Evidence Summary : Oxlumo (Lumasiran)
Geetika Sharma
29 June, 2023
Oxlumo (Lumasiran) An Overview
Primary hyperoxaluria type 1 (PH1) is a rare genetic
disorder causes the body to produce too much oxalate,
which can lead to kidney stones and kidney damage.
It contributes to the formation of painful and recurring
kidney stones, and nephrocalcinosis, progressing to
renal failure and systemic organ dysfunction.
Oxlumo™ (lumasiran) is the first small interfering
ribonucleic acid (RNAi) therapeutics indicated for the
treatment of PH1 to reduce urinary oxalate levels in
paediatric and adult patients.
Oxlumo targets the hydroxyacid oxidase 1 (HAO1)
messenger RNA (mRNA) in hepatic cells to reduce the
glycolate oxidase (GO) enzyme levels
PH1 can affect people of all age groups. It causes a
gradual reduction in renal function that can lead to
end-stage renal failure.
Decline in GO levels reduce the amount of available
glyoxylate, an oxalate-producing substrate that
contributes to the pathophysiology of PH1.
PH1 is more than a kidney stone disease and can
cause serious damage to their kidneys or other
organs.
Oxlumo was developed by Alnylam Pharmaceuticals and
received priority medicines (PRIME) designation from
the European Medicines Agency (EMA) in March 2018.
Oxlumo received regulatory approval from US FDA and EMA in November 2020.
Evidence base for Oxlumo – UK (NICE)
HTA Assessment: Recommended
Decision Date: 19 April 2023
MA Date: 13 July, 2020
Efficacy
• The clinical evidence for Oxlumo included several trials: ILLUMINATE-A (randomized, double-blind, placebo-controlled), ILLUMINATE-B
(phase 3, single-arm, open-label), ILLUMINATE-C (phase 3, single-arm, open-label), ALN-GO1-001B (phase 1/2 randomized, placebocontrolled dosing study), and ALN-GO1-002 (phase 2, open-label extension safety study).
• In the ILLUMINATE-A study, Oxlumo demonstrated a significant reduction in 24-hour urinary oxalate excretion compared to placebo. The
effect size was -53.5%, with a 95% confidence interval of -62.3% to -44.8%.
Safety
• Oxlumo demonstrated a favourable safety profile in the three phase 3 ILLUMINATE trials, which has been confirmed with long-term data
from the phase 2.
Quality of Life
• Health-related quality of life data assessed with the EQ-5D questionnaire did not show a clinically significant difference between the
Oxlumo and placebo arms.
• However, it was noted that the comparability of treatment groups at baseline could not be fully assessed and the committee concluded
that treatment with Oxlumo was likely to have an impact on health-related quality of life, although the magnitude of this effect remained
uncertain given the limited duration of the study.
Economic
Evidence
• The company's economic model compared Oxlumo plus standard care with standard care in a simulated cohort of people with PH1,
using chronic kidney disease (CKD) stages as health states.
• The economic analysis had a lifetime time horizon, adopted an NHS perspective, and used a discount rate of 3.5% per year for both
costs and health outcomes. The model structure was considered to reflect the general course of the condition
Overall
evidence
package
• Oxlumo is recommended as a treatment option for primary hyperoxaluria type 1 (PH1) considering its effectiveness in reducing oxalate
levels, potential improvement in health-related quality of life, recognition of the significant unmet need, and the likelihood of costeffectiveness within the range considered appropriate by NICE for highly specialized technologies.
• The committee recognized the urgent unmet need for effective treatments for PH1, a rare and serious condition impacting
the lives of patients, families, and caregivers.
• Clinical evidence demonstrated Oxlumo's effectiveness in reducing oxalate levels and improving the health-related quality
of life for individuals with PH1.
• Despite uncertainties in the economic model, considering the committee's preferred assumptions, Oxlumo's costeffectiveness was within the acceptable range, leading to its recommendation as a treatment option for PH1.
Key Takeaways
• PH1's nature,
• Clinical effectiveness,
• Cost effectiveness,
• Impact beyond direct
health benefits.
Decision drivers
References: NICE HST25 guidance, NICE committee papers [ID3765], European Medicines Agency (EMA). European Public Assessment Report (EPAR): Oxlumo (lumasiran), NICEHighly Specialised Technology Evaluation Lumasiran for
treating primary hyperoxaluria type 1 [ID3765] Evaluation Report, Garrelfs SF et al 2021, Hulton SA et al, 2021
Evidence base for Oxlumo – Spain (AEMPS)
HTA Assessment: Recommended
Decision Date: 28 July, 2022
MA Date: 19 November, 2020
Efficacy
• The clinical development program for Oxlumo in PH1 consisted of three phase III clinical trials: ILLUMINATE-A (randomized
double-blind study in patients over 6 years old), ILLUMINATE-B (single-arm study in children under 6 years old), and ILLUMINATEC (study in patients with advanced kidney disease).
• In a 6-month double-blind clinical trial, Oxlumo was shown to reduce plasma and urinary oxalate levels (24-hour excretion)
compared to placebo.
• Oxlumo was found to be associated with a significant mean reduction of 53.5% (95% CI -44.8 to -62.3; p < 0.0001) in BSAcorrected 24-hour urinary oxalate values compared to placebo, reflecting a 65.4% reduction versus an 11.8% reduction,
respectively. In ILLUMANATE-B Oxlumo was associated with rapid and sustained reductions in urine oxalate:creatinine ratio, which
were similar across weight subgroups
Safety
• The most frequent adverse effects were local reactions in the injection site and abdominal pain.
• No deaths or serious adverse events (AEs) were observed in the ILLUMINATE-A or ILLUMINATE-B studies.
• No AEs leading to treatment discontinuation or interruption were observed in the ILLUMINATE studies.
Quality of Life
• Health-related quality of life data assessed with the EQ-5D questionnaire did not show a clinically significant difference between the
Oxlumo and placebo arms.
Overall evidence
package
• The Therapeutic Positioning Report of AEMPS for Oxlumo is based on a comprehensive evaluation of its safety, efficacy, and
clinical benefits. The report provides in-depth analysis and insights into the therapeutic positioning of Oxlumo, highlighting its
potential as a valuable treatment option for PH1.
• Oxlumo may be considered as a therapeutic option for patients of any age (children and adults) with mild or moderate
kidney disease who do not respond to standard treatment options for HP-1 in usual clinical practice.
• In addition to reducing urinary oxalate levels, Oxlumo has also shown efficacy in reducing plasmatic levels, which could
potentially lead to a reduction in associated comorbidities.
• There is biological plausibility to suggest that the demonstrated favorable effects of Oxlumo on intermediate variables may
translate into a reduced progression of the disease in HP-1 patients.
Key Takeaways
References: Therapeutic position report, 2022; Garrelfs SF et al 2021; Hulton SA. Et al 2021, Sas Dj et al 2021
• Efficacy,
• Safety, and
• Quality attributes
Decision drivers
Evidence base for Oxlumo – France (HAS)
HTA Assessment: Recommended
Decision Date: 11 May, 2021
MA Date: 19 November, 2020
Efficacy
• The clinical evidence for Oxlumo included several trials: ILLUMINATE-A (randomized, double-blind, placebo-controlled), ILLUMINATEB (phase 3, single-arm, open-label), ILLUMINATE-C (phase 3, single-arm, open-label), ALN-GO1-001B (phase 1/2 randomized,
placebo-controlled dosing study), and ALN-GO1-002 (phase 2, open-label extension safety study).
• The manufacturer claims significant medical benefit and improvement in medical benefit for Oxlumo compared to best supportive
care.
• Oxlumo is expected to delay or halt the progression to renal replacement therapy (RRT) and reduce the need for dialysis, kidney and
liver transplantation, and supportive care.
• Management recommendations may shift away from transplantation with the introduction of Oxlumo.
• Patient care conditions could be modified, reducing the reliance on supportive treatments, dialysis, and transplantation.
Safety
• Oxlumo was shown to have a favourable safety profile in the three phase 3 ILLUMINATE trials, which has been confirmed with longterm data from the phase 2.
Quality of Life
• Prospects for a promising future are evident, and the treatment significantly enhances the overall quality of life for affected individuals
and their families.
Economic
Evidence
• The incremental cost-effectiveness ratio (ICER) of Oxlumo compared to best supportive care is €2,429,397 per quality-adjusted life
year (QALY) over a lifetime horizon.
Overall evidence
package
• The evidence package evaluates Oxlumo for the treatment of primary hyperoxaluria type 1 (HP1). Oxlumo shows promise in
improving the lives of HP1 patients and their families by reducing the need for invasive treatments and improving quality of life.
• However, there are concerns about the high cost and uncertainties regarding its effectiveness, especially for patients with advanced
renal insufficiency. Additional real-life data is needed to support the cost-effectiveness and long-term benefits of Oxlumo.
• The ICER of Oxlumo is considered extremely high, even for an orphan drug, and there is uncertainty regarding patients
with stage 4 or higher renal insufficiency.
• The method used to estimate transition probabilities and link plasma oxalate levels with glomerular filtration rate is
uncertain and not validated.
• Real-life data is needed to support the cost-effectiveness analysis, including the efficacy, long-term impact, and adherence
of Oxlumo treatment.
Key Takeaways
• Potential QoL
improvement
• Clinical effectiveness
• Cost effectiveness
Decision drivers
References: COMMISSION DE LA TRANSPARENCESYNTHESE D’AVIS], European Medicines Agency (EMA). European Public Assessment Report (EPAR): Oxlumo (lumasiran), Garrelfs SF et al 2021, Hulton SA et al, 2021
Evidence base for Oxlumo – Canada (CADTH)
HTA Assessment: Recommended
Decision Date: 8 February, 2023
MA Date: 18 May, 2022
Efficacy
• Oxlumo was associated with a statistically significant reduction in plasma oxalate levels and a high proportion of patients achieving
a 24-hour urine oxalate measure within the normal range.
• Two single-arm phase III trials (ILLUMINATE-B and ILLUMINATE-C) involving patients younger than 6 years and those with
impaired kidney function or on hemodialysis also demonstrated consistent results in terms of urinary and plasma oxalate reduction.
• Patients expressed a need for treatments that maintain kidney function, reduce the likelihood of kidney stones, oxalosis, and the
need for dialysis or organ transplant, and improve the challenges and burden of managing PH1.
Safety
• Oxlumo demonstrated a favourable safety profile in ILLUMINATE studies.
Quality of Life
• In the ILLUMINATE-A trial, the assessment of HRQoL using various scales such as KDQOL, PedsQL, 5-level EQ-5D 5 Levels, EQ5D Youth, and visual analogue scale showed notable improvements from baseline to month 6 and during extended Oxlumo
treatment.
Economic
Evidence
• The cost-effectiveness analysis showed that Oxlumo's incremental cost-effectiveness ratio was $2,165,926 per quality-adjusted
life-year (QALY) gained, exceeding the cost-effectiveness threshold of $50,000 per QALY.
Overall evidence
package
• The evidence package evaluates Oxlumo for the treatment of primary hyperoxaluria type 1 (HP1). Oxlumo shows promise in
improving the lives of HP1 patients and their families by reducing the need for invasive treatments and improving quality of life.
• However, there are concerns about the high cost and uncertainties regarding its effectiveness, especially for patients with
advanced renal insufficiency. Additional real-life data is needed to support the cost-effectiveness and long-term benefits of Oxlumo.
• The trials included a range of patients with different ages, kidney function, and PH1-related symptoms, but treatment with
Oxlumo is uncertain in patients with specific characteristics.
• Long-term data and understanding the relationship between surrogate outcomes and clinical benefit are needed.
• Clinical experts generally felt that the trial results could be generalized to the population of patients with PH1 in Canada,
but emphasized the need for long-term data.
Key Takeaways
References: CADTH Reimbursement Recommendation Lumasiran (Oxlumo), Garrelfs SF et al 2021, Hulton SA et al, 2021
• Clinical evidence
• Patient needs
• Cost effectiveness
• Budget Impact
Decision drivers
Evidence base for Oxlumo – Germany (G-BA)
HTA Assessment: Recommended
Decision Date: 2 July, 2021
MA Date: 19 November, 2020
Efficacy
• In the ILLUMINATE-B study, all children experienced adverse events, but none were severe or led to discontinuation of the study
medication.
• The ILLUMINATE-A study showed a significant reduction in oxalate concentration in urine, supporting the benefit of Oxlumo
compared to baseline.
Safety
• Oxlumo was shown to have a favourable safety profile in the three phase 3 ILLUMINATE trials, which has been confirmed with
long-term data from the phase 2.
Quality of Life
• Health-related quality of life was assessed using the PedsQL and KDQOL-36 questionnaires.
• No conclusive statements regarding the additional benefit of Oxlumo on health-related quality of life could be made based on the
ILLUMINATE-A study.
Overall evidence
package
• The G-BA makes its decision based on the pharmaceutical company's dossier, the evaluations by the G-BA and IQWiG,
• The assessment of Oxlumo's benefit is based on the ILLUMINATE-A and ILLUMINATE-B studies, with low potential for bias in the
ILLUMINATE-A study..
• The strength of the evidence is categorized as "indicative" due to overall low evidence strength and uncertainties related to specific
patient groups and long-term effects..
• ILLUMINATE-A, ILLUMINATE-B, and ILLUMINATE-C trials provide evidence of Oxlumo efficacy and safety in different patient
populations with PH1.
• Oxlumo demonstrated improvements in urine and plasma oxalate levels in all three trials.
• Long-term efficacy and safety data are necessary to confirm findings and understand the impact on outcomes such as hepatic
oxalate production, kidney stone prevention, and progression to ESKD.
• Changes in eGFR and health-related quality of life from baseline were numerically small, and conclusions couldn't be drawn due
to limited patients and short treatment duration.
• Further research is needed to assess the long-term effects of Oxlumo on kidney function and overall quality of life.
Key Takeaways
• Clinical
effectiveness,
• Quality of life
Decision drivers
References: Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM RL) Anlage XII – Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V Lumasiran
(Hyperoxalurie) , Garrelfs SF et al 2021, Hulton SA et al, 2021
Please complete the below table to differentiate the countries based on archetype
Country
Denmark
HTA body
Key reimbursement decision
driver
CE analysis
submitted
CE threshold
(cost/QALY)
Mandatory budget
impact
Danish Medicines Agency (DKMA)
Cost-effectiveness
Y
Varies
Y
Haute Autorité de Santé (HAS)
Cost-effectiveness
Y
€30,000 - €60,000
N
Germany
Federal Joint Committee (G-BA)
Clinical effectiveness
N/A
N/A
N/A
Ireland
Italy
Health Service Executive (HSE)
Italian Medicines Agency (AIFA)
Cost-effectiveness
Cost-effectiveness
Y
Y
€45,000 - €60,000
Varies
N
N
National Health Care Institute (ZIN)
Cost-effectiveness
Y
€20,000 - €80,000
N
Norway
Norwegian Medicines Agency (NoMA)
Cost-effectiveness
Y
N/A
N
Scotland
Scottish Medicines Consortium (SMC)
Cost-effectiveness
Y
£20,000 - £30,000
N
Cost-effectiveness
Y
€30,000 - €60,000
N
Cost-effectiveness
Y
SEK 500,000 - SEK
1,000,000
N
Cost-effectiveness
Y
£20,000 - £30,000
N
Cost-effectiveness
Y
KRW 30,000,000
Y
Cost-effectiveness
Y
Cost-effectiveness
Y
France
Netherlands
Spain
Sweden
UK
South Korea
Canada
Australia
Spanish Agency of Medicines and
Medical Devices (AEMPS)
Dental and Pharmaceutical Benefits
Agency (TLV)
National Institute for Health and Care
Excellence (NICE)
Health Insurance Review and
Assessment Service (HIRA)
Canadian Agency for Drugs and
Technologies in Health (CADTH)
Pharmaceutical Benefits Advisory
Committee (PBAC)
Y, Yes; N, No; N/A, Not applicable
CAD 50,000 - CAD
100,000
AUD 45,000 - AUD
120,000
N
Y
Thank You