Person with PH1
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ILLUMINATE: Pivotal Clinical Trials Evaluating OXLUMO® (lumasiran)
ILLUMINATE-A: The largest interventional study in children and adults with PH11
ILLUMINATE-A is an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial including adults and children ≥6 years with eGFR ≥30 mL/min/1.73 m2 (N=39)1,2
Selected baseline characteristics1,2:
- Mean age at first dose 15 years (range: 6 to 61 years)
- Mean 24-hour UOx level corrected for BSA: 163.80 +/- 55.8 mg
(1.82 ± 0.62 mmol) - Pyridoxine (vitamin B6) use: 56%
- eGFR: ≥90 mL/min/1.73 m2 (33%); 60 to <90 mL/min/1.73 m2
(49%); 30 to <60 mL/min/1.73 m2 (18%)
Including hyperhydration, crystallization inhibitors, and/or pyridoxine, after which they can adjust per the recommendations of their treating physician.
Patients randomized to placebo received starting doses of 3 mg/kg OXLUMO at months 6, 7, and 8; patients randomized to OXLUMO received an ongoing dose of 3 mg/kg OXLUMO at month 6 and placebo at months 7 and 8. At month 9, all patients started receiving OXLUMO every 3 months.
1.5 x ULN, ≤69.4 mg/24 h/1.73 m2 (≤0.771 mmol/24 h/1.73 m2 ); ULN, ≤46.3 mg/24 h/1.73 m2 (≤0.514 mmol/24 h/1.73 m2).
In ILLUMINATE-A, treatment with OXLUMO® (lumasiran) led to rapid, powerful, and sustained reduction in 24-hour UOx1
Rapid onset of reduction in UOx was observed within 1 month, with maximal reduction reached by month 2, and sustained through 24 months in patients initially treated with OXLUMO1
24-hour UOx excretion over time*,†,1,4,5
Mean and 95% CI of actual observed values.
Assessments were conducted monthly until month 9; thereafter, assessments were conducted every 3 months until month 24.
Least squares mean reduction averaged over months 3 through 6, corrected for BSA.1
95% CI: 64%, 95%; P<0.001 vs Placebo. Normal or near-normal (at or below 1.5 x ULN): ≤69.4 mg (≤0.771 mmol)/24 h/1.73 m2.
95% CI: 31%, 72%; P=0.001 vs Placebo. Normal (at or below ULN): ≤46.3 mg (≤0.514 mmol)/24 h/1.73 m2.
The proportion of patients with levels in the near-normal range (32%) was not defined as an endpoint. Near-normal:
45.3-67.9 mg (0.515‑0.771 mmol)/24 h/1.73 m2.
In ILLUMINATE-B, evaluating OXLUMO® (lumasiran) in infants and young children with PH11
The multicenter, phase 3, single-arm, open-label trial includes patients aged <6 years and eGFR >45 mL/min/1.73 m2 (normal serum creatinine was used for patients aged <12 months*) (N=18)1
Selected baseline characteristics1:
- Median age at first dose: 51 months (range: 4 to 74 months)
- Median spot UOx:creatinine ratio at baseline: 0.37 mg/mg (0.47 mmol/mmol)
Above ULN for age.
Including hyperhydration, crystallization inhibitors, and/or pyridoxine therapy.
Patients <10 kg received starting doses 6.0 mg/kg monthly for 3 months and then ongoing doses 3.0 mg/kg monthly; patients ≥10 to <20 kg received starting doses 6.0 mg/kg monthly for 3 months and then ongoing doses 6.0 mg/kg every 3 months; patients ≥20 kg received starting doses 3.0 mg/kg monthly for 3 months and then ongoing doses 3.0 mg/kg every 3 months.6
In ILLUMINATE-B, patients treated with OXLUMO demonstrated reduction in UOx at month 61
Rapid reduction in spot UOx:creatinine through 6 months, sustained through 12 months1
Percent reduction in spot UOx/creatinine ratio (UOx:Cr) over time1,4
LS mean reduction averaged over months 3 through 6.
After month 6, samples are only collected every 3 months for patients in 10 to <20 kg and ≥20 kg weight groups.
For patients in the <10 kg weight group, pharmacodynamic collections are optional at non-quarterly months.Presented as mean ± standard error of the mean.
In ILLUMINATE-C, evaluating OXLUMO in more severely affected patients1,8
ILLUMINATE-C is a multicenter, phase 3, single-arm, open-label trial in patients of all ages with advanced kidney disease (N=21)1,8
Selected baseline characteristics1,8:
- Median age at first dose: 9 years (range, 0 to 59 years)
- Median POx at baseline: Cohort A, 58 µmol/L; Cohort B, 104 µmol/L (pre-hemodialysis)
- Mean (SD) eGFR at baseline: Cohort A, 19.8 (9.6) mL/min/1.73 m2; Cohort B, Not applicable
Above ULN for age.
ULN=12.11 μmol/L (1.09 mg/mL) for plasma oxalate, as determined based on data from 75 healthy adults.
Per protocol, Cohort A patients who experienced progression of kidney impairment over time and required hemodialysis therapy crossed over to Cohort B. No patients crossed over in the 6-month primary analysis period.
Patients <10 kg received starting doses 6.0 mg/kg monthly for 3 months and then ongoing doses 3.0 mg/kg monthly; patients ≥10 to <20 kg received starting doses 6.0 mg/kg monthly for 3 months and then ongoing doses 6.0 mg/kg every 3 months; patients ≥20 kg received starting doses 3.0 mg/kg monthly for 3 months and then ongoing doses 3.0 mg/kg every 3 months.
If administered on hemodialysis days, OXLUMO was administered after hemodialysis.1
In ILLUMINATE-C, significant POx reduction in patients with advanced kidney disease, including those on hemodialysis1
Treatment with OXLUMO led to substantial POx reduction from baseline to 6 months in patients with advanced kidney disease and patients with kidney failure on hemodialysis (N=21)1
ILLUMINATE-C: Reduction in POx with OXLUMO1
Reduction in POx (measured prior to hemodialysis session) from baseline to month 6
(95% CI: 34, 51)*
Mean plasma oxalate decreased from 108 μmol/L (95% CI: 92, 125) at baseline to 62 μmol/L (95% CI: 51, 72) at month 6 in Cohort B*
Reduction in POx from baseline to month 6
(95% CI:15, 82)*
Mean plasma oxalate decreased from 65 μmol/L (95% CI: 21, 108) at baseline to 33 μmol/L (95% CI: 10, 56) at month 6 in Cohort A*,1
Least squares mean reduction averaged over months 3 through 6.
The safety profile of OXLUMO® (lumasiran) was evaluated in infants, children, and adults1
OXLUMO has been studied in 98 patients with PH1, including 71 pediatric patients and 15 patients on hemodialysis1
Overall, 92 patients were treated for at least 6 months, 78 patients for at least 12 months, and 29 patients for at least 24 months.1
In placebo-controlled and open-label clinical studies the most common adverse reaction reported was injection site reaction. Injection site reactions included erythema, swelling, pain, hematoma, pruritus, and discoloration. These symptoms were generally mild and resolved within one day of the injection and did not lead to discontinuation of treatment.1
Safety during the 6-month double-blind period of ILLUMINATE-A
Adverse reactions reported in ≥10% of patients treated with OXLUMO and occurring ≥5% more frequently than in patients treated with placebo1
Grouped term includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
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All adverse events in both the group treated with OXLUMO and the group treated with placebo were mild or moderate in severity1,16
During the extension period of ILLUMINATE-A, months 6-24, the safety profile of OXLUMO was consistent with that observed in the double-blind period23
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The most common adverse reaction was injection site reaction (46%)
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1. OXLUMO [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc. 2. Garrelfs SF, Frishberg Y, Hulton SA, et al. N Engl J Med. 2021;384(13):1216-1226. 3. Hulton SA, Groothoff JW, Frishberg Y, et al. Kidney Int Rep. 2022;7(3):494-506. 4. Data on File. Alnylam Pharmaceuticals, Inc. 5. Lieske J, Groothoff JW, Frishberg Y, et al. Presented at: National Kidney Foundation Spring Clinical Meetings; April 6-10, 2022; Boston, MA. 6. Sas DJ, Magen D, Hayes W, et al. Genet Med. 2022;24(3):654-662. 7. Hayes W, Sas DJ, Magen D, et al. Pediatr Nephrol. 2023;38(4): 1075-1086. 8. Michael M, Groothoff JW, Shasha-Lavsky H, et al. Am J Kidney Dis. 2023;81(2):145-155.e1. 9. Frishberg Y, Michael M, Groothoff J, et al. Presented at: ASN Kidney Week; November 3-6, 2022; Orlando, FL, USA and Virtual.