Background

Oxlumo is a small interfering RNA indicated for the treatment of patients with primary hyperoxaluria type 1 (PH1), a rare condition caused by a genetic mutation that results in buildup of oxalate. It works by targeting messenger RNA for the hydroxyacid oxidase 1 (HAO1) gene to reduce the production of glycolate oxidase and ultimately, oxalate. The dosing of Oxlumo is weight-based and consists of loading doses for the first 3 doses followed by maintenance doses either monthly or quarterly. It is administered as a subcutaneous injection by a health care professional. It should be noted that patients with end stage renal disease (ESRD) defined as an eGFR < 30 mL/min/1.73 m2 were excluded from trials with this drug and thus the risks and benefits of Oxlumo to this population are unknown. Primary hyperoxalurias are rare autosomal recessive inborn errors of glyoxylate metabolism that result in the overproduction of oxalate, primarily by the liver. PH1 is the most common form of primary hyperoxaluria with an estimated prevalence of 1 – 3 cases per 1 million individuals in the population. Each type of primary hyperoxaluria is caused by a different enzyme deficiency resulting from a specific mutation. PH1 results from mutations in the AGXT gene that encodes for a hepatic- > < 30 mL/min/1.73 m 2  were excluded from trials with this drug and thus the risks and benefits of Oxlumo to this population are unknown.

Primary hyperoxalurias are rare autosomal recessive inborn errors of glyoxylate metabolism that result in the overproduction of oxalate, primarily by the liver. PH1 is the most common form of primary hyperoxaluria with an estimated prevalence of 1 – 3 cases per 1 million individuals in the population. Each type of primary hyperoxaluria is caused by a different enzyme deficiency resulting from a specific mutation. PH1 results from mutations in the AGXT gene that encodes for a hepatic- specific peroxisomal enzyme, AGT. Clinical signs and symptoms of PH1 are caused by the buildup of oxalate and include progressive renal damage from tubular oxalate toxicity, nephrocalcinosis, and renal obstruction by stones, which are often accompanied by infection and inflammation. Ultimately, the patient’s eGFR declines and the kidney becomes incapable of excreting all of the oxalate being produced. Plasma oxalate levels then rise and oxalate is deposited into a variety of tissues causing a range of effects depending on the tissue where the oxalate is deposited. Diagnosis is established by identification of biallelic pathogenic variants in AGXT on molecular genetic testing or via a liver biopsy to assay the activity of the AGT enzyme.

Oxlumo is the first specific treatment for PH1. Prior to its approval, patients were encouraged to maintain a high fluid intake and limit oxalate-rich foods. Additional treatment options include oral potassium citrate or sodium citrate to alkalinize the urine and prevent calcium oxalate crystallization and pyridoxine supplementation to reduce oxalate synthesis.

Policy

1. Diagnosis of primary hyperoxaluria type 1 (PH1)

AND

2. Diagnosis has been confirmed by both of the following:
   1. 2.1 One of the following:
      1. Elevated urinary oxalate excretion
      2. Elevated plasma oxalate concentration
      3. Spot urinary oxalate to creatinine molar ratio greater than normal for age

AND

0. 2. 2.2 One of the following:
1. Genetic testing demonstrating a mutation in the alanine: glyoxylate aminotransferase (AGXT) gene
2. Liver biopsy demonstrating absence or reduced alanine: glyoxylate aminotransferase (AGT) activity

AND

3. Patient has not received a liver transplant

AND

4. Prescribed by or in consultation with one of the following:
   1. Hepatologist
   2. Nephrologist
   3. Urologist
   4. Geneticist
   5. Specialist with expertise in the treatment of PH1

References

1. Oxlumo [package insert]. Alnylam Pharmaceuticals. Cambridge, MA. Updated November 2020.
2. Oxlumo Drug Evaluation. Express Scripts. Updated December 2020.
3. Liebow A, Li X, Racie T, et al. An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. J Am Soc Nephrol. 2017;28:494-503.
4. Clinical PharmacologyTM 2022. Tampa FL: Gold Standard, Inc. Lumisiran.
5. Micromedex DrugDex Compendium®. 2022. Lumisiran.
6. Lumisiran In: AHFS Drug Information Online Electronic Medical Library. Bethesda, MD: American Society of Health-System Pharmacists. Updated December 14, 2020.
7. Frishberg Y, Deschenes G, Groothoff JW, et al. Phase ½ study of lumasiran for treatment of primary hyperoxaluria type 1: A placebo-controlled randomized clinical trial. 2021;16:1025-36.
8. Hulton SA, Groothoff JW, Frishberg Y, et al. Randomized clinical trial on the long-term efficacy and safety of lumasiran in patients with primary hyperoxaluria type 1. Kidney Int Rep. 2022;7:494-506.
9. Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. NEJM. 2021;384:1216-26.
10. Sas DJ, Magen D, Hayes W, et al. Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children. Genetics in Medicine. 2022;24:654-62.
11. Michael M, Groothoff JW, Shasha-Lavsky H, et al. Lumasiran for advanced primary hyperoxaluria type 1: Phase 3 ILLUMINATE-C trial. AJKD. 2022;S0272-6386(22):00771-5.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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