Mucopolysaccharidosis Type III (Sanfilippo Syndrome): Developing Drugs for Treatment Guidance for Industry: Draft Guidance for Industy

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01/30/20
Mucopolysaccharidosis Type III
(Sanfilippo Syndrome):
Developing Drugs for Treatment
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Patroula Smpokou at 240-402-
9651 or (CBER) Office of Communication, Outreach, and Development at 240-402-8010.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2020
Clinical/Medical

Mucopolysaccharidosis Type III
(Sanfilippo Syndrome):
Developing Drugs for Treatment
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2020
Clinical/Medical

Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS
I. 	INTRODUCTION..................................................................................................1
II. 	BACKGROUND ....................................................................................................1
III. 	IMPORTANT CONSIDERATIONS FOR CLINICAL TRIALS .....................2
A. 	Eligibility Criteria and Baseline Assessments ................................................................. 2
B. 	Trial Design ........................................................................................................................ 3
C. 	Pharmacodynamic Endpoints .......................................................................................... 4
D. 	Efficacy Endpoints ............................................................................................................ 5
REFERENCES...................................................................................................................7

Contains Nonbinding Recommendations
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Mucopolysaccharidosis Type III (Sanfilippo Syndrome):	1
Developing Drugs for Treatment	2
Guidance for Industry1
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
I. 	INTRODUCTION	15
16
The purpose of this guidance is to provide recommendations to sponsors regarding eligibility	17
criteria, trial design considerations, and efficacy endpoints to enhance clinical trial data quality	18
and foster greater efficiency in development programs for drugs2 to treat mucopolysaccharidosis	19
type III (MPS III; also called Sanfilippo syndrome).	20
21
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	22
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	23
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	24
the word should in Agency guidances means that something is suggested or recommended, but	25
not required.	26
27
28
II. 	BACKGROUND	29
30
MPS III is a rare, autosomal recessive, inborn error of glycosaminoglycan (GAG) metabolism	31
with an estimated incidence of 0.28–4.1 per 100,000 live births. It belongs to a group of genetic	32
disorders called mucopolysaccharidoses, which are caused by different single enzyme defects	33
affecting lysosomal GAG breakdown. MPS III is caused by deficient activity of any one of four	34
enzymes involved in the breakdown of the GAG heparan sulfate (HS) in lysosomes. The disease	35
is divided into four distinct subtypes based on the gene defect and corresponding enzyme	36
deficiency as follows: MPS IIIA (SGSH (N-sulfoglucosamine sulfohydrolase) gene; heparan N-	37
1 This guidance has been prepared by the Division of Gastroenterology and Inborn Errors Products in the Center for
Drug Evaluation and Research and by the Center for Biologics Evaluation and Research at the Food and Drug
Administration.
2 For purposes of this guidance, unless otherwise specified, references to drugs include drugs submitted for approval
or approved under section 505(b) or (j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and biological
products licensed under section 351 of the Public Health Service Act, other than biological products that also meet
the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)).

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sulfatase deficiency), MPS IIIB (NAGLU (N-acetyl-alpha-glucosaminidase) gene; N-acetyl-α-	38
glucosaminidase deficiency), MPS IIIC (HGSNAT (heparan-α-glucosaminide N-	39
acetyltransferase) gene; acetyl CoA:α-glucosaminide N-acetyltransferase deficiency), and MPS	40
IIID (GNS (N-acetylglucosamine-6-sulfatase) gene; N-acetylglucosamine 6-sulfatase deficiency)	41
(Valstar et al. 2008). These enzymatic defects result in progressive intralysosomal accumulation	42
of HS, which is believed to lead to or initiate a cascade of events leading to cellular damage and	43
progressive tissue and organ dysfunction. Currently, there are no approved disease-modifying	44
therapies for MPS III.	45
46
The central nervous system is the organ primarily affected in MPS III. The natural history and	47
rate of progression of the neurologic manifestations are not well characterized in any of the four	48
MPS III subtypes. Some limited natural history information is available in MPS IIIA. In	49
general, genotype alone does not appear to be a reliable sole predictor of disease severity or rate	50
of neurological progression in MPS III (Valstar et al. 2008; Valstar et al. 2011). However, in	51
MPS IIIA, patients with onset of signs and symptoms in early childhood may have a more	52
rapidly progressive course (severe MPS IIIA) compared to patients diagnosed later in childhood	53
or adolescence (attenuated MPS IIIA). In severe MPS IIIA, clinical symptoms manifest in early	54
childhood (2–6 years of age) and include developmental delay (primarily of speech and	55
language) and behavioral problems (e.g., hyperactivity, inattention, anxiety, autistic features,	56
aggression, lack of fear). Other symptoms variably include the following: disturbance of the	57
normal sleep cycle, frequent upper respiratory and ear infections, hearing and visual impairment,	58
and motor deficits. Hepatomegaly is found in some patients (splenomegaly is rare), but it is	59
generally much less common and less severe in MPS III compared to other	60
mucopolysaccharidoses.	61
62
The following describes the general disease trajectory in severely affected patients (also called	63
rapid progressors) with MPS IIIA (Shapiro et al. 2016). Typically, a patient’s initial period of	64
normal or near normal development (up to 2 years of age) is followed by a period of slowing in	65
developmental progression (between 2 and 4 years of age). Development appears to arrest	66
around 4 years of age in severely affected patients with MPS IIIA. Subsequently, patients enter a	67
phase of progressive neurocognitive decline characterized by developmental regression and loss	68
of previously acquired skills, which eventually leads to complete loss of cognitive, language, and	69
motor abilities culminating in dementia. Motor abilities are usually not affected until later in the	70
disease course. Median age at death in MPS IIIA is reported as 15 years of age, ranging between	71
8.5 and 25.5 years of age (Valstar et al. 2008). There is insufficient information regarding the	72
general disease trajectory and natural history of manifestations in patients with MPS IIIB, IIIC,	73
and IIID.	74
75
76
III. 	IMPORTANT CONSIDERATIONS FOR CLINICAL TRIALS	77
78
A. 	Eligibility Criteria and Baseline Assessments	79
80
All eligible patients should have clinical signs and symptoms consistent with a diagnosis of MPS	81
III, which should be confirmed by both biochemical testing (HS concentration) and molecular	82
genetic testing. Ideally, enrolled patients should be in the early stages of the disease (i.e., before	83

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irreversible neurological damage has occurred). For gene/enzyme-specific therapies targeting a	84
specific MPS III subtype, enrolled patients should have the same MPS III subtype. If	85
appropriate, (depending on the drug’s mechanism of action) sponsors can enroll in the same trial	86
patients of different ages, patients with different MPS subtypes and/or patients who are at	87
different stages of the disease. Baseline laboratory assessments should include, at a minimum,	88
genotyping (if not already available) and assessment of HS concentration in relevant tissues	89
(blood, urine, and/or cerebrospinal fluid (CSF)). As part of baseline laboratory assessments in	90
enzyme replacement therapy and gene therapy trials, sponsors should collect and store blood (or	91
other relevant tissues) for use in the assessment of cross-reactive immunologic material (CRIM)	92
status. Baseline clinical assessments should include standard evaluations of hearing, vision,	93
cognition, and adaptive behavior to ensure that enrolled patients are able to sufficiently complete	94
trial assessments.	95
96
B. 	Trial Design	97
98
Because of the current paucity of natural history knowledge and the clinical heterogeneity of	99
MPS III, appropriately designed and executed natural history studies could provide crucial	100
information to help guide and inform essential aspects of a clinical development program.3	
101
102
Given the rarity of MPS III, a single adequate and well-controlled trial (as described in 21 CFR	103
314.126), showing a clinically meaningful treatment effect on core disease manifestations,	104
accompanied by additional confirmatory evidence can be used to support approval. Such	105
confirmatory evidence could be based on different lines of evidence (e.g., data showing a	106
treatment effect on disease-specific biochemical markers (e.g., CSF HS) in treated patients;	107
nonclinical data showing biochemical and functional treatment effects in a well-characterized	108
MPS III animal model).4	
109
110
If a large treatment effect and/or an effect on objective clinical measures (e.g., survival) are not	111
expected within a specified trial duration, FDA strongly recommends a randomized, parallel-	112
group trial design with an appropriate concurrent control group. Because of the uncertainties	113
related to the lack of a well-characterized natural history, the variable rate of neurologic disease	114
progression among patients, and the nonlinear developmental trajectory observed in many MPS	115
III patients (Ghosh et al. 2017), such randomized, concurrently controlled trial design would	116
provide the most informative and reliable data for an evaluation of efficacy in the most efficient	117
and expedient way. Given the small patient population, sponsors should use randomization as	118
early as in the first clinical trial involving MPS III patients to allow for maximal and most	119
efficient use of efficacy data for regulatory purposes.	120
3 See the draft guidance for industry Rare Diseases: Natural History Studies for Drug Development (March 2019).
When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.
4 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible. FDA
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be
suitable, adequate, validated, and feasible. FDA will consider if the alternative method could be assessed for
equivalency to an animal test method.

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121
When natural history information becomes available and can reliably predict the disease course	122
in a given patient cohort, and when a large treatment effect size is anticipated based on	123
preliminary information, an externally controlled clinical trial may be acceptable. Sponsors can	124
consider innovative and adaptive trial designs and should discuss these early in development	125
with the appropriate review division.5, 6	
126
127
A patient’s symptomatic treatment regimen (e.g., concomitant drugs, physical and occupational	128
therapy, other interventions) should be optimized in advance of trial entry, and efforts should be	129
made to maintain the stability of these background treatments during the trial. Any changes in	130
the patient’s background treatment regimen made during the trial should be carefully	131
documented.	132
133
As most drugs would be intended to slow or arrest the neurological disease progression rather	134
than to reverse it, a clinical trial should be of sufficient duration, at least 2–3 years to observe an	135
effect on neurological disease aspects. In addition, patients with different disease severity would	136
be expected to have different rates of neurocognitive decline, which would necessitate different	137
durations of observation to assess treatment effects on selected endpoints. For gene therapy	138
products, sponsors should be aware of special considerations regarding the length of long-term	139
follow-up.7	
140
141
C. 	Pharmacodynamic Endpoints	142
143
Assessment of changes in HS concentration in CSF could provide evidence of in vivo biological	144
activity of the drug, demonstrate proof-of-concept, and help characterize the dose-response	145
relationship in early phase trials. Changes in plasma or urine HS should be considered of limited	146
utility given the neurologic nature of MPS III. Assessment of changes in organ volume (e.g.,	147
liver, spleen) should be considered of limited utility given that organomegaly is not a common	148
finding in MPS III patients and that changes in organ volume are of unclear clinical significance	149
in a disease that is fundamentally neurologic. Quantitation of pharmacodynamic biomarkers	150
(e.g., HS, HS derivatives, enzyme activity) should be conducted at a central laboratory using	151
appropriately validated methods to ensure reliability of the results. Understanding the variability	152
of the test(s) used is fundamental to the interpretation of any treatment effects on those	153
biomarkers.	154
155
5 For sponsors interested in discussing complex innovative trial designs, see also the FDA Complex Innovative Trial
Design pilot meeting program web page available at https://www.fda.gov/drugs/development-resources/complex-
innovative-trial-designs-pilot-program.
6 See the draft guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (September 2018).
When final, this guidance will represent the FDA’s current thinking on this topic.
7 See the draft guidance for industry Long Term Follow-Up After Administration of Human Gene Therapy Products
(July 2018). When final, this guidance will represent the FDA’s current thinking on this topic.

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D. 	Efficacy Endpoints	156
157
Demonstration of a clinically meaningful treatment effect on neurological disease manifestations	158
that are important to patients and their families can form the basis for traditional approval.	159
Sponsors should assess multiple, distinct clinical endpoints in trials to provide a global	160
characterization of treatment effects on disease manifestations. At this time, additional evidence	161
should be provided to support the use of HS reduction in CSF or other tissues (blood or urine) as	162
a surrogate endpoint reasonably likely to predict clinical benefit to support accelerated approval.8	
163
164
The selection and prioritization of efficacy endpoints should take into consideration patients’ and	165
parents’/caregivers’ preferences to ensure that sponsors assess outcomes that are clinically	166
meaningful to patients and their families. The selection of efficacy endpoint(s) should also	167
consider the mechanism of action and anticipated clinical effects of the drug on the different	168
disease manifestations. Furthermore, given the multiple clinical manifestations of MPS III,	169
which may differentially affect patients’ daily functioning, sponsors can consider the use of a	170
multiple-endpoint strategy.9 FDA strongly encourages sponsors to engage in early and	171
continuous discussions with the appropriate review division regarding the selection of the most	172
informative and clinically meaningful endpoint(s) for demonstration of efficacy.10	
173
174
Standardized clinical outcome assessment (COA) instruments should be used to evaluate	175
treatment effects on major neurological disease aspects (e.g., cognition, behavior) (Janzen et al.	176
2017). Appropriate standardized tests of cognitive performance should be selected based on	177
patients’ baseline level of functioning. When selecting COA instruments to evaluate cognitive	178
performance, sponsors should also consider whether there may be anticipated floor effects of the	179
particular instrument in the enrolled population as this could affect interpretability of the data.	180
Sponsors should also consider that the selection of particular COA tests may also inform the	181
frequency of the corresponding assessments (Van der Lee et al. 2017).	182
183
All COA instruments should be administered by trained personnel who are familiar with the	184
instruments and with the special challenges of MPS III patients as they relate to patients’	185
behavioral problems, inattention, hyperactivity, sensory impairment (hearing, vision), speech and	186
language deficits, fatiguability, and motor impairment as those can interfere with test	187
administration and interpretation of test results. Instructions, training materials, and case report	188
forms should include detailed information on all specific methods that should be utilized when	189
administering these tests. Assessments can be divided into multiple short sessions, and the	190
trained personnel should allow adequate time for the completion of each assessment. In addition,	191
assessments should be administered in an environment familiar to the patient, and the testing	192
environment should be free of items that may cause distraction.	193
194
8 See section 506(c) of the FD&C Act; 21 CFR part 314, subpart H; and 21 CFR part 601, subpart E.
9 See the draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017). When final, this
guidance will represent the FDA’s current thinking on this topic.
10 See the draft guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development:
Collecting Comprehensive and Representative Input (June 2018). When final, this guidance will represent the
FDA’s current thinking on this topic.

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The amount of time used and other contextual features of performance-based assessments should	195
be recorded and accounted for in data analyses. Other factors that may affect patients’	196
behavioral and cognitive performances, such as uncontrolled or insufficiently controlled seizures	197
(which can be part of the underlying disease), should be carefully assessed and documented	198
throughout the trial and should be considered in the interpretation of treatment effects. FDA	199
strongly encourages sponsors to discuss all proposed COAs with the appropriate review division	200
early in development (i.e., pre-investigational new drug application phase).	201
202

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REFERENCES	203
204
Ghosh A, Shapiro E, Rust S, et al., 2017, Recommendations on Clinical Trial Design for	205
Treatment of Mucopolysaccharidosis Type III, Orphanet J Rare Dis, 12(1):117–131.	206
207
Janzen D, Delaney KA, and Shapiro EG, 2017, Cognitive and Adaptive Measurement Endpoints	208
for Clinical Trials in Mucopolysaccharidoses Types I, II, and III: A Review of the Literature,	209
Mol Genet Metab, 121(2):57–69.	210
211
Shapiro EG, Nestrasil I, Delaney KA, et al., 2016, A Prospective Natural History Study of	212
Mucopolysaccharidosis Type IIIA, J Pediatr, 170:278–287.	213
214
Valstar MJ, Marchal JP, Grootenhuis M, Colland V, Wijburg FA, 2011, Cognitive Development	215
in Patients with Mucopolysaccharidosis Type III (Sanfilippo Syndrome), Orphanet J Rare Dis,	216
6:43–48.	217
218
Valstar MJ, Ruijter GJ, Van Diggelen OP, Poorthuis BJ, Wijburg FA, 2008, Sanfilippo	219
Syndrome: A Mini-Review, J Inherit Metab Dis, , 31(2):240–252.	220
221
Van der Lee JH, Morton J, Adams HR, et al., 2017, Cognitive Endpoints for Therapy	222
Development for Neuronopathic Mucopolysaccharidoses: Results of a Consensus Procedure,	223
Mol Genet Metab, 121(2):70–79.	224