Avlayah Drug Information
Generic name: TIVIDENOFUSP ALFA-EKNM
Uses of Avlayah
is indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. This indication is approved under accelerated approval based on the reduction of cerebrospinal fluid heparan sulfate . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Limitations of Use AVLAYAH is not recommended for use in combination with other enzyme replacement therapies for the treatment of Hunter syndrome. AVLAYAH is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment.
This indication is approved under accelerated approval based on reduction of cerebrospinal fluid heparan sulfate observed in patients treated with AVLAYAH. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). Limitations of Use AVLAYAH is not recommended for use in combination with other enzyme replacement therapies.
Dosage & Administration of Avlayah
| a Do not escalate the dosage level if the current dosage level is not tolerated | |
|---|---|
| Week 1 to Week 4 | 3 mg/kg once weekly |
| Week 5 to Week 8 | 7.5 mg/kg once weekly |
| Week 9 and beyond | 15 mg/kg once weekly (maintenance dosage) |
Side Effects of Avlayah
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 AVLAYAH was evaluated in male pediatric patients with Hunter syndrome in Trial 1 . A total of 47 male patients (age range: 3 months to 13 years) received intravenous AVLAYAH at 3 mg/kg to 30 mg/kg (0.2 to 2 times the approved recommended maintenance dose) weekly, and the majority of patients received 15 mg/kg intravenously weekly after Week 24. The median (minimum, maximum) duration of exposure was 117 weeks. In Trial 1, the most common adverse reactions (≥20%) reported in AVLAYAH-treated patients were infusion-associated reaction (IAR), upper respiratory tract infection, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria.
Dose interruptions of AVLAYAH due to an adverse reaction occurred in 91% of patients. The most frequently reported adverse reaction leading to dose interruption was IAR (31 patients). Other frequently reported adverse reactions leading to dose interruption were COVID-19 (18 patients), pyrexia, upper respiratory tract infection, nasal congestion, and vomiting. Dose interruption included skipped infusions due to an adverse reaction as well as temporary infusion pauses with subsequent completion during the same visit.
Dose reductions of AVLAYAH due to adverse reactions occurred in 57% of patients; the majority of these reactions were IARs. In Trial 1, one (2%) AVLAYAH-treated patient experienced anaphylaxis, which occurred in the first month of treatment. Table 4 summarizes adverse reactions that occurred in >15% of AVLAYAH-treated pediatric patients with Hunter syndrome.
Table 4: Adverse Reactions That Occurred in >15% in AVLAYAH-treated Pediatric Patients With Hunter Syndrome (Trial 1) Adverse Reaction Any Severity N (%) (N = 47) a Infusion-associated reaction includes infusion-related reaction. b Ear infection includes ear infection, otitis media, otitis media acute, otitis externa. c Anemia includes anemia, iron deficiency anemia, and decreased hemoglobin. Infusion-associated reaction a 41 (87%) Upper respiratory tract infection 28 (60%) Ear infection b 26 (55%) Pyrexia 26 (55%) Anemia c 24 (51%) Cough 22 (47%) Vomiting 20 (43%) Diarrhea 19 (40%) Rash 19 (40%) COVID-19 18 (38%) Rhinorrhea 18 (38%) Nasal congestion 17 (36%) Fall 11 (23%) Headache 11 (23%) Skin abrasion 11 (23%) Urticaria 10 (21%) Constipation 8 (17%) Contusion 8 (17%) Gastroenteritis 8 (17%) Infusion site extravasation 8 (17%) Insomnia 8 (17%) Neutropenia 8 (17%) Description of Selected Adverse Reactions Infusion-Associated Reaction Three (6%) AVLAYAH-treated patients experienced severe IARs. One patient permanently discontinued treatment due to an IAR. Anemia Two (4%) AVLAYAH-treated patients experienced severe anemia (defined as hemoglobin <8 g/dL) prior to Week 24. One (2%) AVLAYAH-treated patient, aged 0.5 years, experienced moderate anemia (hemoglobin 9.2 g/dL), which was considered serious due to the patient's age.
Membranous Nephropathy A case of biopsy-confirmed, steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an AVLAYAH-treated patient.
Warnings & Cautions for Avlayah
Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported
in patients treated with enzyme replacement therapies (ERTs), including AVLAYAH . Symptoms of anaphylaxis that have occurred with AVLAYAH have included tachycardia, hypotension, wheezing, vomiting, hives, and lip and tongue swelling. Anaphylaxis has occurred during the early course of ERT and after extended duration of therapy. Administer AVLAYAH under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.
Initiate AVLAYAH in a healthcare setting with appropriate medical monitoring and support measures including access to cardiopulmonary resuscitation equipment. Prior to AVLAYAH administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue AVLAYAH and immediately initiate appropriate medical treatment, including use of epinephrine.
Consider the risks and benefits of re-administering AVLAYAH following a severe hypersensitivity reaction (including anaphylaxis). If the decision is made to re-administer AVLAYAH, re-evaluate pre-treatment medications (e.g., antihistamines, antipyretics, and/or corticosteroids), slow the infusion rate, and/or reduce the AVLAYAH dose. Monitor patients closely upon re-administration of AVLAYAH. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and to seek immediate medical care should symptoms occur. If a mild or moderate hypersensitivity reaction occurs, temporarily hold the infusion and/or reduce the infusion rate by at least 50% from the current rate, then titrate up to the recommended infusion rate as tolerated (see Table 3 ). Re-evaluate the pre-treatment medication regimen . If the dose has been decreased due to an adverse reaction, evaluate when it is appropriate to increase the dose and follow the recommended dose escalation regimen to achieve the maintenance dosage of 15 mg/kg once weekly.
Infusion-Associated Reactions Infusion-associated reactions (IARs) have been reported in patients treated with
AVLAYAH . IARs are defined as adverse reactions occurring during or within 24 hours of the infusion. Symptoms of IARs observed with AVLAYAH can include (but are not limited to) chills, angioedema, hypotension, tachycardia, urticaria, vomiting, wheezing, pyrexia, flushing, erythema, rash, cough, diarrhea, abdominal pain, retching, headache, irritability, and papules. IARs have been reported more frequently in ERT-naïve patients compared to ERT-experienced patients.
Cases of infusion-associated reactions occurring 2 hours or more after completion of the infusion have occurred with AVLAYAH. Prior to AVLAYAH administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. IARs may still occur in patients after receiving pre-treatment. Onset of IARs was most common during the first 8 weeks of treatment with a median time to onset of approximately 2 weeks for the first IAR; IARs declined in frequency with continued use of AVLAYAH. IARs may still occur despite extended duration of AVLAYAH treatment.
Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during AVLAYAH administration. If a severe IAR occurs, discontinue AVLAYAH and immediately initiate appropriate medical treatment. Consider the risks and benefits of re-administering AVLAYAH following a severe IAR. If the decision is made to re-administer AVLAYAH, re-evaluate pre-treatment medications, slow the infusion rate, and/or reduce the AVLAYAH dose.
Monitor patients closely upon re-administration of AVLAYAH. If a mild or moderate IAR occurs, temporarily hold the infusion, and/or reduce the infusion rate by at least 50% from the current rate, then titrate up to the recommended infusion rate as tolerated. If the dose has been decreased due to an adverse reaction, evaluate when it is appropriate to increase the dose and follow the recommended dose escalation regimen to achieve the maintenance dosage of 15 mg/kg once weekly . Patients with Hunter syndrome may have compromised cardiac and respiratory function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac and respiratory function following AVLAYAH administration.
Anemia Anemia has been reported in patients treated with
AVLAYAH . The incidence of anemia after initiation of AVLAYAH was higher in patients with pre-existing anemia compared to those without pre-existing anemia. Reductions in hemoglobin levels were generally observed by Week 13, though the occurrence was observed up to one year in some patients. Overall, the incidence and severity of anemia decreased over time, with the majority of patients recovering by Week 24. Anemia did not result in treatment discontinuation; management may include supplementation with iron.
Obtain hemoglobin levels prior to initiating AVLAYAH, at 3 months after initiation, and periodically thereafter as clinically indicated. Administer appropriate supportive measures for anemia based on clinical judgment.
Membranous Nephropathy
A case of steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an AVLAYAH-treated patient . Monitor serum creatinine and urinary protein to creatinine ratio. If membranous nephropathy is suspected, conduct diagnostic evaluation and initiate appropriate treatment. Consider risks and benefits of continuing AVLAYAH in patients who develop membranous nephropathy.
Pregnancy Safety for Avlayah
Pregnancy Risk Summary There are no available data on the use of AVLAYAH during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal studies to evaluate the potential for embryofetal developmental toxicity and pre- and postnatal developmental toxicity of tividenofusp alfa-eknm have not been conducted. The background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pediatric Use of Avlayah
Pediatric Use The safety and effectiveness of AVLAYAH have been established under accelerated approval for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment and the information on this use is discussed throughout the labeling . The safety and effectiveness of AVLAYAH have not been established in pediatric patients weighing less than 5 kg.
Clinical Studies of Avlayah
Trial 1 (NCT04251026) was a Phase 1/2 multi-center, international, multi-cohort, single-arm, open-label trial of AVLAYAH in 47 pediatric patients with Hunter syndrome including 44 patients with neuronopathic Hunter syndrome and 3 patients with non-neuronopathic Hunter syndrome. Of the 47 patients enrolled, 46 patients completed part 1 of the study (up to Week 24) and 1 patient discontinued the study due to an adverse reaction prior to Week 24. In part 1 of Trial 1, patients received a starting dosage of AVLAYAH ranging from 3 mg/kg to 15 mg/kg weekly and a maximum dosage ranging from 3 mg/kg to 30 mg/kg weekly (0.2 to 2 times the approved recommended maintenance dosage). Patients who received 30 mg/kg weekly dosage (2 times the approved recommended maintenance dosage) did not show additional reductions from baseline in cerebrospinal fluid (CSF) or urine heparan sulfate (HS) concentration compared to patients who received 15 mg/kg weekly. The most common AVLAYAH dosage (57% of the patients) in Trial 1 was 15 mg/kg administered once weekly.
All 47 patients in Trial 1 were male, with a baseline median age of 5 years (range: 3 months to 13 years of age). The patient population consisted of 27 White (57%), 4 Black or African American (9%), 4 Asian (9%), 3 who were more than one race (6%), 1 of another race (2%), and 8 of an unknown race (17%). Ethnicity consisted of 7 patients who were Hispanic or Latino (15%), 38 who were Not Hispanic or Latino (81%), and 2 of an unknown ethnicity (4%). Of the 47 patients, 15 patients were enzyme replacement therapy (ERT)-naïve, and 32 patients were ERT-experienced, 2 of whom had a history of prior treatment for Hunter syndrome with hematopoietic stem cell transplantation (HSCT), and 2 of whom had a history of prior treatment for Hunter syndrome with gene therapy. The median duration of previous ERT treatment was 26 months (range: 1 to 134 months). In Trial 1, treatment with AVLAYAH resulted in a significant reduction of CSF HS. For the 44 patients who had measurements at Week 24, the CSF HS mean percent reduction from baseline was 91% (95% CI: 89%, 92%); the minimum and maximum percent change in CSF HS from baseline were 72% and 98%, respectively. At baseline, 0% (0 of 47) of patients had CSF HS levels below the upper limit of normal (ULN). At Week 24, 93% (41 of 44) of AVLAYAH-treated patients had CSF HS levels below the ULN.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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