`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`761195Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE)
`Epidemiology: ARIA Sufficiency
`
`
`Date:
`Reviewer:
`
`Team Leader:
`
`Deputy Division Director:
`
`Subject:
`Drug Name:
`Application Type/Number:
`Applicant/sponsor:
`OSE RCM #:
`
`
`December 15, 2021
`Silvia Perez-Vilar, PharmD, PhD
`Division of Epidemiology I
`Kira Leishear, PhD, MS
`Division of Epidemiology I
`CAPT Sukhminder K. Sandhu, PhD, MPH, MS
`Division of Epidemiology I
`ARIA Sufficiency Memo for Pregnancy Safety Concerns
`VYVGART™ (efgartigimod alfa – fcab)
`BLA 761195
`Argenx BV
`2021-2292
`
`
`
`
`Reference ID: 4905330
`
`Page 1 of 7
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`Expedited ARIA Sufficiency for Pregnancy Safety Concerns
`
`
`1. BACKGROUND INFORMATION
`1.1. Medical Product
`
`
`
`1.2. Describe the Safety Concern
`
`
`
` Efgartigimod alfa – fcab (VYVGART™, Argenx BV) is an intravenously administered human IgG1
`antibody fragment that binds to the neonatal Fc receptor (FcRn) resulting in the reduction of
`circulating immunoglobulin G (IgG) including IgG autoantibodies. Efgartigimod does not reduce
`the levels of other immunoglobulins (IgA, IgD, IgE, or IgM), or those of albumin. Each 20 mL
`single-dose vial contains 400 mg of efgartigimod alfa – fcab at a concentration of 20 mg/mL. It is
`a new molecular entity (NME) not currently approved or marketed in any country. The
`proposed indication is for the treatment of adult patients with generalized myasthenia gravis.
`VYVGART will be approved for the treatment of adults with generalized myasthenia gravis who
`are anti-acetylcholine receptor antibody positive. Currently FDA-approved treatments for
`myasthenia gravis include pyridostigmine bromide and eculizumab. 1 Treatments such as
`prednisone, azathioprine, mycophenolate mofetil, tacrolimus, rituximab, plasmapheresis, and
`intravenous immunoglobulin are used off-label. Thymectomy is also a treatment option for
`some patients. 2
`The proposed dosing regimen for VYVGART is 10 mg/kg as a 1-hour intravenous infusion to be
`administered in treatment cycles of once weekly infusions for 4 weeks. Efgartigimod alfa – fcab
`exhibits linear pharmacokinetics and is expected to be degraded by proteolytic enzymes into
`small peptides and amino acids. The terminal half-life is 80 to 120 hours (3 to 5 days). 3
`The Biologic License Application (BLA) submission included safety data on adults with
`generalized myasthenia gravis exposed to at least one dose of efgartigimod alfa – fcab during
`enrollment in an exploratory phase 2, double-blind, placebo-controlled, randomized clinical
`trial, a pivotal phase 3, double-blind, placebo-controlled, randomized clinical trial, and/or a
`Phase 3 long-term open label, single-arm multicenter study. Common adverse reactions
`associated with treatment included respiratory tract infections, urinary tract infections,
`myalgia, headaches, and hypo/hyperesthesia. 4 The proposed label (as of December 15, 2021)
`includes warnings and precautions for infections and hypersensitivity reactions. 5
`
`
` The Division of Neurology 1 (DN1) requested that the Division of Epidemiology (DEPI)
`assess the sufficiency of ARIA for broad-based signal detection studies of VYVGART during
`pregnancy. Safety during pregnancy due to drug exposure is a concern for women who are
`pregnant or of childbearing potential. In the U.S. general population, the estimated background
`1 Eculizumab is indicated for treatment of acetylcholine receptor myasthenia gravis, but is not indicated for
`muscle specific kinase antibody positive or low-density lipoprotein receptor-related protein 4 antibody
`positive patients.
`2 Efgartigimod alfa – fcab (VYVGART™, Argenx BV). Draft integrated review dated November 23, 2021.
`Division of Neurology 1. U.S. Food and Drug Administration
`3 Proposed VYVGART labeling dated December 15, 2021
`4 See footnote 2
`5 See footnote 3
`
`
`
`Reference ID: 4905330
`
`Page 2 of 7
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`

`

`risk of major birth defects in clinically recognized pregnancies is 2–4% (Centers for Disease
`Control and Prevention 2008, Food and Drug Administration 2014). Myasthenia gravis is a
`serious, life-threatening, chronic autoimmune disease in which antibodies bind to acetylcholine
`receptors, muscle-specific kinase, or lipoprotein-related peptide 4 in the postsynaptic
`membrane at the neuromuscular junction (Gilhus 2016, Koneczny and Herbst 2019). Different
`antibodies can result in different subgroups of myasthenia gravis with variable phenotypes and
`severity. In most patients, the antibodies bind to acetylcholine receptors (Gilhus 2020).
`Coexisting conditions are common; approximately 15% of patients have a second autoimmune
`disease, 10% have a thymoma, and although rare, myocarditis occurs with an increased
`frequency in patients with myasthenia gravis (Gilhus 2016). Myasthenia gravis is a rare
`disorder, with an estimated prevalence in the general population of 150–250 individuals per
`million, and with an annual incidence of 8–10 individuals per million. Myasthenia gravis with
`onset below 50 years, thymic hyperplasia, and acetylcholine receptor antibodies is more
`common in females than in males. As both prevalence and incidence increase with increasing
`age, the prevalence and incidence are somewhat lower among females of reproductive age. The
`muscle weakness, the circulating autoantibodies, the hyperplastic thymus, and any autoimmune
`comorbidity may influence both mother and child health during pregnancy and also during
`breastfeeding. Despite this, most pregnancy complications occur with a similar frequency in
`women with and without myasthenia gravis. However, preterm rupture of amniotic membranes
`shows an increased frequency, and especially in those with myasthenia gravis deterioration
`during the pregnancy. Around 10% of the newborn develop neonatal myasthenia during the
`first few days after birth, which is transient and usually mild. In rare cases, transplacental
`transfer of acetylcholine receptor antibodies leads to permanent muscle weakness in the child,
`and arthrogryposis with joint contractures (Gilhus 2020).
` There are no data on pregnancy exposure during clinical trials to inform the risk of maternal,
`fetal, and infant outcomes associated with the use of efgartigimod alfa – fcab.6 A full battery of
`reproductive toxicology studies was conducted in Sprague-Dawley rats and New Zealand White
`rabbits. In all studies, efgartigimod alfa – fcab was administered by intravenous injection at
`doses of 0, 30, or 100 mg/kg. Efgartigimod alfa – fcab was administered daily to male rats
`(20/group) beginning 4 weeks prior to mating until the day before sacrifice on study day 43 or
`44 and to females (20/group) beginning 2 weeks prior to mating until gestational day 7; there
`were no effects on the number of females pregnant, females with live fetuses, or the number of
`resorptions. When pregnant rats (25/group) were administered efgartigimod alfa – fcab daily
`from gestational day 6 to gestational day 17, no effects on embryofetal development were
`observed. A slight dose-related increase in pre-implantation loss was noted. Pregnant rabbits
`(20/group) received efgartigimod alfa – fcab daily from gestational day 6 to gestational day 28.
`Two low dose females (gestational day 28; 9.1% incidence) and one high dose female
`(gestational day 20; 4.8% incidence) aborted. This rate was slightly greater than the historical
`spontaneous abortion rate at this facility (4.26% ± 4.18 with a range of 0.0 to 9.5%). There were
`no significant effects on Cesarean parameters or on embryofetal development. Cerebral
`hemorrhage was observed in three high dose pups in different litters (15% litter incidence).
`The total fetal incidence was within the historical control range; however, litter incidence for
`historical controls was not provided. Another animal study administered efgartigimod alfa –
`fcab daily to pregnant rats (25/group) from gestational day 6 to lactation day. One pregnant rat
`who received the high dose died prematurely (gestational day 21). This death was considered
`due to “incipient abortion.” No test article-related effects were observed on gestation length,
`gestation index, or preweaning litter parameters (including implantation, liveborn pups,
`6 See footnote 2
`
`Page 3 of 7
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`Reference ID: 4905330
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`
`
`postnatal survival). There were also no drug-related effects on postnatal developmental
`landmarks or neurobehavioral function. However, the learning and memory evaluation did not
`include a complex maze as is usually expected. There were no significant effects on mating
`parameters in offspring or on F2 fetal development. There was a slight reduction in the number
`of pregnant F1 females, but the effect was not dose-related in magnitude. 7
` The currently proposed labeling, as of December 15, 2021, 8 states in “Section 8.1 (Pregnancy):
` “Risk Summary
`
`
`There are no available data on the use of VYVGART during pregnancy. There is no evidence of
`adverse developmental outcomes following the administration of VYVGART at up to 100
`mg/kg/day in rats and rabbits (see Data).
`
`The background rate of major birth defects and miscarriage in the indicated population is
`unknown. In the U.S. general population, the estimated background rate of major birth defects and
`miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
`
`Clinical Considerations
`Fetal/neonatal adverse reactions
`
`Monoclonal antibodies, are increasingly transported across the placenta as pregnancy progresses,
`with the largest amount transferred during the third semester. Therefore, efgartigimod alfa-fcab
`may be transmitted from the mother to the developing fetus.
`
`As VYVGART is expected to reduce maternal IgG antibody levels, reduction in passive protection to
`the newborn is anticipated. Risk and benefits should be considered prior to administering live or
`live-attenuated vaccines to infants exposed to VYVGART in utero [see Warnings and Precautions
`(5.1)].
`
`Data
`Animal Data
`
`Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg/kg/day) to pregnant rats
`and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development
`in either species. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10
`mg/kg, on a body weight (mg/kg) basis.
`
`Intravenous administration of efgartigimod alfa-fcab (0, 30, or 100 mg/kg/day) to rats
`throughout gestation and lactation resulted in no adverse effects on pre- or postnatal
`development. The doses tested are 3 and 10 times the recommended human dose (RHD) of 10
`mg/kg, on a body weight (mg/kg) basis.”
`
`
`
`
`
`Reference ID: 4905330
`
` The language in Section 8.2 (Lactation) is as follows:
`
`7 Efgartigimod alfa – fcab (VYVGART™, Argenx BV). Non-clinical appendix to draft integrated review dated
`November 23, 2021. Division of Neurology 1. U.S. Food and Drug Administration
`8 See footnote 3
`
`Page 4 of 7
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`

`
`
`“Risk Summary
`
`There is no information regarding the presence of efgartigimod alfa-fcab in human milk, the
`effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be
`present in human milk.
`
`The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for VYVGART and any potential adverse effects on the breastfed infant from
`VYVGART or from the underlying maternal condition.
`
`
`
`1.3. FDAAA Purpose (per Section 505(o)(3)(B))
`- Please ensure that the selected purpose is consistent with the other PMR documents in DARRTS
`
`
`
`Purpose (place an “X” in the appropriate boxes; more than one may be chosen)
`
`Assess a known serious risk
`
`Assess signals of serious risk
`Identify unexpected serious risk when available data indicate potential for serious risk X
`
`
`2. REVIEW QUESTIONS
`2.1. Why is pregnancy safety a safety concern for this product? Check all that apply.
`
`
`
`
`☐ Specific FDA-approved indication in pregnant women exists and exposure is expected
`☐ No approved indication, but practitioners may use product off-label in pregnant women
`☒ No approved indication, but there is the potential for inadvertent exposure before a pregnancy
`is recognized
`☒ No approved indication, but use in women of child bearing age is a general concern
` 2.2. Regulatory Goal
`☒ Signal detection – Nonspecific safety concern with no prerequisite level of statistical precision
`and certainty
`☐ Signal refinement of specific outcome(s) – Important safety concern needing moderate level of
`statistical precision and certainty. †
`☐ Signal evaluation of specific outcome(s) – Important safety concern needing highest level of
`statistical precision and certainty (e.g., chart review). †
`
` †
`
` If checked, please complete General ARIA Sufficiency Template.
`
`
`
`2.3. What type of analysis or study design is being considered or requested along with ARIA?
`Check all that apply.
`
`
`
`Reference ID: 4905330
`
`Page 5 of 7
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`(b) (4)
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`

`

`
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`2.4. Which are the major areas where ARIA not sufficient, and what would be needed to
`make ARIA sufficient?
`
`
`☐ Pregnancy registry with internal comparison group
`☐ Pregnancy registry with external comparison group
`☐ Enhanced pharmacovigilance (i.e., passive surveillance enhanced by with additional actions)
`☐ Electronic database study with chart review
`☐ Electronic database study without chart review
`☒ Other, please specify: Descriptive pregnancy safety study
`☒ Study Population
`☐ Exposures
`☒ Outcomes
`☒ Covariates
`☒ Analytical Tools
` For any checked boxes above, please describe briefly:
` Study Population: ARIA lacks the capacity to identify lactating women.
` Outcomes: ARIA lacks access to detailed narratives. Given that the study for broad-based
`surveillance being considered is descriptive, without sample size requirements, and without a
`comparison group, having detailed narratives are deemed necessary to identify and validate
`outcomes, assess exposure-outcome temporality, and to conduct causality assessments.
` Covariates: ARIA does not have detailed information on potential confounders. The descriptive
`pregnancy safety study being considered would collect detailed narratives with information on
`potential covariates, such as IgG anti-acetylcholine receptor antibodies, baseline motor strength,
`cardiac and respiratory status, and pulmonary function tests, and lifestyle factors, such as
`prenatal supplement use and iodine intake.
` Analytical tools: ARIA analytic tools are not sufficient to assess the regulatory question of
`interest because data mining methods have not been fully tested and implemented in post-
`marketing surveillance of maternal and fetal outcomes. The ARIA analytic tools that assess drug
`use in pregnancy (and maternal and neonatal outcomes) currently include only women with a
`live-born delivery.
` The following language has been proposed by DN1, as of October 28, 2021, for the PMR related
`to pregnancy outcomes:
`
`
`2.5. Please include the proposed PMR language in the approval letter.
`
`
`Conduct a worldwide descriptive study that collects prospective and retrospective data in women
`exposed to VYVGART (Efgartigimod alfa – fcab) during pregnancy and/or lactation to assess risk
`of pregnancy and maternal complications, adverse effects on the developing fetus and neonate,
`and adverse effects on the infant. Infant outcomes will be assessed through at least the first year of
`life. The minimum number of patients will be specified in the protocol.
`
`
`
`Reference ID: 4905330
`
`Page 6 of 7
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`3. REFERENCES
`
`
` Centers for Disease Control and Prevention (2008). "Update on overall prevalence of major birth
`defects--Atlanta, Georgia, 1978-2005." MMWR Morb Mortal Wkly Rep 57(1): 1-5.
`Food and Drug Administration. (2014). "Pregnancy, Lactation, and Reproductive Potential: Labeling
`for Human Prescription Drug and Biological Products — Content and Format. Draft Guidance."
`Guidance for Industry Retrieved November 24, 2021, from
`https://www.fda.gov/media/90160/download.
`Gilhus, N. E. (2016). "Myasthenia Gravis." N Engl J Med 375(26): 2570-2581.
`Gilhus, N. E. (2020). "Myasthenia Gravis Can Have Consequences for Pregnancy and the Developing
`Child." Front Neurol 11: 554.
`Koneczny, I. and R. Herbst (2019). "Myasthenia Gravis: Pathogenic Effects of Autoantibodies on
`Neuromuscular Architecture." Cells 8(7).
`
`
`
`
`
`Reference ID: 4905330
`
`Page 7 of 7
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`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`SILVIA PEREZ-VILAR
`12/15/2021 02:39:32 PM
`
`KIRA N LEISHEAR
`12/15/2021 02:40:44 PM
`
`SUKHMINDER K SANDHU
`12/15/2021 02:46:15 PM
`
`JUDITH W ZANDER
`12/15/2021 02:49:22 PM
`
`PATRICIA L BRIGHT
`12/15/2021 04:31:39 PM
`
`ROBERT BALL
`12/15/2021 04:40:43 PM
`
`Reference ID: 4905330
`
`

`

`
`
`
`From:
`
`
`
`CC:
`
`Subject:
`
`
`BLA:
`
`
`Tracy Peters, Associate Director for Labeling, (DN I)
`
`Samuel Fasanmi, PharmD, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Aline Moukhtara, RN, MPH, Team Leader, OPDP
`
`OPDP Labeling Comments for Vyvgart (efgartigimod alfa-fcab) injection,
`for intravenous use
`
`761195
`
`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`December 01, 2021
`
`
`To:
`
`
`Rainer Paine, M.D.
`Division of Neurology I (DN I)
`
`Michael Matthews, Regulatory Project Manager, (DN I)
`
`
`In response to DN I consult request dated January 19, 2021, OPDP has reviewed the
`proposed product labeling (PI), and carton and container labeling for the original BLA
`submission for Vyvgart (efgartigimod alfa-fcab) injection, for intravenous use.
`
`PI: OPDP’s comments on the proposed PI are based on the draft labeling received by
`electronic mail from DN I (Michael Matthews) on November 23, 2021, and are provided below.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`container labeling submitted by the Sponsor to the electronic document room on October 20,
`2021, and we do not have any comments.
`
`Thank you for your consult. If you have any questions, please contact Samuel Fasanmi at
`(301) 796-5188 or samuel.fasanmi@fda.hhs.gov.
`
`
`
`
`
`
`Reference ID: 4897350
`
`1
`
`15 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`SAMUEL A FASANMI
`12/01/2021 03:51:55 PM
`
`Reference ID: 4897350
`
`

`

`
`
`
`To 
`
`Date 
`From 
`
`Clinical Inspection Summary  
`10/13/2021 
`Cara Alfaro, Pharm.D., Clinical Analyst 
`Phillip Kronstein, M.D., Team Leader 
`Kassa Ayalew, M.D., M.P.H., Branch Chief/Acting Division 
`Director 
`Good Clinical Practice Assessment Branch  
`Division of Clinical Compliance Evaluation 
`Office of Scientific Investigations 
`Michael Matthews, Regulatory Project Manager 
`Rainer Paine, M.D., Medical Officer 
`Laura Jawidzik, M.D., Team Leader 
`Division of Neurology 1 
`Office of Neuroscience 
`BLA # 
`761195 
`Applicant 
`Argenx 
`Drug  
`Efgartigimod 
`NME 
`Yes 
`Proposed Indication 
`Treatment of generalized myasthenia gravis in adults 
`Consultation Request Date  1/25/2021 
`Summary Goal Date 
`10/15/2021 
`Priority/Standard Review 
`Standard 
`Action Goal Date 
`12/17/2021 
`PDUFA Date  
`12/17/2021 
`
` 
`I. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS 
` 
`
`The clinical sites of Drs. Karam, Peric, and Szczechowski were inspected in support of this 
`BLA and covered Protocol ARGX‐113‐1704. Despite some protocol deviations noted at the 
`sites of Drs. Karam and Peric, the studies appear to have been conducted adequately, and 
`the data generated by these sites appear acceptable in support of the respective 
`indication. 
` 
`Inspections did not identify any data discrepancies between source and sponsor data line 
`listings for primary efficacy data (Myasthenia Gravis‐Activities of Daily Living [MG‐ADL] 
`scores) but did identify discrepancies for key secondary efficacy data (Quantitative 
`Myasthenia Gravis [QMG] scores) at the sites of Drs. Karam and Peric. Specifically, QMG 
`individual items for some subjects were incorrectly scored at these sites which impacted 
`the calculation of QMG total scores. The incorrect scores were not identified by the 
`sponsor such that the sponsor data line listings include these errors. We recommend that 
`the review division request that the sponsor review individual item QMG scores and QMG 
`
`Reference ID: 4871557
`
`

`

`Clinical Inspection Summary  
` 
`Page 2                                          
`                                                                                                                                            BLA #761195 Efgartigimod 
` 
`
`
`
`total scores for all clinical sites and submit corrected datasets for reanalysis by the review 
`division. 
` 
`Forced vital capacity, assessed via spirometry, was an individual item included in the 
`calculation of the QMG total score. Inspections noted that spirometry results with quality 
`control Grade F (unacceptable spirometer test results) were used in calculating QMG total 
`scores for some subjects. The sponsor had not included any information in the submission 
`regarding the use of Grade F spirometry results in some subjects. This finding was 
`communicated to the review division with the recommendation that the sponsor flag all 
`spirometry results with quality control Grade F (unacceptable spirometer test results) so 
`that adequate review and sensitivity analyses could be conducted to determine any 
`impact on the efficacy analyses for QMG total scores. 
`II. BACKGROUND 
` 
`
` 
`
`Reference ID: 4871557
`
`Efgartigimod injection for intravenous use is being developed under BLA 761195 (IND 132953) 
`for the treatment of adults with generalized Myasthenia Gravis (MG). Efgartigimod is a human 
`IgG1 antibody fragment with affinity to the neonatal Fc receptor resulting in the reduction of 
`circulating IgGs including IgG autoantibodies. 
` 
`The sponsor has submitted one Phase 3 study (ARGX‐113‐1704) to support the efficacy 
`and safety of efgartigimod for the treatment of adults with generalized MG. 
` 
`Protocol ARGX‐113‐1704 
` 
`Title: “A randomized, double‐blind, placebo‐controlled multicenter Phase 3 trial to 
`evaluate the efficacy, safety, and tolerability of ARGX‐113 [efgartigimod] in patients 
`with myasthenia gravis having generalized muscle weakness” 
`Subjects: 167 randomized 
`Sites: 51 sites in 15 countries; North America (19 sites [US 17]), Eastern Europe (11 
`sites), Western Europe (9 sites), Asia/Pacific (9 sites), Middle East/Central Asia (3 sites) 
`Study Initiation and Completion Dates: 8/22/2018 to 4/6/2020 
`
`This was a randomized, double‐blind, placebo‐controlled study in subjects with 
`generalized myasthenia gravis (MG). Included were males or females >18 years of age 
`with a diagnosis of MG (MG Foundation of America clinical classification Class II to IV) 
`with generalized muscle weakness and confirmation of diagnosis supported by at least 
`one of the following:   
` History of abnormal neuromuscular transmission demonstrated by single‐fiber 
`electromyography or repetitive nerve stimulation, or 
` History of positive edrophonium chloride test, or 
`
`

`

`Clinical Inspection Summary  
` 
`Page 3                                          
`                                                                                                                                            BLA #761195 Efgartigimod 
` 
`
`
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` Demonstrated improvement in MG signs on oral acetylcholinesterase (AChE) 
`inhibitors as assessed by the treating physician 
`
` 
`Additionally, subjects must have a total Myasthenia Gravis Activities of Daily Living 
`(MG‐ADL) score of >5 points at screening and baseline with >50% of the total score 
`due to non‐ocular symptoms, IgG levels >6 g/L at screening, and on a stable dose of 
`their MG medication.  
` 
`The study was comprised of two phases: 
`Screening Phase– approximately 2 weeks 
` 
`Double‐Blind Treatment Phase – 26 weeks 
`Subjects were randomized (1:1) to one of the following Investigational products (IP) 
`added to concomitant MG medication: 
` Efgartigimod (ARGX‐113) 10 mg/kg  
` Placebo 
`
`
`This 26‐week phase included a first Treatment Cycle (TC1) and a variable number of 
`subsequent treatment cycles administered “as needed”. Each treatment cycle 
`consisted of a treatment period of 3 weeks (4 weekly infusions) and a follow‐up period 
`of 5 weeks. The time between Treatment Cycles was based on the duration of the 
`treatment effect and varied between and within subjects.  
` 
`Each subject started a new Treatment Cycle when all of the following criteria were 
`met: 
` Subject had completed the previous Treatment Cycle 
` Subject had a total MG‐ADL score >5 points with >50% of the total score due to 
`non‐ocular symptoms 
` The Treatment Cycle can start at the latest on Day 127 and can be completed 
`within the timeframe of the study (26 weeks) 
`If the subject lost response – defined as no longer showing a decrease of at least 
`2 points on the total MG‐ADL score compared to the corresponding Treatment 
`Cycle baseline 
`
`
`
` 
`Randomization was stratified by Japanese vs. non‐Japanese, acetylcholine receptor‐
`antibody (AChR‐Ab) status (seropositive/seronegative), and non‐steroidal 
`immunosuppressive drug use (yes/no). The protocol allowed a maximum of 20% of 
`AChR‐Ab seronegative subjects to be enrolled. 
` 
`
` 
`
` 
`
`Reference ID: 4871557
`
`

`

`Clinical Inspection Summary  
` 
`Page 4                                          
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` 
`
`
`
`The primary efficacy endpoint was the percent of MG‐ADL responders after the first 
`Treatment Cycle (TC1) in the AChR‐antibody seropositive population (efgartigimod 
`compared to placebo). MG‐ADL responder was defined as a decrease of >2 points 
`from the corresponding treatment cycle baseline on the total MG‐ADL score for at 
`least 4 consecutive weeks with the first decrease occurring no later than one week 
`after the last infusion of the corresponding cycle. A key secondary endpoint was the 
`percent of Quantitative Myasthenia Gravis (QMG) responders after TC1 in the AChR‐
`antibody seropositive population (efgartigimod compared to placebo). A QMG 
`responder was defined as a decrease of >3 points from the corresponding treatment 
`cycle baseline on the total QMG score for at least 4 consecutive weeks with the first 
`decrease occurring no later than one week after the last infusion of the corresponding 
`cycle. 
`
`
`Rationale for Site Selection 
` 
`The clinical sites were chosen primarily based on risk ranking in the site selection tool and 
`numbers of AChR‐Ab seropositive subjects enrolled. 
`
`III. RESULTS 
` 
`1. Chafic Karam, MD 
`Site #USA0012 
`Oregon Health and Science University 
`3181 SW Sam Jackson Park Road 
`Portland, OR 97239 
`Inspection Dates: 4/26/2021 – 5/3/2021 
` 
`At this site for Protocol ARGX‐113‐1704, 5 subjects were screened, all of whom were 
`randomized and completed the study.  
` 
`Signed informed consent forms, dated prior to participation in the study, were present for all 
`subjects who were screened. An audit of the study records all enrolled subjects was 
`conducted. Records reviewed included, but were not limited to, source documents, 
`monitoring documents, IRB/sponsor communications, financial disclosure, test article 
`accountability, inclusion/exclusion criteria, adverse event reports, laboratory results, 
`spirometry tracings and reports, concomitant medications, protocol deviations, primary 
`efficacy data (Myasthenia Gravis‐Activities of Daily Living scores [MG‐ADL]), and key 
`secondary efficacy data (Quantitative Myasthenia Gravis [QMG] scores). 
` 
`All source documents were in paper format. MG‐ADL and QMG scores on source documents 
`were verified against sponsor data line listings. No discrepancies in MG‐ADL scores (the 
`primary efficacy endpoint) were identified. 
` 
`
`Reference ID: 4871557
`
`

`

`Clinical Inspection Summary  
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`Discrepancies between paper source and sponsor data line listings for QMG individual item 
`scores were identified for four of five randomized subjects (see Table 1). For example, an 
`individual item left hand grip value of 40 seconds was scored as 1 [mild] but should have been 
`scored as 0 [none] which impacted the QMG total score, a key secondary endpoint. 
` 
`Table 1. Discrepancies in QMG Individual Item Scores (Site USA0012) 
`Subject 
`Treatment 
`Treatment 
`QMG Individual Item 
`Arm 
`Cycle (TC)/
`Item Description and 
`Correct 
`Visit 
`Result on Source 
`Score 
`Number 
` 
`TC2V9 
`
`Placebo 
`
`Left Hand Grip = 40 KgW  
`
`0 
`
`Incorrect 
`Score in 
`Sponsor Data 
`Listing 
`
`1 
`
`Efgartigimod  TC2V3 
`
`Efgartigimod  TC1V2 
`TC2V7 
`TC2V9 
`
`Efgartigimod  TC1V7 
`
`TC1V8 
`
`Head Lifted = 25 seconds 
`Left Leg Outstretched = 22 
`seconds 
`Left Hand Grip = 35.3 KgW  0 
`Left Hand Grip = 40 KgW 
`0 
`Right Leg Outstretched = 
`2 
`26 seconds 
`Left Leg Outstretched = 30 
`seconds 
`Right Arm Outstretched = 
`76 seconds 
`Left Arm Outstretched = 
`76 seconds 
`Right Hand Grip = 11 KgW  1 
`Left Hand Grip = 13 KgW 
`1 
`
`2 
`2 
`
`2 
`
`2 
`
`2 
`
`1 
`1 
`
`1 
`1 
`1 
`
`1 
`
`1 
`
`1 
`
`2 
`2 
`
` 
`The inspection also noted the following: 
` For two of five randomized subjects, Forced Vital Capacity (FVC) data from a 
`quality control Grade F (unacceptable spirometer test results) spirometry report 
`were used in the calculation of the QMG.  
`o Subject 
`, randomized to efgartigimod: 6 of 10 visits in 
`TC1 and 6 of 9 visits in TC2 had a Grade F spirometry report 
`o Subject 
` randomized to efgartigimod: 5 of 11 visits in 
`TC1, 3 of 9 visits in TC2 had a Grade F spirometry report 
` 
`For cases where the spirometry report received a quality control Grade F, the 
`report recommended to repeat the test. 
`
` 
`
`Reference ID: 4871557
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`

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`Clinical Inspection Summary  
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` One of five randomized subjects did not meet criteria for re‐treatment. Criteria for 
`re‐treatment required a total MG‐ADL score of >5 points with >50% of the total 
`score due to non‐ocular symptoms. Subject 
`, randomized to placebo, 
`began cycle two with 50% of the total MG‐ADL score due to non‐ocular symptoms. 
`This protocol deviation was reported to the sponsor and included in the sponsor 
`data line listings. 
` 
` For one of five enrolled subjects, a prior MG medication (IVIG) received by Subject 
` within 12 months prior to screening was not reported to the 
`sponsor. Subject
` was randomized to efgartigimod. 
`
` 
`There was no evidence of underreporting of adverse events and no serious adverse events 
`were reported by this site. 
` 
`Reviewer’s comment: Discrepancies in QMG total scores were noted for four of five 
`randomized subjects. Three of these study visits occurred in the time period of interest for 
`efficacy analysis, TC1. Due to discrepancies noted at this site and Site SRB0001, we 
`recommend that the review division ask the sponsor to review individual QMG item scores and 
`total QMG scores for all clinical sites and submit