Crovalimab-akkz (PiaSky)

Number: 1064

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 crovalimab-akkz (PiaSky) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of crovalimab-akkz (PiaSky) is required of all Aetna participating providers and members in applicable plan designs. For precertification of crovalimab-akkz (PiaSky), 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 information on site of service for crovalimab-akkz (PiaSky), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Criteria for Initial Approval

   Aetna considers crovalimab-akkz (PiaSky) medically necessary for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) when all of the following criteria are met:

   1. Member is 13 years of age or older; and
   2. Member has a body weight of at least 40 kg; and
   3. The diagnosis of PNH was confirmed by detecting a deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-APs) (e.g., at least 5% PNH cells, at least 51% of GPI-AP deficient poly-morphonuclear cells); and
   4. Flow cytometry is used to demonstrate GPI-APs deficiency; and
   5. Member has and exhibits clinical manifestations of disease (e.g., LDH greater than 1.5 ULN, thrombosis, renal dysfunction, pulmonary hypertension, dysphagia); and
   6. The requested medication will not be used in combination with another complement inhibitor (e.g., Empaveli, Fabhalta, Soliris, Ultomiris) for the treatment of PNH.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of crovalimab-akkz (PiaSky) therapy medically necessary for treatment in members requesting reauthorization when all of the following criteria are met: 

   1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; and
   2. The member demonstrates a positive response to therapy (e.g., improvement in hemoglobin levels, normalization of lactate dehydrogenase [LDH] levels); and
   3. The requested medication will not be used in combination with another complement inhibitor (e.g., Empaveli, Fabhalta, Soliris, Ultomiris) for the treatment of PNH.

3. Related Policies

   For Empaveli and Fabhalta, see pharmacy benefit plans.

   See also:

   1. CPB 0807 - Eculizumab
   2. CPB 0946 - Ravulizumab-cwvz (Ultomiris).

Dosage and Administration

Crovalimab-akkz is available as PiaSky and supplied in 340 mg/2 mL (170 mg/mL) single-dose vials for intravenous or subcutaneous use. PiaSky should be administered by healthcare providers only.

The recommended dosage regimen, based on the person's body weight, consists of one loading dose administered by intravenous (IV) infusion (on Day 1), followed by four additional weekly loading doses administered by subcutaneous (SUBQ) injection (on Days 2, 8, 15, and 22).

The maintenance dose starts on Day 29 and is then administered every 4 weeks by SUBQ injection. Modification of the maintenance dose is required if the person’s body weight changes to become consistently greater than or lower than 100 kg during the course of therapy. 

Table: Dosage Regimen Based on Body Weight

Body weight	Loading dose	Maintenance dose
Greater than or equal to 40 kg to less than 100 kg	Day1: 1,000 mg IV Day 2, 8, 15, 22: 340 mg SUBQ	Day 29 and every 4 weeks thereafter: 680 mg SUBQ
Greater than or equal to 100 kg	Day 1: 1,500 mg IV Day 2, 8, 15, 22: 340 mg SUBQ	Day 29 and every 4 weeks thereafter: 1,020 mg SUBQ

For individuals switching from another complement inhibitor, the first loading dose of PiaSky should be administered no sooner than the time of the next scheduled complement inhibitor administration. See Full Prescribing Information for considerations when switching from another C5 inhibitor.

Source: Genentech, 2024

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96401 – 96402, 96413 - 96415	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Crovalimab-akkz (PiaSky) – no specific code
Other HCPCS codes related to the CPB:
Pegcetacoplan, Iptacopan-no specific code
J1300	Injection, eculizumab, 10 mg
J1303	Injection, ravulizumab-cwvz, 10 mg
ICD-10 codes covered if selection criteria are met:
D59.5	Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli]

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Background

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

• PiaSky is in indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg.

Crovalimab-akkz, a complement C5 inhibitor, is branded as PiaSky (Genentech, Inc.). Crovalimab-akkz is a monoclonal antibody that specifically binds to the complement protein C5, inhibiting its cleavage into C5a and C5b. This prevents the formation of the membrane attack complex (MAC), a structure comprised of complement proteins C5b-9 that binds to plasma membranes and induces cell destruction (cytolysis). Crovalimab-akkz inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH).

PiaSky carries a boxed warning for increased risk of serious and life-threatening infections caused by Neisseria meningitidis. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. PiaSky is contraindicated in patients with an unresolved serious N. meningitidis infection. Moreover, because of the risk of serious meningococcal infections, PiaSky is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called PiaSky REMS.

Patients should complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of PiaSky, according to the Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. However, it is important to note that vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Thus, close monitoring for early signs and symptoms are warranted.  

PiaSky is contraindicated in patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients.

Patients who are switching from another C5 inhibitor (e.g., eculizumab or ravulizumab) to PiaSky or from PiaSky to another C5 inhibitor are at risk of serious Type III hypersensitivity reactions related to the formation of drug-target-drug-complexes (DTDCs), as PiaSky and these other C5 inhibitors bind different epitopes of C5. These DTDCs are expected to be cleared within approximately 8 weeks (in the case of eculizumab) or longer (in the case of ravulizumab).

Due to its mechanism of action, PiaSky may increase susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria spp. but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with PiaSky may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Per the Prescribing Information, patients should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. 

Administration of PiaSky may cause infusion-related reactions or systemic injection-related reactions, depending on the route of administration.

In case of PiaSky discontinuation, patients who do not switch to another treatment for PNH must be closely monitored for at least 20 weeks for signs and symptoms of serious hemolysis, identified by elevated lactate dehydrogenase (LDH) levels, along with a sudden decrease in hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, erectile dysfunction or renal impairment.

The most common adverse drug reactions (incidence 10% or more) were infusion-related reaction, respiratory tract infection, viral infection, and Type III hypersensitivity reactions.

There are no data on the presence of crovalimab-akkz in either human or animal milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, patients are advised to not breastfeed during treatment with PiaSky and for 9 months after the final dose. 

Paroxysmal Nocturnal Hemoglobinuria (PNH) 

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, complement-mediated hemolytic anemia that can be associated with aplastic anemia (AA) and/or myelodysplastic syndromes (MDS). PNH is caused by an acquired gene mutation in hematopoietic stem cells that causes reduced or absent production of glycosylphosphatidylinositol (GPI), which links the complement inhibitor proteins, CD55 and CD59, to blood cell membranes. The incidence of clinically significant PNH is estimated to be at least 1 to 10 cases per million population; however, this may be an underestimate as some individuals remain undiagnosed. PNH is mostly a disease of adults, with a median age of onset in the 30s, but childhood cases have been reported. There is no known racial or ethnic association, and PNH has been reported worldwide (Brodsky, 2022).

The diagnosis of PNH is established by flow cytometry that demonstrates a population of granulocytes and RBCs that are deficient in GPI-linked proteins in an appropriate clinical setting, such as DAT-negative hemolytic anemia, thrombosis, unexplained abdominal pain, AA, or MDS (Brodsky, 2022). 

In June 2024, the FDA approved PiaSky (crovalimab-akkz) for the treatment of adult and pediatric patients 13 years and older with PNH and body weight of at least 40 kg. Approval was based on the efficacy results from the COMMODORE 2 (NCT04434092) trial which showed crovalimab's non-inferiority to eculizumab in hemolysis control and red blood cell (RBC) transfusion avoidance.

The COMMODORE 2 trial was an active-controlled, open-label, non-inferiority, phase 3 study that randomized 204 patients (body weight 40 kg or more) with PNH not previously treated with a complement inhibitor in a 2:1 ratio to receive either crovalimab (n=135) or eculizumab (n=69). The study additionally enrolled 6 pediatric patients (aged greater than 12 years and body weight greater than or equal to 40 kg) to receive crovalimab in a separate non-randomized cohort. A single intravenous loading dose of crovalimab was given on Day 1 (1,000 mg for patients weighing 40 kg or more to less than 100 kg, or 1,500 mg for patients weighing greater than 100 kg), followed by four additional weekly subcutaneous loading doses of 340 mg on Days 2, 8, 15 and 22. Starting at Day 29, maintenance subcutaneous doses were given every 4 weeks (680 mg for patients weighing 40 kg or more to less than 100 kg, or 1,020 mg for patients weighing 100 kg or more). The study consisted of a primary treatment period of 24 weeks, after which patients had the option to continue or switch to crovalimab in an extension period. Efficacy was based on hemolysis control, as measured by the mean proportion of patients with LDH less than or equal to 1.5 x ULN from Week 5 to Week 25; and the proportion of patients who achieved transfusion avoidance, defined as patients who were pRBC transfusion-free, from baseline through Week 25. Other efficacy endpoints included the proportion of patients with breakthrough hemolysis and the proportion of patients with stabilized hemoglobin. Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH greater than or equal to 2 x ULN after prior reduction of LDH to less than or equal to 1.5 x ULN on treatment. Hemoglobin stabilization was defined as avoidance of a greater than or equal to 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. In the adult population, hemolysis control was achieved in 79.3% of patients with crovalimab compared to 79.0% with eculizumab (odds ratio 1.02, 95% CI: 0.57, 1.82; non-inferiority met). Transfusion avoidance was achieved in 65.7% of patients with crovalimab compared to 68.1% with eculizumab (difference -2.8, 95% CI: -15.7, 11.1; non-inferiority met).

The efficacy of crovalimab was evaluated in 12 pediatric patients (with body weight greater than or equal to 40 kg) treated with crovalimab in COMMODORE 2 (n=7; 13−17 years old), COMMODORE 1 (n=2, 13 – 16 years old) and in a single arm study in patients who were complement-inhibitor naïve, COMMODORE 3 (NCT04654468; n=3; 15−17 years old). Nine pediatric patients were treatment-naïve, two patients switched from standard dose eculizumab and one patient switched from ravulizumab. The proportion of patients with a history of transfusions in the prior 12 months was 58%, with a median number of 1.3 pRBC units (range: 0-40.5) transfused, and a baseline median LDH of 6.4 x ULN (range 1.1-26.6). Aplastic anemia was reported in 50% of patients. All pediatric patients received the same dosing as adult patients based on body weight. Hemolysis control from baseline to week 25 was achieved in 7 of the 9 patients who were treatment-naïve, and the 3 patients switching from eculizumab or ravulizumab to crovalimab maintained hemolysis control through 24 weeks of crovalimab treatment. Nine (six patients who were treatment-naïve and three patients who switched from culizumab or ravulizumab) out of the 12 pediatric patients achieved transfusion avoidance and hemoglobin stabilization, and no patients had a breakthrough hemolysis event during the 24-week treatment period. Overall, the treatment effect of crovalimab in pediatric patients with PNH was consistent with that observed in adults with PNH. 

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References