Accelerating a Path to New Treatments for Rare Neuronopathic MPS Diseases

Pictured: Eliza O'Neill, far right (Sanfilippo Typ

Pictured: Eliza O’Neill, far right (Sanfilippo Typ

Representing Denali Therapeutics, I recently participated in a workshop that brought together FDA representatives, patient advocates, academic physicians and scientists and industry to discuss strategies to speed therapies for patients with rare degenerative illnesses.

Pictured: Eliza O’Neill, far right (Sanfilippo Type A) and her family/Glenn O’Neill

At Denali Therapeutics, where I serve as chief medical officer and head of development, we are eager to develop new treatments for progressive and debilitating neuronopathic mucopolysaccharidoses diseases with our novel technology. We are not alone—several other biopharma companies also have drug candidates that have shown promise in clinical testing. Unfortunately, as so many families and physicians know, the road to approval of new treatments for rare diseases is long and slow.

Mucopolysaccharidoses diseases (MPS) are extremely rare, inherited metabolic diseases caused by enzyme deficiencies that result in the buildup of toxic waste in cells throughout the body and brain. They affect fewer than 1,000 patients in the U.S. MPS diseases that affect the brain begin at a young age and result in progressive brain damage and severe debilitation. Current treatments do not address the neurologic components of these diseases.

MPS families describe losing the race against the clock, and every day without treatment leads to progressive loss of speech, hearing and cognitive capabilities. Ultimately, the lives of these children are cut short, and the impact on families is devastating.

Today, we have the opportunity to change the course for these patients. As a scientific and medical community, we are reaching a critical turning point. Last week, the Reagan-Udall Foundation for the FDA hosted an impactful meeting with agency representatives, patient advocates, academic scientists and physicians and industry representatives. The discussion in which I took part focused on the use of heparan sulfate (HS) as a biomarker to support accelerated approval in neuronopathic MPS.

During the workshop, leading experts in academia and biotech unanimously agreed that science and innovation have delivered a biomarker that can hasten the development of new therapies. Now, we need the FDA to respond to what was said and open the accelerated approval pathway for MPS.

A Long Road to Therapies for Rare MPS Diseases

Developing therapies to treat neuronopathic MPS and demonstrating evidence of effectiveness is challenging for multiple reasons. Recruiting patients for clinical trials is difficult given the extremely low prevalence of these diseases. Additionally, the onset and progression of MPS diseases varies across patients, resulting in variability that necessitates larger and longer studies to demonstrate a statistically significant treatment effect. Patients and families bear the burden of this, with children sustaining irreversible brain damage while waiting to see if therapies are working based on traditional drug development approaches.

To enable an enrollment target of 54 patients with MPS II for Denali’s ongoing Phase II/III study, we are recruiting and dosing individuals across 14 countries and 35 clinical sites. Even so, families have had to relocate to new cities or drive many hours every week to receive weekly intravenous infusions.

Enrolling younger patients—babies under two years old—for clinical trials is often considered optimal and has been requested by the FDA given that current clinical trial endpoints are anticipated to be most sensitive and have the largest benefit in children who have not yet lost development milestones. However, newborn screening is only available in limited geographies and only for a subset of MPS diseases, and for many of these MPS disorders, children only present with symptoms after the age of two. At Denali, we have worked closely with the patient community to find babies under two years old with early diagnosis, usually by connection to families with an older child with the disease who have tested the younger sibling. Still, this exhaustive search for younger patients loses sight of the critical fact that stopping the progression of disease in older patients is equally important to families dealing with the increasing support required to manage the pain and suffering of their child as the disease inexorably progresses.

From an industry perspective, current development timelines for MPS diseases that affect the brain are expected to take more than eight to 10 years from start to availability on the market and cost in excess of half a billion dollars. Accelerated approval could cut this timeline in half.

CSF Heparan Sulfate: An Effective Biomarker

The FDA recognized these challenges. In 2020, the agency published a guidance for industry on Rare, Low-Prevalence, Single Enzyme Defects with Substrate Deposition. This guidance provided a path to support accelerated approval based on reduced levels of a biomarker, which in these diseases would refer to heparan sulfate accumulation.

However, despite fitting the intended disease characteristics for which this guidance was written, it has not been applied to neuronopathic MPS diseases. This is not for lack of a biomarker: heparan sulfate is a disease specific primary substrate that can be reliably measured with sensitive, specific and analytically validated mass spectroscopy assays. Published preclinical data across multiple disease models support that heparan sulfate measured in the cerebrospinal fluid (CSF heparan sulfate) reflects brain heparan sulfate across several animal models of disease where we can access the brain to understand these correlations. In the clinic, CSF heparan sulfate can be measured by collecting fluid with a lumbar puncture. In sum, CSF heparan sulfate assays reliably reflect the accumulation of toxic waste accumulation in the brain.

Emerging science gives us an understanding of the disease process whereby sustained reductions in CSF heparan sulfate are reasonably likely to predict clinical benefit in children with neuronopathic MPS disorders. Data from a number of promising therapies in the clinic provide a totality of evidence across multiple therapeutic treatment modalities—intravenous delivered brain penetrating enzyme replacement, gene therapy, intrathecal delivered enzyme replacement—and multiple MPS diseases, that reduction in CSF heparan sulfate is associated with disease-related improvements in biomarker and clinical measures.

With Denali’s intravenously delivered tividenofusp alfa (DNL310), for example, reduction and normalization of CSF heparan sulfate is accompanied by correction in elevated lysosomal proteins that are known to affect the brain from other monogenic diseases and correction in elevated neurofilament light chain, a biomarker of neuronal injury. Denali’s biomarker data is further supported by data from an open-label extension study demonstrating clinical skill gain and objective measures of improvement in auditory response.

We are facing an urgent need. Children are dying and current treatment does not address the toxic waste that causes brain damage in these diseases. We need the FDA to open the door to using this biomarker to support accelerated approval in neuronopathic MPS. As Cara O’Neill, chief science officer at the Cure Sanfilippo Foundation, concluded at the Reagan-Udall Foundation meeting, “We truly mean now, or we’re going to lose another generation of our kids.”

Carole Ho, M.D., chief medical officer and head of development at Denali Therapeutics, previously served as vice president of clinical development at Genentech and is a neurologist by training.