Givosiran (Givlaari)

Number: 0961

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses givosiran (Givlaari) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of givosiran (Givlaari) is required of all Aetna participating providers and members in applicable plan designs. For precertification of givosiran (Givlaari) call 866-752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

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.

1. Criteria for Initial Approval

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

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

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of givosiran (Givlaari) therapy medically necessary for treatment of an indication listed in Section I for members who are experiencing benefit from therapy while receiving givosiran (Givlaari) (e.g., reduction in porphyria attacks that required hospitalizations, urgent healthcare visit, or intravenous hemin administration).

Dosage and Administration

Givosiran (Givlaari) is supplied as 189 mg/mL single-dose vials for subcutaneous injection. Givlaari is intended for subcutaneous use by a healthcare professional only.

Acute Hepatic Porphyria (AHP)

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

Source: Alnylam Pharmaceuticals, 2023

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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
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

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Background

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

• Givlaari is indicated for the treatment of adults with acute hepatic porphyria (AHP).

Givosiran is available as Givlaari (Alnylam Pharmaceuticals) for subcutaneous injection. Givosiran is an aminolevulinate synthase 1-directed small interfering RNA.

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, 2023).

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, 2019; 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, 2019; FDA, 2019). 

Balwani and colleagues (2020) noted that up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in AHP.  Givosiran, an RNA interference therapy, inhibits ALAS1 expression.  In a double-blind, placebo-controlled, phase-III clinical trial, these researchers randomly assigned symptomatic patients with AHP to receive either subcutaneous givosiran (2.5 mg/kg body weight) or placebo monthly for 6 months.  The primary endpoint was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of AHP.  Composite porphyria attacks resulted in hospitalization, an urgent healthcare visit, or intravenous (IV) administration of hemin at home.  Key secondary endpoints were levels of ALA and porphobilinogen and the annualized attack rate among patients with AHP, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.  A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group).  Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74 % lower rate in the givosiran group (p < 0.001); the results were similar among the 94 patients with AHP.  Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo.  Key adverse events (AEs) that were observed more frequently in the givosiran group were elevations in serum alanine aminotransferase (ALT) levels, changes in serum creatinine (Cr) levels and the estimated glomerular filtration rate (eGFR), and injection-site reactions.  The authors concluded that among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo.  The increased efficacy was accompanied by a higher frequency of hepatic and renal AEs.

Other Indications

5-Aminolevulinic Acid Dehydratase (ALAD) Porphyria

Graff et al (2022) noted that 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an autosomal recessive disease characterized by a profound deficiency in ALAD, the 2nd enzyme in the heme biosynthetic pathway, and acute neuro-visceral attacks with abdominal pain and peripheral neuropathy.  Hemin infusions are often effective in treating and preventing such attacks.  Givosiran was recently approved for prevention of attacks of AHPs, including ADP.  However, to the authors’ knowledge, givosiran has not yet been employed in patients with this ultra-rare disease.  These investigators updated the clinical course and reported new treatment outcomes of a 32-year-old man with ADP managed for many years with weekly prophylactic hemin infusions.  He has developed evidence of iron overload and was more recently found to have compensated cirrhosis.  The patient was started on givosiran that is effective in preventing frequently recurring attacks of AIP, the most common type of AHP.  The authors concluded that no adverse effects of givosiran on the liver were observed in this patient with cirrhosis during 6 months of treatment with givosiran.  However, these researchers stated that further investigation in patients with other types of acute porphyria and co-existing liver disease is needed.  The patient has continued to have recurrent attacks, with transient decreases in ALA levels only as related to treatment of his attacks with hemin.  These investigators stated that their experience limited to 1 patient with ADP suggested that givosiran may not be effective in this type of acute porphyria.  Since ADP may have an erythropoietic component, treatment with hydroxyurea, which was beneficial in 1 previous case, is planned.

Cancer Therapy

Kara et al (2022) noted that over the last 10 years, non-coding RNA-based therapeutics have proven as a great potential for the development of targeted therapies for cancer and other diseases.  The discovery of the critical function of microRNAs (miRNAs) has generated great excitement in developing miRNA-based therapies.  The dysregulation of miRNAs contributes to the pathogenesis of various human diseases and cancers by modulating genes that are involved in critical cellular processes, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, drug resistance, and tumorigenesis.  miRNA (miRNA mimic, anti-miRNA/antagomir) and siRNA can inhibit the expression of any cancer-related genes/mRNAs with high specificity via RNAi; therefore, representing a remarkable therapeutic tool for targeted therapies and precision medicine.  siRNA and miRNA-based therapies have entered clinical trials and recently 3 novel siRNA-based therapeutics were approved by the FDA, indicating the beginning of a new era of targeted therapeutics.  The successful clinical applications of miRNA and siRNA therapeutics rely on safe and effective nano-delivery strategies for targeting tumor cells or tumor micro-environment.  For this purpose, promising nano-delivery/NP-based approaches have been developed using a variety of molecules for systemic administration and improved tumor targeted delivery with reduced side effects.  The authors presented an overview of RNAi-based therapeutics, the major pharmaceutical challenges, and the perspectives for the development of promising delivery systems for clinical translation.  These researchers also highlighted the passive and active tumor targeting nano-delivery strategies and focused on the current applications of NP-based delivery formulations for tumor targeted RNAi molecules and their recent advances in clinical trials in human cancers.

Chen and Xu (2022) stated that as the discovery of RNAi and the gradual conquering of a series of technical issues, a few of RNAi therapeutics have been approved in the non-tumor field abroad.  With the advantages of high specificity, long duration of efficacy, and high success rate of development, RNAi therapeutics have become the emerging field globally.  There are no RNAi therapeutics approved in oncology so far, and people are hoping for a breakthrough in the field.  These researchers described the characteristics and potential anti-tumor mechanism of RNAi therapeutics, difficulties in delivery system and progress in oncology.  The authors also analyzed the potential reasons why the success RNAi therapeutics in non-tumor field is difficult to be simply replicated in tumor field, providing reference for research and clinical transformation of RNAi therapeutics in oncology.

COVID-19 Disease / Respiratory Diseases

Zhang et al (2022) noted that since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe.  Currently, the FDA has issued emergency approval for the use of some anti-viral drugs.  However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new therapeutic strategies are urgently needed.  RNAi-based gene therapy provides a tractable target for anti-viral treatment.  Ensuring cell-specific targeted delivery is important to the success of gene therapy.  The use of NPs as carriers for the delivery of siRNAs to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19.  These investigators described a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarized the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery.  They also discussed the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration.  These researchers also discussed currently available animal models that are used for pre-clinical assessment of RNAi-based gene therapy.  The authors concluded that advances in this field have the potential for anti-viral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.

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References