Pombiliti Drug Information

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

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 POMBILITI in combination with Opfolda including: 85 patients in the randomized, double-blind, active-controlled trial in adults (Trial 1) , 37 patients in the open-label extension trial where patients switched from a non‑U.S.‑approved alglucosidase alfa product to POMBILITI in combination with Opfolda, 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 POMBILITI in combination with Opfolda.

In these trials, 78% (n=117) of the patients received previous ERT (ERT‑experienced) with a mean treatment duration of 7.7 years. In these trials, serious adverse reactions reported in 2 or more patients treated with POMBILITI in combination with Opfolda were anaphylaxis and urticaria. A total of 5 patients treated with POMBILITI in combination with Opfolda in these trials permanently discontinued POMBILITI due to adverse reactions, including 4 of these patients who discontinued the treatment because of a serious adverse reaction.

The most common adverse reactions (≥5%) reported in the pooled safety population of patients treated with POMBILITI in combination with Opfolda in the 3 clinical trials were headache, diarrhea, fatigue, nausea, abdominal pain and pyrexia. In these trials, IARs were reported in 48 (32%) patients treated with POMBILITI in combination with Opfolda. IARs reported in more than 1 patient included headache, myalgia, diarrhea, nausea, fatigue, muscle spasms, pyrexia, dizziness, cough, chills, rash, vomiting, dyspnea, pain, abdominal distension, tachycardia, urticaria, flatulence, pruritus, abdominal pain, chest discomfort, flushing, hyperhidrosis, dysgeusia, hypotension, and hypertension.

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 POMBILITI in combination with Opfolda or a non-U.S.-approved alglucosidase alfa product with placebo. 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 POMBILITI in combination with Opfolda 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 POMBILITI in combination with Opfolda in Trial 1 were headache and diarrhea. Table 2 summarizes frequent adverse reactions that occurred in patients treated with POMBILITI in combination with Opfolda in Trial 1. Trial 1 was not designed to demonstrate a statistically significant difference in the incidence of adverse reactions in the POMBILITI in combination with Opfolda 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 POMBILITI in Combination with Opfolda (n=85) N (%) A Non-U.S.-Approved Alglucosidase alfa Product with Placebo (n=38) N (%) Headache∗ 7 3 Diarrhea 5 2 Dizziness 4 2 Dyspnea 3 0 Abdominal distention 3 2 Pyrexia 3 1 Rash † 3 0 Abdominal pain ‡ 2 4 Nausea 2 5 Chills 2 0 Dysgeusia 2 0 Flushing 2 0 Muscle spasms 2 0 Pruritus 2 2 Tachycardia § 2 0 Urticaria ¶ 2 0 Additional adverse reactions reported in at least 2% of patients treated with POMBILITI in combination with Opfolda 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. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions in Trial 1 Anaphylaxis or serious infusion-associated reactions (IARs) occurred in 1 (1.5%) POMBILITI‑treated patient (who previously received U.S.-approved alglucosidase alfa or a non-U.S.-approved alglucosidase alfa product) who had peak anti-cipaglucosidase alfa-atga antibody titer of 6,553,600 during the 52-week treatment period .

Pregnancy Risk Summary Based on findings from animal reproduction studies, POMBILITI in combination with Opfolda 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 cipaglucosidase alfa-atga in combination with miglustat at 16-fold and 3-fold, respectively, the MRHD of POMBILITI and Opfolda 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 cipaglucosidase alfa-atga (400 mg/kg) in combination with miglustat, 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 POMBILITI and Opfolda were 20-fold and 4-fold, respectively, based on plasma AUC exposure (see Data ). There are no available human data on POMBILITI in combination with Opfolda 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, cipaglucosidase alfa-atga (30, 70, or 175 mg/kg) was administered intravenously every other day to pregnant females during organogenesis (Gestation Day 7 through GD 19). Additional experimental groups received 25 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 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 cipaglucosidase alfa-atga and miglustat at 16-fold and 3-fold the MRHD of POMBILITI and Opfolda, respectively, based on plasma AUC exposure.

A NOAEL for the combination was not identified. One fetus treated with cipaglucosidase alfa-atga alone (175 mg/kg) and one fetus treated with miglustat alone (25 mg/kg), each showed a similar cluster of these great vessel and cardiac malformations. In a rat embryo-fetal development study, cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) was administered intravenously every other day to pregnant rats during organogenesis (GD 6 through GD 18). Additional experimental groups received 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 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 cipaglucosidase alfa‑atga (400 mg/kg) was 20-fold the POMBILITI MRHD based on plasma AUC exposure. The margin at the NOAEL for miglustat (60 mg/kg) was 4-fold the Opfolda MRHD based on plasma AUC exposure.

In a pre-and post-natal development study in rats, cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) was administered intravenously every other day to pregnant females from GD 6 through GD 18, and from Lactation Day (LD) 1 through LD 19. Additional experimental groups received 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa‑atga 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 POMBILITI and Opfolda were 20-fold and 4-fold, respectively, based on plasma AUC exposure.

Pediatric Use Safety and effectiveness of POMBILITI in combination with Opfolda have not been established in pediatric patients with late-onset Pompe disease.

in combination with Opfolda is contraindicated in pregnancy. Pregnancy