Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical evidence for avalglucosidase alfa (AVAL) is primarily based on the COMET study, which demonstrated non-inferiority to alglucosidase alfa (ALGLU) in terms of forced vital capacity (FVC%) and the 6-minute walk test (6MWT). However, the improvements were not statistically significant, indicating comparable efficacy without a clear advantage. The evidence is limited, particularly for infantile-onset Pompe disease (IOPD), where data is sparse and relies on assumptions about efficacy.
Cost effectiveness
The cost-effectiveness estimates for AVAL in late-onset Pompe disease (LOPD) are below what NICE considers an acceptable use of Healthcare resources. The committee concluded that AVAL is likely to be cost-effective, even with uncertainties in the clinical evidence. The economic model used was deemed appropriate for decision-making.
Quality of life
Health-related quality of life data from the COMET study indicated that utility values were generally higher over time than at baseline for both treatments, suggesting a moderate improvement in quality of life. However, the lack of statistically significant benefits in clinical outcomes limits the strength of this evidence.
Supporting Domains
Safety and Adverse Effects
AVAL demonstrated a very good safety profile, with adverse events similar to those of ALGLU. The most common adverse events were mild to moderate, indicating that AVAL is well-tolerated. This supports a strong safety profile relative to existing therapies.
Comparator Selection
The clinical trials compared AVAL against the appropriate standard of care (ALGLU), which is the only existing treatment for Pompe disease. This direct comparison strengthens the evidence base, although the reliance on non-inferiority design introduces some limitations.
Patient Population and Subgroups
The patient population in the trials included individuals with LOPD, but the evidence for IOPD is limited and uncertain due to small sample sizes and heterogeneity. While the core population is covered, significant gaps exist in subgroup analyses, particularly for IOPD.
Care Pathway Integration
AVAL is expected to integrate well into existing treatment pathways for Pompe disease, requiring only minor adjustments. The committee noted that it could be administered similarly to ALGLU, which facilitates its adoption in clinical practice.
Resource Use and Cost Implications
The budget impact of AVAL is manageable and aligned with planning, as the cost-effectiveness estimates suggest it is a dominant use of Healthcare resources. However, uncertainties in the IOPD population could raise concerns about resource allocation.
Evidence Quality and Robustness
The evidence base is limited, primarily relying on two studies with small sample sizes and uncertain outcomes. While the studies are methodologically sound, the overall robustness is compromised by the limited data available, particularly for IOPD.
Uncertainty, Sensitivity, and Broader Impacts
While there are uncertainties regarding the clinical effectiveness and cost-effectiveness estimates, the committee accepted these uncertainties due to the high burden of Pompe disease and the rarity of the condition. This context supports a favorable view despite the uncertainties.
