Givosiran (Givlaari)

Number: 0961

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of givosiran (Givlaari) is required of all Aetna participating providers and members in applicable plan designs. For precertification of givosiran call 866-752-7021, or fax (866) 267-3277. 

Note: Site of Care Utilization Management Policy applies for givosiran (Givlaari). For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers givosiran (Givlaari) medically necessary for the treatment of acute hepatic porphyria (AHP) when all of the following criteria are met: 

• The member is actively symptomatic; and 
• The member has an elevated urine porphobilinogen (PBG), or an elevated porphyrin level (plasma or fecal).

Aetna considers continuation of givosiran (Givlaari) medically necessary for members with AHP who are experiencing benefit from from therapy.

Aetna considers givosiran (Givlaari) experimental and investigational for all other indications.

Dosing Recommendations

Givlaari (givosiran) is available for injection in 189 mg/mL single-dose vials. Givlaari is intended for subcutaneous use by a healthcare professional only.

The recommended dose of Givlaari is 2.5 mg/kg administered via subcutaneous injection once monthly. Dosing is based on actual body weight.

Source: Alnylam Pharmaceuticals, 2019b

Background

Givosiran (Givlaari) is an aminolevulinate synthase 1-directed small interfering RNA.

U.S. Food and Drug Administration (FDA)-Approved Indications

• For the treatment of adults with acute hepatic porphyria (AHP).

Labeled warnings and precautions include risk of anaphylactic reation (less than 1% of patients in clinical trials), hepatic toxicity (transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients treated with Givlaari in the placebo-controlled trial), renal toxicity (15% of patients in the Givlaari arm in the placebo-controlled trial), and injection site reactions (25% of patients in the placebo-controlled trial). The most common adverse reaction (20% and greater) included nausea and injection site reactions (Alnylam, 2019b).

Acute Hepatic Porphyria (AHP)

Acute hepatic porphyrias (AHP) includes a family of rare, genetic diseases in which there is a defect, or deficiency, in one of the enzymes within the heme biosynthetic pathway in the liver that can result in accumulation of porphyrins, a heme precursor that can be toxic to the tissues at high levels, and neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG). Hepatic porphyrias is comprised of four subtypes which include acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), which are autosomal dominant disorders, and aminolevulinic acid dehydratase deficiency porphyria (ALAD), which is autosomal recessive and very rare. AHPs are characterized by episodic neurological attacks (seizures, psychosis, severe abdominal and back pain, and an acute polyneuropathy), which can occur suddenly and can produce permanent neurological damage and death; and, to a lesser extent, present with cutaneous manifestations, usually a photosensitive blistering rash or hypertrichosis. The most common presenting symptom is neuropathic abdominal pain. Management of these individuals can be challenging because the disease manifestations are diverse and potentially life-threatening due to neurologic complications (e.g., seizures or paralysis) (Anderson, 2018; Bissell and Wang, 2015; Kothadia et al., 2019; Sood and Anderson, 2019).

Evaluating a person for AHP involves the clinician to gather a detailed history, perform a thorough physical examination, and follow-up with the following investigations when AHP is suspected. “Urine porphobilinogen (PBG) is the most important first-line screening test, which is both highly sensitive and highly specific. Through feedback, the reduced production of heme brings about elevated production of heme precursors, with PBG among the first substances in the porphyrin synthesis pathway. In fact, in almost all cases of acute hepatic porphyrias, urinary PBG is significantly elevated. Of note, repeat testing during an acute attack may be needed to diagnose a porphyria, as levels may be normal or almost normal between attacks” (Kothadia et al, 2019). Plasma and feces can be tested for quantitative determination of ALA, PBG, and porphyrin levels. Decreased erythrocyte porphobilinogen deaminase (PBGD) activity is seen in the approximately 90% of patients. It can also be seen in asymptomatic patients. Mild elevation of transaminases is common, but other liver function tests generally remain normal. Kothadia and colleagues (2019) note that AHPs are very rare diseases and that general hospital labs usually do not have the technology, the staff time, or the expertise to conduct testing for them. Commonly, such testing involves sending the samples of blood, urine, and stool to a reference laboratory.

Therapy requires confirmation that the individual indeed has acute porphyria, based on the finding of elevated urinary porphobilinogen (PBG), either at present or previously, but it does not require a diagnosis of the exact type of acute porphyria (Kothadia et al., 2019). The goal of treatment for an acute attack of hepatic porphyria has been to abate the attack as quickly as possible and to provide appropriate supportive care and symptomatic care until the acute attack resolves. Treatment of acute attacks include intravenous administration of hemin, especially for those individuals requiring hospitalization, opioid analgesia, or condition is accompanied by nausea/vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus or hyponatremia.  Carbohydrate loading is also recommended as a temporary measure if hemin is not immediately available. Glucose and other carbohydrates reduce excretion of porphyrin precursors by downregulating hepatic ALAS enzyme, delta-aminolevulinic acid synthase (ALAS1), an effect mediated by decreases in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha). However, the effects of glucose are weak compared with those of hemin (Kothadia et al., 2019; Sood and Anderson, 2019). In contrast to acute attacks, subacute or chronic symptoms are unlikely to respond to acute administration of hemin. Hemin represses hepatic delta-aminolevulinic acid synthase (ALAS1) for only a few days before it is rapidly metabolized to biliverdin and bilirubin by hepatic heme oxygenase and biliverdin reductase. A trial of hemin may be warranted in persons with subacute symptoms, but chronic pain and other symptoms are treated symptomatically, often with consultation with a pain management specialist (Sood and Anderson, 2019).

Givosiran has been studied as a treatment option for adults with AHP. On November 20, 2019, the U.S. Food and Drug Administration (FDA) approved Givlaari (givosiran) for the treatment of adults with acute hepatic porphyria. Givosiran is a subcutaneously administered RNAi therapeutic which targets aminolevulinic acid synthase 1 (ALAS1) in order to lower liver-induced ALAS1 levels and decrease related intermediates. The FDA granted Breakthrough Therapy designation, Priority Review designation, as well as, Orphan Drug designation to Alynylam Pharmaceuticals for Givlaari based on the results of a Phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial (ENVISION) that evaluated the efficacy and safety of givosiran in patients with acute hepatic porphyrias (AHP) (Alnylam Pharmaceuticals, 2019a; FDA, 2019).

The ENVISION trial enrolled 94 adult patients (range 19 to 65 years) with acute hepatic porphyria (AHP). Eligible patients were randomized 1:1 to receive once monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo (normal saline) during the 6-month double-blind period. In this study, inclusion criteria specified a minimum of 2 porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home in the 6 months prior to study entry. Exclusion criteria included anticipated liver transplantation, active HIV, hepatitis C virus, or hepatitis B virus infection, and history of recurrent pancreatitis. Hemin use during the study was permitted for the treatment of acute porphyria attacks. Givosiran and placebo arms were balanced with respect to historical porphyria attack rate, hemin prophylaxis prior to study entry, use of opioid medications, and patient-reported measures of pain symptoms between attacks. Efficacy in the 6-month double-blind period was measured by the rate of porphyria attacks that required hospitalizations, urgent healthcare visit, or intravenous hemin administration at home. On average, AHP patients on givosiran experienced 70% fewer porphyria attacks compared to placebo. The ENVISION trial is ongoing with an estimated study completion date of September 2021 (Alnylam Pharmaceuticals, 2019a, 2019b; FDA, 2019). 

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
84110	Porphobilinogen, urine; quantitative
84126	Porphyrins, feces, quantitative
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
HCPCS codes covered if selection criteria are met:
J0223	Injection, givosiran, 0.5 mg
ICD-10 codes covered if selection criteria are met:
E80.20	Unspecified porphyria
E80.21	Acute intermittent (hepatic) porphyria
E80.29	Other porphyria

The above policy is based on the following references: