerase inhibitor differs in patients 1) this is not requested by and pan-genotypic without cirrhosis and the FDA. NS5A inhibitor patients with (Microbiology/Virology fixed-dose compensated Reviews, Application combination for the cirrhosis Nr. 208341 Orig1s000, treatment of chronic (Child FDA) genotype 1-6 -Pugh A) hepatitis C virus And 2) with infection decompensated cirrhosis (Child -Pugh B or C). elbasvir and once-daily, single Yes, genotype must Studies in chimpanzees

15 grazoprevir tablet, NS5A be determined. have been performed, replication complex but were not requested. inhibitor and (one model) NS3/4A protease (Microbiology/Virology inhibitor reviews, Application combination for the Nr: 208261 treatment of chronic Orig1s000, FDA) hepatitis C virus genotype 1 and 4 infections

Table S5: Approvals for anti-bacterial/fungal diseases 2012-2016

Drug Description Companion Animal models for diagnostic efficacy 2012 bedaquilinie oral diarylquinoline Yes, obtain The bactericidal and antimycobacterial susceptibility sterilizing activity of drug indicated for information for the bedaquiline as the treatment of background regimen monotherapy and in pulmonary multi- against combination with first drug resistant Mycobacterium line drugs was tuberculosis tuberculosis isolate investigated in the if possible. murine model. (one model) (Briefing package, Division of Anti- Infective Products Office of Antimicrobial Products CDER, FDA,NDA: 204-384) 2013 luliconazole azole antifungal Yes, testing for Guinea pig models indicated for the infections with were successfully used topical treatment of Trichophyton to show efficacy. (three interdigital tinea rubrum and models) (Microbiology pedis, tinea cruris, Epidermophyton Reviews, Application and tinea corporis floccosum. Nr: 204153Orig1s000, FDA) 2014 dalbavancin second generation Yes, indicated for Dalbavancin was lipoglycopeptide infections caused by efficacious in a number antibiotic for the susceptible isolates of animal infection treatment of adult of the studies, at lower and patients with following Gram- less frequent doses than complicated skin positive comparators, and was in and skin structure microorganisms: some cases efficacious infections, including Staphylococcus with a single dose. those caused by aureus, Models included

16 methicillin-resistant Streptococcus acute septicemia in Staphylococcus pyogenes, mice (a prophylaxis aureus Streptococcus model) induced by agalactiae, intraperitoneal (IP) Streptococcus dys injection of S. aureus, galactiae, S. pyogenes and other Streptococcus pathogens, and organ- anginosus or site -specific group and infections such as Enterococcus granuloma pouch (in faecalis rats), neutropenic (vancomycin mouse thigh, susceptible strains). endocarditis (in rats and Two devices are rabbits) and pneumonia approved by the (in rats). (six models) FDA, but not (Microbiology mentioned in Reviews, Application package insert. Nr: 021883Orig1s000, FDA) efinaconazole topical triazole Yes, testing for the Guinea pigs with tinea antifungal for the species pedis were used treatment of Trichophyton successfully. (one onychomycosis of rubrum and model) (Microbiology the toenails Trichophyton Reviews, mentagrophytes. 203567Orig1s000, FDA) tavaborole oxaborole antifungal Yes, testing for the Only murine models of indicated for the species systemic infections topical treatment of Trichophyton were used and onychomycosis of rubrum or tavaborole failed to the toenails Trichophyton prevent death of the mentagrophytes. infected animals, but this was not relevant for the approval as onychomycosis should be treated, not systemic infection (not performed). (Microbiology/Virology Reviews, Application Nr: 204427Orig1s000, FDA) oritavancin semi-synthetic Yes, indicated for The efficacy of lipoglycopeptide the treatment of oritavancin has been antibiotic for the adult patients with investigated in a treatment of acute acute bacterial skin number of animal bacterial skin and and skin structure models of infection skin structure infections caused or including infections suspected to be 1) staphylococci and caused by enterococci susceptible bloodstream infections

17 isolates of the in mice; 2) endocarditis following Gram models of staphylococci -positive and enterococci microorganisms: infections in rabbits and Staphylococcus rats; 3) mouse and rat aureus, S. pneumoniae Streptococcus infection models; 4) pyogenes, biofilm S. aureus Streptococcus infection models in agalactiae, mouse; 5) meningitis Streptococcus models of S. dysgalactiae, pneumonia Streptococcus infection in rabbits; and anginosus 6) B. anthracis group mouse infection and models. (six models) Enterococcus (Microbiology/Virology faecalis Reviews, Application (vancomycin Nr: 206334Orig1s000, -susceptible isolates FDA) only). tedizolid phosphate oxazolidinone Yes, susceptibility The applicant has antibiotic drug testing is strongly provided data from a indicated for the recommended, variety of animal treatment of acute active against models including 1) bacterial skin and Staphylococcus staphylococcal systemic skin structure aureus, infections in mice; 2) infections Streptococcus enterococcal systemic pyogenes, infections in mice; 3) Streptococcus streptococcal systemic agalactiae, infections in mice; 4) Streptococcus MRSA skin and soft anginosus Group, tissue infection in mice; and Enterococcus 5) mouse thigh faecalis. infection model with MRSA and MSSA; 6) rat skin and soft tissue infection; 7) lung infection and epithelial lining fluid exposure in mice; 8) a neutropenic mouse pneumonia model; 9) an S. aureus endocarditis model in rabbits; 10) and a mouse Streptococcus pneumoniae model. Efficacy was demonstrated in all models tested. (ten

18 models) (Micrology/Virology Reviews, Application Nr. 205436Orig1s000, FDA) finafloxacin otic fluoroquinolone Yes, susceptibility Efficacy was tested in suspension antimicrobial for the testing should be several models treatment of acute performed, active including acute otitis otitis externa, against susceptible externa, sepsis models, commonly known as strains of respiratory tract swimmer’s ear Pseudomonas infection, aeruginosa gastrointestinal and and intra-abdominal Staphylococcus infections, skin and soft aureus. tissue infections, and urinary tract infections using different animals and pathogens. (16 models) (Microbiology Reviews, 206307Orig1s000, FDA) ceftolozane and cephalosporin and Yes, susceptibility Efficacy in different tazobactam beta-lactamase should be tested. animal models was inhibitor shown, including combination for the sepsis, pneumonia, treatment of urinary tract infection, complicated intra- burn wound infection, abdominal infections thigh infection in and complicated different animals and urinary tract sing different infections pathogens. (13 models) (Microbiology/Virology Reviews, Application NR. 206829Orig1s000, FDA) 2015 ceftazidime- next generation, Yes, should be used Efficacy was tested in avibactam non-β lactam β- to treat only several animal models, lactamase inhibitor indicated infections including murine and third-generation, that are proven or systemic infection, antipseudomonal strongly pneumonia immune- cephalosporin suspected to be compromised mice, antibiotic caused by pyelonephritis immune- combination for the susceptible bacteria. compromised mice, treatment of meningitis immune- complicated intra- competent rabbit, and abdominal infections murine thigh infection. and complicated (five models) urinary tract (Microbiology/ infections Virology Reviews,

19 Application Nr: 206494Orig1s000, FDA) isavuconazonium azole antifungal Yes, specimens for Tested in different sulfate indicated for the fungal culture and animal models treatment of invasive other relevant including aspergillosis aspergillosis and laboratory studies model, neutropenic invasive (including murine model, non- mucormycosis histopathology) to neutropenic murine isolate and identify model, pulmonary causative aspergillosis model, and organism(s) should mucormycosis model in be obtained prior to different animals using initiating antifungal different pathogens . therapy. (eight models) (Microbiology/Virology Reviews, Application Nr: 207500Orig1s000 / 207501Orig1s000, FDA)

Table S6: Approvals for monogenetic orphans 2012-2016

Drug Description Companion Animal models for diagnostic efficacy 2012 ivacaftor for the treatment of Yes, only indicated Data not available. cystic fibrosis in for patients with (Pharmacology Reviews, patients age 6 years mutation in the Application Nr: and older who have a CFTR gene. 203188Orig1s000, FDA) G551D mutation in the CFTR gene Taliglucerase alfa used as long-term Yes, indicated for No animal models enzyme replacement adults with a reviewed for efficacy. therapy in patients confirmed diagnosis (Pharmacology Reviews, with Type 1 Gaucher of Type 1 Application Nr: disease Gaucher disease. 022458Orig1s000, FDA) 2013 factor XIII peri-operative Yes, dose adjustment FXIII knockout mouse concentrate management of using the Berichrom models were used (human) surgical bleeding in activity assay must successfully. (two adult and pediatric be performed. models) (Summary of patients with Non-clinical Studies in congenital Factor STN 125385/0, FDA) XIII deficiency coagulation factor for routine Yes, titration of the Data not available. IX (recombinant) prophylaxis to dose based on the prevent or reduce the patient's clinical frequency of response and bleeding episodes in individual

20 adults with pharmacokinetics, in Hemophilia B particular incremental recovery and half-life is required. 2014 elosulfase alfa treatment of patients Yes, determination No animal models with of reported for efficacy. Mucopolysaccharido mucopolysaccharido (Pharmacology Reviews, sis type IVA sis type IVA (MPS Application Nr. (Morquio A IVA; Morquio A 125460Orig1s000, FDA) syndrome) syndrome) metreleptin adjunct to diet as no Animal studies using replacement therapy lipodystrophic mice have to treat the been used to show the complications of efficacy of leptin, leptin deficiency in metreleptin was not patients with used. (one model) congenital or (Pharmacology Reviews, acquired generalized Application Nr: lipodystrophy 125390Orig1s000, FDA) coagulation factor for control and Yes, monitoring of Efficacy was shown in IX (recombinant), prevention of the plasma Factor IX different mouse models. Fc fusion protein bleeding episodes, activity by (four models) perioperative performing the one (Pharmacology management, and -stage clotting assay -Toxicology Primary routine prophylaxis is required Discipline Review, July to prevent or reduce 28, 2013 – Alprolix, the frequency of FDA) bleeding episodes in adults and children with Hemophilia B antihemophilic treatment of adults Yes, performing of a Genetically modified factor and children with validated test (e.g., Factor VIII-deficient (recombinant), Fc Hemophilia A one stage clotting hemophilic mice and fusion protein) (congenital Factor assay), to confirm dogs, monkeys and rats VIII deficiency) for that adequate Factor were used successfully. control and VIII levels have been (four models) (Final prevention of achieved and BLA Review bleeding episodes, maintained is Memorandum, File BLA perioperative required. 125487/0/0 management, and (cross reference: IND routine prophylaxis 14134), FDA) to prevent or reduce the frequency of bleeding episodes C1-esterase Treatment of acute Yes, test for No animal models for inhibitor attacks of hereditary hereditary efficacy were reviewed (recombinant) angioedema in adult angioedema should in the FDA reviews. and adolescent be performed patients

21 2015 human factor X treatment of patients Yes, measurement of Nonclinical in vivo with hereditary post-infusion plasma studies of primary Factor X Deficiency Factor X levels for pharmacodynamics were each patient before not performed in and after surgery is animals due to the lack required, to ensure of an available animal that hemostatic model for Factor X levels are obtained deficiency. and maintained. (Pharmacology/Toxicolo gy review File BLA 125506/0/0, FDA) asfotase alfa for the treatment of Yes, testing of Asfotase alfa prevents patients with alkaline phosphatase craniosynostosis (the perinatal/infantile- activity for diagnosis premature fusion of and juvenile-onset is required. cranial bones) and hypophosphatasia additional craniofacial skeletal abnormalities in Alpl(-/-) mice. (one model) (Summary Review, Application Nr. 125513Orig1s000, FDA) recombinant von indicated for on- Yes, monitoring of Nonclinical studies to Willebrand factor demand treatment plasma levels of assess the primary (rhVWF) and control of VWF:RCo and factor pharmacologic activity bleeding episodes in VIII activities is in hemostasis were adults diagnosed with required. conducted in vivo using von Willebrand congenitally VWF- disease deficient dogs, and mice that were genetically engineered to delete expression of the murine VWF gene (i.e., VWF- knockout) mice. (two models) (Pharmacology/Toxicolo gy Secondary Review, STN BLA #: 125577/0, FDA) sebelipase alfa indicated for the Yes, test for biallelic A rat model of lysosomal treatment of patients pathogenic variants acid lipase deficiency with a diagnosis of in LIPA or deficient was successfully used to lysosomal acid lipase LAL enzyme activity show efficacy. (one deficiency in peripheral blood model) (Pharmacology leukocytes, Reviews, Application fibroblasts, or dried Nr. 125561Orig1s000, blood spots is FDA) required. 2016 recombinant indicated for the on- Monitoring of A canine model of fusion protein demand control and Factor Hemophilia B

22 linking prevention of IX plasma levels by (i.e. dogs with a coagulation factor bleeding episodes, a one-stage clotting naturally occurring IX with albumin perioperative assay is required to mutation and/or deletion (rIX-FP) management of confirm that of FIX function) and FIX bleeding, and routine adequate FactorIX knock-out mice have prophylaxis to levels have been been used. (two models) prevent or reduce the achieved and (Pharmacology/Toxicolo frequency of maintained. gy Primary Discipline bleeding episodes Review, Original BLA STN 125582/0, FDA) eteplirsen treatment of Yes, testing for Studies in mdx mice and Duchenne muscular patients who have a CXMD dogs showed dystrophy (DMD) in confirmed mutation efficacy. (two models) patients who have a of the DMD gene (Pharmacology reviews, confirmed mutation that is amenable to Application Nr: of the DMD gene exon 51 skipping. 206488Orig1s000, FDA) that is amenable to exon 51 skipping lumacaftor/ivacaft treatment of cystic Yes, test for patients Ivacaftor was approved or fibrosis in patients which are before, for lumacaftor no age 6-11 year old homozygous for the animal models were who are homozygous F508del mutation in reported in the reviews. for the F508del the CFTR gene. (Summary Review, mutation in the Application Nr: CFTR gene 206038Orig1s000, FDA) nusinersen treatment of spinal Conduct the In spinal muscular muscular atrophy in following laboratory atrophy mouse models pediatric and adult tests at baseline and nusinersen appeared to patients prior to each dose of promote SMN2 exon 7 nusinersen and as splicing, showing clinically needed: activity at tissue Platelet count concentrations achieved Prothrombin time, clinically. (one model) activated partial (Pharmacology Reviews, thromboplastin time, Application Nr: Quantitative spot 209531Orig1s000) urine protein testing