Coverage Policy Manual
Policy #: 2020009
Category: Pharmacy
Initiated: April 2020
Last Review: September 2023
  Givosiran (e.g., GIVLAARI®)
Description:
Givosiran is a small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference. The proposed mechanism of action for its use in treating porphyria involves reducing the levels of potentially neurotoxic intermediates--aminolevulinic acid and porphobilinogen—via the gene-silencing effect of iRNA therapy on inhibition of hepatic ALAS1 mRNA production.
 
Porphyria is a group of eight genetic disorders that cause defective production of heme, the oxygen-carrying component of red blood cells. Acute hepatic porphyria (AHP) is a form of porphyria with 4 subtypes: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase-deficiency porphyria (ADP). In AHP, defective enzymes in the heme biosynthesis pathway allow aminolevulinic acid and other neurotoxic heme intermediates to accumulate. This accumulation can trigger a porphyria attack.
 
AHP occurs primarily in women and has an onset in young adulthood. Porphyria attacks are characterized by severe abdominal and neuropathic pain, many nonspecific symptoms, hypertension, hyponatremia, and red urine. Attacks can last for days and can be life-threatening. It can be triggered or exacerbated by factors that increase ALAS1 activity and ALA accumulation. This includes inadequate carbohydrate intake, stress, pain, female hormonal changes, smoking, excessive alcohol use, and drugs or substances that induce ALAS1 activity. Long-term complications of AHP include liver disease, hepatocellular carcinoma, chronic kidney disease, and hypertension.
  
Givosiran is an FDA-approved treatment for prophylaxis of attacks of acute hepatic porphyria (AIP, ADP, VP, and HCP). It works by muting ALAS1 via RNA interference through monthly subcutaneous injections administered by a healthcare professional. This drug is not approved for other forms of porphyria, such as cutaneous forms of porphyria, where standard treatment typically includes regularly scheduled phlebotomies.
 
Regulatory Status:
On June 4, 2019, the FDA approved the use Givosiran injection for the treatment of adults with acute hepatic porphyria (AHP).
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Effective April 1, 2020, Prior Approval is required for Givosiran (e.g., Givlaari).
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
Effective September 1, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
 
The use of givosiran for the prophylaxis of acute attacks caused by acute hepatic porphyria meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the below are confirmed:
 
    1. Individual is 18 years of age or older; AND has a confirmed diagnosis of acute hepatic porphyria, and confirmation of one of the following subtypes (APF 2010-2019) (Balwani, 2019):
a.  Acute intermittent porphyria (AIP); OR  
b.  Hereditary coproporphyria (HCP), OR  
c.  Variegate porphyria (VP), OR  
d.  ALA dehydratase-deficiency porphyria (ADP); AND
 
2. Individual has documentation of elevated urinary or plasma porphobilinogen (PBG) or delta-aminolevulinic acid (ALA) within the past year (Balwani, 2019); AND
 
3. Individual meets one of the following criteria:
a.  Individual has active symptomatic disease, with at least two documented porphyria attacks requiring acute care within the last six months (Balwani, 2019; Sood, 2020), OR
b.  Individual is currently on prophylactic hemin treatment due to a history of severe or frequent porphyria attacks AND
 
4. Individual does not have any of the following:
a.  Porphyria cutanea tarda OR
b.  Erythrocytic OR
c.  Erythrocytic protoporphyria AND
 
5. The individual's prescriber agrees to both of the following (Balwani, 2019),
a.  Prescriber agrees to monitor liver function tests (LFTs) AND
b.  Prescriber agrees to monitor renal function AND
 
6. The individual is not receiving concurrent hemin as prophylaxis (Balwani, 2019), AND
 
7. A healthcare professional will be available to administer medication and give medical support if necessary for anaphylactic reaction, AND
 
8. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 1 year:
 
    1. Individual is age 18 years of age and older AND
    2. Individual must have acute hepatic porphyria (AHP) AND  
    3. Documentation individual has experienced a clinical response to therapy (i.e., a reduction in the number of porphyria attacks or reduction in hemin requirements for acute attacks) since initiating therapy, AND
    4. Porphobilinogen (PBG) or delta-aminolevulinic acid (ALA) concentration has not increased from baseline AND
    5. Individual does not have severe or clinically significant transaminase elevations, defined as alanine aminotransferase (ALT) greater than 5 times the upper limit of normal AND
    6. Prescriber agrees to monitor renal function AND
    7. A healthcare professional will be available to administer mediation and give medical support if necessary for anaphylactic reactions.
 
Dosing and Administration
Dosing per FDA Guidelines
 
The use of givosiran is allowed up to 189 mg (one vial) or 2.5mg/kg whichever comes first.  The use of more than a single vial per dose is not routinely allowed.
 
Givosiran is available as 189 mg single-use vials and is administered subcutaneously once monthly with appropriate medical support.   
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Givosiran for any indication or circumstance other than those described above including but not limited to porphyria cutanea tarda, erythrocytic, erythrocytic  protoporphyria, etc., for any additional indication in the treatment of acute hepatic porphyrias other than acute attack prophylaxis,  and for all other conditions or indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes
 
For members with contracts without primary coverage criteria, the use of Givosiran for any indication or circumstance other than those described above including but not limited to porphyria cutanea tarda, erythrocytic, erythrocytic protoporphyria, etc., for any additional indication in the treatment of acute hepatic porphyrias other than acute attack prophylaxis, and for all other conditions or indications is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective April 1, 2020, Prior Approval is required for Givosiran (e.g., Givlaari).
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
Effective September 28, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of givosiran for the prophylaxis of acute attacks caused by acute hepatic porphyria meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when ALL of the below are confirmed:
 
Initiation (Coverage for 6 months)
 
  1. Individual is 18 years of age or older; AND has a confirmed diagnosis of acute hepatic porphyria, and confirmation of one of the following subtypes (APF 2010-2019) (Balwani, 2019):
        • Acute intermittent porphyria (AIP) ;OR  
        • Hereditary coproporphyria (HCP), OR  
        • Variegate porphyria (VP); OR  
        • ALA dehydratase-deficiency porphyria (ADP); AND
2.  Individual has documentation of elevated urinary or plasma porphobilinogen (PBG) or delta-aminolevulinic acid (ALA) within the past year (Balwani, 2019); AND
3.  Individual meets one of the following criteria:
        • Individual has active symptomatic disease, with at least two documented porphyria attacks requiring acute care within the last six months (Balwani, 2019; Sood, 2020), OR
        • Individual is currently on prophylactic hemin treatment due to a history of severe or frequent prophyria attacks AND
4. The individual's prescriber agrees to both of the following (Balwani, 2019),
        • Prescriber agrees to monitor liver function tests (LFTs) AND
        • Prescriber agrees to monitor renal function AND
5. The individual is not receiving concurrent hemin as prophylaxis (Balwani, 2019), AND
6.  A healthcare professsional will be available to administer medication and give medical support if necessary for anaphylactic reaction.
 
Continuation (Coverage for 1 year)
 
  1. Individual is age 18 years of age and older AND
  2. Individual must have acute hepatic prophyria (AHP) AND  
  3. Documentation individual has experienced a clinical response to therapy (i.e., a reduction in the number of porphyria attacks or reduction in hemin requirements for acute attacks) since initiating therapy, AND
  4. Porphobilinogen (PBG) or delta-aminolevulinic acid (ALA) concentration has not increased from baseline AND
  5. Individual does not have severe or clinically significant transaminase elevations, defined as alanine aminotransferase (ALT) greater than 5 times the upper limit of normal AND
  6. Prescriber agrees to monitor renal function AND
  7. A healthcare professional will be available to administer mediation and give medical support if necessary for anaphylactic reactions.
 
Dosing and Administration
 
    • Givosiran is supplied in 189 mg single-use vials and is administered SQ once monthly with appropriate medical support.  
    • The use of givosiran is allowed up to 189 mg (one vial) or 2.5mg/kg whichever comes first.  
    • The use of more than a single vial per dose is not routinely allowed.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Givosiran does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of other types of porphyria (other than those listed above) including but not limited to porphyria cutanea tarda, erythrocytic, erythrocytic  protoporphyria, etc, for any additional indication in the treatment of acute hepatic porphyrias other than acute attack prophylaxis,  and for all other conditions or indications.
 
For members with contracts without primary coverage criteria, the use of Givosiran is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 1, 2021 to September 27, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of givosiran for the prophylaxis of acute attacks caused by acute hepatic porphyria meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when ALL of the below are confirmed:
 
Initiation (Coverage for 6 months)
 
  1. Individual is 18 years of age or older; AND has a confirmed diagnosis of acute hepatic porphyria, and confirmation of one of the following subtypes (APF 2010-2019) (Balwani, 2019):
        • Acute intermittent porphyria (AIP) ;OR  
        • Hereditary coproporphyria (HCP), OR  
        • Variegate porphyria (VP); OR  
        • ALA dehydratase-deficiency porphyria (ADP); AND
2.  Individual has documentation of elevated urinary or plasma porphobilinogen (PBG) or delta-aminolevulinic acid (ALA) within the past year (Balwani, 2019); AND
3.  Individual has active symptomatic disease, with at least two documented severe porphyria attacks within the last six months or 3-4 attacks per year (requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home) (Balwani, 2019; Sood, 2020), AND
4. The member does not have a history of (or is not currently evaluated for) liver transplant or have a history of recurrent pancreatitis (Balwani, 2019), AND
5. The member is not receiving concurrent hemin as prophylaxis (Balwani, 2019), AND
6.  Must be prescribed by or in consultation with a specialist in porphyria treatment (e.g. hepatologist, hematologist, neurologist)
 
Continuation (Coverage for 1 year)
 
  1. Individual has experienced a reduction in the number of porphyria attacks; AND  
  2. Individual does not have severe or clinically significant transaminase elevations, defined as alanine aminotransferase (ALT) greater than 5 times the upper limit of normal and/or has not undergone a liver transplant.
 
Dosing and Administration
 
    • Givosiran is supplied in 189 mg single-use vials and is administered SQ once monthly with appropriate medical support.  
    • The use of givosiran is allowed up to 189 mg (one vial) or 2.5mg/kg whichever comes first.  
    • The use of more than a single vial per dose is not routinely allowed.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Givosiran does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of other types of porphyria (other than those listed above) including but not limited to porphyria cutanea tarda, erythrocytic, erythrocytic  protoporphyria, etc, for any additional indication in the treatment of acute hepatic porphyrias other than acute attack prophylaxis,  and for all other conditions or indications.
For members with contracts without primary coverage criteria, the use of Givosiran is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to November 1, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of givosiran for the prophylaxis of acute attacks caused by acute hepatic porphyria meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when ALL of the below are confirmed:
 
Initiation (Coverage for 6 months)
 
  1. Individual is 18 years of age or older; AND has a confirmed diagnosis of acute hepatic porphyria, and confirmation of one of the following subtypes (APF 2010-2019):
        • Acute intermittent porphyria (AIP) ;OR  
        • Hereditary coproporphyria (HCP), OR  
        • Variegate porphyria (VP); OR  
        • ALA dehydratase-deficiency porphyria (ADP); AND
2.  Individual has documentation of elevated urinary or plasma porphobilinogen (PBG) or delta-aminolevulinic acid (ALA) within the past year; AND
3.  Individual has active symptomatic disease, with at least two documented severe porphyria attacks within the last six months (requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home), AND
4. The member does not have a history of (or is not currently evaluated for) liver transplant or have a history of recurrent pancreatitis, AND
5. The member is not receiving concurrent hemin as prophylaxis, AND
6.  Must be prescribed by or in consultation with a specialist in porphyria treatment (e.g. hepatologist, hematologist, neurologist)
 
Continuation (Coverage for 1 year)
 
  1. Individual has experienced a reduction in the number of porphyria attacks; AND  
  2. Individual does not have severe or clinically significant transaminase elevations, defined as alanine aminotransferase (ALT) greater than 5 times the upper limit of normal and/or has not undergone a liver transplant.
 
Dosing and Administration
 
    • Givosiran is supplied in 189 mg single-use vials and is administered SQ once monthly with appropriate medical support.  
    • The use of givosiran is allowed up to 189 mg (one vial) or 2.5mg/kg whichever comes first.  
    • The use of more than a single vial lperdose is not routinely allowed.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Givosiran does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of other types of porphyria (other than those listed above) including but not limited to porphyria cutanea tarda, erythrocytic, erythrocytic  protoporphyria, etc, for any additional indication in the treatment of acute hepatic porphyrias other than acute attack prophylaxis,  and for all other conditions or indications.
For members with contracts without primary coverage criteria, the use of Givosiran is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
The efficacy of givosiran in patients with acute hepatic porphyria (AHP) was assessed in a randomized, double-blind, placebo-controlled, multinational clinical trial (ENVISION trial; NCT03338816). The study enrolled 94 patients with AHP (89 patients with acute intermittent porphyria, 2 patients with variegate porphyria, 1 patient with hereditary coproporphyria, and 2 patients with no identified mutation) with a minimum of two porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home in the 6 months prior to trial entry. Patients were randomized 1:1 to receive once monthly subcutaneous injections of either givosiran 2.5 mg/kg or placebo over a 6-month double-blind period. Use of hemin was allowed during the study for the treatment of acute porphyria attacks. The primary efficacy endpoint was the rate of porphyria attacks that required hospitalizations, urgent healthcare visit, or intravenous hemin administration at home, which was significantly lower with givosiran treatment (mean rate, 1.9; 95% CI, 1.3 to 2.8) compared to placebo (mean rate, 6.5; 95% CI, 4.5 to 9.3). According to the prescribing information for givosiran, study results suggest that AHP patients receiving givosiran experienced 70% fewer porphyria attacks than patients receiving placebo (95% CI, 60% to 80%).
 
2021 Update
In a double-blind, placebo-controlled, phase 3 trial, symptomatic patients with acute hepatic porphyria were randomly assigned to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, 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 acute hepatic porphyria. 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 that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.
 
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 adverse events. (NCT03338816) (Balwani M, Sardh E, Ventura P, et.al., 2020)
 
2022 Update
Long-term efficacy and safety of givosiran in acute hepatic porphyria was evaluated.
 
Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.
 
Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period.
 
Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life. (Ventura P, Bonkovsky HL, Gouya L, et.al., 2022).
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement.
 
CPT/HCPCS:
J0223Injection, givosiran, 0.5 mg
J3490Unclassified drugs
References: Balwani M, Gouya L, Rees DC, et al.(2019) 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. April 13, 2019. European Association for the Study of the Liver (EASL) 54th Annual International Liver Congress. Vienna, Austria

Balwani M, Sardh E, Ventura P, et.al.(2020) ENVISION Investigators. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147. PMID: 32521132.

Sardh E, Harper P, Balwani M, et al.(2019) Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med. 2019 Feb 7;380(6):549-558.

Sood GK, Anderson KE.(2020) Acute intermittent porphyria: Management. Accessed at https://www.uptodate.com/contents/acute-intermittent-porphyria-management?search=givlaari§ionRank=2&usage_type=default&anchor=H10&source=machineLearning&selectedTitle=2~7&display_rank=1#. Last accessed August 19, 2021.

U.S. Food and Drug Administration (FDA).(2019) Givosiran. Prescribing Information. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/0212194s000lbl.pdf. Last accessed August 18, 2021.

Ventura P, Bonkovsky HL, Gouya L, Aguilera-Peiró P, Montgomery Bissell D, Stein PE, Balwani M, Anderson DKE, Parker C, Kuter DJ, Monroy S, Oh J, Ritchie B, Ko JJ, Hua Z, Sweetser MT, Sardh E; ENVISION Investigators.(2021) Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int. 2022 Jan;42(1):161-172. doi: 10.1111/liv.15090. Epub 2021 Nov 16. PMID: 34717041; PMCID: PMC9299194.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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