Alnylam Presents New Results from the ILLUMINATE-C Phase 3 Study of Lumasiran in Patients with Advanced Primary Hyperoxaluria Type 1

By AIT News Desk On May 25, 2022

– Lumasiran Demonstrated Evidence of Improvements in Exploratory Endpoints of Systemic Oxalosis, Including Echocardiographic Structure and Function, Nephrocalcinosis, and Kidney Stone Events –

– Expands Upon Previously Reported Reductions in Plasma Oxalate in PH1 Patients with Severe Renal Impairment –

Alnylam Pharmaceuticals, Inc., the leading RNAi therapeutics company, announced new positive results from the six-month primary analysis period of the ILLUMINATE-C Phase 3 open-label study of lumasiran, an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – that is being investigated for the treatment of patients of all ages with advanced primary hyperoxaluria type 1 (PH1). As previously reported, treatment with lumasiran resulted in substantial reductions in plasma oxalate (POx) at six months. Results from new exploratory analyses provide evidence that lumasiran treatment resulted in improvements in cardiac measures, nephrocalcinosis and kidney stone events. In addition, some patients treated with lumasiran experienced improvements in their most burdensome symptoms (as assessed by the investigator), including fatigue, nausea, and bone pain, with no patients reporting worsening of those symptoms. These data were presented at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress being held both in Paris, France, and as a virtual event on May 19-22.

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“Patients with compromised renal function due to advanced PH1 tend to have elevated levels of plasma oxalate, which can lead to systemic spread of oxalate to organs beyond the kidneys, including the heart”

“Patients with compromised renal function due to advanced PH1 tend to have elevated levels of plasma oxalate, which can lead to systemic spread of oxalate to organs beyond the kidneys, including the heart,” said Professor Jaap Groothoff, M.D., Ph.D., Head of the Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, The Netherlands. “The ILLUMINATE-C study of lumasiran shows impressive plasma oxalate lowering in patients with severely impaired kidney function or who are on dialysis. These data, along with previous findings from ILLUMINATE-A and ILLUMINATE-B Phase 3 studies, provide evidence supporting the potential of lumasiran to benefit not only these patients, but those across the full spectrum of PH1 severity.”

“We are thrilled to be presenting preliminary data on clinical outcomes from our ILLUMINATE-C study. We believe the reductions in plasma oxalate seen with lumasiran in this study, along with this newly reported evidence of improvements in exploratory endpoints of cardiac measures, kidney stone events and nephrocalcinosis, are encouraging and signal the potential to establish lumasiran as a therapeutic option across the spectrum of PH1 disease severity,” said Pushkal Garg, M.D., Chief Medical Officer at Alnylam. “We look forward to further analyzing these endpoints over a longer period of time in the ongoing extension period of up to 54 months to continue to assess the impact of treatment with lumasiran on long-term clinical outcomes, including the manifestations of systemic oxalosis.”

Results

ILLUMINATE-C enrolled a total of 21 patients, including six who were not on dialysis at study start (Cohort A) and 15 who were on hemodialysis (Cohort B). As previously presented at the American Society of Nephrology (ASN) Kidney Week Meeting in 2021, in Cohorts A and B, respectively, treatment with lumasiran led to 33 percent and 42 percent mean reductions in POx from baseline to Month 6. Additionally, treatment with lumasiran led to 35 µmol/L (Cohort A) and 48 µmol/L (Cohort B) mean absolute reductions in POx from baseline to Month 6.

In new exploratory analyses, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured to assess the impact of lumasiran on the cardiac manifestations of systemic oxalosis. Among patients with abnormal LVEFⁱ at baseline across Cohort A (N=1) and Cohort B (N=4), the patient in Cohort A and two of four patients in Cohort B experienced a ≥ 5 percent improvement following six months of treatment with lumasiran. Among patients with abnormal GLSⁱⁱ at baseline across Cohort A (N=1) and Cohort B (N=3), all four patients showed a ≥2 percent improvement at Month 6.

In patients with medullary nephrocalcinosis at baseline in Cohort A (N=5), two patients remained stable, three improved (two unilateral and one bilateral improvement) and none worsened following six months of treatment with lumasiran. In Cohort A, one patient did not have nephrocalcinosis at baseline and had bilateral worsening at six months. In patients with nephrocalcinosis at baseline in Cohort B (N=2), both improved (one unilateral and one bilateral improvement) following six months of treatment with lumasiran.

In Cohort A, the rate of kidney stone events per person-year decreased from 3.2 (95% CI: 2, 5.2) in the 12 months prior to consent to 1.5 (95% CI: 0.6, 3.9) during the first six months of treatment with lumasiran. As expected, given patients in Cohort B are on hemodialysis, the rate of kidney stone events was low: 0.07 (95% CI: 0.01, 0.71) in the 12 months prior to consent and 0.0 (95% CI: 0.0, 0.53) during the first six months of treatment with lumasiran. For patients in both cohorts, the most burdensome symptoms at baseline (as assessed by the investigator), including fatigue, nausea/decreased appetite, bone pain and decreased mobility, improved or remained stable following six months of treatment with lumasiran; none of the symptoms worsened.

The most common adverse event related to lumasiran was injection-site reaction (ISR) reported in 5 of 21 patients (24 percent). All ISRs were mild and transient, and the most common symptoms included erythema, discoloration, and hematoma.

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A separate analysis presented at ERA-EDTA demonstrated that the recommended weight-based dosing regimens of lumasiran showed equivalent efficacy in patients of all ages and degrees of kidney function, including patients on hemodialysis.

OXLUMO^® (lumasiran) INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

OXLUMO is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients.

Important Safety Information

Adverse Reactions

The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

Pregnancy and Lactation

No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

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