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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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
33267274dft.docx 
01/30/20   
Mucopolysaccharidosis Type III 
(Sanfilippo Syndrome):  
Developing Drugs for Treatment 
Guidance for Industry 
 
Additional copies are available from: 
 
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Food and Drug Administration 
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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Draft  Not for Implementation 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 
Draft  Not for Implementation 
1  Mucopolysaccharidosis Type III (Sanfilippo Syndrome):  
2  Developing Drugs for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  The purpose of this guidance is to provide recommendations to sponsors regarding eligibility 
18  criteria, trial design considerations, and efficacy endpoints to enhance clinical trial data quality 
19  and foster greater efficiency in development programs for drugs2 to treat mucopolysaccharidosis 
20  type III (MPS III; also called Sanfilippo syndrome). 
21   
22  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
23  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
24  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
25  the word should in Agency guidances means that something is suggested or recommended, but 
26  not required. 
27   
28   
29  II.  BACKGROUND 
30   
31  MPS III is a rare, autosomal recessive, inborn error of glycosaminoglycan (GAG) metabolism 
32  with an estimated incidence of 0.284.1 per 100,000 live births.  It belongs to a group of genetic 
33  disorders called mucopolysaccharidoses, which are caused by different single enzyme defects 
34  affecting lysosomal GAG breakdown.  MPS III is caused by deficient activity of any one of four 
35  enzymes involved in the breakdown of the GAG heparan sulfate (HS) in lysosomes.  The disease 
36  is divided into four distinct subtypes based on the gene defect and corresponding enzyme 
37  deficiency as follows: MPS IIIA (SGSH (N-sulfoglucosamine sulfohydrolase) gene; heparan N-
                                                 
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)). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  sulfatase deficiency), MPS IIIB (NAGLU (N-acetyl-alpha-glucosaminidase) gene; N-acetyl--
39  glucosaminidase deficiency), MPS IIIC (HGSNAT (heparan--glucosaminide N-
40  acetyltransferase) gene; acetyl CoA:-glucosaminide N-acetyltransferase deficiency), and MPS 
41  IIID (GNS (N-acetylglucosamine-6-sulfatase) gene; N-acetylglucosamine 6-sulfatase deficiency) 
42  (Valstar et al. 2008).  These enzymatic defects result in progressive intralysosomal accumulation 
43  of HS, which is believed to lead to or initiate a cascade of events leading to cellular damage and 
44  progressive tissue and organ dysfunction.  Currently, there are no approved disease-modifying 
45  therapies for MPS III.   
46   
47  The central nervous system is the organ primarily affected in MPS III. The natural history and 
48  rate of progression of the neurologic manifestations are not well characterized in any of the four 
49  MPS III subtypes.  Some limited natural history information is available in MPS IIIA.  In 
50  general, genotype alone does not appear to be a reliable sole predictor of disease severity or rate 
51  of neurological progression in MPS III (Valstar et al. 2008; Valstar et al. 2011).  However, in 
52  MPS IIIA, patients with onset of signs and symptoms in early childhood may have a more 
53  rapidly progressive course (severe MPS IIIA) compared to patients diagnosed later in childhood 
54  or adolescence (attenuated MPS IIIA).  In severe MPS IIIA, clinical symptoms manifest in early 
55  childhood (26 years of age) and include developmental delay (primarily of speech and 
56  language) and behavioral problems (e.g., hyperactivity, inattention, anxiety, autistic features, 
57  aggression, lack of fear).  Other symptoms variably include the following: disturbance of the 
58  normal sleep cycle, frequent upper respiratory and ear infections, hearing and visual impairment, 
59  and motor deficits.  Hepatomegaly is found in some patients (splenomegaly is rare), but it is 
60  generally much less common and less severe in MPS III compared to other 
61  mucopolysaccharidoses.  
62   
63  The following describes the general disease trajectory in severely affected patients (also called 
64  rapid progressors) with MPS IIIA (Shapiro et al. 2016).  Typically, a patients initial period of 
65  normal or near normal development (up to 2 years of age) is followed by a period of slowing in 
66  developmental progression (between 2 and 4 years of age).  Development appears to arrest 
67  around 4 years of age in severely affected patients with MPS IIIA.  Subsequently, patients enter a 
68  phase of progressive neurocognitive decline characterized by developmental regression and loss 
69  of previously acquired skills, which eventually leads to complete loss of cognitive, language, and 
70  motor abilities culminating in dementia.  Motor abilities are usually not affected until later in the 
71  disease course.  Median age at death in MPS IIIA is reported as 15 years of age, ranging between 
72  8.5 and 25.5 years of age (Valstar et al. 2008).  There is insufficient information regarding the 
73  general disease trajectory and natural history of manifestations in patients with MPS IIIB, IIIC, 
74  and IIID. 
75   
76   
77  III.  IMPORTANT CONSIDERATIONS FOR CLINICAL TRIALS 
78   
79  A.  Eligibility Criteria and Baseline Assessments 
80   
81  All eligible patients should have clinical signs and symptoms consistent with a diagnosis of MPS 
82  III, which should be confirmed by both biochemical testing (HS concentration) and molecular 
83  genetic testing.  Ideally, enrolled patients should be in the early stages of the disease (i.e., before 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
84  irreversible neurological damage has occurred).  For gene/enzyme-specific therapies targeting a 
85  specific MPS III subtype, enrolled patients should have the same MPS III subtype.  If 
86  appropriate, (depending on the drugs mechanism of action) sponsors can enroll in the same trial 
87  patients of different ages, patients with different MPS subtypes and/or patients who are at 
88  different stages of the disease.  Baseline laboratory assessments should include, at a minimum, 
89  genotyping (if not already available) and assessment of HS concentration in relevant tissues 
90  (blood, urine, and/or cerebrospinal fluid (CSF)).  As part of baseline laboratory assessments in 
91  enzyme replacement therapy and gene therapy trials, sponsors should collect and store blood (or 
92  other relevant tissues) for use in the assessment of cross-reactive immunologic material (CRIM) 
93  status.  Baseline clinical assessments should include standard evaluations of hearing, vision, 
94  cognition, and adaptive behavior to ensure that enrolled patients are able to sufficiently complete 
95  trial assessments.  
96   
97  B.  Trial Design 
98   
99  Because of the current paucity of natural history knowledge and the clinical heterogeneity of 
100  MPS III, appropriately designed and executed natural history studies could provide crucial 
101  information to help guide and inform essential aspects of a clinical development program.3  
102   
103  Given the rarity of MPS III, a single adequate and well-controlled trial (as described in 21 CFR 
104  314.126), showing a clinically meaningful treatment effect on core disease manifestations, 
105  accompanied by additional confirmatory evidence can be used to support approval.  Such 
106  confirmatory evidence could be based on different lines of evidence (e.g., data showing a 
107  treatment effect on disease-specific biochemical markers (e.g., CSF HS) in treated patients; 
108  nonclinical data showing biochemical and functional treatment effects in a well-characterized 
109  MPS III animal model).4  
110   
111  If a large treatment effect and/or an effect on objective clinical measures (e.g., survival) are not 
112  expected within a specified trial duration, FDA strongly recommends a randomized, parallel-
113  group trial design with an appropriate concurrent control group.  Because of the uncertainties 
114  related to the lack of a well-characterized natural history, the variable rate of neurologic disease 
115  progression among patients, and the nonlinear developmental trajectory observed in many MPS 
116  III patients (Ghosh et al. 2017), such randomized, concurrently controlled trial design would 
117  provide the most informative and reliable data for an evaluation of efficacy in the most efficient 
118  and expedient way.  Given the small patient population, sponsors should use randomization as 
119  early as in the first clinical trial involving MPS III patients to allow for maximal and most 
120  efficient use of efficacy data for regulatory purposes.   
                                                 
3 See the draft guidance for industry Rare Diseases: Natural History Studies for Drug Development (March 2019).  
When final, this guidance will represent the FDAs 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. 
 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
121   
122  When natural history information becomes available and can reliably predict the disease course 
123  in a given patient cohort, and when a large treatment effect size is anticipated based on 
124  preliminary information, an externally controlled clinical trial may be acceptable.  Sponsors can 
125  consider innovative and adaptive trial designs and should discuss these early in development 
126  with the appropriate review division.5, 6  
127   
128  A patients symptomatic treatment regimen (e.g., concomitant drugs, physical and occupational 
129  therapy, other interventions) should be optimized in advance of trial entry, and efforts should be 
130  made to maintain the stability of these background treatments during the trial.  Any changes in 
131  the patients background treatment regimen made during the trial should be carefully 
132  documented.   
133   
134  As most drugs would be intended to slow or arrest the neurological disease progression rather 
135  than to reverse it, a clinical trial should be of sufficient duration, at least 23 years to observe an 
136  effect on neurological disease aspects.  In addition, patients with different disease severity would 
137  be expected to have different rates of neurocognitive decline, which would necessitate different 
138  durations of observation to assess treatment effects on selected endpoints.  For gene therapy 
139  products, sponsors should be aware of special considerations regarding the length of long-term 
140  follow-up.7  
141   
142  C.  Pharmacodynamic Endpoints 
143   
144  Assessment of changes in HS concentration in CSF could provide evidence of in vivo biological 
145  activity of the drug, demonstrate proof-of-concept, and help characterize the dose-response 
146  relationship in early phase trials.  Changes in plasma or urine HS should be considered of limited 
147  utility given the neurologic nature of MPS III.  Assessment of changes in organ volume (e.g., 
148  liver, spleen) should be considered of limited utility given that organomegaly is not a common 
149  finding in MPS III patients and that changes in organ volume are of unclear clinical significance 
150  in a disease that is fundamentally neurologic.  Quantitation of pharmacodynamic biomarkers 
151  (e.g., HS, HS derivatives, enzyme activity) should be conducted at a central laboratory using 
152  appropriately validated methods to ensure reliability of the results.  Understanding the variability 
153  of the test(s) used is fundamental to the interpretation of any treatment effects on those 
154  biomarkers. 
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 FDAs 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 FDAs current thinking on this topic.  
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
156  D.  Efficacy Endpoints 
157   
158  Demonstration of a clinically meaningful treatment effect on neurological disease manifestations 
159  that are important to patients and their families can form the basis for traditional approval.  
160  Sponsors should assess multiple, distinct clinical endpoints in trials to provide a global 
161  characterization of treatment effects on disease manifestations.  At this time, additional evidence 
162  should be provided to support the use of HS reduction in CSF or other tissues (blood or urine) as 
163  a surrogate endpoint reasonably likely to predict clinical benefit to support accelerated approval.8   
164   
165  The selection and prioritization of efficacy endpoints should take into consideration patients and 
166  parents/caregivers preferences to ensure that sponsors assess outcomes that are clinically 
167  meaningful to patients and their families.  The selection of efficacy endpoint(s) should also 
168  consider the mechanism of action and anticipated clinical effects of the drug on the different 
169  disease manifestations.  Furthermore, given the multiple clinical manifestations of MPS III, 
170  which may differentially affect patients daily functioning, sponsors can consider the use of a 
171  multiple-endpoint strategy.9 FDA strongly encourages sponsors to engage in early and 
172  continuous discussions with the appropriate review division regarding the selection of the most 
173  informative and clinically meaningful endpoint(s) for demonstration of efficacy.10 
174   
175  Standardized clinical outcome assessment (COA) instruments should be used to evaluate 
176  treatment effects on major neurological disease aspects (e.g., cognition, behavior) (Janzen et al. 
177  2017).  Appropriate standardized tests of cognitive performance should be selected based on 
178  patients baseline level of functioning.  When selecting COA instruments to evaluate cognitive 
179  performance, sponsors should also consider whether there may be anticipated floor effects of the 
180  particular instrument in the enrolled population as this could affect interpretability of the data.  
181  Sponsors should also consider that the selection of particular COA tests may also inform the 
182  frequency of the corresponding assessments (Van der Lee et al. 2017).   
183   
184  All COA instruments should be administered by trained personnel who are familiar with the 
185  instruments and with the special challenges of MPS III patients as they relate to patients 
186  behavioral problems, inattention, hyperactivity, sensory impairment (hearing, vision), speech and 
187  language deficits, fatiguability, and motor impairment as those can interfere with test 
188  administration and interpretation of test results.  Instructions, training materials, and case report 
189  forms should include detailed information on all specific methods that should be utilized when 
190  administering these tests.  Assessments can be divided into multiple short sessions, and the 
191  trained personnel should allow adequate time for the completion of each assessment.  In addition, 
192  assessments should be administered in an environment familiar to the patient, and the testing 
193  environment should be free of items that may cause distraction.   
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 FDAs 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 
FDAs current thinking on this topic.   
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
195  The amount of time used and other contextual features of performance-based assessments should 
196  be recorded and accounted for in data analyses.  Other factors that may affect patients 
197  behavioral and cognitive performances, such as uncontrolled or insufficiently controlled seizures 
198  (which can be part of the underlying disease), should be carefully assessed and documented 
199  throughout the trial and should be considered in the interpretation of treatment effects.  FDA 
200  strongly encourages sponsors to discuss all proposed COAs with the appropriate review division 
201  early in development (i.e., pre-investigational new drug application phase).  
202   
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
203  REFERENCES 
204   
205  Ghosh A, Shapiro E, Rust S, et al., 2017, Recommendations on Clinical Trial Design for 
206  Treatment of Mucopolysaccharidosis Type III, Orphanet J Rare Dis, 12(1):117131. 
207   
208  Janzen D, Delaney KA, and Shapiro EG, 2017, Cognitive and Adaptive Measurement Endpoints 
209  for Clinical Trials in Mucopolysaccharidoses Types I, II, and III: A Review of the Literature, 
210  Mol Genet Metab, 121(2):5769. 
211   
212  Shapiro EG, Nestrasil I, Delaney KA, et al., 2016, A Prospective Natural History Study of 
213  Mucopolysaccharidosis Type IIIA, J Pediatr, 170:278287. 
214   
215  Valstar MJ, Marchal JP, Grootenhuis M, Colland V, Wijburg FA, 2011, Cognitive Development 
216  in Patients with Mucopolysaccharidosis Type III (Sanfilippo Syndrome), Orphanet J Rare Dis, 
217  6:4348. 
218   
219  Valstar MJ, Ruijter GJ, Van Diggelen OP, Poorthuis BJ, Wijburg FA, 2008, Sanfilippo 
220  Syndrome: A Mini-Review, J Inherit Metab Dis, , 31(2):240252. 
221   
222  Van der Lee JH, Morton J, Adams HR, et al., 2017, Cognitive Endpoints for Therapy 
223  Development for Neuronopathic Mucopolysaccharidoses: Results of a Consensus Procedure, 
224  Mol Genet Metab, 121(2):7079. 
7