Breakthrough Clinical Results
Ultragenyx's investigational gene therapy, UX111, for Sanfilippo syndrome type A, was rejected by the FDA due to manufacturing concerns. The FDA's complete response letter focused on issues not related to the drug's efficacy, with the agency acknowledging the robust neurodevelopmental data. Ultragenyx plans to resubmit the application within the next few months, anticipating a six-month review period. This rejection follows disappointing results for another Ultragenyx asset, UX143, and has led to a significant drop in the company's stock price. The company is also facing a securities investigation.
Key Highlights
- FDA rejected Ultragenyx's gene therapy UX111 for Sanfilippo syndrome type A.
- Rejection was due to manufacturing issues, not efficacy concerns; the FDA acknowledged robust neurodevelopmental data.
- Ultragenyx plans to resubmit the application within months, expecting a six-month review.
- This follows disappointing Phase II/III results for another Ultragenyx asset and a securities investigation.
Incidence and Prevalence
Global Epidemiology of Sanfilippo Syndrome (MPS III)
Incidence and Prevalence
Sanfilippo syndrome (mucopolysaccharidosis [MPS] type III) is a rare autosomal recessive inherited metabolic disorder with four subtypes (A, B, C, and D). According to a 2022 systematic review and meta-analysis, the pooled global birth prevalence of MPS III was 0.76 cases (95% CI: 0.57-0.96) per 100,000 live births. This comprehensive meta-analysis included 25 studies screened from 1,826 records and was the first comprehensive systematic review presenting quantitative data for evaluating the global epidemiology of MPS III.
A 2019 systematic literature review found that the lifetime risk at birth for all four subtypes of MPS III together ranges from 0.17-2.35 per 100,000 live births, confirming that all four subtypes are exceptionally rare but have devastating effects on children.
Based on the global population size (7.8 billion) and the life span of patients, it is estimated that there would be 12-19 thousand MPS III patients worldwide.
In specific regions, the incidence varies: - In the Netherlands, the incidence has been estimated at 1:24,000 - The United Kingdom shows a similar high incidence to the Netherlands - The Cayman Islands have a particularly high incidence of a clinically severe form of MPS-IIIA with a carrier frequency of 0.1
Distribution of Subtypes
The distribution of MPS III subtypes varies globally:
Global Subtype Prevalence
According to the 2022 meta-analysis, the pooled global birth prevalence of MPS III subtypes was: - Type A: 0.52 cases (95% CI: 0.33-0.72) per 100,000 live births - Type B: 0.21 cases (95% CI: 0.12-0.30) per 100,000 live births - Type C: 0.01 cases (95% CI: 0.005-0.02) per 100,000 live births
Globally, the most prevalent subtypes of MPS III are A and B followed by C and D subtypes.
Regional Variations
- In the Netherlands and United Kingdom, MPS IIIA is the most common subtype
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A 2023 study in Egypt found that MPS type III was the most common MPS type among referred cases, accounting for 31% of all diagnosed MPS cases
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In Egypt, MPS IIIB was the most common subtype (49.3% of MPS III cases)
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MPS IIIA accounted for 20.6% of MPS III cases in Egypt
- A 2019 study in Taiwan found that MPS IIIB is the most frequent subtype among MPS III in the Taiwanese population
Historical Data and Limitations
Earlier data from 1999 showed that within the group of mucopolysaccharidoses (MPSs), MPS III comprised 47% of all MPS cases diagnosed with a combined birth prevalence of 1.89 per 100,000 live births. In that earlier study, MPS IIIA had an estimated birth prevalence of 1.16 per 100,000.
For MPS IIIA specifically, the 2019 review found that the lifetime risk at birth ranges from 0.00-1.62 per 100,000 live births.
The 2019 systematic review noted that higher-quality epidemiological data are needed to appropriately target resources for disease research and management. Due to the mild somatic disease compared to other MPS disorders, there is difficulty in diagnosing mild cases of MPS-III, hence Sanfilippo syndrome may be underdiagnosed, especially in patients with mild mental retardation.
Information regarding the natural history of this disorder in Asian populations is limited.
Mechanism of Action
Information on Mechanisms of Action for Sanfilippo Syndrome Drugs
Based on the review of all available information, there is no specific data regarding the mechanisms of action for drugs being tested for Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III). The requested information about the three most common mechanisms of action in clinical trials for unapproved drugs targeting this condition is not available in the provided materials.
Similarly, there is no information available about the most commonly investigated pharmacological pathways or molecular targets for experimental therapeutics for Mucopolysaccharidosis type III that remain in the clinical development pipeline.
Without specific data on these topics, a comprehensive analysis of the mechanisms of action or molecular targets for Sanfilippo syndrome treatments cannot be provided.
Drug used in other indications
UX111 Clinical Trials Beyond Sanfilippo Syndrome
Based on the provided context, there is no information available about UX111 being trialed for indications other than Sanfilippo syndrome (Mucopolysaccharidosis type III). The context does not contain any details about:
- Additional clinical indications beyond Mucopolysaccharidosis type III
- Intervention methodologies, dosing regimens, or administration protocols for non-Mucopolysaccharidosis type III trials
- The mechanism of action of UX111 that might suggest potential therapeutic benefits for other indications
The context appears to be empty or does not contain relevant information about UX111 clinical trials.