CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-527
`22-527
`
`
`APPLICA TION NUMBER:
`
`SUMMARY REVIEW
`
`SUMMARY REVIEW
`
`
`
`
`
`

`

`September 19, 2010
`
`Director
`Division of Neurology Products/HFD-120
`
`MEMORANDUM
`
`DATE:
`
`FROM:
`
`
`
`TO:
`
`SUBJECT: Recommendation for Action on NDA 22-527, for the use of Gilenya
`(fingolimod) in the treatment of adults with relapsing forms of Multiple Sclerosis
`(MS)
`
`NDA 22-527, for the use of Gilenya (fingolimod) in the treatment of adults with
`relapsing forms of Multiple Sclerosis (MS), was submitted by Novartis
`Pharmaceuticals Corporation on 12/18/09. Gilenya is an oral sphingosine-1-
`phosphate (S1P) modulator whose mechanism of action presumably relates to its
`ability to bind to S1P receptors on various lymphocytes, preventing their egress
`out of lymphoid tissue into the peripheral circulation and thereby into the Central
`Nervous System (CNS) with a resulting decrease in inflammatory response.
`Fingolimod itself is inactive, but is phosphorylated to the active moiety,
`fingolimod-P.
`
`The sponsor has submitted the results of two definitive controlled trials that
`purport to provide substantial evidence of effectiveness as well as safety data
`and the requisite other data adequate for review. Because Gilenya is the first
`NDA for an oral treatment for MS to be submitted, it was granted Fast Track
`status and was given a priority review designation. The application was
`discussed at a meeting of the Peripheral and Central Nervous Systems Advisory
`Committee (PCNS AC) on 6/10/10.
`
`The application has been reviewed by Dr. Heather Fitter, medical officer, Dr.
`Sharon Yan, statistician, Dr. Lourdes Villalba, safety reviewer, Dr. Sally Yasuda,
`safety team leader, Drs. Ju-Ping Lai and Jagan Parapelly, clinical
`pharmacologists, Dr. Richard Siarey, pharmacologist, Dr. Lois Freed, supervisory
`pharmacologist, Dr. Wendy Wilson, chemist, Dr. Gwynn Ison, Division of
`Oncology Products, Dr. Marc Cavaille-Coll, Division of Special Pathogen and
`Transplant Products, Dr. John Senior, Office of Surveillance and Epidemiology
`(OSE), Dr. Shari Targum, Division of Cardiovascular and Renal Products, Dr.
`Wiley Chambers, Division of Ophthalmology Products, Dr. Brian Porter, Division
`of Pulmonary, Allergy, and Rheumatology Products, Felicia Duffy and Dr. Denise
`Baugh, Division of Medication Error Prevention and Analysis, Dr. Quynh-Van
`Tran, Division of Drug Marketing, Advertising, and Communications, Dr. Antoine
`El-Hage, Division of Scientific Investigations, Dr. Alicja Lerner, Controlled
`Substance Staff, Drs. Yasmine Choudhry and Marcia Britt, Office of Surveillance
`and Epidemiology, and Dr. Eric Bastings, Deputy Director and Cross-Discipline
`
`
`
`File, NDA 22-527
`
`
`
`1
`
`

`

`Team Leader (CDTL), DNP. The review team (with the exception of Dr. Siarey),
`recommends that the application be approved, albeit with numerous post-
`marketing requirements and commitments.
`
`Dr. Bastings’s CDTL memo provides a detailed review of the relevant
`effectiveness and safety data, and I will not repeat all of the details here. I will
`very briefly summarize the relevant data, and offer the rationale for the division’s
`recommendations.
`
`Clinical Pharmacology
`
`As noted above, fingolimod is phosphorylated to the active S-enantiomer
`fingolimod-P. Fingolimod-P reaches Tmax at about 6 hours; the Tmax for
`fingolimod is about 12 hours. Fingolimod and fingolimod-P each have a T1/2 of
`about 6-9 days, and steady state is achieved in about 1-2 months.
`
`In addition to being phosphorylated, fingolimod is metabolized by CYP 4F2, and
`non-polar ceramide analogs of fingolimod are also formed. After single doses,
`fingolimod represents about 23% of circulating moieties, with fingolimod-P
`representing about 10%, with numerous other metabolites (presumably inactive)
`at lesser concentrations.
`
`Fingolimod and fingolimod-P are not excreted in the urine, but about 81% of a
`dose is excreted in the urine as inactive metabolites.
`
`Effectiveness
`
`Briefly, as noted above, the sponsor has submitted the results of two randomized
`controlled trials. Study 2301 was a two year randomized trial in which 1272
`patients with Relapsing-Remitting MS (RRMS) were randomized to receive
`fingolimod 0.5 mg/day, 1.25 mg/day, or placebo. Study 2302 was a one year
`study in which 1292 patients with RRMS were randomized to either fingolimod
`0.5 mg/day, 1.25 mg/day, or Avonex (interferon beta-1a), 30 mcg once weekly
`(this study utilized “double dummy” blinding). Each study examined the effects of
`fingolimod on the annualized relapse rate (ARR) and on disease progression, as
`defined by time to confirmed (i.e., confirmed persistent change at 3 months)
`progression on the Expanded Disability Severity Scale (EDSS; progression
`defined as a 1 point change if the baseline EDSS was less than 5.5, and a 0.5
`point change otherwise).
`
`In each study, patients receiving fingolimod had a statistically significant benefit
`on the primary outcome (annualized relapse rate; ARR) compared to control.
`The following table presents these results:
`
`
`
`P-value vs control
`
`Adjusted ARR
`
`
`
`
`
`2
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.16
`0.18
`0.40
`
`0.20
`0.16
`0.33
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`<0.001
`<0.001
`
`
`<0.001
`<0.001
`
`
`Study 2301
`
`Fingolimod 1.25
`Fingolimod 0.5
`Placebo
`
`
`
`Study 2302
`
`Fingolimod 1.25
`Fingolimod 0.5
`Avonex
`
`
`
`Time to confirmed relapse was significantly delayed for both fingolimod groups
`compared to placebo in Study 2301 (p-values 0.012 and 0.026 for fingolimod
`1.25 mg and 0.5 mg, respectively; the percentage of patients without progression
`at Month 24 was 85%, 83%, and 78% for fingolimod 1.25, 0.5, and placebo,
`respectively, with p-values of 0.008 and 0.043, respectively).
`
`In Study 2302, there were no statistically significant differences on time to
`confirmed disability among any of the groups. The number of patients who
`progressed at Month 12 was 10.3%, 10.1%, and 14.1% in the fingolimod 1.25
`mg, 0.5 mg, and Avonex groups, respectively. The mean change in the baseline
`score of EDSS was -0.1, -0.8, and 0.2 in the fingolimod 1.25, 0.5, and Avonex
`groups, respectively (the 1.25-Avonex comparison was nominally significant with
`p-value 0.04).
`
`The sponsor also assessed the number of new or newly enlarged Ts lesions on
`MRI at study end. The following table gives the results for both studies:
`
`
`
`Study 2301
`
`
`
`Fingolimod 1.25
`Fingolimod 0.5
`Placebo
`
`
`
`Study 2302
`
`Fingolimod 1.25
`
`
`
`
`
`Mean # of new or newly enlarged T2 lesions P-value
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.5
`2.5
`9.8
`
`2.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`<0.001
`<0.001
`
`0.02
`
`
`
`3
`
`

`

`
`
`
`
`
`
`
`
`3.5
`4.9
`
`
`
`
`
`
`
`0.05
`
`Fingolimod 0.5
`Avonex
`
`
`Pharmacokinetic-pharmacodynamic (PK/PD) modeling suggests that a dose of
`0.25 mg/day would be effective, albeit at a level somewhat less than that
`achieved with the 0.5 mg/day dose.
`
`
`
`Safety
`
`Fingolimod has been studied in 2615 patients at a dose of 0.5 mg/day or greater,
`with 1843 exposed for at least one year, and 1224 exposed for at least two
`years.
`
`Fingolimod has been studied in renal-transplant patients at doses up to 5
`mg/day, and at those doses is associated with numerous significant adverse
`events, including cardiac, respiratory, and ophthalmic. The Agency’s detailed
`safety review has concentrated on an assessment of the experience at the
` doses for MS, namely 0.5 and 1.25 mg/day.
`
`
`As discussed by the review team, there were 14 deaths in the MS program, one
`in a patient receiving 0.5 mg/day (8 occurred in patients receiving 1.25 mg/day).
`The death in the patient receiving 0.5 mg/day occurred 1 year after drug
`discontinuation. An autopsy revealed diffuse B cell lymphoma of the brain
`(Epstein-Barr associated), and, according to Dr. Yasuda, accompanying “non-
`methotrexate-associated iatrogenic immunodeficiency associated
`lymphoproliferative disorder” of the lung, kidney, thyroid, jejunum, and T cell
`lymphoma of the skin. Several deaths in the 1.25 mg dose group were
`considered likely related to treatment (2 cases of herpes infections), or possibly
`related (2 cases of unusual MS progression and 2 metastatic tumors.
`
`In the MS experience, there was, in general, a low rate of serious adverse events
`including the following:
`
`
`Event
`
`
`
`1.6
`
`Bradycardia
`0.4
`First degree AV block
`Second degree AV block 0.4
`Herpes infection
`
`0.4
`LFT abnormality
`
`0.7
`Macular Edema
`
`0.4
`
`0.5
`
`
`
`N=854
`
`0.7
`0.1
`0.1
`0.2
`0.5
`0.1
`
`
`
`
`
`
`
`
`Placebo
`
`N=511
`
`0.2
`0
`0.2
`0
`0.2
`0
`
`
`
`
`
`
`
`
`
`1.25
`
`
`
`N=943
`
`
`
`
`
`
`
`
`
`
`
`
`4
`
`(b) (4)
`
`

`

`0.3
`
`
`
`0
`
`
`
`0
`
`1.25
`
`
`
`N=943
`
`
`
`
`
`
`
`0.5
`
`
`
`N=854
`
`3.4
`0.1
`0
`0
`0
`
`
`
`
`
`
`
`Placebo
`
`N=511
`
`1.4
`0
`0.2
`0
`0
`
`Lymphopenia
`
`
`The following events led to discontinuation (taken from Dr. Bastings’s Table 9,
`page 15 of his memo):
`
`
`Event
`
`
`
`4.1
`
`LFT abnormalities
`1.1
`
`Macular edema
`0.5
`
`Bradycardia
`0.3
`First degree AV block
`Second degree AV block 0.2
`
`Common adverse events are discussed by Dr. Bastings (page 16 of his memo);
`they are consistent with the events described as serious and are of no additional
`significance.
`
`Laboratory data
`
`Fingolimod causes a peripheral lymphopenia, consistent with its primary
`pharmacologic action. Lymphocyte counts drop to about 28% of baseline at 0.5
`mg daily (about 23% of baseline at 1.25 mg daily) and persist during treatment.
`In general, levels essentially return to baseline within 3 months of discontinuation
`of treatment. In about 20% of patients, the nadir of lymphocyte counts was about
`10% of baseline.
`
`Systematic collection of routine electrolytes was not performed in the Phase 2
`and 3 MS studies.
`
`Fingolimod causes changes in blood pressure. After the initial dose, there is an
`acute hypotensive effect, followed by a hypertensive effect with chronic
`treatment, as described in the following tables:
`
`Acute dosing
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`BP Changes
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DBP < 50 or
`>15 mm decrease
`from baseline
`
`
`SBP < 90 or
`>20 mm decrease
`From baseline
`
`
`
`
`
`5
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`29%
`23%
`17%
`
`>15 mm Hg increase
`
`in DBP
`
`
`
`
`
`
`
`
`
`25%
`22%
`20%
`
`20 mm Hg I ncrease
`
`In SBP
`
`
`
`27%
`22%
`20%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`23%
`19%
`16%
`
`
`
`
`
`
`
`
`
`Bradycardia
`
`
`
`Fing 1.25
`Fing 0.5
`Placebo
`
`
`
`
`
`<50 bpm or
`>15 bpm decrease
`From baseline
`
`
`
`
`
`48%
`33%
`13%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fing 1.25
`Fing 0.5
`Placebo
`
`
`Chronic dosing
`
`
`
`
`
`
`
`
`
`
`Fing 1.25
`Fing 0.5
`Placebo
`
`There were small dose dependent increases in mean blood pressure (systolic
`and diastolic) that peaked at about 6 months and continued during treatment
`(see Dr. Bastings’s Table 13, page 18 of his memo). There were also small dose
`dependent increases in the percentage of patients who met outlier criteria for
`both SBP and DBP (see Dr. Bastings’s Table 15, page 19).
`
`Issues of interest
`
`Bradycardia and AV block
`
`Fingolimod causes significant bradycardia at all doses, including at 0.5 mg,
`apparent after the first dose, reaching a nadir at about 5-6 hours, as described
`earlier. With continued daily treatment, the heart rate essentially returns to
`baseline in about 1 month. Although there were a few serious AEs and
`discontinuations related to cardiac reasons (most commonly bradycardia,
`followed by second and first degree AV block), almost all occurred in the 1.25 mg
`group; only one patient discontinued in the 0.5 mg group for a cardiac reason.
`
`Patients in studies 2301 and 2302 were monitored for 6 hours (at least) for
`cardiac events; 18%, 12%, and 3% of fingolimod 1.25 mg, 0.5 mg, and placebo
`required more extended monitoring because of persistent effects. A total of 2%
`
`
`
`6
`
`

`

`of fingolimod 0.5 mg patients required observation in the hospital, compared to
`0% of the placebo patients.
`
`Because of cardiac lesions seen in animal studies, some patients were assessed
`with echocardiography. Although the assessments were limited, Dr. Targum,
`cardiology consultant, concluded that there were no significant findings.
`
`Macular edema
`
`Because macular edema was noted in studies of renal transplant patients (at
`higher doses the rate was about 4%), patients in the MS studies were monitored
`for macular edema with periodic Optical Coherence Tomography (OCT). There
`were 4 serious cases of macular edema in the 1.25 mg group and 1 serious case
`(0.1%) in the 0.5 mg group. These all led to discontinuation of treatment. In all
`studies combined, there were 0.2% serious cases in the 0.5 mg group.
`
`In MS controlled trials, the DSMB ophthalmologist diagnosed ME in 0.8%, 0.9%,
`and 0.3% in fingolimod 1.25 mg. 0.5 mg, and placebo patients, respectively.
`
`There were very few differences on OCT between the 0.5 mg group and the
`placebo group. Most cases of ME were diagnosed on testing, and were
`asymptomatic. The median time to detection was 99 days, with a mean time to
`detection of 207 days. Dr. Chambers, ophthalmology consultant, concluded that
`there were only a small number of cases of ME in the 0.5 mg group, and that
`they were reversible upon discontinuation of treatment.
`
`Pulmonary changes
`
`Based on animal findings of pulmonary fibrosis and hypertrophy of the smooth
`muscle as well as findings of dyspnea and pulmonary edema in the renal
`transplant experience, patients in MS trials were monitored with High Resolution
`CT scans (HRCT) in a subset of patients, and pulmonary function tests (FEV1,
`FVC and carbon monoxide diffusing capacity [DLCO]).
`
`As described by Dr. Bastings (Figures 4, 5, and 7 in his memo, pages 26-7),
`there were dose dependent decrements in all of these measures. Specifically,
`there was an initial drop (about a 0.1 L/sec decrement at the 0.5 mg dose in
`FEV1 that remained abnormal but did not further deteriorate; about a 0.25
`mL/min/mmHg change in DLCO that increased to about a 1 mL/min/mmHg
`change at month 12, and then approached baseline at month 24; it should be
`noted that for DLCO, there were considerably fewer patients assessed at later
`time points compared to earlier time points). A greater percentage of patients in
`the 0.5 mg group had a DLCO <80% of baseline compared to placebo (16% vs
`12%, respectively). Although FEV1 changes resolved with drug discontinuation,
`this was not true for DLCO changes. These changes did not correlate with any
`
`
`
`7
`
`

`

`pulmonary symptoms. There were no material differences between the results at
`the 0.5 mg group and placebo on HRCT or FVC.
`
`Liver abnormalities
`
`Fingolimod causes an increase in liver enzymes.
`
`In controlled MS trials, there was a 10%, 9%, and 2% incidence in the percent of
`patients who experienced an increase of at least 3 XULN in ALT in the fingolimod
`1.25 mg, 0.5 mg, and placebo groups, respectively. The corresponding
`percentages for AST were 1.5%, 2%, and 1%. For GGT, the corresponding
`percentages were 9%, 7%, and 1%. The incidence of ALT or AST increases of
`>5 XULN were much less, and minimally different from placebo. For GGT, the
`percentages of patients with elevations >5 X ULN were 3%, 2%, and 0%. There
`were no important changes in bilirubin. There was one patient with an ALT
`elevation and jaundice who was diagnosed with Hepatitis E.
`
`
`
`
`Non-clinical issues
`
`As noted above, Dr. Siarey, the reviewing pharmacologist, has recommended
`that the application not be approved at this time. As described by Dr. Freed, his
`reasons are:
`
`
`1) reproductive and developmental studies are inadequate because of a lack
`of fetal assessment at all doses
`2) in the in vitro genetox studies, there is inadequate information on the
`amount of phosphorylated fingolimod formed by the metabolic activation
`system used
`3) the mouse carcinogenicity study was inadequate because of a high
`reported rate of autolysis, and
`4) the safety of metabolites M2 and M3, which are markedly elevated in
`patients with severe renal impairment, have not been adequately
`assessed
`
`
`Dr. Freed has, in my view, adequately dealt with these issues in her memo.
`
`Briefly, with regard to the first issue, there were inadequate numbers of mid dose
`females (MDF) in the fertility study and there was no assessment of skeletal
`abnormalities in the low dose (LD) and mid-dose (MD) embryo-fetal development
`study in the rat. According to Dr. Freed, however, the latter concern is mitigated
`by the fact that there were no abnormalities seen at the high dose (HD). The
`former concern is mitigated by the fact that there were adequate numbers of high
`dose females (HDF).
`
`
`
`8
`
`

`

`
`Regarding the second issue, Dr. Freed agrees that the genetox battery was
`inadequate (for reasons beyond those cited by Dr. Siarey, although she agrees
`with his reason as well). However, as she notes, the carcinogenicity studies
`clearly demonstrate a signal for malignant lymphomas (see below), so no
`additional genetox studies are necessary.
`
`Regarding the issue of the adequacy of the mouse carcinogenicity study, Dr.
`Freed concludes that autolysis did not materially interfere with the adequate
`assessment of neoplastic findings (indeed, there were positive findings).
`Although this may have interfered with the assessment of non-neoplastic
`findings, as she points out, this is not the purpose of a carcinogenicity study.
`
`Finally, regarding the assessment of the toxicity of M2 and M3, Dr. Freed notes
`that levels of M2 and M3 have been adequately assessed except in the pre-and
`post-natal development study and the carcinogenicity studies. However, as she
`notes, the levels of M2 and M3 in the mouse carcinogenicity study were likely to
`have been “…at least similar…” to those seen in patients with severe renal
`impairment. For this reason, she believes that no additional non-clinical studies
`need be done to evaluate these metabolites.
`
`As noted earlier, fingolimod causes lung pathology, but the primary finding of
`importance not detectable in the clinical studies to date is a dose-related
`increase in malignant lymphomas in MD and HD male and female mice (0.25 and
`2.5 mg/kg/day).
`
`Risk Evaluation and Mitigation Strategies (REMS)
`
`Because of the various adverse events associated with the use of fingolimod, the
`sponsor has proposed a REMS consisting of a Medication Guide, a Dear Health
`Care Practitioner letter, and an information sheet to be given to prescribers.
`
`
`
`Comments
`
`The sponsor has submitted the results of two randomized controlled trials that
`purport to establish substantial evidence that GILENYA is effective in reducing
`relapses and delaying the accumulation of disability in adults with RRMS.
`Further, the sponsor has submitted detailed reports of relevant safety data as
`well as other required data.
`
`As noted above, due to the panoply of adverse events caused by fingolimod, the
`application was discussed at a meeting of the PCNS AC on June 10, 2010.
`Following is a brief account of the responses to the questions we asked the
`committee to consider.
`
`
`
`9
`
`

`

`
`1) The committee voted unanimously that there was substantial evidence of
`effectiveness for fingolimod in reducing the incidence of relapses in patients with
`RRMS, and voted 24-1 that there was substantial evidence of effectiveness inn
`delaying the accumulation of physical disability in these patients.
`
`2) The committee voted 20-5 that the sponsor should be required to evaluate the
`effectiveness of doses lower than 0.5 mg/day, and unanimously that this could be
`done post-approval.
`
`3) The committee voted unanimously that the safety data for 0.5 mg daily justified
`approval, and also voted unanimously that patients should receive the first dose
`in a monitored setting. Most members recommended that this be true for all
`patients, but the cardiologists felt that only patients at high risk for
`arrhythmias/bradycardia be monitored.
`
`4) The committee voted 20-4 (one abstention) that routine ophthalmologic
`monitoring was not sufficient to detect ME, and, in discussion, most members felt
`that a baseline exam, including dilated fundoscopy, be performed.
`
`5) The committee voted 17-7 (one abstention) that routine vigilance was
`insufficient to mitigate the pulmonary risk, and the committee’s pulmonology
`consultant felt that patients should have baseline PFTs.
`
`6) The sponsor had proposed a 5 year, 5000 patient post-marketing study of the
`0.5 mg dose in routine care, to further assess its adverse effects, especially in
`populations excluded from the MS studies (e.g., diabetes, cardiovascular
`disease). The committee agreed that such assessments should be performed.
`
`7) The committee voted 21-3 (one abstention) that fingolimod should not be
`reserved for patients intolerant of, or who have had an inadequate response to,
`other available MS treatments.
`
`We agree that the sponsor has provided substantial evidence of effectiveness for
`GILENYA as a treatment for relapses in patients with RRMS. Further, although
`they have submitted only one study (2301) that demonstrates a significant effect
`on the accumulation of disability, we also agree that it is appropriate to grant this
`claim. The lack of a significant effect on this outcome in Study 2302 is not
`unexpected: In this study, fingolimod was not compared to placebo, and the
`study was only one year in duration. The very robust finding on relapse rate in
`both studies (including compared to an active control), as well as the robust
`finding on disability in Study 2301 make granting the disability claim appropriate,
`in our view.
`
`Further, we believe it is appropriate to grant these claims for patients with
`relapsing forms of MS, not just for patients with relapsing-remitting MS.
`
`
`
`10
`
`

`

`Relapsing forms of MS are those in which patients do not recover completely
`between relapses, and these are, in general, patients who have more severe
`disease. In these two studies, the drug clearly had an effect on patients with high
`EDSS scores (i.e., more severe patients) as well as in those with lower scores.
`We believe that this finding makes it reasonable to conclude that the drug is
`effective in reducing relapses and accumulated disability in patients with other
`relapsing forms of MS in addition to RRMS (also, it is worth noting that the other
`approved treatments carry this expanded indication).
`
`It is important to note that there were no important differences between the
`effectiveness at 0.5 mg/day and 1.25 mg/day, and that significant adverse events
`were dose related. For these reasons, we believe that 0.5 mg/day should be the
`recommended dose in labeling. Further, the similarity in effectiveness of these
`two doses suggests that a lower dose might be as effective, and be associated
`with less risk. For this reason, we recommend that the sponsor should evaluate
`lower doses in a post-marketing study.
`
`Regarding the safety of GILENYA, it is clear that it is associated with numerous
`adverse effects, including bradycardia and AV block, macular edema, pulmonary
`complications, infections, and liver injury in patients. In animals, in addition,
`fingolimod causes fetal injury and malignant lymphomas.
`
`The clinical findings of concern are clearly dose-related, and the incidence of
`significant adverse events is quite low, and, we agree, acceptable, at the 0.5
`mg/day dose. However, we also believe that appropriate monitoring should be
`undertaken to either detect the onset, or mitigate the risks, of these potential
`events. Toward this end, we recommend that all patients be monitored for at
`least 6 hours after the first dose (although a case could be made to monitor only
`those patients with cardiovascular risk factors, this could be difficult to
`operationalize, and our only experience in MS patients has been collected under
`these conditions; we have no information about how well patients will tolerate the
`first-dose bradycardia in an unsupervised out-patient setting). In addition, we
`believe that patients should have an ophthalmologic evaluation at baseline and at
`3-4 months, as well as at any time they complain of visual symptoms.
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`Regarding potential pulmonary adverse events, we believe, given the real, but
`minimal changes seen in PFTs, that routine monitoring is not necessary
`(especially given the large intra-patient variability in these tests), although
`appropriate testing should be performed in patients who become symptomatic.
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`Of considerable concern is the fact that MS patients with significant concomitant
`illnesses, especially patients with diabetes and cardiovascular disease, were
`excluded from clinical trials. The experience with the renal transplant program
`suggests that these patients are at increased risk for many of the adverse events
`seen with fingolimod, although, of course, the renal patients were treated with
`much higher doses than 0.5 mg/day. Nonetheless, the lack of data in these
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`patients at the lower dose is unfortunate, and labeling must make clear that the
`risks in these patients are unknown. As discussed above, the sponsor has
`proposed a 5000 patient study in which MS patients with these concomitant
`illnesses will be enrolled, treated, and followed, and we agree that it will be
`important for the sponsor to conduct a trial that will by design will be capable of
`adequately characterize these toxicities of GILENYA in an appropriate MS
`population.
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`In addition, an unknown, but important, issue is the potential for GILENYA to
`cause life-threatening infections and/or cancer at the recommended dose.
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`The data suggest that serious, life threatening infections can occur in patients
`treated with GILENYA, though this has not definitively occurred at the 0.5 mg
`dose. Nonetheless, as exposure at this dose increases, this is a real possibility.
`In addition, based on GILENYA’S mechanism of action, and the suspicion raised
`by the results of the mouse carcinogenicity study, the possibility for fingolimod to
`cause cancer is also real. We believe the proposed large prospective study will
`yield useful information on these important points.
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`Given these considerations, we believe that the data taken as a whole support
`the approval of the NDA. However, the following post marketing studies will be
`done:
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`Post-marketing requirements (PMRs)
`
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`1) A deferred 24 month randomized study in pediatric patients
`2) An observational prospective study comparing fingolimod to another
`disease modifying treatment. Patients should be representative of the
`population with MS, and should be evaluated for events of concern (e.g.,
`eye, cardiovascular, pulmonary, hepatic toxicity and infections and
`lymphoma, sample size to be determined.
`3) A pregnancy registry
`4) An in vitro study to evaluate the potential for fingolimod-P to induce
`CYP450 isozymes
`5) An in vitro study to evaluate the potential of fingolimod to inhibit CYP2C8
`and of fingolimod-P to inhibit CYP2B6
`6) An in vitro study to evaluate the potential for statins to induce CYP4F2
`7) An integrated summary of safety to include pooled results of previous
`studies and Study 2309 (the latter study is on-going at this time)
`8) A juvenile rat study
`9) An interaction study to determine the effects of carbamazepine on
`fingolimod kinetics
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`Post-marketing commitments (PMCs)
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`1) a randomized controlled trial in patients with MS evaluating the safety and
`effectiveness of fingolimod 0.5 mg/day, 0.25 mg/day, and an appropriate
`control
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`In addition, as noted above, the sponsor has proposed a REMS consisting of a
`Medication Guide and Communication plan; we agree that this is appropriate.
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`We have agreed with the sponsor on product labeling, the Medication Guide and
`other elements of the REMS, and on the specific PMRs and PMC. For this
`reason, we recommend that the NDA be approved.
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`Russell Katz, M.D.
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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/
`----------------------------------------------------
`
`RUSSELL G KATZ
`09/21/2010
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`Reference ID: 2838571
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`