FDA Releases Draft Guidelines for Clinical Trials in Sanfilippo Patients

The U.S. Food and Drug Administration (FDA) has released draft guidelines for the design of clinical trials evaluating investigational therapies in people with Sanfilippo syndrome.

“There are no approved therapies to treat this disease and we hope that this guidance will foster greater efficiency and consistency among [therapy] development programs, and ultimately benefit patients,” Janet Woodcock, MD, director of the FDA’s center for drug evaluation and research, said in a press release.

The draft, “Mucopolysaccharidosis Type III (Sanfilippo Syndrome): Developing Drugs for Treatment,” and subtitled “Guidance for Industry,” was issued by the FDA’s Center for Drug Evaluation and Research (CDER) and its Center for Biologics Evaluation and Research (CBER).

Public comments about the draft are being accepted through March 4. When finalized, the guidance will represent the agency’s current thinking on the topic.

This draft follows last month’s FDA release of a similar draft guidance for therapy development and clinical evaluation in rare diseases; it is part of the agency’s commitment to support the development of therapies for rare diseases.

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare genetic lysosomal storage disorder. It is characterized by the absence or reduced activity of one of four enzymes involved in the breakdown of a complex sugar molecule called heparan sulfate, leading to its toxic accumulation.

The central nervous system (CNS, brain and spinal cord) is the most affected organ in these patients, who develop progressive and severe neurodegeneration.

Sanfilippo is divided into four subtypes, known as A, B, C, and D. Each subtype is caused by mutations in a different gene containing the instructions to produce one of the enzymes necessary for the complete breakdown of heparan sulfate. While the different subtypes have similar signs and symptoms, Sanfilippo type A is the most severe.

Despite increasing efforts in the development of specific therapies for Sanfilippo syndrome, there is still no approved treatment.

FDA’s draft guidance aims to help pharmaceutical companies and other sponsors of clinical trials testing investigational treatments for Sanfilippo syndrome be more efficient and successful in their development programs, potentially resulting in faster treatment approvals.

The document starts with a background on the disease, in which it is emphasized there is a lack of a comprehensive characterization of the natural history and rate of progression of neurologic symptoms in all disease subtypes.

“Because of the current paucity [lack] of natural history knowledge and the clinical heterogeneity of MPS III, appropriately designed and executed natural history studies could provide crucial information to help guide and inform essential aspects of a clinical development program,” the agency stated in its document.

The draft continues by providing trial guidelines on participants’ eligibility criteria, design and structure, use of biomarkers, and effectiveness goals.

If a considerable treatment effect is not expected within a specified trial duration, the FDA recommends use of a randomized trial design with an appropriate control group, in which patients receive a placebo. This recommendation is based on the limited understanding on the natural history of the disease and variable neurologic disease progression among these patients.

“Such randomized, concurrently controlled trial design would provide the most informative and reliable data for an evaluation of efficacy in the most efficient and expedient way,” the agency wrote.

“When natural history information becomes available and can reliably predict the disease course in a given patient cohort, and when a large treatment effect size is anticipated based on preliminary information, an externally controlled clinical trial may be acceptable,” the document states.

The use of heparan sulfate levels in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — as a Sanfilippo biomarker is recommended for clinical assessments before and after treatment.

While a decrease in heparan sulfate levels in the CSF are suggested to provide evidence supporting treatment’s effect, additional evidence is said to be required to support its use as a surrogate effectiveness goal.

It also is advised that sponsors take into consideration patients’ and caregivers’ preferences when selecting and prioritizing effectiveness goals, to ensure that these goals are clinically meaningful to patients and their families.

The draft also provides guidelines in terms of trial duration, suggesting that a clinical study on Sanfilippo patients should have a minimum duration of two to three years, so that an effect on neurodegeneration progression can be effectively assessed. And this duration may vary depending on the participants’ disease severity and therapy type.

The agency also strongly encouraged sponsors to discuss all of these aspects with the appropriate review division in the early stages of clinical trial design.

“The FDA is committed to fostering innovation in drug development, especially for rare diseases. Patients who are suffering with rare diseases frequently have few or no treatments available to treat their condition and new approvals can often mean hope for an enhanced quality of life and in some cases, survival,” Woodcock said.