FDA Approves New Orphan Indications for Three Marketed Drugs

Rare Daily Staff

The U.S. Food and Drug Administration granted additional approvals to three company’s already marketed drugs for orphan indications: Sanofi’s Sarclisa in multiple myeloma, Jazz Pharmaceuticals’ Vyxeos in pediatric leukemia, and United Therapeutics’ Tyvaso for pulmonary hypertension associated with interstitial lung disease.

Sanofi’s Sarclisa was approved in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received one to three prior lines of therapy. It is the second FDA approval for Sarclisa, which was first approved one year ago in combination with pomalidomide and dexamethasone for the treatment of adults with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Multiple myeloma (MM) is the second most common hematologic malignancy, affecting more than 130,000 patients in the United States. Despite available treatments, MM remains an incurable malignancy, and most patients will relapse or no longer respond to therapy.

Sarclisa is a monoclonal antibody that binds to a specific epitope on the CD38 receptor, which is highly and uniformly expressed on the surface of MM cells. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immune-modulatory activity.

The FDA approval is based on data from the phase 3 IKEMA study, a randomized, multi-center, open label clinical trial that enrolled 302 patients with relapsed multiple myeloma. In this study, Sarclisa combination therapy reduced the risk of disease progression or death by 45 percent versus standard of care alone in patients with multiple myeloma. The median progression free survival (PFS) for Sarclisa combination therapy was not reached at the time of the pre-planned interim analysis. This study enrolled a difficult-to-treat patient population, including those who are elderly, have high cytogenetic risk or renal impairment. Overall, demographic and disease characteristics at baseline were balanced between the two treatment groups.

Serious adverse reactions that occurred in more than 5 percent of patients who received Sarclisa combination therapy were pneumonia and upper respiratory tract infections. Permanent discontinuation of treatment because of adverse reactions occurred in 8 percent of treated patients treated, and 2.8 percent of patients discontinued due to an infection.

The FDA approved a revised label for Jazz Pharma’s Vyxeos to include a new indication to treat newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in pediatric patients aged one year and older.

AML is a rare cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. It can sometimes spread to other parts of the body including the lymph nodes, liver, spleen, central nervous system, and testicles. AML in children makes up a small portion of the overall AML population (4.5 percent occurs in patients less than 20 years old). Further, t-AML and AML-MRC in pediatric AML are very rare subtypes of this group accompanied by poor prognosis. Patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes may have a particularly poor prognosis, and a hematopoietic stem cell transplant may be a curative treatment option for patients.

Vyxeos is a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor, that is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

Safety and pharmacokinetics of Vyxeos in children and young adults were established in two clinical studies that enrolled patients with AML or relapsed/refractory hematologic malignancies. Thirty-eight pediatric patients aged one to 21 years of age with AML in first relapse were enrolled in the phase 1/2 AAML1421 study conducted by Children’s Oncology Group, and 27 patients aged one to 19 years with relapsed/refractory hematologic malignancies were enrolled in the phase 1 CPX-MA-1201 study conducted by Cincinnati Children’s Hospital. Both studies found no differences in the safety profile based on age. The use of Vyxeos for this indication is supported by evidence of effectiveness from study CPX351-301 in adult patients.

Vyxeos has a boxed warning as it cannot be substituted with other daunorubicin and/or cytarabine-containing products. In the phase 3 study, the most common adverse reactions were bleeding events, fever, rash, swelling, nausea, sores in the mouth or throat, diarrhea, constipation, muscle pain, tiredness, stomach pain, difficulty breathing, headache, cough, decreased appetite, irregular heartbeat, pneumonia, blood infection, chills, sleep disorders and vomiting.

The FDA also approved United Therapeutics’ Tyvaso Inhalation Solution for the treatment of patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) to improve exercise ability. This is the second FDA-approved indication for Tyvaso (treprostinil), a prostacyclin mimetic first approved in July 2009 for the treatment of pulmonary arterial hypertension to improve exercise ability.

Interstitial lung disease (ILD) is a group of lung diseases in which marked scarring occurs within the lungs. It is often complicated by pulmonary hypertension (PH), which further symptoms and decreases survival. PH is estimated to affect at least 15 percent of patients with early-stage ILD (approximately 30,000 PH-ILD patients in the United States) and may affect up to 86 percent of patients with more severe ILD.

FDA approval of Tyvaso for PH-ILD is supported by data from INCREASE, the largest and most comprehensive completed study of adult patients with PH-ILD. The multicenter, randomized, double-blind, placebo-controlled, 16-week, parallel-group study of 326 patients met its primary endpoint, demonstrating a significant improvement in six-minute walk distance (6MWD). Results also showed benefits across several key subgroups, including etiology of PH-ILD, disease severity, age, gender, baseline hemodynamics, and dose. Significant improvements were also observed in each of the secondary endpoints, including reduction in the cardiac biomarker NT-proBNP, time to first clinical worsening event, change in peak 6MWD at week 12, and change in trough 6MWD at week 15. Additional observations included placebo-corrected improvements in forced vital capacity (FVC) and significantly fewer exacerbations of underlying lung disease in patients receiving Tyvaso. Treatment with Tyvaso of up to 12 breaths per session, four times daily, in the INCREASE study was well tolerated and the safety profile was consistent with previous Tyvaso studies and known prostacyclin-related adverse events.