Medical Policy

Policy Num:       M5.001.020
Policy Name:     Givosiran for Acute Hepatic Porphyria
Policy ID:          [M5.001.020] [Ac/MA/ M/ P ][0.00.00]

Last Review:       June 25, 2024
Next Review:      June 20, 2025
 

Related Policies: None

Givosiran for Acute Hepatic Porphyria

Summary

Description

Acute hepatic porphyria (AHP) is a rare disease with a prevalence of 5 to 10 cases/100,000 people in the US and effects primarily females (age range 15 to 45 years). The induction of the enzyme aminolevulinate synthase 1 (ALAS1) results in increased production and accumulation of toxic heme intermediates delta aminolevulinic acid and porphobilinogen in the plasma and urine. The accumulation of these toxic heme intermediates results in acute attacks characterized by severe abdominal pain, muscle weakness, seizures, psychiatric dysfunction, irreversible neurologic damage, and increased risk of hepatic malignancy. Givosiran (Givlaari®) is a double-stranded small interfering RNA that causes degradation of ALAS1 mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to decreased circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of acute hepatic porphyria.

Summary of Evidence

For individuals with AHP who receive givosiran, the evidence includes a randomized controlled trial (RCT) and interim data from a long-term extension of the RCT. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results from the double-blind, placebo-controlled, ENVISION RCT revealed that patients administered givosiran monthly for 6 months experienced a significant improvement in daily worst pain score and significant reductions in porphyria attacks, hemin use, and urinary ALA and PBG levels as compared to placebo. The increased efficacy of givosiran was accompanied by an increased frequency of hepatic and renal adverse events. Results from the interim data analysis of the long-term, open-label ENVISION extension confirmed the continuing benefits of givosiran therapy with safety findings consistent with the initial double-blind period. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Policy Statements

Initial Treatment

Givosiran may be considered medically necessary if all of the following conditions are met:

1. Individual is 18 years of age or older.

2. Individual has a diagnosis of acute hepatic porphyria (AHP) and confirmation of 1 of the following subtypes:

   1. Acute intermittent porphyria (AIP)

   2. Hereditary coproporphyria (HCP)

   3. Variegate porphyria (VP)

   4. Delta-aminolevulinic acid (ALA) dehydratase deficiency (ADP).

3. Documentation is provided that the individual has an elevated porphobilinogen (PBG)- or ALA in the urine or plasma within the past year.

4. Individual meets any 1 of the following criteria:

   1. Individual has documented active symptomatic disease with at least 2 porphyria attacks within the last 6 months.

   2. Individual is currently on prophylactic hemin treatment due to a history of severe or frequent porphyria attacks.

5. Individual will not be receiving prophylactic hemin treatment and givosiran concurrently.

6. Prescriber agrees to monitor liver function tests (LFTs).

7. Prescriber agrees to monitor renal function.

Initial authorization is for 12 months.

Continuation of Treatment

Incremental reauthorization for givosiran may be considered medically necessary if the following conditions are met:

1. Individual continues to meet the initial treatment criteria cited above.

2. Documentation is provided that the individual has experienced a clinical response to therapy (e.g., a reduction in rate of porphyria attacks or reduction in hemin requirements for acute attacks) since initiating therapy.

3. PBG or ALA concentration has not increased from baseline.

4. Individual does not have severe or clinically significant transaminase elevations, defined as alanine aminotransferase (ALT) greater than 5 times the upper limit of normal.

Reauthorization period is for 12 months.

Givosiran is considered investigational for all other indications.

Policy Guidelines

Givosiran

The recommended dose of givosiran is 2.5 mg/kg administered via subcutaneous injection once monthly by a healthcare professional, and medical support is readily available to appropriately manage anaphylactic reactions. Dosing is based on actual body weight.

In individuals 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 individuals 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.

• Givosiran is a ready-to-use solution that does not require additional reconstitution or dilution prior to administration, supplied in single-dose vials of 189 mg/mL;

• Calculate volume required based on recommended dosage: individual weight in kg × 2.5 mg/kg × 1 mL/189 mg = mL of givosiran to administer;

• If the total volume of givosiran per dose is >1.5 mL, divide the dose into multiple injections of approximately equal volumes.

Transaminase elevations (ALT) of at least 3 times times the upper limit of normal (ULN) were observed in 15% of patients treated with givosiran in the ENVISION trial. It is recommended that the prescriber measure liver function tests prior to initiating treatment with givosiran, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter.

Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with givosiran. It is recommended that the prescriber monitor renal function during treatment as clinically indicated.

In the ENVISION trial, a patient was eligible for the study without genetic testing that identified a variant in a porphyria-related gene if the patient had both clinical features and diagnostic biochemical criteria consistent with AHP. This is reported to be < 5% of the total number of AHP cases.

Coding

See the Codes table for details.

DOSAGE/ADMINISTRATION

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

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 [see Warnings and Precautions (5.2)]. 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 dose of 2.5 mg/kg once monthly.

GIVLAARI is intended for subcutaneous use by a healthcare professional only.

RATIONALE

This evidence review was created in June 2022 with a search of the PubMed database. The most recent literature update was performed through April 28, 2023.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Acute Hepatic Porphyria

Clinical Context and Therapy Purpose

The purpose of givosiran in patients who have acute hepatic porphyria (AHP) is to provide a treatment option that is an alternative to existing therapeutic management including pharmacologic (eg, hemin) and/or non-pharmacologic (eg, discontinuation of porphyrinogenic medications and carbohydrate loading) approaches.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest is adults with AHP.

Interventions

The therapy being considered is givosiran. It is a small interfering ribonucleic acid (RNA) that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, eventually reducing elevated levels of porphobilinogen (PBG) and aminolevulinic acid (ALA). This leads to decreased circulating levels of the neurotoxic intermediates ALA and PBG, factors associated with attacks and other disease manifestations of AHP.

Comparators

The following therapies are currently being used to make decisions about the treatment of AHP: nonpharmacologic and pharmacologic approaches that treat symptoms. These include avoiding or discontinuing porphyrinogenic medications and maintenance of a balanced diet without prolonged fasting or crash dieting. In the early stages of an acute AHP attack, management includes oral administration of calories (ie, carbohydrate loading) and rehydration as well as the potential administration of intravenous hemin. For patients who experience frequent recurrent attacks, which primarily involves women and may be associated with menstrual cycle changes, ovulatory suppression with a gonadotropin-releasing hormone analogue may be beneficial. Other medications may be necessary for symptom management on an individualized basis (eg, opiates for pain).

Outcomes

The general outcomes of interest are symptoms, quality of life, hospitalizations, and resource utilization. Health outcome measures relevant to AHP in adults are summarized in Table 1.

Table 1. Health Outcome Measures Relevant to AHP in Adults

AHP: acute hepatic porphyria; AIP: acute intermittent porphyria; IV: intravenous.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

The pivotal double-blind, placebo-controlled, phase 3 ENVISION trial (NCT03338816) evaluated the efficacy and safety of monthly givosiran as compared to placebo for 6 months in 94 symptomatic patients with AHP.^3, Key study characteristics of ENVISION are summarized in Table 2. Results are summarized presented in Table 3. Results were reported for the 89 patients with the acute intermittent porphyria (AIP) subtype of AHP only. Treatment with givosiran was associated with a significant reduction in the rate of porphyria attacks and improvement in other disease manifestations as compared to placebo.

After the 6-month, double-blind period of ENVISION, all on-study patients were administered givosiran during an open-label extension. Ventura et al (2022) reported interim data from the patients in ENVISION who completed at least 24 months on study (N=87).^4, Patients who continued to receive givosiran had a sustained annualized attack rate reduction. For patients who initially received placebo in the double-blind period but then crossed over to givosiran in the open-label extension, the median annualized attack rate decreased from 10.7 to 1.4. Long-term givosiran therapy was also associated with sustained reductions in hemin use and ALA and PBG levels. Safety findings were consistent with those observed in the initial double-blind period.

Table 2. Summary of Key RCT Characteristics

a Diagnosis based on clinical features, at least 1 documented urinary or plasma PBG or ALA value ≥ 4 × ULN within the past year prior to or during screening, AND 1 of the following: Either documented genetic evidence of mutation in a porphyria-related gene, defined as ANY of the following: AIP (variant in HMB gene also referred to as the PBGD gene), HCP (variant in CPOX gene), VP (variant in PPOX gene) and ADP (variant in ALAD homozygous or compound heterozygous genes) OR if the results of a patient’s genetic testing do not identify a variant in a porphyria-related gene (< 5% of cases), a patient may be eligible for the study if they have both clinical features and diagnostic biochemical criteria consistent with AHP.ADP: ALA dehydratase-deficiency porphyria; AHP: acute hepatic porphyria; AIP: acute intermittent porphyria; ALA: aminolevulinic acid dehydratase; CPOX: coproporphyrinogen oxidase; EU: European Union; HCP: hereditary coproporphyria; HMBS: hydroxymethylbilane synthase; PBG: porphobilinogen; PBGD: porphobilinogen deaminase; PPOX: protoporphyrinogen oxidase; RCT: randomized controlled trial; ULN: upper limit of normal; VP: variegate porphyria.

Table 3. Summary of Key RCT Results: ENVISION

CI: confidence interval; RCT: randomized controlled trial a Attacks that require hospitalization, urgent healthcare visits, or intravenous hemin administration at home.b Adjusted for prior hemin prophylaxis status and historical attack rates. A ratio <1 represents a favorable outcome for givosiran.

The purpose of the study limitations tables (see Table 4) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. A gap in relevance for ENVISION is related to the lack of data on individuals with non-AIP AHP. No major gaps were identified in study design and conduct.

Table 4. Study Relevance Limitations

AHP: acute hepatic porphyria; AIP: acute intermittent porphyria; HCP: hereditary coproporphyria; VP: variegate porphyria.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Section Summary: Acute Hepatic Porphyria

Results from a single double-blind, placebo-controlled RCT (ENVISION) comparing givosiran to placebo for 6 months concluded that givosiran therapy was associated with a significant reduction in the rate of acute porphyria attacks and other disease manifestations in patients with AHP as compared to placebo. There was an increase in injection site reactions, nausea, fatigue, and hepatic- and renal-related adverse events with givosiran therapy. The efficacy benefits seen in the double-blind period of the ENVISION trial were confirmed in an interim analysis of the open-label, long-term ENVISION extension with safety findings consistent with the initial ENVISION trial results.

Summary of Evidence

For individuals with AHP who receive givosiran, the evidence includes a randomized controlled trial (RCT) and interim data from a long-term extension of the RCT. Relevant outcomes are symptoms, quality of life, hospitalizations, and resource utilization. Results from the double-blind, placebo-controlled, ENVISION RCT revealed that patients administered givosiran monthly for 6 months experienced a significant improvement in daily worst pain score and significant reductions in porphyria attacks, hemin use, and urinary ALA and PBG levels as compared to placebo. The increased efficacy of givosiran was accompanied by an increased frequency of hepatic and renal adverse events. Results from the interim data analysis of the long-term, open-label ENVISION extension confirmed the continuing benefits of givosiran therapy with safety findings consistent with the initial double-blind period. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

REQUIRED MEDICAL INFORMATION

Text

EXCLUSION CRITERIA

None

BENEFIT APPLICATION

This medical policy applies to  Medicare Advantage LOB.

There is no medicare LCD or NCD specifically defined for this drug.

OTHER CRITERIA

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan

BACKGROUND

Acute Hepatic Porphyria

Porphyrias are inborn errors of metabolism that cause deficient activity within the 8-step heme synthetic pathway, leading to accumulation of heme precursors and subsequent clinical manifestations of disease. Porphyrias are generally classified in 1 of 2 ways: by main site of heme precursors (hepatic or erythropoietic) or cardinal clinical features (acute or cutaneous).

Acute hepatic porphyria (AHP) is a group of inherited diseases comprised of 4 subtypes: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and aminolevulinic acid (ALA) dehydratase-deficiency (ADP) porphyria. Three (ie, AIP, HCP, and VP) arise from autosomal dominant mutations of genes that control normal hepatic heme biosynthesis; AIP is the most common. The fourth type (ADP porphyria) is an autosomal recessive condition that is very rare. AHP is a rare disease with a prevalence of 5-10 cases/100,000 people in the US and affects primarily females (age range 15 to 45 years). The induction of enzyme aminolevulinate synthase 1 (ALAS1) results in increased production and accumulation of toxic heme intermediates delta ALA and porphobilinogen (PBG) in the plasma and urine. Clinically, the accumulation of toxic heme intermediates results in acute attacks characterized by severe abdominal pain, muscle weakness, seizures, psychiatric dysfunction, irreversible neurologic damage, and increased risk of hepatic malignancy.^1,Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms.

Porphyrias are rare disorders with nonspecific clinical manifestations similar to those of many other more common diseases. As a result, their diagnosis and appropriate treatment are often delayed. The condition is typically a diagnosis of exclusion and is usually considered only after several attack-related emergency department visits. First-line screening tests are sensitive for diagnosis of these disorders, and additional second-line testing readily differentiates the various types of porphyria. Diagnostic confirmation by DNA analysis is readily available. If suspected, establishing or ruling out an AHP diagnosis involves requesting a quantitative estimation of urine porphobilinogen (PBG), delta-aminolevulinic acid (ALA), and porphyrins via a spot sample, with results normalized to urine creatinine. In a symptomatic patient, a normal urine PBG excludes the 3 most common AHPs as the etiology of symptoms.

Treatment

The goal of therapy for an acute attack of AIP is to abate the attack as rapidly as possible and to provide appropriate supportive and symptomatic care. Hospitalization is usually required. Treatment of attacks consists of hemin Panhematin®), which is an enzyme inhibitor derived from processed red blood cells. Other long-term management considerations include discontinuation of medications that are harmful to patients with AHP during acute attacks; avoiding cigarettes, alcohol, and marijuana; and maintaining a diet high in carbohydrates (60% to 70% of total calories). Liver transplant, when available, is also an option. ^2,

Regulatory Status

In November 20, 2019, Givlaari® (givosiran) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with AHP.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Gastroenterological Association

The American Gastroenterological Association Institute Clinical Practice Updates Committee published best practice advice from a review of the published literature and from expert opinion on diagnosis and management of acute hepatic porphyrias (AHP). ^6, The best practice advise on management of the disease include the following:

• Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein.
• In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present.
• Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications.
• Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year).
• Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy.
• Patients with AHP should be monitored annually for liver disease.
• Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months.
• Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate.
• Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.

National Institute for Health and Care Excellence

On November 24, 2021 the National Institute for Health and Care Excellence (NICE) issued highly specialized technologies guidance on givosiran for treating AHP.^7,Givosiran is recommended as an option for treating AHP in adults and young people aged 12 and older, only if they have clinically confirmed severe recurrent attacks (4 attacks or more within 12 months) and the company provides it according to the commercial arrangement.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force (USPSTF) recommendations for givosiran have been identified.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

References

1. Bissell DM, Wang B. Acute Hepatic Porphyria. J Clin Transl Hepatol. Mar 2015; 3(1): 17-26. PMID 26357631
2. Wang B, Rudnick S, Cengia B, et al. Acute Hepatic Porphyrias: Review and Recent Progress. Hepatol Commun. Feb 2019; 3(2): 193-206. PMID 30766957
3. Balwani M, Sardh E, Ventura P, et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. Jun 11 2020; 382(24): 2289-2301. PMID 32521132
4. Ventura P, Bonkovsky HL, Gouya L, et al. Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int. Jan 2022; 42(1): 161-172. PMID 34717041
5. Prescribing Label: Givlaari (givosiran) injection, for subcutaneous use. Initial U.S. Approval: 2019. Available at https://www.alnylam.com/sites/default/files/pdfs/GIVLAARI-Prescribing-Information.pdf. Accessed May 3, 2023.
6. Wang B, Bonkovsky HL, Lim JK, et al. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology. Mar 2023; 164(3): 484-491. PMID 36642627
7. National Institute for Health and Care Excellence. Givosiran for treating acute hepatic porphyria. Highly specialized technologies guidance. Reference number:HST16. Published: 24 November 2021. Available at https://www.nice.org.uk/guidance/hst16. Accessed May 3, 2023.

Codes

Policy History