GIVLAARI for Acute Porphyria

GIVLAARI is a treatment used to prevent acute hepatic porphyria (AHP) 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 effects3-5. 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 PBG.  Less ALA and PBG are released into circulation4,6. 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 hemin1,3
  • Prophylactic hemin use during the study was not permitted2

Treatment with GIVLAARI led to a signigicant reduction in porphyria attacks1*

  • 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

Reference1. 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
    Reference1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 

 


 

GIVLAARI for Acute Porphyria – Getting Started

Alnylam Assist®

As you begin your treatment with GIVLAARI® (givosiran), Alnylam Assist® will provide you with a dedicated Alnylam Case Manager and Patient Education Liaison for ongoing support throughout treatment. Once you and your healthcare provider choose to begin treatment, you should complete a Start Form together and submit it to Alnylam Assist®.

Upon receipt of the Start Form, an Alnylam Case Manager will reach out to you within 1-2 business days and will provide ongoing support throughout treatment. Alnylam Assist® services include:

  • Navigating your insurance benefits
  • A dedicated support team
  • Financial assistance

Visit: AlnylamAssist.com
Call: 1-833-256-2748
Monday-Friday, 8 AM-6 PM ET