Cold Agglutinin Disease

ENJAYMO (sutimlimab-jome) is indicated for the treatment of hemolysis in adults with cold agglutinin disease (CAD).

2.1 Recommended Vaccinations

Vaccinate patients against encapsulated bacteria at least 2 weeks prior to initiation of ENJAYMO therapy according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with persistent complement deficiencies [see Warnings and Precautions (5.1)]. If urgent ENJAYMO therapy is indicated in an unvaccinated patient, administer vaccine(s) as soon as possible.

2.2 Recommended Dosage Regimen

The recommended dosage of ENJAYMO for patients with CAD is based on body weight. For patients weighing 39 kg to less than 75 kg, the recommended dose is 6,500 mg and for patients weighing 75 kg or more, the 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.

2.3 Preparation and Administration

ENJAYMO is for intravenous infusion only.

Each vial of ENJAYMO is intended for single dose only.

ENJAYMO can either be used as an undiluted or diluted preparation.

5.1 Serious Infections

ENJAYMO may increase susceptibility to serious infections, including infections caused by encapsulated bacteria such as Neisseria meningitidis (any serogroup), Streptococcus pneumoniae, and Haemophilus influenzae.

Serious infections (bacterial and viral) were reported in 15% (10/66) of patients receiving ENJAYMO from the two phase 3 studies. These infections included urinary tract infection with sepsis, respiratory tract infection, pneumonia, otomastoiditis, and skin infections One patient (1.5%) died due to klebsiella pneumonia.

Vaccinate patients for encapsulated bacteria according to the most current ACIP recommendations for patients with persistent complement deficiencies. Revaccinate patients in accordance with ACIP recommendations.

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.

If ENJAYMO treatment is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection. Some infections may become rapidly life-threatening or fatal if not recognized and treated promptly. Inform patients of these signs and symptoms and steps to be taken to seek immediate medical care. Consider interruption of ENJAYMO treatment in patients who are undergoing treatment for serious infection. ENJAYMO has not been studied in patients with chronic systemic infections such as hepatitis B, hepatitis C, or HIV. Consider patients' immune status when initiating treatment with ENJAYMO.

5.2 Infusion-Related Reactions

ENJAYMO is contraindicated in patients with known hypersensitivity to sutimlimab-jome or any of the inactive ingredients [see Contraindications (4)] . Administration of ENJAYMO may result in infusion-related reactions. In the two phase 3 studies, 19 of 66 (29%) patients treated with ENJAYMO experienced infusion-related reactions (e.g., shortness of breath, rapid heartbeat, nausea, flushing, headache, hypotension, chest discomfort, pruritus, rash, injection site reaction, and dizziness) were reported in patients from the two clinical studies. One patient permanently discontinued ENJAYMO due to an infusion-related reaction.

Monitor patients for infusion-related reactions and interrupt if a reaction occurs. Discontinue ENJAYMO infusion and institute appropriate supportive measures if signs of hypersensitivity reactions, such as cardiovascular instability or respiratory compromise, occur.

5.3 Risk of Autoimmune Disease

Based on its mechanism of action, ENJAYMO may potentially increase the risk for developing autoimmune diseases such as systemic lupus erythematosus (SLE). Development of systemic lupus erythematosus (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. In clinical trials, 3/66 (4.5%) patients developed a relapse or worsening of preexisting autoimmune disease. Monitor patients being treated with ENJAYMO for signs and symptoms and manage medically.

5.4 Recurrent Hemolysis After ENJAYMO Discontinuation

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. Consider restarting ENJAYMO if signs and symptoms of hemolysis occur after discontinuation.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ENJAYMO in patients with a confirmed diagnosis of CAD was evaluated in a placebo-controlled study (CADENZA) in Part A (n=42) followed by an open-label single-arm study in Part B (n=39) and an open-label single-arm study (CARDINAL) (n=24) [see Clinical Studies (14)] . The median duration of treatment exposure to ENJAYMO was 104 weeks (patients randomized to ENJAYMO in CADENZA Part A) and 93 weeks (patients randomized to placebo in CADENZA Part A) and 143 weeks for CARDINAL.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the 66 patients with CAD in clinical studies of ENJAYMO, 65% were 65 years of age and over, including 27% who were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action

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 patients with CAD.

12.2 Pharmacodynamics

Greater than 90% inhibition of CP was observed following a single sutimlimab-jome infusion and sustained in patients with CAD when sutimlimab-jome concentrations were greater than or equal to 100 mcg/mL. C4 levels returned to normal levels (0.2 g/L) in patients with CAD within one week following the first dose of sutimlimab-jome. Complete CP inhibition following initiation of sutimlimab-jome treatment led to inhibition of hemolysis as evidenced by normalization of bilirubin, decrease in LDH, increase in haptoglobin, and decrease in reticulocytes.

After the first treatment with sutimlimab-jome, near normalization of bilirubin associated with a greater than 1 g/dL increase in hemoglobin was observed, demonstrating the effect of CP inhibition. The extent and duration of the pharmacodynamic response in patients with CAD were exposure dependent for sutimlimab-jome.

12.3 Pharmacokinetics

Following administration of the approved weight-based recommended dosages, the exposure of sutimlimab-jome increases proportionally over a dosage range of 60 mg/kg to 100 mg/kg by intravenous infusion (0.3 to 1.5 times the maximum approved recommended dosage based on 75 kg body weight). Steady state was achieved by Week 7 after starting sutimlimab-jome treatment, with an accumulation ratio of less than 2.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of sutimlimab-jome or of other sutimlimab products.

During the treatment period in CARDINAL and CADENZA, 8/66 (12%) ENJAYMO-treated patients developed anti-sutimlimab-jome antibodies (duration of exposure up to 177 weeks). There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of ENJAYMO over the treatment duration [see Clinical Studies (14)] .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with sutimlimab-jome.

Effects of sutimlimab-jome on male and female fertility have not been studied in animals. In repeat-dose studies in cynomolgus monkeys with sutimlimab-jome administered once-weekly at exposures 3 to 4 times the human exposures at the maximum recommended human doses of sutimlimab-jome, no effects on male or female reproductive tissues were observed.

14.1 CADENZA

The efficacy of ENJAYMO was assessed in a placebo-controlled 6-month trial in 42 patients (CADENZA, NCT 03275454). 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. The trial included a 9 week safety follow-up after the last dose of ENJAYMO. Patients with a confirmed diagnosis of CAD based on chronic hemolysis, polyspecific direct antiglobulin test (DAT), monospecific DAT specific for C3d, cold agglutinin titer ≥64 at 4°C, an IgG DAT ≤1+ and no history of transfusion within 6 months, or more than one blood transfusion in the 12 months prior to enrollment in the trial were administered 6.5 g or 7.5 g ENJAYMO (based on body weight) intravenously over approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter; or placebo. Patients with cold agglutinin disease 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.

Major baseline characteristics of the study population are summarized in Table 5.

Efficacy was based on the proportion of patients who met the following criteria: an increase from baseline in Hgb level ≥1.5 g/dL at the treatment assessment time point (mean value from Weeks 23, 25, and 26), 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. Efficacy was further assessed based on the effect of ENJAYMO on Hgb, laboratory measures of hemolysis including mean change from baseline in total bilirubin and LDH. Supportive efficacy data collected included transfusion usage after five weeks of treatment. In addition, mean change from baseline in symptoms and impacts of fatigue were assessed using a patient-reported outcome instrument, the FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue).

The data from this study demonstrated a statistically significant treatment effect of ENJAYMO over placebo in terms of the rate of patients who met the efficacy criteria (responder) as well as improving symptoms and impacts of fatigue (FACIT-Fatigue). The responder rate difference between ENJAYMO and placebo was 58.78% (95% CI: 34.6% to 82.96%) with a p-value of 0.0004. At the treatment assessment timepoint (TAT), 16 of 22 patients on ENJAYMO (72.7%; 95% CI: 49.8% to 89.3%) and 3 of 20 patients on placebo (15.0%; 95% CI: 3.2% to 37.9%) met primary criteria. Efficacy of ENJAYMO in the inhibition of hemolysis in patients with CAD was demonstrated across multiple end points as described in the table below (see Table 6).

During Part A, an increase in mean hemoglobin level of 2.02 g/dL was observed in patients on ENJAYMO at Week 3; in the placebo group the mean hemoglobin level decreased by 0.31g/dL. At treatment assessment timepoint, a mean decrease in bilirubin of 1.29 mg/dL compared to baseline was reported in patients on ENJAYMO (n=17) versus 0.11 mg/dL on placebo (n=18). In the ENJAYMO group, bilirubin levels normalized in 88.2% (n=15) of patients compared to 22.2% (n=4) of patients in the placebo arm. At treatment assessment timepoint, a mean decrease in LDH of 150.83 U/L compared to baseline was reported in patients on ENJAYMO (n=19) versus an increase of 7.6 U/L on placebo (n=20). In the ENJAYMO group, LDH levels were < 1.5 × ULN in 94.7% (n=18) of patients compared to 70% (n=14) in the placebo arm.

In Part B, mean hemoglobin levels were maintained at >10.5 g/dL. Sustained normalization of mean bilirubin levels was also observed indicating a sustained decrease in hemolysis. Mean hemoglobin level of 11.58 g/dL (range: 6.90–15.30) and 1.01 mg/dL (range: 0.29–5.54) for bilirubin was observed at the last on-treatment visit.

After the last dose of ENJAYMO in the study, signs and symptoms of recurrent hemolysis were observed, nine weeks after the last dose in Part B; mean hemoglobin decreased by 2.41 g/dL (SE: 0.373) and mean bilirubin increased by 1.27 mg/dL (SE: 0.182) from the last available values during treatment.

14.2 CARDINAL

The efficacy of ENJAYMO was assessed in an open-label, single-arm, 6-month trial in 24 patients (CARDINAL, NCT03347396). Following the completion of the 6-month treatment period (Part A), patients continued to receive ENJAYMO in a long-term safety and durability of response extension phase (Part B) for an additional 24 months following last patient out from Part A. The trial included a 9 week safety follow-up after the last dose of ENJAYMO.

Patients with a confirmed diagnosis of CAD based on chronic hemolysis, polyspecific direct antiglobulin test (DAT), monospecific DAT specific for C3d, cold agglutinin titer ≥64 at 4°C, and IgG DAT ≤1+ and a recent blood transfusion in the 6 months prior to enrollment were administered 6.5 g or 7.5 g ENJAYMO (based on body weight) intravenously over approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter. Patients with cold agglutinin syndrome 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. Major baseline characteristics of the trial population are summarized in Table 7.

Efficacy was based on the proportion of patients who met the following criteria: an increase from baseline in Hgb level ≥2 g/dL or a Hgb level ≥12 g/dL at the treatment assessment time point (mean value from Weeks 23, 25, and 26), 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.

Efficacy of ENJAYMO in patients with CAD is described in Table 8.

In Part A, among 14 patients with baseline and follow-up bilirubin values, the mean was 3.23 mg/dL (2.7-fold ULN) at baseline and 0.91 mg/dL (0.8-fold ULN) at the treatment assessment time point. The least-squares (LS) mean change was reduction of -2.23 mg/dL (95% CI: -2.49 to -1.98). Among 17 patients with baseline and follow-up LDH values, the mean LDH was 424 U/L (1.7-fold ULN) at baseline and 301 U/L (1.2-fold ULN) at the follow-up time point. The least squared mean change in LDH at the treatment assessment time point was reduction of -126 (95% CI: -218 to -35).

In CARDINAL, an increase in mean hemoglobin level of 2.29 g/dL (SE: 0.308) was observed at Week 3 and 3.18 g/dL (SE: 0.476) at treatment assessment time point. The observed model mean change in hemoglobin level from baseline at treatment assessment time point was an improvement of 2.60 g/dL (95% CI: 0.74, 4.46).

In Part B, mean hemoglobin levels were maintained at >10 g/dL. Sustained normalization of mean bilirubin levels was also observed indicating a sustained decrease in hemolysis. Mean hemoglobin level of 12.23 g/dL (range: 9.20–14.40) and 0.96 mg/dL (range: 0.4–1.7) for bilirubin was observed at the last on-treatment visit.

After the last dose of ENJAYMO in the study, signs and symptoms of recurrent hemolysis were observed, nine weeks after the last dose in Part B; mean hemoglobin decreased by 2.28 g/dL (SE: 0.402) and mean bilirubin increased by 1.42 mg/dL (SE: 0.192) from the last available values during treatment.

How Supplied

ENJAYMO (sutimlimab-jome) injection is a clear to slightly opalescent, colorless to slightly yellow, preservative-free solution supplied as one 1,100 mg/22 mL (50 mg/mL) single-dose vial per carton (NDC 80203-347-01).

Storage and Handling

Store ENJAYMO vials refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not freeze. Do not shake.

Discard unused portion.

Serious Infections

Advise patients of the potential increased risk of infections including infections caused by encapsulated bacteria such as Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. These infections may be serious or life-threatening. Inform patients that they are required to receive vaccinations against these bacteria according to current medical guidelines prior to initiation of and during treatment with ENJAYMO. Educate patients on the symptoms of infections and advise them to seek immediate medical attention if any new symptoms of infection occur [see Warnings and Precautions (5.1)] .

Infusion-Related Reactions

Advise patients that administration of ENJAYMO may result in infusion-related reactions including hypersensitivity reactions. Hypersensitivity reactions may be serious or life-threatening (e.g., anaphylaxis). Educate patients on the symptoms of infusion-related reactions and advise them to seek medical attention if any new symptoms of infusion-related reactions occur [see Contraindications (4) and Warnings and Precautions (5.2)] .

Risk of Autoimmune Disease

Educate patients that there may be an increased risk of developing an autoimmune disease such as SLE during ENJAYMO therapy. Advise patients on signs and symptoms of SLE and to report any new symptoms of SLE and seek medical attention [see Warnings and Precautions (5.3)] .

Discontinuation

Inform patients with CAD that they may develop hemolysis due to CAD when ENJAYMO is discontinued and that they should be monitored by their healthcare provider following ENJAYMO discontinuation [see Warnings and Precautions (5.4)] .

This product's labeling may have been updated. For the most recent prescribing information, please visit www.enjaymo.com.