Elapegademase-Lvlr

1 INDICATIONS AND USAGE REVCOVI is indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients. REVCOVI is a recombinant adenosine deaminase indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients. ( 1 )

2 DOSAGE AND ADMINISTRATION Patients transitioning from Adagen to REVCOVI : The starting dose of REVCOVI is 0.2 mg/kg weekly, intramuscularly. See Full Prescribing Information (FPI) for conversion formula from Adagen to REVCOVI. ( 2.1 ) Adagen-naïve patients : The starting dose of REVCOVI is 0.4 mg/kg weekly based on ideal body weight or actual weight whichever is greater, divided into two doses (0.2 mg/kg twice a week), intramuscularly. ( 2.1 ) For complete information, maintenance dosing and therapeutic monitoring, see FPI. ( 2.1 , 2.3 ) REVCOVI is for intramuscular injection only. See FPI for administration instructions. ( 2.2 ) 2.1 Recommended Dosage Patients transitioning from Adagen to REVCOVI If a patient's weekly Adagen dose is unknown, or a patient's weekly Adagen dose is at or lower than 30 U/kg, the recommended minimum starting dose of REVCOVI is 0.2 mg/kg, intramuscularly, once a week. If a patient's weekly Adagen dose is above 30 U/kg, an equivalent weekly REVCOVI dose (mg/kg) should be calculated using the following conversion formula: REVCOVI dose in mg/kg = Adagen dose in U/kg 150 Subsequent doses may be increased by increments of 0.033 mg/kg weekly if trough ADA activity is under 30 mmol/hr/L, trough deoxyadenosine nucleotides (dAXP) are above 0.02 mmol/L, and/or the immune reconstitution is inadequate based on the clinical assessment of the patient. The total weekly dose may be divided into multiple intramuscular (IM) administrations during a week. Adagen-naïve patients The starting weekly dose of REVCOVI is 0.4 mg/kg based on ideal body weight or actual weight whichever is greater, divided into two doses (0.2 mg/kg twice a week), intramuscularly, for a minimum of 12 to 24 weeks until immune reconstitution is achieved. After that, the dose may be gradually adjusted down to maintain trough ADA activity over 30 mmol/hr/L, trough dAXP level under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the patient. The optimal long-term dose and schedule of administration should be established by the treating physician for each patient individually and may be adjusted based on the laboratory values for trough ADA activity, trough dAXP level, and/or on the treating physician's medical assessment of the patient's clinical status . 2.2 Administration Instructions REVCOVI is for IM injection only. Follow sterile IM administration technique guidelines appropriate to the patient's age and anatomy (i.e. choice of needle gauge and length, site of administration). Take precautions not to inject into or near an artery or nerve. Alternate the injection site periodically. Preparation of Injection and Procedure Instructions REVCOVI should not be diluted nor mixed with any other drug prior to administration. Visually inspect REVCOVI for particulate matter and discoloration prior to administration. REVCOVI is a clear, colorless solution; discard if solution is discolored, cloudy or contains particulate matter. Do not freeze or shake. REVCOVI should not be used if there are any indications that it may have been frozen. Once removed from refrigeration, allow REVCOVI to equilibrate to room temperature for 30 minutes. REVCOVI is to be administered using polypropylene syringes. Draw the solution from the vial with a 25- gauge needle or larger. Change the needle to a size and gauge appropriate for the patient's intramuscular administration. REVCOVI should be administered immediately after syringe preparation. Any remaining medication in the vial must be discarded immediately. 2.3 Therapeutic Monitoring Schedule The treatment of ADA-SCID with REVCOVI should be monitored by measuring trough plasma ADA activity, trough dAXP levels, and/or total lymphocyte counts. Monitoring should be more frequent if therapy was interrupted or if an enhanced rate of clearance of plasma ADA activity develops. Collect blood samples for the analysis of trough plasma ADA activity and trough dAXP level prior to the first administration of REVCOVI for the week. ADA Activity Once treatment with REVCOVI has been initiated, a target trough plasma ADA activity should be at least 30 mmol/hr/L. In order to determine an effective dose of REVCOVI, trough plasma ADA activity (pre-injection) should be determined every 2 weeks for Adagen-naïve patients and every 4 weeks for patients previously receiving Adagen therapy, during the first 8 - 12 weeks of treatment, and every 3 - 6 months thereafter. A decrease of ADA activity below this level suggests noncompliance to treatment or a development of antibodies (anti-drug, anti-PEG, and neutralizing antibodies). Antibodies to REVCOVI should be suspected if a persistent fall in pre-injection levels of trough plasma ADA activity below 15 mmol/hr/L occurs. In such patients, testing for antibodies to REVCOVI should be performed. If a persistent decline in trough plasma ADA activity occurs, immune function and clinical status should be monitored closely and precautions should be taken to minimize the risk of infection. If antibodies to REVCOVI are found to be the cause of a persistent fall in trough plasma ADA activity, then adjustment in the dosage of REVCOVI and other measures may be taken to induce tolerance and restore adequate ADA activity. Erythrocyte dAXP Two months after starting REVCOVI treatment, trough erythrocyte dAXP levels should be maintained below 0.02 mmol/L, and monitored at least twice a year. Immune Function The degree of immune function may vary from patient to patient. Each patient will require appropriate monitoring consistent with immunologic status. Total and subset lymphocytes should be monitored periodically as follows: Adagen-naïve patients: every 4 – 8 weeks for up to 1 year, and every 3 – 6 months thereafter Other patients: every 3 - 6 months Immune function, including the ability to produce antibodies, generally improves after 2 - 6 months of therapy, and matures over a longer period. In general, there is a lag between the correction of the metabolic abnormalities and improved immune function. Improvement in the general clinical status of the patient may be gradual (as evidenced by improvement in various clinical parameters) but should be apparent by the end of the first year of therapy.

6 ADVERSE REACTIONS The most common adverse reactions reported were cough (50%) and vomiting (33%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. REVCOVI was administered intramuscularly in two prospective, open-label, single-arm, multi‑center studies to evaluate efficacy, safety, tolerability, and pharmacokinetics in patients with ADA-SCID: Study 1 was performed in the US and Study 2 was performed in Japan [see Clinical Studies ( 14 )] . Overall, 10 patients were treated and adverse reactions reported are summarized below. Study 1 Study 1 is a one-way crossover study, conducted in the US, to evaluate the safety, efficacy, and pharmacokinetics of REVCOVI in patients with ADA‑SCID who were receiving therapy with Adagen. Six patients, 8 to 37 years of age enrolled in the study. Patients' exposure to REVCOVI ranged from 2 weeks to 146 weeks. No deaths were reported and one patient discontinued treatment due to injection site pain associated with an earlier drug product formulation that was consequently modified. The most common adverse reactions were cough (3/6 patients) and vomiting (2/6 patients). Other adverse reactions that were reported in one patient each were: abdominal pain upper, arthralgia, asthenia, cerumen impaction, conjunctivitis, convulsion, dental caries, diarrhea, ear canal irritation, ear lobe infection, epistaxis, fatigue, fungal skin infection, gait disturbance, gastrointestinal infection, groin abscess, hematochezia, haemophilus infection (pulmonary), hemoptysis, influenza, injection site discomfort, laceration, lymphadenopathy, migraine, nasal edema, nausea, nephrolithiasis, oral candidiasis, oropharyngeal pain, otitis externa, productive cough, rash, stoma site infection, swelling face, tooth abscess, tooth extraction and upper respiratory tract infection, regardless of investigator causality assessment. Study 2 Study 2 is a single-arm clinical study that was conducted to assess the safety, efficacy and pharmacokinetics of REVCOVI in patients with ADA-SCID. Four patients 3.4 months to 25 years of age, all Asian, were enrolled in the study and received REVCOVI. Three patients received REVCOVI for 21 weeks and one patient received REVCOVI for 15 weeks. One death due to CMV pneumonitis and respiratory failure was observed in an infant, who had also experienced pulmonary hemorrhage, respiratory failure and upper respiratory tract infection that represented serious adverse events. Neutropenia was a serious adverse reaction reported by one of the patients. There were 22 reported adverse events for four patients. Most common adverse events were respiratory infections (2/4 patients). 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity results from Study 1 and Study 2 suggest that patients who previously received Adagen may present an immunologic response to REVCOVI. Therefore, monitoring for changes in ADA levels during REVCOVI treatment is recommended. [see Dosage and Administration ( 2.3 )] The observed incidence of antibodies (including neutralizing antibodies) is dependent on assay sensitivity and specificity, assay methodology, and concomitant medications. Therefore, the comparison of the incidence of antibodies to REVCOVI with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience with ADAGEN The following postmarketing adverse reactions were voluntarily reported for Adagen, the same class of enzyme replacement therapy used in the treatment of ADA-SCID, and may also be seen with REVCOVI treatment: Hematologic: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia Dermatological: injection site erythema, urticaria Lymphomas Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

12.3 Pharmacokinetics The pharmacokinetics (PK) of REVCOVI were evaluated based on steady state plasma ADA activity in six patients with ADA-SCID (five adults and one pediatric) from two studies (Study 1 and Study 2) who received weekly IM injections at doses ranging from 4.99 to 19.6 mg [see Clinical Studies ( 14 )] . The PK results are summarized in Table 1. Table 1 Individual Estimates of Steady State Plasma Pharmacokinetic Parameters of REVCOVI Following Weekly IM Administration in ADA-SCID Patients Study Patient's Age (yrs), Sex, Race Weekly Dose (mg) [mg/kg] T max (hr) DN AUC 0-168hr (hr*mmol/hr/L)/ (mg/kg) b DN C max (mmol/hr/L)/ (mg/kg) b C trough (mmol/hr/L) c a PK data calculated over the dosing interval after weekly IM administration of REVCOVI at a stable REVCOVI dose for at least five consecutive weeks b Dose-normalized (DN) AUC 0-168hr and C max estimates based on mg/kg/week dose of REVCOVI c Non-dose normalized steady state C trough ADA activity in plasma at Day 7 prior to administration of next weekly dose Study 1 a 19, Male, Hispanic/Latino 10.0 [0.188] 47.7 32710 237 29.0 21, Male, Hispanic/Latino 10.2 [0.224] 71.9 31343 219 37.7 37, Male, Black/African American 19.6 [0.2] 48.2 42400 292 46.2 30, Female, White/Caucasian 10.0 [0.209] 72.0 24564 166 23.5 Study 2 a 25, Male, Asian 10.0 [0.167] 48.0 37605 251 33.5 16, Female, Asian 4.99 [0.233] 27.2 19013 150 20.2 In Study 1, steady state ADA activity levels were reached following seven consecutive once weekly IM doses of REVCOVI. In addition, dAXP activity levels in all patients at the majority of all sampling timepoints in Study 1 were less than 0.02 mmol/L.