“Doing nothing is the biggest risk in Sanfilippo”

December 14, 2021

Sanfilippo Syndrome is ideal for the FDA’s Accelerated Approval Pathway.

Families are willing to accept modest benefit regarding a treatment, even if it contains risk, documents study.

Glenn O’Neill closed his presentation at the 2021 Rare Disease Scientific Workshop by repeating the urgent sentiments of a fellow parent of a child with Sanfilippo, “Doing nothing is the biggest risk in Sanfilippo!” He also shared the Sanfilippo community’s hope that the U.S. Food & Drug Administration will be understanding and respond soon to extensive change recommendations from the Sanfilippo patient community, spearheaded by the Foundation, that were submitted May 2020 in response to its draft guidance on drug development.

O’Neill, President of Cure Sanfilippo Foundation, began his Workshop presentation on the current and future barriers to the utilization of Accelerated Approval Pathway for Sanfilippo Disease with a brief overview of Sanfilippo Syndrome’s cause, progression, and impact on children. He then shared his family’s personal experience as parents of a child, Eliza, now 12, with Sanfilippo, and how it led them to create the Foundation in 2013, which has grown ever since.

O’Neill pointed out the results of a published, Foundation-led, research study capturing the preferences of caregivers of children with Sanfilippo. The study highlighted the difference between what is important to researchers versus what is important to Sanfilippo families and caregivers.

Currently, most research is focused on changes in mentation and motor activity associated when evaluating with a new treatment. In contrast, Sanfilippo caregivers also feel issues of speech, walking, sleeping, pain, bowel and bladder control and function, hyperactivity, irritability, self-harm and harm to others, and frequent infections are equally important.

“This study and follow up feedback also highlighted the modest benefit that families would be very willing to accept — in fact, want to accept and try — regarding a treatment. Even if that treatment contains risk.”

Following a discussion of the holistic needs of patients and their caregivers, O’Neill shared the current status of clinical trials for Sanfilippo treatment. Alarmingly, he related that of four research studies since 2016, three have been abandoned, with only one study surviving today.

In addition to the decrease in new studies for Sanfilippo, O’Neill presented two FDA guidances impacting Sanfilippo research. The first appeared as a draft in 2018 and the final version in March 2020 entitled “Slowly Progressive, Low-Prevalence Rare Diseases With Substrate Deposition That Result From Single Enzyme Defects: Providing Evidence of Effectiveness for Replacement or Corrective Therapies-Guidance for Industry.”

The details of the March 2020 FDA guidance were well done and included many elements that would improve the research in rare diseases, especially Sanfilippo, said O’Neill.

However, in February 2020 a second draft guidance specific to Sanfilippo was published, “Mucopolysaccharidosis Type III (Sanfilippo Syndrome): Developing Drugs for Treatment Guidance for Industry).” Unfortunately, this guidance modifies a number of key features to the 2018 guidance regarding acceptable measures and endpoints, imposes more restriction on eligible patients, and returns to focusing on cognitive measures and less on those ancillary measures identified by the CSD study.

In response to these changes, the Foundation rallied an “all hands on deck” meeting of key Sanfilippo stakeholders, which included six biotech companies, academic clinicians/trial principal investigators, and multiple patient advocacy groups in May 2020 to draft a reply.

The group produced the Sanfilippo community’s submitted written reply to this specific policy paper concluding that:

  1. Sanfilippo Syndrome is the IDEAL DISEASE for accelerated approval of new treatments.
  2. Sanfilippo is a serious condition with unmet needs.
  3. Measuring clinical benefit can take many years (5+).
  4. Surrogate endpoint option: Overwhelming evidence support. heparan sulfate as surrogate endpoint (accumulation is result of the primary gene defect). (It is believed this is “reasonably likely” to predict clinical benefit based on more functional enzyme activity = less heparan sulfate storage = slower disease course)
  5. Follow on confirmatory studies can be created with comparator retrospective data both through medical record collection and previous natural history studies.

As yet, there has been no response from the FDA on the community’s submission or its Sanfilippo-specific draft guidance, O’Neill reported.

As part of his presentation closing, O’Neill emphasized that Sanfilippo is a tragic, childhood, congenital disease desperately in need of more quality research focused. Not only on the brain and neurological impact, but also on the problems and issues children and their caregivers face in daily life, which are so impactful for patients and their families.

Watch the presentation by O’Neill and others at the Rare Disease Scientific Workshop.

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