Sutimlimab-jome (Enjaymo)

Number: 1006

Table Of Contents

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

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses sutimlimab-jome (Enjaymo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of sutimlimab-jome (Enjaymo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of sutimlimab-jome (Enjaymo), 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 sutimlimab-jome (Enjaymo), see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Criteria for Initial Approval

   Aetna considers sutimlimab-jome (Enjaymo) medically necessary for the treatment of cold agglutinin disease (CAD) when all of the following criteria are met:

   1. Confirmed diagnosis of primary cold agglutinin disease (CAD) based on all of the following:

      1. Evidence of hemolysis as indicated by both of the following:

         1. Lactate dehydrogenase (LDH) level above the upper limit of normal; and
         2. Haptoglobin level below the lower limit of normal; and
            
      2. Positive polyspecific direct antiglobulin test (DAT) result; and
      3. Monospecific DAT result strongly positive for C3d; and
      4. Cold agglutinin titer of 1:64 or higher measured at 4°C; and
      5. DAT result for IgG of 1+ or less; and
         

   2. Secondary CAD has been ruled out (e.g., cold agglutinin syndrome secondary to infection, rheumatologic disease, or active hematologic malignancy).

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers sutimlimab-jome (Enjaymo) therapy medically necessary for members requesting reauthorization when there is no evidence of unacceptable toxicity or disease progression while on the current regimen and member demonstrates a positive response to therapy (e.g., improvement in hemoglobin levels, markers of hemolysis [e.g., bilirubin, haptoglobin, lactate dehydrogenase [LDH], reticulocyte count], and a reduction in blood transfusions). 

3. Related Policies

   1. CPB 0314 - Rituximab - for autoimmune hemolytic anemia

Dosage and Administration

Enjaymo is supplied as a 22 mL single-dose vial which contains 1,100 mg of sutimlimab-jome at a concentration of 50 mg/mL. Enjaymo is diluted with 0.9% Sodium Chloride Injection, USP prior to administration. Enjaymo is for intravenous infusion only.

For adults with cold agglutinin disease (CAD), the recommended dosage of Enjaymo is based on body weight.

• 39 kg to less than 75 kg: recommended dose is 6,500 mg
• 75 kg or more: recommended dose is 7,500 mg

Administer Enjaymo intravenously weekly for the first two weeks, with administration every two weeks thereafter. 

Administer Enjaymo at the recommended dosage regimen time points, or within two days of these time points. If a dose is missed, administer as soon as possible; thereafter, resume dosing every two weeks. If the duration after the last dose exceeds 17 days, administer Enjaymo weekly for two weeks, with administration every two weeks thereafter.

Vaccinate against encapsulated bacteria at least two weeks prior to treatment.

Source: Bioverativ USA, 2023

---

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:
82247	Bilirubin; total
82248	Bilirubin; direct
83010	Haptoglobin; quantitative
83012	Haptoglobin; phenotypes
83615	Lactate dehydrogenase (LD), (LDH)
83625	Lactate dehydrogenase (LD), (LDH); isoenzymes, separation and quantitation
85044	Blood count; reticulocyte, manual
85045	Blood count; reticulocyte, automated
85046	Blood count; reticulocytes, automated, including 1 or more cellular parameters (eg, reticulocyte hemoglobin content [CHr], immature reticulocyte fraction [IRF], reticulocyte volume [MRV], RNA content), direct measurement
86156	Cold agglutinin; screen
86157	Cold agglutinin; titer
86880	Antihuman globulin test (Coombs test); direct, each antiserum
96413 - 96417	Chemotherapy administration
96365 – 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J1302	Injection, sutimlimab-jome, 10 mg
ICD-10 codes covered if selection criteria are met:
D59.12	Cold autoimmune hemolytic anemia

---

Background

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

• Enjaymo is indicated for the treatment of hemolysis in adults with cold agglutinin disease (CAD).

Sutimlimab-jome, a classical complement inhibitor, is available as Enjaymo (Bioverativ USA Inc.). Sutimlimab-jome is an immunoglobulin G (IgG), subclass 4 (IgG4) monoclonal antibody (mAb) that inhibits the classical complement pathway (CP) and specifically binds to complement protein component 1, s subcomponent (C1s), a serine protease which cleaves C4. Sutimlimab-jome does not inhibit the lectin and alternative pathways. Inhibition of the classical complement pathway at the level of C1s prevents deposition of complement opsonins on the surface of RBCs, resulting in inhibition of hemolysis in persons with cold agglutinin disease (CAD) (Bioverativ USA, 2023).

Labeled warning and precautions for Enjaymo include serious infections, infusion-related reactions, risk of autoimmune disease, and recurrent hemolysis after Enjaymo discontinuation. 

Enjaymo may increase susceptibility to serious infections, including infections caused by encapsulated bacteria such as Neisseria meningitides (any serogroup), Streptococcus pneumoniae, and Haemophilus influenzae. Serious infections (bacterial and viral) were reported in 17% (4/24) of patients receiving Enjaymo in a single-arm open-label clinical trial. It is recommended that patients receive vaccination for encapsulated bacteria according to the most current Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations for patients with persistent complement deficiencies. Revaccinate patients in accordance with ACIP recommendations. It is recommended to immunize patients without a history of vaccination against encapsulated bacteria at least two weeks prior to receiving the first dose of Enjaymo. If urgent Enjaymo therapy is indicated in an unvaccinated patient, administer vaccine(s) as soon as possible. Vaccination reduces, but does not eliminate, the risk of encapsulated bacterial infections (Bioverativ USA, 2023).  

Administration of Enjaymo may result in infusion-related reactions. In the CARDINAL study, 2 of 24 patients (8%) treated with Enjaymo experienced infusion-related reactions (shortness of breath, rapid heartbeat, nausea, flushing, and headache). 

Based on its mechanism of action, Enjaymo may potentially increase the risk for developing autoimmune diseases such as systemic lupus erythematosus (SLE). Development of SLE has been associated with inherited classical complement deficiency. Patients with SLE or autoimmune disease with positive anti-nuclear antibody were excluded from clinical trials with Enjaymo.

If treatment with Enjaymo is interrupted, closely monitor patients for signs and symptoms of recurrent hemolysis, e.g., elevated levels of total bilirubin or lactate dehydrogenase (LDH) accompanied by a decrease in hemoglobin, or reappearance of symptoms such as fatigue, dyspnea, palpitations, or hemoglobinuria. According the Prescribing Information, consider restarting Enjaymo if signs and symptoms of hemolysis occur after discontinuation.

The common adverse reactions (incidence 10% or more) include respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema.

In January 2023, the FDA approved a revision to the indication for Enjaymo for the treatment of hemolysis in adults with cold agglutinin disease (CAD). Enjaymo was previously approved to decrease the need for red blood cell transfusion due to hemolysis in adults with CAD. The approval was based on a placebo-controlled study (CADENZA) which included 42 patient responders with CAD and no history of transfusion within 6 months, or more than one blood transfusion in the 12 months prior to enrollment in the trial. Following the completion of the 6-month treatment period (Part A) in which 22 patients received Enjaymo and 20 patients received placebo, 39 patients (19 patients on Enjaymo and 20 patients on placebo) continued to receive Enjaymo in a long-term safety and durability of response extension phase (Part B) for an additional 12 months following last patient out from Part A. Efficacy was based on the proportion of patients who had an increase from baseline in hemoglobin level greater than or equal to 1.5 g/dL at the treatment assessment time point, no blood transfusion from week 5 through week 26, and no treatment for CAD beyond what was permitted per protocol from week 5 through week 26. The responder rate was 72.7% with Enjaymo and 15% with placebo (p = 0.0004). The updated labeling for Enjaymo also includes long-term data from the previous CARDINAL study (Bioverative USA, 2023; Optum, 2023).

Cold Agglutinin Disease 

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) in which exposure to cold temperature provoke self-targeting cold agglutinin antibodies to mistakenly bind to red blood cells (RBCs) causing them to clump together (agglutinate) and prematurely rupture (hemolysis), resulting in anemia. The disease is called “cold” agglutinin disease because the red cell destruction occurs at cold temperatures.

"The development of cold agglutinin syndrome is relatively uncommon, at least in the classic chronic form. Various reports state that 7-25% of cases of autoimmune hemolytic anemia are cold agglutinin mediated. Thus, while the incidence of cold and warm autoimmune hemolytic anemia (combined) is approximately 1 in 80,000, the incidence of cold agglutinin disease is approximately 1 in 300,000 [in the United States]. Among autoimmune hemolytic anemias, cold agglutinin disease is the second most common cause, after warm autoantibody–induced immune hemolysis" (Collie, 2022).

Primary cold agglutinin disease (also called idiopathic CAD) is diagnosed in the absence of an underlying disorder such as bacterial, viral or parasitic infections, certain malignancies, or other autoimmune disorders. The vast majority of cold agglutinins are IgM autoantibodies; however, IgG have been reported, and in other rare cases, IgG may accompany IgM which may lead to more severe hemolysis. These autoantibodies bind to RBCs and are the basis for agglutination. The RBC-bound cold agglutinins recruit and activate C1, initiating the classical complement pathway, eventually leading to hemolysis. Cold agglutinins react with RBCs at colder temperatures than normal core body temperature. The temperature range at which they are active is referred to as the thermal range or thermal amplitude. The typical thermal amplitude for normally occurring cold agglutinins is in the range of 3° to 4° C (i.e., refrigerator temperature), but many antibodies are active at higher temperatures such as occur in colder, peripheral areas of the body. Hemolysis in CAD is primarily extravascular and mediated by complement (Brugnara and Berentsen, 2021).

In patients suspected of CAD, a titer should be measured. The titer reflects the strength (concentration and avidity) of the antibody. Titer is determined by testing serial dilutions of patient serum for their ability to agglutinate RBCs. The titer is the highest dilution at which cold-induced agglutination of RBCs occurs. Generally, a titer of 1:64 or more measured at 4°C is considered clinically significant for a CAD diagnosis; however, typical cold agglutinin titers in CAD are quite high (above 512). In addition to cold agglutinin titer of 1:64 or more at 4°C, accepted diagnostic criteria include evidence of hemolysis (e.g., high reticulocyte count, high lactate dehydrogenase (LDH), high indirect bilirubin, low haptoglobin) and positive direct antiglobulin test (DAT; direct Coombs test) for C3d only (or, in a minority, C3d plus weak IgG) (Brugnara and Berentsen, 2021).

Jäger et al (2020) state that in autoimmune hemolytic anemia (AIHA), evidence for hemolysis includes evaluating for reticulocytosis, elevated LDH levels, decreased haptoglobin, elevated indirect bilirubin, positive serum free hemoglobin, and positive urine hemosiderin. However, of these, haptoglobin and LDH appear to be the most helpful in hemolysis classification. "Using a Boolean analysis for the separation of hemolytic from nonhemolytic disorders, an increased LDH and haptoglobin <25 mg/dL is 95% specific for hemolysis while a normal LDH and haptoglobin >25 mg/dL are 92% sensitive for the absence of hemolysis".

Treatment has been directed at supportive care and reducing antibody production. Therapy includes minimizing cold-induced symptoms, maintaining an acceptable hemoglobin level, and, if not considered primary or idiopathic disease, addressing underlying disorders. In typical primary CAD, with or without a detectable low-grade bone marrow lymphoproliferative disorder, treatment is indicated for those who have symptomatic anemia or cold-induced ischemic symptoms interfering with activities of daily living. Medications such as rituximab, which has been used in combination with bendamustine, has been used as first-line treatment. Bortezomib or ibrutinib have been used as a second-line option (Brugnara and Berentsen, 2021; Collie, 2022; NORD, 2020). "Therapies targeting complement are emerging options. Inhibitors of C1q, C1s, and C3 are attractive approaches because they block the classical complement pathway and C3 opsonization" (Brugnara and Berentsen, 2021).

On February 4, 2022, the U.S. FDA approved sutimlimab-jome infusion, brand Enjaymo (Bioverativ USA Inc, a Sanofi Company), to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with cold agglutinin disease (CAD). FDA approval was based on outcomes from the CARDINAL study (NCT03347396).

Röth and colleagues (2021) state that CAD is caused by activation of the classic complement pathway and that sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. The investigators conducted a 26-week multicenter, open-label, single-arm study (CARDINAL) to assess the efficacy and safety of intravenous sutimlimab in 24 patients with confirmed diagnosis of primary CAD who had a history of transfusion within 6 months of enrollment. Confirmed diagnosis were based on chronic hemolysis, a positive polyspecific direct antiglobulin test (DAT), monospecific DAT strongly positive for C3d, cold agglutinin titer greater than or equal to 64 at 4 degree Celsius, immunoglobulin G (IgG) DAT less than or equal to (less than or equal to) 1+, and no overt malignant disease. Patients with CAD secondary to infection, rheumatologic disease, systemic lupus erythematosus, or overt hematologic malignancy were excluded, whereas patients with a history of or concomitant low-grade lymphoproliferative disease were not excluded. Sutimlimab was administered as 6.5 g or 7.5 g (based on body weight) intravenously over approximately 60 minutes on Day 0, 7, and every 14 days thereafter through week 25. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. Of the 24 patients, 13 (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. The investigators concluded that in patients with CAD who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. 

---

References