CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`761079Orig1s000
`
`
`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 Templates
`Version: 2018-01-24
`
`Date:
`Reviewer(s):
`
`Team Leader:
`
`Division Deputy Director:
`
`Subject:
`Drug Name:
`Application Type/Number:
`Applicant/sponsor:
`OSE RCM #:
`
`
`
`May 22, 2018
`Michelle R. Iannacone, PhD, MPH
`Division of Epidemiology I
`Patricia L. Bright, PhD, MSPH
`Division of Epidemiology I
`Sukhminder Sandhu, PhD, MS MPH
`Division of Epidemiology 1
`Active Risk Identification and Assessment (ARIA) Sufficiency Memo
`for Pregnancy Safety Concerns
`Palynziq (pegvaliase)
`
`BLA 761079
`Biomarin Pharmaceutical, Inc.
`2017 - 1327
`
`
`
`
`
`Reference ID: 4266959
`
`Page 1 of 5
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`A. Expedited ARIA Sufficiency Template for Pregnancy Safety Concerns
`
`
`1. BACKGROUND INFORMATION
`1.1. Medical Product
`
`
`
` Palynziq (pegvaliase) is an enzyme substitution therapy indicated to reduce blood phenylalanine
`(Phe) concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood
`phenylalanine concentrations > 600 µmol/L on existing management. Palynziq substitutes for the
`deficient PAH enzyme in patients with PKU by providing an alternate pathway for Phe breakdown
`via the enzymatic conversion of Phe to trans-cinnamic acid (t-CA) and ammonia, both excreted in
`the urine. Palynziq is administered daily as a subcutaneous injection through a single-dose
`prefilled syringe. The proposed dosing follows an induction, titration, and maintenance (I/T/M)
`dosage regimen by which the dose is slowly increased over a period of a few weeks. The Applicant
`proposes that a patient should stay at 20 mg daily for 24 weeks and the dose may be increased to
`40 mg daily based on individual patient response (Phe concentration) and tolerability. If a patient
`does not achieve at least a 20% reduction in blood Phe concentration from their pre-treatment
`baseline after an additional 16 weeks of treatment with 40mg daily, then the product should be
`discontinued.
` 1.2. Describe the Safety Concern
`Elevated maternal blood Phe concentration during early pregnancy is teratogenic and may result in
`Phe embryopathy. The embryopathic effects of elevated Phe levels during pregnancy in maternal
`PKU include growth retardation, microcephaly, psychomotor retardation, and congenital heart
`defects.1 Available data from the Maternal Phenylketonuria Collaborative Study on 468
`pregnancies and 331 live births in PKU-affected women demonstrated that uncontrolled
`phenylalanine concentrations above 600 micromol/L are associated with an increased risk for
`miscarriage, major birth defects (including microcephaly, major cardiac malformations),
`intrauterine fetal growth retardation, and future intellectual disability with low IQ. To reduce the
`risk of hyperphenylalaninemia-induced teratogenic effects, target blood phenylalanine
`concentrations of 120 to 360 micromol/L should be maintained for 3 months before conception
`and throughout pregnancy.2
`There is limited data on the developmental effects of Palynziq use in pregnant woman. Based on
`the 120-day safety update report and cumulative pregnancy data, 10 female subjects became
`pregnant during treatment, with information on timing of exposure missing.1 In summary, the 10
`pregnancies included 3 therapeutic/induced abortions, 1 missed abortion, 1 stillbirth, 1 normal
`delivery, 1 delivery of an infant with transient systolic murmur which resolved without
`intervention, and 3 ongoing at the time of the Safety Update data cutoff. As described above, it is
`known that pregnant patients with PKU are at increased developmental risk with elevated Phe
`levels, so causality can be difficult to establish with limited subject details and lab data. In addition,
`1 Biologic License Application (BLA) Multi-Disciplinary Review and Evaluation. BLA 761079 Palynziq
`(pegvaliase-pqpz). Accessed May 16, 2018. DARRTS Reference ID: Pending.
` Palynziq product label. Revised May 2018. DARRTS Reference ID: Pending.
`
`Page 2 of 5
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`Reference ID: 4266959
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`

`

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`9 female partners of male study subjects (partner pregnancies) became pregnant during
`treatment.1 Two male subjects have female partners who were pregnant twice, for a total of 11
`partner pregnancies. In the 11 partner pregnancies, 6 pregnancies had a reported normal outcome.
`The remaining 5 partner pregnancies included 1 delivery of an infant with neonatal respiratory
`distress who was discharged after receiving 2 days of respiratory support, 1 delivery with no
`additional data, 2 with unknown outcomes of the delivery, and 1 ongoing at the time of the Safety
`Update data cutoff.
` Embryofetal malformations (of the skeleton, kidneys, lungs, and eyes) and embryofetal toxicity
`(increased resorptions, reduced fetal weight) were observed in the offspring of pregnant rabbits
`(without PKU) treated with Palynziq in the nonclinical program at a dosage which was 7.5 times
`higher than the maximum recommended daily dose; these adverse fetal effects in the rabbit study
`were associated with strong signs of maternal toxicity, including marked reductions in weight gain
`and food consumption, and death.1 A reproduction study in rats (without PKU) demonstrated an
`increase in skeletal variations, but with no malformations observed. The effects occurred at 4.2
`times the maximum recommended daily dose. In a pre-/post-natal development study in rats
`(without PKU), Palynziq produced decreases in survival of offspring when administered daily at
`19.4 times the maximum recommended daily dose. The effects on rat embryo-fetal and post-natal
`development were associated with maternal toxicity. The significance of these findings for humans
`remains unknown.
` It is discussed in the label that Palynziq may cause fetal harm with supporting animal and human
`data, although the data is limited and insufficient to determine a drug-associated risk of adverse
`developmental outcomes.2 Further evaluation in the post-marketing setting is necessary for
`appropriate education of patients and prescribers when considering the use of Palynziq during
`pregnancy. A post-approval pregnancy monitoring program has been proposed to further evaluate
`safety risks associated with Palynziq treatment in pregnant women with PKU and their offspring.
`In addition, the product label includes the following language: “There is a pregnancy surveillance
`should report Palynziq exposure by calling 1 866 906 6100.”
`
`
`
`program for Palynziq. If Palynziq is administered during pregnancy, or if a patient becomes pregnant
`while receiving Palynziq or within one month following the last dose of Palynziq, healthcare providers
`
`1.3. FDAAA Purpose (per Section 505(o)(3)(B))
`
`
`
`Purpose
`
`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
`
`Page 3 of 5
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`Reference ID: 4266959
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`

`
`
`
`
`make ARIA sufficient?
`
`
`
`
`2.3. What type of analysis or study design is being considered or requested along with ARIA?
`Check all that apply.
`
`
`☒ 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).
`☐ 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: A Pregnancy Monitoring Program is being considered to further
`evaluate a nonspecific safety concern associated with Palynziq treatment in pregnant women
`with PKU and their offspring.
` 2.4. Which are the major areas where ARIA not sufficient, and what would be needed to
`☒ Study Population
`☐ Exposures
`☒ Outcomes
`☒ Covariates
`☒ Analytical Tools
` For any checked boxes above, please describe briefly:
` Study Population and Outcomes and Covariates: ARIA is not sufficient to identify the study
`population (babies that experienced in utero exposure or postpartum exposure through lactation)
`because the mother and baby records are not currently linked in Sentinel. Thus, the exposure
`corresponding to the mother and potential outcomes corresponding to the infant cannot be
`connected. This lack of linkage between mother and baby records renders ARIA insufficient for
`both the study population and outcome identification.
` Covariates: ARIA is not sufficient to capture maternal blood phenylalanine concentrations during
`pregnancy making it impossible to examine the associations between Palynziq treatment, blood
`Phe levels and adverse outcomes in the pregnant women and their offspring.
` Analytical Tools: ARIA analytic tools are not sufficient to assess the regulatory question of interest
`because data mining methods have not been tested for birth defects and other pregnancy
`
`
`
`Reference ID: 4266959
`
`Page 4 of 5
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`

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`2.5. Please include the proposed PMR language in the approval letter.
`
`outcomes.
` Other parameters were not formally discussed given that the mother-infant linkage is not
`currently available in ARIA.
` The following language (still in draft form) has been proposed for PMRs related to pregnancy
`outcomes:
`
`
`A prospective, observational study to assess the risks of pregnancy complications and adverse
`effects on the developing fetus and newborn (including, but not limited to, fetal malformations
`and pre-natal and post-natal growth restriction) from Palynziq treatment during pregnancy.
`The study will collect and analyze data on blood phenylalanine concentrations during pregnancy
`in treated pregnant women with PKU and examine associations between Palynziq treatment,
`blood phenylalanine concentrations, and adverse outcomes in the pregnant women and their
`offspring (fetus/newborn). The study duration will be at a minimum of 10 years. An interim
`report will be submitted every two years during the conduct of the study.
`
` The finalized PMR language will be issued upon approval.
`
`
`
`
`
`
`Reference ID: 4266959
`
`Page 5 of 5
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`

`

`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MICHELLE R IANNACONE
`05/23/2018
`
`PATRICIA L BRIGHT
`05/23/2018
`
`SUKHMINDER K SANDHU
`05/23/2018
`
`JUDITH W ZANDER
`05/23/2018
`
`MICHAEL D NGUYEN
`05/23/2018
`
`ROBERT BALL
`05/23/2018
`
`Reference ID: 4266959
`
`

`

`
`
`
`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 Memo for Palynziq PMR
`Version: 2018-01-24
`
`Date:
`Reviewer:
`
`Team Leader:
`
`Deputy Division Director:
`
`Subject:
`Drug Name:
`Application Type/Number:
`Applicant/sponsor:
`OSE RCM #:
`
`
`May 22, 2018
`Michelle R. Iannacone, PhD, MPH
`Division of Epidemiology I
`Patricia L. Bright, PhD, MSPH
`Division of Epidemiology I
`Sukhminder Sandhu, PhD, MS MPH
`Division of Epidemiology I
`Active Risk Identification and Assessment (ARIA) Sufficiency Memo:
`Immune-mediated adverse reactions associated with Palynziq
`treatment in PKU patients
`Palynziq (pegvaliase)
`BLA 761079
`Biomarin Pharmaceutical, Inc.
`2017-1327
`
`
`
`
`Reference ID: 4266947
`
`Page 1 of 7
`
`

`

`
`1. BACKGROUND INFORMATION
`
`EXECUTIVE SUMMARY (place “X” in appropriate boxes)
`-Initial
`-Interim
`-Final
`-Peri-approval
`-Post-approval
`-Yes
`-No
`-Surveillance or Study Population
`-Exposure
`-Outcome(s) of Interest
`-Covariate(s) of Interest
`-Surveillance Design/Analytic Tools
`
`1.1. Medical Product
`
`Palynziq (pegvaliase) is an enzyme substitution therapy indicated to reduce blood phenylalanine
`(Phe) concentrations in adult patients with phenylketonuria who have uncontrolled blood
`phenylalanine concentrations > 600 µmol/L on existing management. Palynziq substitutes for the
`deficient PAH enzyme in patients with PKU by providing an alternate pathway for Phe breakdown
`via the enzymatic conversion of Phe to trans-cinnamic acid (t-CA) and ammonia, both excreted in
`the urine. Palynziq is administered daily as a subcutaneous injection through a single-dose prefilled
`syringe. The proposed dosing follows an induction, titration, and maintenance (I/T/M) dosage
`regimen by which the dose is slowly increased over a period of a few weeks. The Applicant
`proposes that a patient should stay at 20 mg daily for 24 weeks and the dose may be increased to 40
`mg daily based on individual patient response (Phe concentration) and tolerability. If a patient does
`not achieve at least a 20% reduction in blood Phe concentration from their pre-treatment baseline
`after an additional 16 weeks of treatment with 40mg daily, then the product should be
`discontinued1.
`
`The primary safety signal identified with Palynziq is the high immunogenicity manifesting with
`various rates and severities of hypersensitivity events, including anaphylaxis. The safety review1
`1 Biologic License Application (BLA) Multi-Disciplinary Review and Evaluation. BLA 761079 Palynziq
`(pegvaliase-pqpz). Accessed May 16, 2018. DARRTS Reference ID: Pending.
`
`
`
`
`X
`
`X
`
`
`
`X
`
`X
`
`X
`X
`
`
`Page 2 of 7
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`
`
`
`
`Memo type
`
`Source of safety concern
`
`Is ARIA sufficient to help characterize the safety concern?
`
`If “No”, please identify the area(s) of concern.
`
`A. General ARIA Sufficiency Template
`
`1.2. Describe the Safety Concern
`
`
`
`
`
`
`Reference ID: 4266947
`
`

`

`
`
`focused on describing and analyzing the immunogenicity profile and related safety events in the
`exposed patient population.
` The primary safety concern from the phase 2 and phase 3 clinical trials is the long-term risks of
`immune-mediated adverse reactions (including but not limited to hypersensitivity reactions,
`anaphylaxis, injection-site reactions, generalized skin reactions, and arthralgia)1.
` The overall incidence of anaphylaxis in the phase 2 and 3 trials of Palynziq (pegvaliase) was 9%
`(among all doses used) in the induction, titration, and maintenance (I/T/M) population and
`decreased with longer duration of exposure. This corresponds to 26 out of 285 subjects who had
`37 anaphylactic reactions. The exposure-adjusted rate of anaphylaxis was 0.15 event rate/person-
`year in the induction/titration phase which decreased to 0.04 event rate/person-year in the
`maintenance phase. In the clinical trials, anaphylaxis generally occurred within 1 hour after
`injection (84%; 28/37 episodes); however, delayed reactions have occurred (up to 48 hours). Most
`episodes of anaphylaxis occurred within the first year of dosing (78%; 29/37 episodes), but cases
`have occurred at any time, even more than two years from initiation of treatment. Eighteen out of
`the 26 (69%) patients who experienced anaphylaxis were rechallenged with Palynziq and 5
`patients had recurrence of anaphylaxis1.
` The anaphylaxis rate noted with Palynziq treatment appears to be comparable to that of other
`biologic products approved for IEM (e.g. enzyme replacement therapies for lysosomal storage
`disease). However, the mechanism of anaphylaxis appears to be mediated by immune
`complex/complement activation, but the specifics are unknown, as there was no predictive
`antibody or titer level. The mechanism is most consistent with a non-IgE Type III immune complex-
`mediated reaction1.
` The product will be labeled with a boxed warning stating “Anaphylaxis has been reported after
`administration of Palynziq, and may occur at any time during treatment
` (5.1).”
` In the clinical trials, injection site reactions occurred as early as the first dose and at any time
`during treatment. Injection site reactions were more frequent during the induction/titration phase
`(1.9 episodes/patient-year) and decreased over time (0.4 episodes/patient-year in the Maintenance
`Phase). The mean duration of injection site reaction was 8 days, and 92% of injection site reactions
`had a duration of less than 14 days. Injection site reactions persisted up to 970 days (0.7% of
`injections site reactions persisted at least 180 days), and 99% of injection site reactions resolved by
`the time of the data cut-off2.
` In clinical trials, 125 out of 285 (44%) patients treated with Palynziq experienced generalized skin
`reactions (not limited to the injection site) lasting more than 14 days. Generalized skin reactions
`were more frequent during the Induction/Titration Phase (0.7 episodes/patient-year), and
`decreased over time (0.3 episodes/patient-year in the Maintenance Phase).
` The product will be labeled to include injection site reactions and generalized skin reactions in the
`Adverse Reactions section (6.1)2.
`
`
`
`
`2 Palynziq product label. Revised May 2018. DARRTS Reference ID: Pending.
`
`
`
`Reference ID: 4266947
`
`Page 3 of 7
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`(b) (4)
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`

`

` 1.3. FDAAA Purpose (per Section 505(o)(3)(B))
`
`X
`Assess a known serious risk
`
`Assess signals of serious risk
`
`Identify unexpected serious risk when available data indicate potential for serious
`risk
`1.4. Statement of Purpose
`
`The Division of Gastroenterology and Inborn Error Products (DGIEP), with concurrence by OSE,
`requires a post-market observational study to assess the known serious risk for immune-mediated
`adverse reactions from Palynziq. DGIEP specifically requires information about immunologic
`factors (i.e., anti-drug antibodies and neutralizing antibodies against Palynziq) associated with
`anaphylaxis. DGIEP requires detailed information from post-market settings to inform appropriate
`clinical strategies for mitigating the risk for anaphylaxis from Palynziq to supplement existing
`labeling efforts (i.e., boxed warning).
`
`1.5. Effect Size of Interest or Estimated Sample Size Desired
` A sample size of 750 subjects has been proposed by the Sponsor for the postmarket study.
`However, the Agency has not finalized the negotiation for sample size at the time of the Memo. If an
`agreement on the sample is not reached prior to approval, the Agency will negotiate the final
`sample size during the review of the postmarket protocol.
`
`
` Palynziq is a phenylalanine–metabolizing enzyme indicated to reduce blood phenylalanine
`concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine
`concentrations greater than 600 micromol/L on existing management. The patient population will
`include adult patients from the indicated population.
`
`2.2 Is ARIA sufficient to assess the intended population?
` No. Although adults with PKU could be identified using ARIA by limiting the age range for analysis
`to 18 years and older and identifying patients in that population with an ICD-10 code of E70.0
`(classical phenylketonuria), ARIA could not identify those with uncontrolled blood phenylalanine
`concentrations greater than 600 micromol/L on existing management. Non-standard laboratory
`tests are not routinely captured by ARIA tools in Sentinel.
`
` The exposure of interest is incident use of Palynziq.
`
`
`
`Purpose (place an “X” in the appropriate boxes; more than one may be chosen)
`
`
`
`
`
`2. SURVEILLANCE OR DESIRED STUDY POPULATION
`
`2.1 Population
`
`3 EXPOSURES
`
`3.1 Treatment Exposure(s)
`
`
`
`Reference ID: 4266947
`
`Page 4 of 7
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`3.2 Comparator Exposure(s)
`
`
`
`
`Is ARIA sufficient to identify the exposure of interest?
`
`
`
`4 OUTCOME(S)
`
`4.1 Outcomes of Interest
`
`
`
` Not applicable. The study population is Palynziq exposed patients. There is no comparator drug
`available3. Because Palynziq is self-administered daily (following a weekly initiation phase) this
`also makes self-controlled designs challenging.
`
`Initial dosage of Palynziq is 2.5 mg once per week for 4 weeks. Titration of dosage is administered
`in a step-wise manner over at least 5 weeks based on tolerability to achieve a dosage of 20 mg
`subcutaneously once daily. Consideration will be given to increasing the dosage to a maximum of
`40 mg subcutaneously once daily in patients who have been on 20 mg once daily continuously for at
`least 24 weeks who have not achieved a 20% reduction in blood phenylalanine concentration from
`baseline or a blood phenylalanine concentration ≤600 micromol/L.
`ARIA is sufficient to capture patients with pharmacy benefits who receive at least one dispensing of
`Palynziq. ARIA is also sufficient to capture procedure codes in outpatient, physician-supervised
`administration of subcutaneous injections, such as Palynziq, which may occur with the first few
`injections. However, if data are needed on the self-administered dose during titration, such dose
`levels could only be approximated from the available data. Therefore, ARIA may be sufficient to
`identify the exposure, but would not be fully sufficient to identify anaphylaxis risk factors including
`dose and titration information, although these might be estimated from the available data.
`
` The outcomes of interest include immune-mediated adverse reactions, including hypersensitivity
`reactions. The main hypersensitivity reactions of interest include anaphylaxis, injection-site
`reactions, and generalized skin reactions.
` No. Depending on the safety application, diagnostic codes in outpatient administration claims may
`or may not capture with acceptable accuracy the outcome of anaphylaxis4 or hypersensitivity
`reactions other than anaphylaxis5. However, there is the potential for low sensitivity in detecting
`hypersensitivity reactions, anaphylaxis, injection-site reactions, generalized skin reactions, and
`arthralgia related to Palynziq exposure.
`3 Although Kuvan is indicated to reduce blood phenylalanine (Phe) levels in patients with
`hyperphenylalaninemia (HPA) due to tetrahydrobiopterin-(BH4-) responsive PKU, Palynziq appears to
`benefit different patients with PKU than Kuvan based on different mechanism of action.
`4 Pharmacoepidemiol Drug Saf. 2013 Sep 5; 22(11):1205-13. doi: 10.1002/pds.3505. Validation of
`Anaphylaxis in the Food and Drug Administration’s Mini-Sentinel. Walsh KE, Cutrona SL, Foy S, Baker MA,
`Forrow S, Shoaibi A, Pawloski PA, Conroy M, Fine AM, Nigrovic LE, Selvam N, Selvan MS, Cooper WO, Andrade
`S. 5 Pharmacoepidemiol Drug Saf. 2012 Jan; 21(S1), 248-55. doi: 10.1002/pds.2333. A Systematic Review of
`Validated Methods for Identifying Hypersensitivity Reactions other than Anaphylaxis (Fever, Rash, and
`Lymphadenopathy), Using Administrative and Claims Data. Schneider G, Kachroo S, Jones N, Crean S, Rotella
`P, Avetisyan R, Reynolds MW.
`
`
`4.2 Is ARIA sufficient to assess the outcome of interest?
`
`
`
`Reference ID: 4266947
`
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`Patients using Palynziq will have, and be educated on, the use of injectable epinephrine. It is
`unknown what proportion of hypersensitivity reactions, anaphylaxis, injection-site reactions,
`generalized skin reactions, and arthralgia will be captured by insurance claims across the Sentinel
`data partners. If the patient does not receive medical treatment for these events or if the diagnosis
`is not captured in the billing codes, the sensitivity for detecting the events of interest could be low.
`A study evaluating anaphylactic reactions associated with intravenous iron products in claims data
`from the U.S. fee-for-service Medicare program suggests a low sensitivity for detecting anaphylaxis
`(8%-35%)6. Identifying injection-site reactions, generalized skin reactions, and arthralgia may
`correspond to an even lower sensitivity than anaphylaxis if these events do not cause the patient to
`report to a medical facility for treatment.
` Conversely, angioedema appears to have a more robust algorithm in claims data based on a study7
`using an ICD-9-CM code of 995.1 (recorded in any position during an outpatient, inpatient, or
`emergency department encounter). That algorithm was validated with a positive predictive value
`(PPV) from 90% to 95% in claims data. However, the clinical trial data did not identify a signal for
`angioedema in isolation of other hypersensitivity events and the clinical team concluded that
`assessing angioedema distinct from other hypersensitivity events would not be sufficient to assess
`the known serious risk for immune-mediated adverse reactions from Palynziq. Furthermore,
`capturing the information necessary to determine risk factors associated with hypersensitivity
`reactions requires longitudinal, prospective data collection.
` 5 COVARIATES
` 5.1 Covariates of Interest
` Several covariates, including diet, anti-drug and neutralizing antibody titers against Palynziq,
`immunologic and inflammatory responses on major organ function, frequency pharmacologic
`intervention use, and laboratory abnormalities were deemed highly desirable by OND to help
`clarify clinical factors and develop mitigation strategies. Collection of this data on factors that may
`help reduce the incidence of adverse events and increase the safe use of Palynziq could possibly be
`used to inform the product label.
`
`No. Answers to the safety concern requires that patients track their diet and requires results from
`non-standard laboratory tests conducted on blood collected prospectively per a schedule fixed by a
`protocol.
` 6
`
`5.2 Is ARIA sufficient to assess the covariates of interest?
`
`
`SURVEILLANCE DESIGN / ANALYTIC TOOLS
`
`
`6.1 Surveillance or Study Design
`
`
`6 Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. Wang C, Graham DJ,
`Kane RC, Xie D, Wernecke M, Levenson M, MaCurdy TE, Houstoun M, Ryan Q, Wong S, Mott K, Sheu TC, Limb S,
`Worrall C, Kelman JA, Reichman ME. JAMA. 2015 Nov 17; 314(19):2062-8. doi: 0.1001/jama.2015.15572.
`
`
`
`7 Arch Intern Med. 2012 Nov 12; 172(20):1582-9. doi: 10.1001/2013.jamainternmed.34. Comparative risk for
`angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Toh S1,
`Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF, Levenson M, Li L, McCloskey C,
`Shoaibi A, Wu E, Zornberg G, Hennessy S
`
`
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`Reference ID: 4266947
`
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`6.2 Is ARIA sufficient with respect to the design/analytic tools available to assess the
`
`question of interest?
`
`The study design would be a longitudinal, prospective study for up to 10 years of follow-up.
` Yes. ARIA is sufficient with respect to design / analytic tools available to assess the question of
`interest.
`As a result of the Signal Assessment Meeting deliberations and documented in this ARIA memo,
`ARIA was deemed insufficient to study hypersensitivity events and the potential associated risk
`factors among PKU patients using Palynziq treatment. The next step is to communicate
`expectations for the PMR with OND. OSE suggests the following language (the finalized language
`for the observational PMR will be issued upon approval):
` Prospective, longitudinal, observational study to assess long-term risks of severe immune-
`
`
`7 NEXT STEPS
`
`
`mediated adverse reactions in adult patients with phenylketonuria (PKU) treated with Palynziq.
`Each patient will be treated with Palynziq over a minimum of 10 years. Evaluate the incidence
`rates of immune-mediated adverse reactions (including, but not limited to, hypersensitivity
`reactions, anaphylaxis, generalized skin reactions, and arthralgia), and collect information,
`including a full description of clinical features of the adverse reactions, to investigate
`associations and temporal relationships between the incidence and severity of all immune-
`mediated adverse reactions and other potential associated risk factors. Evaluate immunologic
`and inflammatory responses (immunologic testing, inflammatory markers), their effects on major
`organ function (e.g., kidney function), and immune-mediated effects on blood phenylalanine
`therapeutic response. Collect and analyze additional information, including, but not limited to,
`PAH genotype, dietary practices, and prior medical history. Specify concise case definitions,
`validation methods, and procedures for all study outcomes. An interim report will be submitted
`every two years during the conduct of the study.
`
`
`
`Reference ID: 4266947
`
`Page 7 of 7
`
`

`

`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MICHELLE R IANNACONE
`05/23/2018
`
`PATRICIA L BRIGHT
`05/23/2018
`
`SUKHMINDER K SANDHU
`05/23/2018
`
`JUDITH W ZANDER
`05/23/2018
`
`MICHAEL D NGUYEN
`05/23/2018
`
`ROBERT BALL
`05/23/2018
`
`Reference ID: 4266947
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Date: 5/8/18
`
`To: BLA 761079 File
`
`From: Amy S. Rosenberg MD, DBRR3, OBP
`
`Amy S.
`Rosenberg -S
`
`Digitally signed by Amy S. Rosenberg -S
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People,
`0.9.2342.19200300.100.1.1=1300045963,
`cn=Amy S. Rosenberg -S
`Date: 2018.05.10 14:14:21 -04'00'
`
`Through: Daniela Verthelyi, Ph.D., M.D., Chief, Laboratory of
`Immunology, DBRR3, OBP
`Daniela I.
`Verthelyi -S
`Re: Consult regarding Immunogenicity and toxicology issues for Pegvaliase
`Biologics License Application (BLA 761079)
`
`Digitally signed by Daniela I Verthelyi S
`DN: c=US o=U S Government ou=HHS
`ou=FDA ou=People
`0 9 2342 19200300 100 1 1=1300130295
`cn=Daniela I Verthelyi S
`Date: 2018 05 10 14:16:35 04'00'
`
`I am writing this memorandum to 1) express my opinion that the approval
`for this product, in the face of an unrelenting, high titer immune mediated
`antibody response, and with evidence of Type III immune complex
`formation that likely induces clinical manifestations of skin and joint
`disease, as well as a significant occurrence of Type I immediate
`hypersensitivity responses, in the setting of a disease that is not considered
`life-threatening, should be fully vetted before an Advisory Committee
`composed of external experts as well as before a full Center Director
`Briefing and 2) to address the questions that were initially posed to the
`Immunogenicity Review Committee pertaining to this BLA, including the
`toxicological issues regarding CIC and administration of high doses of PEG
`daily, as PEG is non-biodegradable and its fate in such patients over an
`extended period of time is not clear.
`
`To my knowledge, approval of this product with its associated
`immunogenicity profile and issues is unprecedented. Firstly, 100% of
`patients mount high titer and sustained antibody responses, of which the titer
`is >1:1x106, again, an unprecedented level for a chronically administered
`drug. Importantly, the neutralizing antibody titer incidence continues to rise
`
`Reference ID: 4261382
`
`1
`
`

`

`over the 36 week time frame of measure to encompass nearly 80% of
`patients. (Fig 12.2.1.1.1 and Fig 14.6.3.2 below). Moreover, amon