Avlayah

Avlayah (tividenofusp alfa-eknm) is a prescription enzyme replacement therapy (ERT) for Hunter syndrome (MPS II) used to treat neurologic symptoms of the disease. Hunter syndrome, or mucopolysaccharidosis type II, is caused by a deficiency of the IDS enzyme, which leads to the buildup of harmful glycosaminoglycans (GAGs) in the body.

Avlayah works by delivering the IDS enzyme to the central nervous system to help break down accumulated GAGs. This approach is intended to help reduce the neurologic effects of Hunter syndrome, including cognitive and behavioral decline.

Avlayah is administered as a weekly intravenous infusion.

This medicine should not be used in combination with other enzyme replacement therapies.

Avlayah is FDA-approved for the treatment of neurologic manifestations of Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), in certain pediatric patients.

Avlayah may be used in pediatric patients who weigh at least 5 kg, and when treatment is:

• started in presymptomatic or symptomatic pediatric patients
• initiated before advanced neurologic impairment has developed

Avlayah received accelerated approval based on its ability to reduce cerebrospinal fluid heparan sulfate in treated patients. Continued approval may depend on confirmation of clinical benefit in the Phase 2/3 COMPASS study.

Avlayah (tividenofusp alfa-eknm) is a fusion protein that combines the iduronate-2-sulfatase (IDS) enzyme with proprietary TransportVehicle™ (TV) technology. This technology binds to the transferrin receptor (TfR), helping deliver the IDS enzyme to both body tissues and the central nervous system (CNS).

Once delivered, the IDS enzyme helps break down harmful glycosaminoglycans (GAGs) that contribute to neurologic damage in Hunter syndrome.

Avlayah is a hydrolytic lysosomal glycosaminoglycan-specific enzyme replacement therapy.

Avlayah has a boxed warning for serious allergic reactions, including anaphylaxis. A boxed warning is the strongest safety-related warning issued by the FDA.

Avlayah can cause serious allergic reactions, including anaphylaxis, a severe reaction that can be life-threatening. These reactions can happen when treatment first begins or even after receiving Avlayah for a long time.

Avlayah should be given in a medical setting where healthcare providers can watch for reactions and provide emergency care if needed.

If a severe allergic reaction occurs, treatment with Avlayah should be stopped immediately, and emergency treatment should be given.

Avlayah can cause infusion-related reactions during treatment or within 24 hours after an infusion. Your healthcare provider will monitor you during and after treatment for signs of a reaction.

Anemia has also been reported with Avlayah. To help manage this risk, your healthcare provider may check your hemoglobin levels before treatment begins, about 3 months after starting treatment, and later if needed.

Kidney problems, including membranous nephropathy, have also been reported in some patients receiving Avlayah. Your healthcare provider may monitor your kidney health with blood tests and urine tests during treatment.

Pregnancy

Tell your healthcare provider if you are pregnant, planning a pregnancy, or become pregnant. 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.

Breastfeeding

Tell your healthcare provider if you are breastfeeding or planning to breastfeed. When deciding whether to breastfeed during treatment with Avlayah, you and your healthcare provider should consider the benefits of breastfeeding, your need for treatment, and any possible risks to your baby from Avlayah or from your underlying condition.

In Trial 1 (NCT04251026), a Phase 1/2 clinical study of 47 pediatric patients with Hunter syndrome, Avlayah treatment led to a 91% mean reduction in cerebrospinal fluid (CSF) heparan sulfate at Week 24 among 44 patients with available measurements (95% CI: 89% to 92%).

At baseline, 0 of 47 patients had CSF heparan sulfate levels below the upper limit of normal. By Week 24, 41 of 44 patients (93%) with available measurements were below the upper limit of normal.

The ongoing Phase 2/3 COMPASS study is continuing to evaluate Avlayah and its clinical benefit.

The most common Avlayah side effects include infusion-related reactions, upper respiratory tract infection, ear infection, fever, anemia, cough, vomiting, diarrhea, rash, COVID-19, runny nose, nasal congestion, falls, headache, skin abrasion, and hives.

These side effects occurred in 20% or more of patients in Trial 1 (NCT04251026).

Also see the “Warning and precautions” and “Boxed warning” sections.

Talk to your healthcare provider right away if you have questions about Avlayah side effects, Avlayah warnings, or symptoms that develop during or after infusion.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088

Avlayah is given once weekly as an intravenous (IV) infusion under the supervision of a healthcare professional experienced in managing hypersensitivity reactions, including anaphylaxis. Treatment should begin in a healthcare setting with appropriate monitoring and access to cardiopulmonary resuscitation equipment.

Recommended Avlayah Dosage

Pediatric patients weighing at least 5 kg:

• Starting dose: 3 mg/kg once weekly by IV infusion
• Dose escalation:
• Maintenance dose: 15 mg/kg once weekly by IV infusion

See detailed dosing instructions for

• Dosage and Administration Modifications and Monitoring
• Preparation Instructions
• Infusion Volumes
• Administration Instructions (including Infusion Rate and Infusion Duration)

Before starting treatment, baseline hemoglobin should be checked. Pretreatment with antihistamines, antipyretics, and/or corticosteroids may also be considered to help reduce the risk of infusion-related reactions.

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

Active ingredients: tividenofusp alfa-eknm (150 mg)

Inactive ingredients: dibasic sodium phosphate (5 mg), methionine (7.5 mg), monobasic sodium phosphate (7.7 mg), 12 polysorbate 20 (3 mg), sodium chloride (14.6 mg), and sucrose (300 mg).

The pH is 6.5 after reconstitution.

Manufactured for: Denali Therapeutics Inc. 161 Oyster Point Boulevard South San Francisco, CA 94080