OPFOLDA

1 INDICATIONS AND USAGE OPFOLDA is indicated, in combination with Pombiliti, for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg and who are not improving on their current enzyme replacement therapy (ERT). OPFOLDA is an enzyme stabilizer indicated, in combination with Pombiliti, a hydrolytic lysosomal glycogen-specific enzyme, for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg and who are not improving on their current enzyme replacement therapy (ERT). ( 1 )

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential prior to initiating treatment. (2.1) Administer OPFOLDA in combination with Pombiliti. (2.2) Recommended OPFOLDA dosage (based on actual body weight), administered orally every other week, is: (2.2) 260 mg for patients weighing ≥50 kg. 195 mg for patients weighing ≥40 kg to <50 kg. Start OPFOLDA in combination with Pombiliti 2 weeks after the last ERT dose. (2.2) Take OPFOLDA with an unsweetened beverage approximately 1 hour before the start of Pombiliti infusion; do not consume other beverages or food for at least 2 hours prior to and 2 hours after taking OPFOLDA. (2.2) Missed dose: If the OPFOLDA dosage is missed, Pombiliti should not be administered and treatment should be rescheduled at least 24 hours after OPFOLDA was last taken. If OPFOLDA in combination with Pombiliti are both missed, re-start treatment as soon as possible. (2.2) See full prescribing information for recommended OPFOLDA dosage in patients with renal impairment. (2.3) 2.1 Pregnancy Evaluation Prior to Initiating Treatment Verify the pregnancy status of females of reproductive potential prior to initiating OPFOLDA in combination with Pombiliti [see Use in Specific Populations (8.1, 8.3) ] . 2.2 Recommended Dosage and Administration OPFOLDA must be administered in combination with Pombiliti (see Figure 1 for the dosing timeline). Refer to the Pombiliti Prescribing Information for Pombiliti dosage and administration recommendations. The recommended dosage of OPFOLDA is based on actual body weight. For patients weighing: ≥50 kg, the recommended dosage is 260 mg orally every other week. ≥40 kg to <50 kg, the recommended dosage is 195 mg orally every other week. Start OPFOLDA in combination with Pombiliti 2 weeks after the last ERT dose. Take OPFOLDA approximately 1 hour before intravenous administration of Pombiliti. Swallow the OPFOLDA capsules whole only with unsweetened beverages (e.g., water, tea or coffee with no cream, sugar, or sweeteners). Do not consume other beverages or food for at least 2 hours prior to and 2 hours after administration of OPFOLDA. Missed Dose If the OPFOLDA dosage is missed, Pombiliti should not be administered and treatment should be rescheduled at least 24 hours after OPFOLDA was last taken. If OPFOLDA in combination with Pombiliti are both missed, re-start treatment as soon as possible. Figure 1. Dosing Timeline Figure 1 2.3 Recommended Dosage in Patients with Renal Impairment The recommended dosage of OPFOLDA in patients with moderate or severe renal impairment is shown in Table 1 [see Clinical Pharmacology (12.3) ] . Table 1. Recommended OPFOLDA Dosage in Patients with Moderate or Severe Renal Impairment ∗ Renal function classified by CLcr (creatinine clearance) based on the Cockcroft-Gault equation. Patient Weight Moderate Renal Impairment∗(CLcr 30-59 mL/minute) Severe Renal Impairment∗ (CLcr 15-29 mL/minute) ≥50 kg 195 mg 195 mg ≥40 kg to <50 kg 130 mg 130 mg For patients with mild renal impairment (creatinine clearance based on the Cockcroft-Gault equation, CLcr 60-89 mL/minute), the recommended OPFOLDA dosage is the same as for patients with normal renal function.

4 CONTRAINDICATIONS OPFOLDA in combination with Pombiliti is contraindicated in Pregnancy [see Use in Specific Populations (8.1 )] Pregnancy. ( 4, 5.1, 8.1 )

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for at least 60 days after the last dose. ( 4, 5.1, 8.1, 8.3 ) Risks Associated with Pombiliti: Refer to the Pombiliti Prescribing Information for a description of additional risks for Pombiliti. (5.2) 5.1 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, OPFOLDA in combination with Pombiliti may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. In a rabbit embryo-fetal development study, great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with oral miglustat in combination with cipaglucosidase alfa-atga at 3-fold and 16-fold, respectively, the maximum recommended human dose (MRHD) based on plasma AUC exposure. Verify the pregnancy status in females of reproductive potential prior to initiating treatment with OPFOLDA in combination with Pombiliti. Advise females of reproductive potential to use effective contraception during treatment with OPFOLDA in combination with Pombiliti and for at least 60 days after the last dose [see Use in Specific Populations (8.1, 8.3) ] . 5.2 Risks Associated with Pombiliti OPFOLDA must be administered in combination with Pombiliti. Refer to the Pombiliti Prescribing Information for a description of additional risks for Pombiliti including, but not limited to, the warnings and precautions for Pombiliti.

6 ADVERSE REACTIONS Most common adverse reactions ≥5% are headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amicus Therapeutics at 1-877-4AMICUS 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. Adverse Reactions from the Pooled Clinical Trials Including Trial 1 The pooled safety analysis from 3 clinical trials included 151 adult patients with late-onset Pompe disease (LOPD) treated with OPFOLDA in combination with Pombiliti including: 85 patients in the randomized, double-blind, active-controlled trial in adults (Trial 1) [see Clinical Studies (14) ] , 37 patients in the open-label extension trial where patients switched from a non‑U.S.‑approved alglucosidase alfa product [see Clinical Studies (14) ] to OPFOLDA in combination with Pombiliti, 29 patients in an open-label trial. The total median duration of exposure in these trials was 21 months, with 120 patients having at least 12 months exposure to OPFOLDA in combination with Pombiliti. In these trials, 78% (n=117) of the patients received previous ERT (ERT‑experienced) with a mean treatment duration of 7.7 years. The most common adverse reactions (≥5%) reported in the pooled safety population of patients treated with OPFOLDA in combination with Pombiliti in the 3 clinical trials were headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia. Adverse Reactions from Trial 1 Trial 1 (a randomized, double-blind, active-controlled trial) included 123 adult patients with LOPD who were randomized in a 2:1 ratio to receive treatment with OPFOLDA in combination with Pombiliti or a non-U.S.-approved alglucosidase alfa product with placebo [see Clinical Studies (14) ]. The duration of exposure was similar for both treatment groups (overall mean exposure of 12 months). Most patients (77%) were ERT‑experienced, and a majority of patients in both treatment groups had >5 years of prior treatment with ERT (69% and 63% of patients in the OPFOLDA in combination with Pombiliti group and the non-U.S.-approved alglucosidase alfa product with placebo group, respectively). The most common adverse reactions (≥5%) reported in the patients who received OPFOLDA in combination with Pombiliti in Trial 1 were headache and diarrhea. Table 2 summarizes frequent adverse reactions that occurred in patients treated with OPFOLDA in combination with Pombiliti in Trial 1. Trial 1 was not designed to demonstrate a statistically significant difference in the incidence of adverse reactions in the OPFOLDA in combination with Pombiliti and the non-U.S.-approved alglucosidase alfa product with placebo groups. Table 2. Adverse Reactions that Occurred in Adults with LOPD at an Incidence of ≥2% in Trial 1 LOPD: late-onset Pompe disease ∗ Headache included migraine and migraine with aura. † Rash included erythematous rash and macular rash. ‡ Abdominal pain included upper and lower abdominal pain. § Tachycardia included sinus tachycardia. ¶ Urticaria included mechanical urticaria and urticarial rash. Adverse Reaction OPFOLDA in Combination with Pombiliti (n=85) N (%) A Non-U.S.-Approved Alglucosidase alfa Product with Placebo (n=38) N (%) Headache ∗ 7 (8.2) 3 (7.9) Diarrhea 5 (5.9) 2 (5.3) Dizziness 4 (4.7) 2 (5.3) Dyspnea 3 (3.5) 0 Abdominal distention 3 (3.5) 2 (5.3) Pyrexia 3 (3.5) 1 (2.6) Rash † 3 (3.5) 0 Abdominal pain ‡ 2 (2.4) 4 (10.5) Nausea 2 (2.4) 5 (13.2) Chills 2 (2.4) 0 Dysgeusia 2 (2.4) 0 Flushing 2 (2.4) 0 Muscle spasms 2 (2.4) 0 Pruritus 2 (2.4) 2 (5.3) Tachycardia § 2 (2.4) 0 Urticaria ¶ 2 (2.4) 0 Additional adverse reactions reported in at least 2% of patients treated with OPFOLDA in combination with Pombiliti across the 3 clinical trials include: myalgia, arthralgia, increased blood pressure, pain, tremor, dyspepsia, asthenia, constipation, infusion site swelling, flank pain, malaise, paresthesia, somnolence, and decreased platelet count.

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, OPFOLDA in combination with Pombiliti may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. In a rabbit embryo-fetal development study, great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with miglustat in combination with cipaglucosidase alfa-atga at 3-fold and 16-fold, respectively, the MRHD of OPFOLDA and Pombiliti based on plasma AUC exposure. A No Observed Adverse Effect Level (NOAEL) was not identified for the combination. In a pre- and post-natal development study in rats, increases in pup mortality were seen following maternal treatment with miglustat in combination with cipaglucosidase alfa-atga (400 mg/kg), or with cipaglucosidase alfa-atga (400 mg/kg) alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the Pombiliti MRHD margin). A NOAEL for the combination was not identified. Margins at the lowest observed adverse effect level (LOAEL), relative to exposures at the MRHD of OPFOLDA and Pombiliti were 4-fold and 20-fold, respectively, based on plasma AUC exposure ( see Data ). There are no available human data on OPFOLDA in combination with Pombiliti use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Data Animal Data Reproductive toxicity studies of cipaglucosidase alfa-atga in rats and rabbits included pretreatment with diphenhydramine (DPH) to prevent or minimize hypersensitivity reactions. In a rabbit embryo-fetal development study, 25 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 175 mg/kg, was administered every other day to pregnant females during organogenesis (Gestation Day [GD] 7 through GD 19). Additional experimental groups received cipaglucosidase alfa-atga (30, 70, or 175 mg/kg) with the same dosing frequency during organogenesis. Clusters of great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with the combination of miglustat and cipaglucosidase alfa-atga at 3-fold and 16-fold the MRHD of OPFOLDA and Pombiliti, respectively, based on plasma AUC exposure. A NOAEL for the combination was not identified. One fetus treated with miglustat alone (25 mg/kg) and one fetus treated with cipaglucosidase alfa-atga alone (175 mg/kg), each showed a similar cluster of these great vessel and cardiac malformations. In a rat embryo-fetal development study, 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 400 mg/kg, was administered every other day to pregnant rats during organogenesis (GD 6 through GD 18). Additional experimental groups received cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) with the same dosing frequency during organogenesis. No evidence of adverse effects was noted in pregnant rats or their offspring in any experimental group. The margin at the NOAEL for miglustat (60 mg/kg) was 4-fold the OPFOLDA MRHD based on plasma AUC exposure. The margin at the NOAEL for cipaglucosidase alfa-atga (400 mg/kg) was 20-fold the Pombiliti MRHD based on plasma AUC exposure. In a pre-and post-natal development study in rats, 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 400 mg/kg, was administered to pregnant females every other day from GD 6 through GD 18, and from Lactation Day (LD) 1 through LD 19. Additional experimental groups received cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) with the same dosing frequency during pregnancy and lactation. Maternal and pup mortality were increased with the combination, and pup mortality was also increased with cipaglucosidase alfa-atga 400 mg/kg alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the Pombiliti MRHD margin). A NOAEL was not identified for the combination, for which LOAEL margins at the MRHD of OPFOLDA and Pombiliti were 4-fold and 20-fold, respectively, based on plasma AUC exposure.