NICE Endorses Pegzilarginase for Treating Arginase Deficiency
NICE Backs Pegzilarginase for Arginase Deficiency
The National Institute for Health and Care Excellence (NICE) final draft guidance recommends pegzilarginase arginase deficiency treatment (Loargys, Immedica) as an option for people aged 2 years and over with arginase-1 deficiency (ARG1-D, also known as hyperargininaemia), within its marketing authorisation. This marks the first disease-modifying treatment for this ultra-rare metabolic condition, to be used alongside usual care including dietary protein restrictions, essential amino acid supplementation, and ammonia-lowering drugs. Despite uncertainties in small, short-term clinical trials and economic modelling, the guidance—as detailed in NICE’s announcement—concludes that pegzilarginase demonstrates clinical benefits, primarily a 77.9% reduction in plasma arginine levels, and cost-effectiveness within NICE’s threshold for highly specialised technologies, mandating NHS funding in England within 90 days of final publication.
Arginine Levels Slashed 78%
Pegzilarginase arginase deficiency therapy addresses a critical unmet need by significantly lowering plasma arginine levels, a key surrogate marker for ARG1-D progression, which current management fails to achieve despite restrictive diets. Evidence from the phase 3 PEACE trial (n=32 randomised) and supporting studies (101A and 102A) showed a statistically significant 77.9% mean reduction at week 24 versus placebo plus usual care, with sustained control enabling potential diet liberalisation and reduced ammonia-lowering therapy reliance.
Mobility improvements, such as 9.2% change in timed walk tests and 3.5-point gain in Gross Motor Function Measure-88 Part E (GMFM-E), were observed but lacked statistical significance due to small sample sizes and short durations (up to 150 weeks in extensions), highlighting uncertainty in long-term durability. This positions pegzilarginase as a step-change therapy for a condition causing spastic paraparesis, neurological deterioration, cognitive delays, seizures, and poor survival, with profound quality-of-life impacts on patients and carers.
Trial Data and Modelling Rigor
The recommendation stems from a rigorous evaluation of multicentre trials (PEACE: randomised, double-blind, placebo-controlled with long-term extension; 101A/102A: open-label safety studies) pooled with real-world data like the European burden of illness survey, appraised by an external assessment group (EAG). A lifetime Markov model stratified by Gross Motor Function Classification System (GMFCS) health states (1-5, reflecting mobility), cognitive impairment, hyperammonaemic crises, and death incorporated trial outcomes, Delphi panel consensus on progression (e.g., mean ages in states: GMFCS-1 at 11 years), and NHS-relevant inputs like starting distributions adjusted to 15.625% in GMFCS-2/3 based on UK surveys (n=21 patients).
Economic assumptions favoured plausibility amid ultra-rare disease challenges, including time-invariant transitions post-3 years for pegzilarginase (90% stability observed), EAG-preferred standard care progression (2.66 annual GMFM-DE decline), and confidential commercial discounts on the £4,690 per 2-mg vial list price. These supported probabilistic incremental cost-effectiveness ratio (ICER) estimates of £99,256 per quality-adjusted life year (QALY) gained under committee preferences, applying a 50% QALY weighting for 11-29 QALY gains despite uncertainties in mortality, utilities, and discontinuation.
ICERs Under £100,000 Threshold
Committee-preferred modelling yielded ICERs below £100,000 per QALY, acceptable for highly specialised technologies, balancing uncertainties like life extension (modelled via standardised mortality ratios from HST18 proxy, adjusted for GMFCS-2 at 25% of standard care), 2% annual discontinuation (log-logistic distribution), and utility gains (e.g., 0.04 for 83.3% diet liberalisation, treatment-specific cognitive disutilities in GMFCS 1-3). Costs incorporated 0.14 mg/kg weekly dosing (90% general population weight, 76% female), 10% vial wastage threshold, and carer disutilities without double-counting multiples. This threshold reflects ARG1-D’s severity, innovation as the first targeted enzyme therapy, and patient/carer testimonies on burdensome care, frequent hospitalisations, and delayed diagnosis.
Precedents for Rare Diseases
This guidance exemplifies challenges in ultra-rare diseases, endorsing pegzilarginase despite evidentiary gaps through flexible modelling (e.g., surrogate endpoints like arginine levels, expert Delphi consensus) and partial QALY weighting, potentially accelerating market access for orphan drugs via NHS commissioning and Welsh directions (60 days). Implications include enhanced reimbursement precedents for disease-modifying therapies in metabolic disorders, emphasising real-world evidence integration (e.g., French diet data) and conservative assumptions (e.g., no post-3-year progression) to navigate small trials.
For pricing, confidential arrangements ensure value-for-money, while mandating routine funding underscores prioritisation of QALY gains in progressive, debilitating conditions over perfect data. It highlights needs for longer-term survival data, newborn screening to shift GMFCS distributions leftward, and stop/start rules, informing future appraisals amid rising gene/enzyme therapies and informing global payers on ultra-rare pricing/reimbursement amid high unmet need. Overall, the recommendation advances equitable access, mitigating carer burdens and enabling less restrictive management without equality issues from consanguinity-related prevalence.
