GIVLAARI for Acute Porphyria

Please note: The following content was not reviewed by Alnylam Pharmaceuticals.

GIVLAARI is a treatment used to reduce acute hepatic porphyria (AHP) attacks in adults.There are 4 types of AHP: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA-dehydratase deficient porphyria (ADP). GIVLAARI is given once a month as a subcutaneous injection (under the skin) by a healthcare professional.

GIVLAARI is a double-stranded small interfering RNA (siRNA) therapeutic specifically targeting ALAS1 mRNA, reducing ALAS1 mRNA levels and leading to reductions in urinary ALA and PBG.¹

ALA, delta-aminolevulinic acid; ALAS1, delta-aminolevulinic acid synthase 1; mRNA, messenger RNA; PBG, porphobilinogen.

Patients with AHP have an enzyme deficiency in the heme biosynthesis pathway²

Disease triggers, such as infections or certain medications, can induce ALAS1 and led to overproduction of the neurotoxic intermediates ALA and PBG ^2-3.  ALA and PBG accumulate in the liver, and are further released into circulation, thereby causing neurototoxic effects^3-5. Neurotoxic effects lead to acute attacks ^3-5.

GIVLAARI targets ALAS1 mRNA for degradation¹

Specifically targeting ALAS1 mRNA for degradation reduces the production of the neurotoxic intermediates ALA and PBG¹  .  Less ALA and PBG are released into circulation^4,6. Reductions of ALA and PBG have been associated with fewer attacks⁶.

Treatment with GIVLAARI resulted in robust and sustained reductions in ALA and PBG¹

• Reductions in urinary ALA and PBG were seen with GIVLAARI at day 14¹
• 14 days after the first dose of GIVLAARI, median reductions from baseline in urinary ALA and PBG were 84% and 75%, respectively
• 94% and 95% median reductions from baseline in urinary ALA and PBG, respectively, were seen around Month 3 and sustained with once-monthly dosing of GIVLAARI 2.5 mg/kg  

References: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 2. Balwani M et al; the Porphyrias Consortium of the Rare Diseases Clinical Research Network. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. 3. Puy H et al. Porphyrias. Lancet. 2010;375(9718):924-937. 4. Bissell DM et al. Porphyria. N Engl J Med. 2017;377(9):862-872. 5. Bonkovsky HL et al. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019. doi: 10.1016/j.ymgme.2019.03.002. 6. Sardh E et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380(6):549-558. 7. Data on file. Alnylam Pharmaceuticals, Inc.

ENVISION: The largest interventional study in acute hepatic porphyria (AHP)¹

The efficacy and safety of GIVLAARI^® (givosiran) were evaluated in ENVISION, a randomized, double-blind, placebo-controlled, multinational Phase 3 study in adult patients with AHP (N=94)^1,2

• Patients who experienced an AHP attack during the study were treated according to the local standard of care, which could include hemin^1,3
• Prophylactic hemin use during the study was not permitted²

Treatment with GIVLAARI led to a signigicant reduction in porphyria attacks^1*

• During the 6-month treatment period, patients with AHP experienced 70% fewer attacks (requiring hospitalization, urgent care visit, or IV hemin administration at home¹.
• Patients who experienced an AHP attack during the study were treated according to the local standard of care, which could include hemin^,3
• Prophylactic hemin use during the study was not permitted²
• 50% of patients with AHP treated with GIVLAARI had no attacks during the 6-month treatment period vs 17% of patients treated with placebo.
• Significantly less hemin was used by AHP patients treated with GIVLAARI¹

Safety profile of GIVLAARI in ENVISION¹

*Grouped term includes pruritus, eczema, erythema, rash, rash pruritic, urticaria.
†Grouped term includes blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease (decreased estimated glomerular filtration rate).

• Permanent discontinuation of GIVLAARI occurred in 1 patient (2.1%) due to elevated liver transaminases
• The most frequently occurring (>20%) adverse reactions reported in patients treated with GIVLAARI were nausea (27%) and injection site reactions (25%)

References: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 2. Gouya L et al; ENVISION investigators. ENVISION, a Phase 3 study to evaluate the efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients. Oral presentation at: International Congress on Porphyrins and Porphyrias; September 10, 2019; Milan, Italy. 3. Data on file. Alnylam Pharmaceuticals, Inc. 4. Balwani et al; ENVISION investigators. ENVISION, a Phase 3 study to evaluate the efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients. Poster presented at: European Association for the Study of the Liver International Liver Congress; April 13, 2019; Vienna, Austria. 5. Sardh E et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380(6):549-558.

Once-monthly dosing with GIVLAARI® (givosiran)¹

The recommended dose of GIVLAARI is 2.5 mg/kg administered by a healthcare professional via subcutaneous injection once monthly. Dosing is based on actual body weight. GIVLAARI is intended for subcutaneous use by a healthcare professional only

Reference: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 

Missed Dose

• Administer GIVLAARI as soon as possible after a missed dose. Resume dosing at monthly intervals following administration of the missed dose

Dose Modification for Adverse Reactions

• In patients with severe or clinically significant transaminase elevations, who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly
• In patients who resume dosing at 1.25 mg/kg once monthly without recurrence of severe or clinically significant transaminase elevations, the dose may be increased to the recommended 2.5 mg/kg once monthly

GIVLAARI is administered via injection by a healthcare professional¹

• Ensure that medical support is available to subcutaneous appropriately manage anaphylactic reactions when administering GIVLAARI
• GIVLAARI is intended for subcutaneous use by a healthcare professional only
  Reference: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019.