CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204063Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`Tertiary Pharmacology Review
`
`By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 204063
`Submission date: 2/27/2012
`Drug: dimethyl fumarate
`Applicant: Biogen Idec Inc.
`Indication: Treatment of patients with relapsing forms of multiple
`sclerosis
`Reviewing Division: Division of Neurology Products
`
`
`Discussion:
`The pharm/tox reviewer did not recommend approval of this NDA based on the
`nonclinical data. Renal toxicity in nonclinical species was the specific reason for
`this conclusion. The pharm/tox supervisor agreed that the nonclinical studies
`demonstrate the potential for renal toxicity. It is the pharm/tox supervisor's
`understanding that dimethyl fumarate has demonstrated efficacy for treatment of
`MS and that there is sufficient evidence of safety to support approval of DMF
`based on the human safety data for dimethyl fumarate and the postmarketing
`experience with a related drug (Fumaderm). The supervisor also noted that a
`postmarketing study will be conducted in patients with close monitoring for renal
`toxicity. The supervisor recommends approval with description of the nonclinical
`renal toxicity findings in labeling.
`
`Carcinogenicity studies of dimethyl fumarate were conducted in mice and rats.
`These studies were reviewed by the Executive Carcinogenicity Assessment
`Committee. The studies were found to be acceptable. Neoplasms of the
`nonglandular stomach and kidney were initially identified in mice and rats.
`Interstitial cell adenoma of the testes was determined to be drug-related in rats.
`The sponsor subsequently submitted a re-examination of the microscopic slides
`of the rat kidneys. In the re-examination, there was no drug-related increase in
`renal neoplasms in rats.
`
`Conclusions:
`The pharmacology/toxicology reviewer and supervisor conducted a thorough
`evaluation of the nonclinical information submitted in support of this NDA. I agree
`that the results observed in the animal studies suggest a potential for renal
`toxicity. Additional studies in animals are probably not necessary at this point
`because the concern has already been identified. I agree that there are no clear
`drug-related renal neoplasms in rat. I agree that this NDA may be approved for
`the above indication based in part on an understanding that current and
`additional clinical data will be adequate to address the potential for renal toxicity
`in patients. I agree with the labeling changes suggested by the
`pharmacology/toxicology supervisor. No established pharmacologic class has
`
`
`
`Reference ID: 3282105
`
`1
`
`

`

`been proposed for labeling. This appears appropriate because the mechanism by
`which dimethyl fumarate is effective in MS is unknown.
`
`
`
`Reference ID: 3282105
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PAUL C BROWN
`03/25/2013
`
`Reference ID: 3282105
`
`

`

`MEMORANDUM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
` Public Health Service
`
`
` Food and Drug Administration
`
`
`
`
`
`________________________________________________________________________
`
`Division of Neurology Products (HFD-120)
`Center for Drug Evaluation and Research
`
`Date: February 8, 2013
`
`From: Lois M. Freed, Ph.D.
`
`Supervisory Pharmacologist
`
`Subject: NDA 204-063 (BG-00012, dimethyl fumarate, TECFIDERA)
`________________________________________________________________________
`
`NDA 204-063 was submitted by the sponsor (Biogen Idec) on February 24, 2012
`(received February 27, 2012) for dimethyl fumarate (DMF) for the treatment of patients
`with relapsing forms of multiple sclerosis (MS). A major amendment submitted on
`October 2, 2012 (received October 5, 2012) extended the original PUDFA goal date by
`three months, to March 27, 2013. Clinical development of DMF for MS was conducted
`under IND 73061.
`
`The sponsor conducted a full battery of nonclinical studies in support of NDA 204-063,
`including chronic toxicity studies (rat, dog, monkey), reproductive and developmental
`toxicity studies (rat, rabbit), carcinogenicity studies (mouse, rat), and investigative studies
`in rat to further assess the nephrotoxicity observed in multiple species. These studies
`were reviewed by Dr. Banks-Muckenfuss (cf. Pharmacology/Toxicology NDA Review
`and Evaluation, NDA 204063, Melissa K. Banks-Muckenfuss, Ph.D., 1/28/2013). Based
`on that review, Dr. Banks-Muckenfuss recommends that the NDA not be approved
`“…based on renal toxicity at clinically relevant doses (toxicity in all nonclinical species,
`including tumors in rodents).” Dr. Banks-Muckenfuss acknowledges that nephrotoxicity
`was not observed in humans during clinical development, citing the review of clinical
`safety data (Clinical Review NDA 204063, Gerard Boehm, MD, MPH, 1/4/13), but states
`that “…it is not clear from the nonclinical data that the monitoring conducted would be
`able to detect the toxicity in humans (e.g. due to the marker used, sensitivity and/or the
`duration of the exposures).”
`
`This memo will briefly summarize the nonclinical findings (full details are provided in
`the review by Dr. Banks-Muckenfuss) but will focus on selected toxicities, particularly
`the signal for nephrotoxicity in the nonclinical studies conducted by the sponsor.
`
`
`
`
`
`
`Reference ID: 3258603
`
`1
`
`

`

`Pharmacology
`
`Following oral administration of DMF in animals and humans, plasma levels of DMF are
`low to undetectable, consistent with in vitro studies demonstrating rapid hydrolysis of
`DMF in intestinal cells. A hydrolysis product, mono-methyl fumarate (MMF), is
`detectable in plasma of animals and humans and was the drug-related compound
`quantitated to assess systemic drug exposure. The sponsor conducted a series of in vitro
`and in vivo studies to characterize the pharmacology of DMF and MMF; however, it is
`the pharmacology of MMF that is most relevant to this application.
`
`The sponsor hypothesizes that the ability to activate the nuclear factor (erythroid-derived
`2)-like 2 (Nrf2) antioxidant response pathway is the mechanism by which orally
`administered DMF exerts therapeutic (e.g., neuroprotective, anti-inflammatory) effects.
`MMF was shown to induce Nrf2 activation in vitro in cells transfected with rat Keap-1.
`Keap-1 is a protein which binds to Nrf2 and facilitates its proteolysis. By disrupting this
`binding, MMF inhibits proteolysis of Nrf2, resulting in translocation of Nrf2 to the
`nucleus and subsequent induction of antioxidant response genes. Treatment of cultured
`CNS cells (astrocytes, neurons, oligodendrocytes) with MMF was demonstrated to
`increase cell survival by increasing cellular Nrf2 levels and upregulating antioxidant
`stress genes. In in vivo studies, oral administration of DMF induced transcriptional
`markers of Nrf2 activation and demonstrated beneficial effects in a malonate-induced
`striatal lesion model in rat and in a rat EAE model. Whether or not activation of the Nrf2
`pathway underlies the therapeutic effect of DMF in patients with multiple sclerosis (MS)
`is unclear. Although the pharmacodynamic effects of MMF in vitro and DMF in vivo
`were shown to be, to some extent, dependent on Nrf2, the sponsor notes that “Nrf2
`contributes to, but is not required for” some of these effects and that other mechanisms
`may be involved. In addition, in vivo studies of oral DMF in rodent demonstrated
`increases in transcriptional markers of pharmacodynamic effect (through Nrf2) in various
`tissues (duodenum, jejunum, spleen, liver), which was tissue and dose dependent, but to a
`substantially less extent in CNS tissue (spinal cord, cerebellum, forebrain).
`
`Therefore, the mechanism(s) by which oral DMF exerts its therapeutic effect in MS
`patients has not been established. Activation of the Nrf2 antioxidant response pathway
`may be involved; however, the pharmacological activity of DMF or MMF was not fully
`characterized. (Neither compound was tested in a battery of in vitro receptor binding
`assays.) Published studies report that MMF (but not DMF) is a potent nicotinic acid
`receptor agonist (Hanson J et al. J Clin Invest 120(8):2910-2919, 2010; Hanson J et al.
`Pharmacol Therap 136:1-7, 2012), which is consistent with the flushing commonly
`reported in humans during clinical development. DMF and/or MMF may have additional
`pharmacological activity that has not yet been identified.
`
`Dr. Banks-Muckenfuss discusses the possibility that some of the toxicities observed in
`the nonclinical studies (e.g., forestomach lesions such as hyperkeratosis, renal toxicity
`including tumors) may be mediated through DMF/MMF-induced activation of the Nrf2
`pathway. Although this possibility is supported by published literature (e.g., Slocum SL,
`
`
`
`Reference ID: 3258603
`
`2
`
`

`

`Kensler TW Arch Toxicol 85:273-284, 2011), the available data are not sufficient to
`identify a mode of action for the toxicities observed.
`
`PK/ADME
`
`As noted, DMF, when administered orally, is rapidly hydrolyzed prior to systemic
`absorption and exhibits little or no systemic exposure in animals or humans. MMF, an
`active metabolite detected in plasma of animals and humans, was quantitated to assess
`systemic drug exposure.
`
`Tissue distribution of radioactivity following single doses of radiolabeled DMF to Long
`Evans rats indicated rapid absorption and extensive distribution into all tissues examined,
`except for “fat in the reproductive area.” At 0.5 hours postdose, highest levels of
`radioactivity were detected in kidney, followed by stomach, liver, pancreas, and brain. At
`72 hours postdose, radioactivity was still detectable in all tissues. However, since MMF
`is extensively metabolized in vivo to fumaric acid, citric acid, and glucose and
`considering that the major route of elimination was expired air (as 14CO2), the extent to
`which MMF itself contributed to tissue radioactivity could not be addressed. Although
`drug-related radioactivity distributed extensively to kidney, urine was not a major route
`of elimination, accounting for only approximately 20% of dose in Long Evans rat.
`
`Toxicology
`
`The pivotal oral toxicity studies for DMF were conducted in CD-1 mouse (13-week + 4-
`week recovery), Sprague-Dawley rat (3- and 6-month, both with 4-week recovery),
`cynomolgus monkey (1-year + 4-week recovery), and Beagle dog (4-week + 14-day
`recovery, 11-month + 1 month recovery).
`
`Mouse: In CD-1 mouse, forestomach and kidney were the primary target organs for
`toxicity. In the 13-week study (0, 50, 200, 400 mg/kg/day, by gavage), forestomach
`lesions (including hyperkeratosis, squamous cell hyperplasia, subacute and chronic
`inflammation, microabscess, ulceration) were observed at all doses in both males and
`females, although findings were minimal at the low dose. Splenic changes
`(extramedullary hematopoiesis) were minimal but noted at all doses in males and
`females. Kidney weight was increased at all doses in males (11, 27, and 37%,
`respectively) and at all but the low dose in females (15% at the MD and HD), but there
`were no histopathological correlates. Only forestomach remained affected in recovery
`animals (MD and HD).
`
`In a 28-day dose-ranging study in B57BL/6 mouse (doses of 50, 100, 250, and 400
`mg/kg/day, by gavage), changes in forestomach, spleen (increased extramedullary
`hematopoiesis), testes (tubular degeneration/hypocellularity, tubular giant cells),
`epididymides (sperm granuloma) were the primary findings. Effects on male reproductive
`organs were not observed in the 13-week study in CD-1 mouse.
`
`In the carcinogenicity study (0, 25, 75, 200, 600/400 mg/kg/day, by gavage; HD lowered
`on Day 9), kidney and forestomach lesions were observed at all doses (discussed under
`
`
`
`Reference ID: 3258603
`
`3
`
`

`

`Carcinogenicity); an increased incidence and/or severity of retinal degeneration was
`detected in males and females at the two highest doses.
`
`Rat: In rat, the primary target organs for toxicity were the forestomach, kidney, and male
`reproductive organs. Microscopic changes in pancreas (including acinar epithelial cell
`apoptosis and vacuolization) were only observed (but at all doses) in one 3-month study
`(P00012-04-01). Liver necrosis and/or bile duct hyperplasia were detected in the 6-month
`study, primarily in females. Kidney and forestomach findings were observed in the
`majority of studies in rat, including the 3- and 6-month studies. Forestomach lesions
`(similar to those in mouse) were observed at all doses in both 3-month studies and the 6-
`month study. (The glandular stomach was also affected [e.g., minimal to mild
`inflammation in the 6-month study] but to a lesser extent.) Forestomach tumors
`(squamous cell carcinoma, papilloma) were observed in one 3-month study (P00012-04-
`01; 1 M and 1 F at 250 mg/kg/day) and the 6-month study (1 MDM, 1 HDM).
`
`Selected renal findings from the two 3-month studies are summarized below.
`
`STUDY
`
`RENAL
`FINDINGS
`BUN
`serum creatinine
`kidney wt (A-R)
`proteinosis
` minimal
` mild
`tubular basophilia
` minimal
` mild
`tubular dilatation
` minimal
` mild
`
`0
`--
`--
`--
`
`0/10
`0/10
`
`0/10
`0/10
`
`0/10
`0/10
`
`50
`11%↓
`14%↓
`0-11%↑
`
`2/9
`0/9
`
`1/9
`0/9
`
`0/9
`0/9
`
`0
`--
`--
`--
`
`0/10
`0/10
`
`0/10
`0/10
`
`0/10
`0/10
`
`FEMALES
`100
`8%↓
`--
`22-20%↑
`
`1/10
`0/10
`
`0/10
`0/10
`
`0/10
`0/10
`
`50
`12%↓
`19%↓
`12-17%↑
`
`1/10
`0/10
`
`0/10
`0/10
`
`0/10
`0/10
`
`250
`24%↓
`29%↓
`24-38%↑
`
`1/10
`0/10
`
`0/10
`0/10
`
`0/10
`0/10
`
`MALES
`250
`100
`6%↓
`4%↓
`19%↓
`22%↓
`42-59%↑
`19-21%↑
`
`
`2/10
`1/9
`2/10
`0/9
`
`
`6/10
`0/9
`3/10
`1/9
`
`
`2/10
`0/9
`1/10
`0/9
`RECOVERY
`
`
`proteinosis
`0/5
`0/5
` minimal
`
`tubular basophilia
`
`3/5#
` minimal
`0/5
`--
`--
`BUN
`14-16%↓
`serum creatinine
`--
`40-52%↑
`--
`kidney wt (A-R)
`no renal findings
`histopathology
`*dosing stopped in HD animals after seven days of dosing and 5/sex were sacrificed (clinical chemistry prior to
`necropsy); 5/sex were maintained for 4 weeks of recovery (terminal data for these not included due to lack of relevant
`controls). #discrepancy in study report: narrative indicates 3/5, while tabulated data indicate 1/5.
`
`
`
`
`
`
`
`
`
`
`3-month
`P00012-
`04-01
`
`3-month
`19416-05
`
`
`0/5
`
`0/5
`--
`--
`--
`
`
`--
`
`--
`--
`5%↓
`16-10%↑
`
`
`--
`
`--
`
`
`
`
`
`--
`
`--
`--
`7%↓
`0-11%↑
`
`
`--
`
`--
`
`
`
`
`
`1/5
`
`0/5
`--
`10-12%↓
`20-18%↑
`
`
`
`Reference ID: 3258603
`
`4
`
`

`

`Selected renal findings in the 6-month study are summarized below.
`
`RENAL FINDINGS
`BUN
`serum creatinine
`kidney wt (A-R)
`nephropathy
` minimal
` mild
` moderate
`tubular dilatation
` minimal
` mild
`hyaline droplet, tubule
` minimal
` mild
`hypertrophy, Bowman’s capsule
` minimal
` mild
`hypertrophy, tubule
` minimal
`regeneration, segmental, tubule
` minimal
` mild
`
`0
`
`--
`--
`
`7/15
`1/15
`0/15
`
`4/15
`0/15
`
`0/15
`0/15
`
`1/15
`0/15
`
`0/15
`
`1/15
`0/15
`
`25
`
`--
`12-10%↑
`
`9/15
`1/15
`0/15
`
`7/15
`1/15
`
`4/15
`0/15
`
`7/15
`0/15
`
`2/15
`
`11/15
`1/15
`
`200
`
`11%↓
`62-76%↑
`
`5/15
`5/15
`5/15
`
`6/15
`6/15
`
`7/15
`3/15
`
`3/15
`7/15
`
`13/15
`
`9/15
`6/15
`
`MALES
`100
`no findings
`13%↓
`50-53%↑
`
`5/14
`8/14
`1/14
`
`7/14
`5/14
`
`6/14
`1/14
`
`6/14
`0/14
`
`11/14
`
`6/14
`7/14
`RECOVERY
`no findings
`--
`29-26%↑
`
`2/5
`3/5
`0/5
`
`5/5
`0/5
`
`2/5
`0/5
`
`5/5
`0/5
`
`5/5
`
`3/5
`1/5
`
`0
`--
`--
`--
`
`7/15
`0/15
`0/15
`
`4/15
`0/15
`
`0/15
`0/15
`
`0/15
`0/15
`
`0/15
`
`0/15
`0/15
`
`FEMALES
`100
`12%↓
`9%↓
`19-16%↑
`
`7/15
`1/15
`0/15
`
`4/15
`0/15
`
`3/15
`0/15
`
`1/15
`0/15
`
`12/15
`
`2/15
`0/15
`
`25
`--
`5%↓
`0-2%↑
`
`6/15
`0/15
`0/15
`
`3/15
`0/15
`
`0/15
`0/15
`
`0/15
`0/15
`
`1/15
`
`0/15
`0/15
`
`--
`--
`--
`
`1/5
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`
`0/5
`0/5
`
`--
`--
`--
`
`1/5
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`0/5
`
`2/5
`
`0/5
`0/5
`
`--
`--
`8-12%↑
`
`2/5
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`0/5
`
`0/5
`0/5
`
`5/5
`
`0/5
`0/5
`
`200
`12%↓
`18%↓
`31-34%↑
`
`8/15
`1/15
`0/15
`
`3/15
`0/15
`
`3/15
`1/15
`
`0/15
`0/15
`
`15/15
`
`1/15
`0/15
`
`41%↑
`11%↓
`16-42%↑
`
`2/4
`1/4
`0/4
`
`2/4
`0/4
`
`0/4
`1/4
`
`0/4
`0/4
`
`4/4
`
`1/4
`0/4
`
`5
`
`BUN
`serum creatinine
`kidney wt (A-R)
`nephropathy
` minimal
` mild
` moderate
`dilatation, tubular
` minimal
` mild
`hyaline droplet, tubule
` minimal
` mild
`hypertrophy, Bowman’s capsule
` minimal
` mild
`hypertrophy, tubule
` minimal
`regeneration, segmental, tubule
` minimal
` mild
`
`
`Kidney toxicity (table below) was also demonstrated in the male fertility study in rat;
`males were dosed for 70 days prior to mating and throughout mating until sacrifice.
`
`
`
`
`
`
`13%↓
`34-39%↑
`
`0/5
`4/5
`1/5
`
`2/5
`3/5
`
`4/5
`0/5
`
`3/5
`1/5
`
`5/5
`
`2/5
`3/5
`
`--
`--
`
`5/5
`0/5
`0/5
`
`1/5
`0/5
`
`1/5
`0/5
`
`1/5
`0/5
`
`2/5
`
`1/5
`0/5
`
`--
`--
`
`5/5
`0/5
`0/5
`
`2/5
`0/5
`
`0/5
`0/5
`
`3/5
`0/5
`
`1/5
`
`3/5
`0/5
`
`
`
`Reference ID: 3258603
`
`

`

`STUDY
`
`male
`fertility
`
`DOSES (mg/kg)
`75
`250
`
`
`14/25
`18/25
`11/25
`0/25
`0/25
`0/25
`
`
`17/25
`15/25
`3/25
`2/25
`
`
`17/25
`21/25
`5/25
`1/25
`0/25
`0/25
`
`
`20/25
`1/25
`5/25
`1/25
`
`
`5/25
`14/25
`3/25
`7/25
`0/25
`0/25
`
`375
`
`11/25
`11/25
`2/25
`
`10/25
`2/25
`
`16/25
`4/25
`2/25
`
`8/25
`16/25
`
`17/25
`3/25
`2/25
`
`RENAL FINDINGS
`dilatation, cortical tubules
` minimal
` mild
` moderate
`hyaline droplets, cortical tubules
` minimal
` mild
`nephropathy
` minimal
` mild
` moderate
`nuclear/cellular hypertrophy, cortical tubular
` minimal
` mild
`regeneration, tubular segmental
` minimal
` mild
` moderate
`
`0
`
`4/25
`0/25
`0/25
`
`7/25
`0/25
`
`18/25
`0/25
`0/25
`
`0/25
`0/25
`
`1/25
`0/25
`0/25
`
`
`At the higher doses tested in this study, glandular stomach (as well as forestomach) was
`also affected; mucosal erosion, epithelial and glandular hyperplasia, and mixed cellular
`inflammation were observed only in MD and HD males, with the majority of HDM being
`affected.
`
`In the carcinogenicity study (0, 25, 50, 100 and 150 mg/kg/day, by oral gavage), kidney
`and forestomach changes were observed at all doses in males and females;
`testicular/epididymal changes were evident primarily at doses >50 mg/kg/day (discussed
`under Carcinogenicity). Testicular effects were also observed in the male fertility study,
`i.e., a dose-related increase in incidence and severity of interstitial cell hyperplasia.
`Additional findings in the carcinogenicity study were dose-related increased severity (but
`not incidence) of cardiomyopathy, increased incidence and severity of atrial thrombosis,
`and increased incidence and severity of chronic active inflammation of the arteries in a
`number of organs (including kidney, testes, and epididymides).
`
`Dog: In dog, DMF was administered at doses of 0, 50, 100, and 250 mg/kg/day (oral
`gavage) for 4 weeks and at doses of 0, 5, 25, and 75/50 mg/kg/day (oral capsule) for 11
`months. In the 4-week study (interim sacrifice on Day 13-15 for HD animals [4/sex]
`only), microscopic changes in thymus (atrophy), bone marrow (hypocellularity),
`stomach/esophagus (hemorrhage, erosion), and kidney (vacuolation of tubular
`epithelium) were observed at the interim sacrifice; only the thymus effects appeared
`dose-related in main-study animals sacrificed at the end of the 4-week dosing period.
`
`In the 11-month study, the primary target organs for toxicity were the kidney, testis,
`epididymis, and adrenal gland (hypertrophy of the zona fasciculata). The testicular effects
`consisted of epithelial degeneration (1/4, 0/4, 1/4, and 3/4 at 0, 5, 25, and 75/50
`mg/kg/day, respectively), with increased severity at the MD and increased incidence and
`severity at the HD, and spermatid giant cells (only detected at the HD [2/4, both
`minimal]). Hypospermia (epididymis) occurred only at the HD (3/4, all of moderate
`severity). There was no evidence of GI irritation.
`
`
`
`Reference ID: 3258603
`
`6
`
`

`

`
`Selected kidney findings are provided in the following table (the HD was lowered on Day
`7).
`
`RENAL FINDINGS
`
`UN
`serum creatinine
`kidney wt (A-R)
`tubular hypertrophy
` minimal
` mild
`total
`cortical tubule dilation
` minimal
` mild
`total
`tubular regeneration
` minimal
` mild
`total
`cortical parenchyma atrophy
` minimal
` mild
`total
`infiltration, mixed cell, papilla
` mild
` moderate
`total
`hyperplasia, papillary urothelium
` minimal
` mild
`total
`
`UN
`creatinine
`kidney wt (A-R)
`tubular hypertrophy
` minimal
` mild
`total
`cortical tubule dilation
` minimal
`cortical parenchyma atrophy
` minimal
` mild
`total
`infiltration, mixed cell, papilla
` minimal
`tubular hypertrophy
` minimal
` mild
`total
`
`--
`--
`--
`
`0/4
`0/4
`0/4
`
`0/4
`
`1/4
`0/4
`1/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`18%↑
`6%↓
`7-6%↑
`
`2/4
`0/4
`2/4
`
`0/4
`
`1/4
`0/4
`1/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`
`The study pathologist’s
`kidney findings:
`
`
`
`Reference ID: 3258603
`
`0
`--
`--
`
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`5
`0-11%↓
`0-12%↓
`11-16%↑
`
`1/4
`1/4
`2/4
`
`1/4
`0/4
`1/4
`
`0/4
`0/4
`0/4
`
`1/4
`0/4
`1/4
`
`0/4
`0/4
`0/4
`
`1/4
`0/4
`1/4
`
`MALES
`25
`12-30%↓
`14-20%↓
`41-38%↑
`
`2/4
`1/4
`3/4
`
`0/4
`1/4
`1/4
`
`0/4
`1/4
`1/4
`
`0/4
`1/4
`1/4
`
`0/4
`0/4
`0/4
`
`2/4
`0/4
`2/4
`RECOVERY
`--
`--
`8-13%↓
`
`0/4
`0/4
`0/4
`
`1/4
`
`0/4
`2/4
`2/4
`
`0/4
`
`1/4
`1/4
`2/4
`
`75/50
`29-55%↓
`18-30%↓
`46-58%↑
`
`2/4
`2/4
`4/4
`
`3/4
`1/4
`4/4
`
`1/4
`1/4
`2/4
`
`1/4
`2/4
`3/4
`
`0/4
`1/4
`1/4
`
`2/4
`2/4
`4/4
`
`0
`--
`--
`--
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`1/4
`0/4
`1/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`FEMALES
`25
`13-25%↓
`10-23%↓
`13-23%↑
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`1/4
`0/4
`1/4
`
`0/4
`0/4
`0/4
`
`1/4
`2/4
`3/4
`
`5
`7-18%↓
`5-9%↓
`2-10%↑
`
`0/4
`0/4
`0/4
`
`1/4
`0/4
`1/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`
`75/50
`31-59%↓
`27-36%↓
`54-55%↑
`
`0/4
`0/4
`0/4
`
`3/4
`0/4
`3/4
`
`0/4
`0/4
`0/4
`
`4/4
`0/4
`4/4
`
`1/4
`0/4
`1/4
`
`1/4
`3/4
`4/4
`
`24%↑
`10%↑
`3-6%↓
`
`0/4
`1/4
`1/4
`
`1/4
`
`1/4
`0/4
`1/4
`
`0/4
`
`1/4
`0/4
`1/4
`
`--
`--
`--
`
`0/4
`0/4
`0/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`7%↑
`4%↑
`26-30%↑
`
`0/4
`0/4
`0/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`7%↑
`4%↓
`15-20%↑
`
`0/4
`0/4
`0/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`0/4
`
`1/4
`0/4
`1/4
`
`27%↑
`10%↑
`31-34%↑
`
`0/4
`0/4
`0/4
`
`0/4
`
`0/4
`0/4
`0/4
`
`1/4
`
`0/4
`1/4
`1/4
`
` characterization of selected
`
`7
`
`(b) (4)
`
`

`

`
`
`• Hypertrophy of tubular epithelium: “…characterized by enlarged, cuboidal
`epithelial cells with abundant eosinophilic cytoplasm lining cortical tubules. Some
`of the cells also had enlarged nuclei. The altered cells appeared to involve
`primarily convoluted tubules in the deep cortex.”
`• Regeneration of tubular epithelium in cortex: “…characterized by short segments
`of columnar to cuboidal tubular epithelial cells with increased basophilia and
`nuclear crowding sometimes overlying a thickened basement membrane.
`Regeneration, epithelial hypertrophy and tubular dilation were often seen
`concurrently.”
`• Atrophy of cortical parenchyma: “…characterized by atrophic tubules with or
`without sclerotic/degenerate glomeruli usually with interstitial fibrosis and
`mononuclear infiltrates. This change sometimes had a linear distribution radiating
`outward from the inner cortex towards the capsular surface.”
`Infiltration of mixed inflammatory cells in renal papillae: “…characterized by
`numerous mononuclear cells, especially macrophages, and fewer neutrophils
`within the intertubular interstitium at the tip of the distal papillae. Although this
`finding was observed in only one male and one female from the high-dose
`group…, it was considered to be treatment-related because it has not been seen as
`an incidental finding.”
`• Hyperplasia of papillary urothelial cells lining the renal pelvis: “…characterized
`by an increase in the number of cell layers and cell size. Distribution of this
`change was either locally extensive or multifocal involving one or both kidneys.”
`
`•
`
`5
`2072 ± 837
`
`MALES
`25
`10962 ± 4526
`
`50
`9662 ± 4080
`
`5
`1687 ± 385
`
`FEMALES
`25
`9105 ± 1566
`
`5684 ± 1768
`
`23998 ± 8800
`
`52045 ± 30758
`
`6969 ± 4084
`
`27336 ± 7499
`
`50
`14548 ± 4476
`
`44785 ± 12233
`
`
`The TK (plasma MMF) data from the 11-month study (Day 330) are summarized in the
`table below.
`
`PARAMETER
`Cmax
`(ng/mL)
`AUC
`(ng*hr/mL)
`
` A
`
` no-effect level for renal effects was not identified; however, findings at the LD were,
`for the most part, minimal. Plasma exposure at the LD was similar to (Cmax) or
`approximately one-half (AUC) that in humans at the recommended human dose (480
`mg/day; Cmax: 2.24-2.4 μg/mL; AUC: 10-11.3 μg*hr/mL).
`
`Monkey: the only pivotal toxicity study conducted in monkey was a one-year oral
`(gavage) study testing DMF at doses of 0, 5, 25, and 75 mg/kg/day. Kidney was the only
`identified target organ.
`
`At necropsy, macroscopic findings in kidney were described by the study pathologist
`
`
`
`
`
`
`Reference ID: 3258603
`
`8
`
`(b) (4)
`
`

`

`“…mild bilateral pale discoloration in 4 of 4 males and 2 of 4 females, bilateral
`increased size in 4 of 4 females, and watery consistency in 2 of 4 females given
`75 mg/kg Dimethyl Fumarate. The gross changes correlated microscopically with
`renal tubular epithelial regeneration.”
`
`
` also noted pale discoloration of the kidney, correlated with renal tubular
`epithelial regeneration, in one HD male and one HD female at the end of the recovery
`period. Increases in kidney weight in main-study animals were noted to be associated
`with “treatment-related moderate regeneration of tubular epithelial cells”; in recovery
`animals, increases in kidney weight were noted to be associated with “treatment-related
`tubular epithelial regeneration and interstitial fibrosis in both animals.”
`
`Selected clinical pathology and terminal findings are provided in the following table:
`
`
`
`
`
`
`
`
`Reference ID: 3258603
`
` characterization of the kidney findings in main-study and recovery animals:
`
`In main-study animals: “…Single cell necrosis consisted of individual tubular
`
`9
`
`FINDING
`
`BUN
`serum creatinine
`kidney wt
`tubular necrosis, single cell
` minimal
` mild
`total
`tubular regeneration
` minimal
` mild
` moderate
`total
`
`BUN
`serum creatinine
`kidney wt
`tubular necrosis, single cell
` minimal
`tubular regeneration
` mild
` moderate
`total
`fibrosis, interstitium
` mild
` moderate
`total
`tubules, cortex, atrophy
` mild
` moderate
`total
`
`
`
`0
`--
`--
`--
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`0/4
`
`--
`--
`--
`
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`5
`--
`--
`5%↑
`
`0/3
`0/3
`0/3
`
`0/4
`0/4
`0/4
`0/4
`
`7%↑
`13%↑
`28%↑
`
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`MALES
`75
`25
`16-35%↓
`23-38%↓
`0-10%↓
`12-21%↓
`7%↑
`7%↑
`
`
`1/4
`3/4
`0/4
`0/4
`1/4
`3/4
`
`
`0/4
`1/4
`0/4
`1/4
`0/4
`1/4
`0/4
`3/4
`RECOVERY (W57)
`11%↑
`39%↑
`13%↓
`27%↑
`15%↑
`100%↑
`
`
`0/2
`1/2
`
`
`0/2
`0/2
`0/2
`2/2
`0/2
`2/2
`
`
`0/2
`1/2
`0/2
`1/2
`0/2
`2/2
`
`
`0/2
`1/2
`0/2
`1/2
`0/2
`2/2
`
`0
`--
`--
`--
`
`0/4
`0/4
`0/4
`
`0/4
`0/4
`0/4
`0/4
`
`--
`--
`--
`
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`FEMALES
`5
`25
`15-40%↓
`--
`8-12%↓
`--
`13%↑
`25%↑
`
`
`0/4
`2/5
`0/4
`0/5
`0/4
`2/5
`
`
`0/4
`2/5
`0/4
`0/5
`0/4
`0/5
`0/4
`2/5
`
`28%↑
`5%↓
`--
`
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`7%↓
`16%↓
`--
`
`1/1
`
`1/2
`0/2
`1/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`75
`26-50%↓
`4-27%↓
`92%↑
`
`0/4
`4/4
`4/4
`
`1/4
`0/4
`3/4
`4/4
`
`5%↑
`16%↓
`18↑
`
`0/2
`
`1/2
`1/2
`2/2
`
`0/2
`0/2
`0/2
`
`0/2
`0/2
`0/2
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`epithelial cells in the cortex that were eosinophilic, shrunken, and had pyknotic or
`karyorrhetic nuclei. Some affected cells remained adjacent to the tubular
`basement membrane, while others had become detached and were in the tubular
`lumen. The necrotic cells were in some cases widely scattered in the renal cortex,
`although there were occasionally more than one affected cell in a single tubular
`profile…Tubular regeneration affected entire tubular profiles in some cases, but
`only segments in others, and consisted of scattered individual or clumps of
`cortical tubules in which tubular epithelial cells had one or more of the following
`changes: increased or decreased size, cytoplasmic basophilia, cytoplasmic
`vacuolation, increased or decreased size of the nucleus, irregular shape of nucleus,
`mitotic figures. The nuclei within the affected tubules were often irregularly
`distributed, being sometimes clumped together and sometimes sparse. The lumen
`of some affected tubules appeared large while others were small due to decreased
`or increased size of affected epithelial cells. Small numbers of mononuclear
`inflammatory cells were often in the interstitium adjacent to affected tubules and
`probably represented an inflammatory response to the damaged tubular
`epithelium. Both single cell necrosis of tubular epithelium and regeneration of
`tubular epithelium were sometimes concentrated in the medullary rays.”
`
`In recovery animals: “Treatment-associated histologic findings…in the
`kidney…consisted of single cell necrosis and regeneration of cortical tubular
`epithelial cells and fibrosis in the interstitium associated with mild to moderate
`tubular atrophy. Single cell necrosis of cortical tubular epithelial cells was similar
`to that observed at the Terminal Necropsy…Diffuse moderate interstitial fibrosis
`affected 1 of 2 males given 75 mg/kg/Dimethyl Fumarate and mild multifocal
`interstitial fibrosis affected the other male in this dose group. The change in these
`2 males consisted of increased fibrous connective tissue around and between
`tubules and was quantitatively significantly more severe than the small amounts
`of focal interstitial fibrosis associated with small focal cortical scars. Mild or
`moderate atrophy of tubules was associated with the interstitial fibrosis in these 2
`males. Additional, minimal to mild fibrosis of Bowman’s capsule and mild
`multifocal mononuclear infiltrates were secondary changes associated with the
`interstitial fibrosis…The…findings indicate that single cell necrosis and
`regeneration of renal cortical tubular epithelium did not resolve after a 4 week
`drug-free interval. However, there was a decrease in incidence and severity of
`single cell necrosis for both affected dose groups and a decrease in severity of
`tubular epithelial regeneration for the [HD] females consistent with a trend
`towards recovery for these changes in some dose groups. Additional, the 2 males
`of the 4 animals given [HD] Dimethyl Fumarate had significant multifocal or
`diffuse interstitial fibrosis, a morphologic indication of irreversible loss of tissue
`and function. Renal fibrosis in the most severely affected animal (4006) was
`associated with increased BUN and creatinine at weeks 38, 52, and 56.”
`
`
`Selected individual data for the two HD recovery males, both exhibiting renal fibrosis,
`are provided in the following table. As
` notes, BUN and creatinine were
`
`
`
`Reference ID: 3258603
`
`10
`
`(b) (4)
`
`

`

`increased in HDM-R 4006; however, HDM-R 4005 was also reported to have had loss of
`renal tissue and function but had no changes in these parameters.
`
`
`PARAMETER
`
`BUN
`
`creatinine
`
`kidney wt
`
`SAMPLING
`TIME
`-7
`Day 1
`Week 2
`Week 6
`Week 12
`Week 24
`Week 38
`Week 52
`Week 56
`-7
`Day 1
`Week 2
`Week 6
`Week 12
`Week 24
`Week 38
`Week 52
`Week 56
`Week 57
`
`CONTROL
`20.2±4.0
`23.0±3.3
`19.7±2.7
`18.8±2.6
`23.8±2.8
`23.2±4.2
`23.7±3.7
`23.7±2.3
`22.0±4.2
`0.72±0.72
`0.82±0.10
`0.75±0.08
`0.68±0.12
`0.63±0.08
`0.65±0.12
`0.70±0.06
`0.70±0.06
`0.75±0.07
`14.222 and 11.723 g
`
`HDM-R 4005 HDM-R 4006
`20
`26
`20
`26
`14
`19
`18
`17
`16
`17
`12
`27
`16
`46
`13
`37
`18
`43
`0.9
`0.9
`0.8
`1.0
`0.9
`0.9
`0.7
`0.8
`0.6
`0.7
`0.5
`0.9
`0.6
`1.4
`0.5
`1.1
`0.6
`1.3
`26.187 g
`26.064 g
`
`
`The T