FDA Update: Recent Approvals and Designations for Orphan Drugs

In instances where an investigational drug would be the first available treatment or would have advantages over existing treatments, the U.S. Food and Drug Administration (FDA) can accelerate the progress of a drug’s approval through its “breakthrough therapy” and “orphan drug” designations.

Breakthrough therapy designation, established by the FDA’s Safety and Innovation Act of 2012, applies to an investigational or approved drug that is intended to treat a serious or life-threatening disease or that may demonstrate substantial improvement over existing therapies. The FDA will expedite the development and review of these drugs within 60 days of receipt.

The Orphan Drug Act of 1983 provides special status to an FDA-approved drug or biologic product that treats a rare disease or condition affecting fewer than 200,000 Americans. Orphan drug status can also be given to a product that treats a disease affecting more than 200,000 people, but only in cases in which the manufacturer is not expected to recover the costs of development and marketing the product. With orphan drug designation, the drug’s sponsor is provided various development incentives, including tax credits for qualified clinical testing.

Below is a list of agents that were recently granted breakthrough designation or were approved as orphan therapies.

Complications of Hematopoietic Cell Transplantation

Ruxolitinib: The JAK1 and JAK2 inhibitor ruxolitinib received breakthrough therapy designation for the treatment of patients with acute graft-versus-host disease (aGVHD), a condition that has no approved treatments specific to the disease. Its approval was based on results from a retrospective analysis of patients who developed corticosteroid-refractory aGVHD or chronic GVHD (cGVHD) following allogeneic hematopoietic cell transplantation (HCT) for a hematologic malignancy. The overall response rate (ORR) was 81.5 percent (n=44) in the aGVHD group and 85.4 percent (n=35) in the cGVHD cohort, with a median time to response of 1.5 weeks and three weeks, respectively. Ruxolitinib is also approved for the treatment of myelofibrosis and polycythemia vera.

Ibrutinib: The tyrosine kinase inhibitor ibrutinib received breakthrough therapy and orphan drug designation for the treatment of patients with cGVHD after failure of one or more lines of systemic therapy. The FDA’s decision was based on data from a phase Ib/II study of patients with steroid-dependent or refractory cGVHD who received single-agent ibrutinib. The ORR (defined as reduction in cGVHD per National Institutes of Health Consensus Response Criteria) was 55 percent. Ibrutinib is also approved for the treatment of Waldenström macroglobulinemia and previously treated chronic lymphocytic leukemia and mantle cell lymphoma.

Defibrotide sodium: The FDA granted approval and orphan drug status for defibrotide sodium for adults and children with hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after receiving HCT – making it the first FDA-approved treatment for severe hepatic VOD. The approval was based on the results of three studies that showed 38 to 45 percent of patients treated with defibrotide sodium were alive at 100 days post-HCT. Patients with bleeding complications or those taking blood thinners or other medications to reduce blood clots should not receive defibrotide sodium.

Clotting and Bleeding Disorders

Plasminogen therapy: The FDA granted “Fast Track” designation to a plasminogen drug candidate for the treatment of patients with congenital plasminogen deficiency. The investigational plasminogen therapy is composed of a naturally occurring protein that is synthesized by the liver and circulates in the blood. The drug is being investigated in a phase II/III clinical trial of patients with congenital plasminogen deficiency, where it has demonstrated a rapid response in lesion resolution and decreased the need for surgery.

Coagulation factor IX (recombinant), albumin fusion protein (albutrepenonacog alfa): The FDA approved albutrepenonacog alfa for use in children and adults with hemophilia B for on-demand control and prevention of bleeding episodes, the management of peri-operative bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes. This is the first coagulation factor–albumin fusion protein product and the second factor IX fusion protein product to be approved in the United States.

Kovaltry™ antihemophilic factor (recombinant): Kovaltry™ antihemophilic factor (recombinant) – an unmodified, full-length factor VIII compound – was granted orphan drug designation for the treatment of hemophilia A in children and adults. The approval was based on results from three multicenter, open-label, uncontrolled studies, in which the drug demonstrated control of and protection from bleeds when used prophylactically two to three times per week.


CPX-351: The FDA granted breakthrough therapy designation for CPX-351 for the treatment of adult patients with therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes. The designation was based on the results from a phase III study of older patients with previously untreated high-risk AML or AML with myelodysplasia-related changes; patients treated with CPX-351 had a 31 percent reduction in the risk of death, compared with those treated with the standard “7+3” chemotherapy regimen.

Venetoclax: Venetoclax was approved as an orphan drug for the treatment of patients with chronic lymphocytic leukemia (CLL) who harbor the 17p deletion (del17p) and who have received at least one prior therapy. This is the first U.S. FDA-approved treatment that targets the B-cell lymphoma 2 protein. The approval was based on the results of a phase II, single-arm clinical trial, where venetoclax led to an ORR of 80 percent. Patients receiving venetoclax should not be given live attenuated vaccines.

Iomab-B: Iomab-B, a radioimmunoconjugate composed of BC8 (a novel urine monoclonal antibody) and iodine-131 radioisotope, was granted orphan drug designation for the treatment of relapsed/refractory AML prior to HCT in older patients. A multicenter, phase III trial will begin soon to evaluate Iomab-B in patients ≥55 years old with relapsed/refractory AML.

Ibrutinib: Ibrutinib was approved as a first-line treatment for patients with CLL, based on results of the phase III RESONATE-2 trial that compared the use of ibrutinib versus chlorambucil. Ibrutinib improved PFS and reduced the risk of disease progression or death by 84 percent, compared with chlorambucil.

Midostaurin: Midostaurin, an oral, multi-targeted kinase inhibitor, was granted breakthrough therapy designation for adults with newly diagnosed FLT3-mutated AML who are eligible to receive standard induction and consolidation chemotherapy. The decision was based on the results of the phase III RATIFY clinical trial, which found that patients treated with midostaurin and standard induction and consolidation chemotherapy had a significant 23 percent improvement in OS.

Ofatumumab: The anti-CD20 monoclonal antibody ofatumumab was approved as maintenance therapy for patients with CLL who have achieved complete or partial response after receiving at least two lines of therapy for recurrent or progressive disease. The approval was based on results from the phase III PROLONG trial that compared ofatumumab with observation. Ofatumumab resulted in a 50 percent reduction in the risk of disease progression and a longer time to next therapy.

Lymphoma & Myeloma

Daratumumab: The FDA granted breakthrough therapy designation for daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone for the treatment of multiple myeloma (MM) in patients who have received at least one prior therapy. Daratumumab was previously granted accelerated approval by the FDA for patients with MM who have failed at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. The FDA noted that patients who need a blood transfusion should inform blood banks that they are receiving daratumumab because the drug may interfere with certain tests that they perform.

Nivolumab: Nivolumab was approved as an orphan drug for the treatment of patients with classic Hodgkin lymphoma (cHL) who have relapsed or progressed after autologous HCT and post-transplantation brentuximab vedotin. The approval was based on results from two multicenter studies evaluating safety and efficacy, in which nivolumab led to an objective response rate of 65 percent and an estimated duration of response of 8.7 months. Nivolumab carries a boxed warning for complications with allogeneic HCT that occurs following therapy with nivolumab.

Pembrolizumab: Pembrolizumab, a humanized monoclonal anti-PD-1 therapy, received breakthrough designation for the treatment of patients with relapsed/refractory cHL. The designation was based on results of the ongoing phase Ib KEYNOTE-013 and phase II KEYNOTE-087 studies evaluating pembrolizumab as a single-agent therapy for cHL. In both trials, pembrolizumab achieved high objective response rates greater than 64 percent.

Melphalan: The FDA approved a new formulation of melphalan injection for use as a high-dose conditioning treatment prior to HCT in multiple myeloma. The approval was based on results from a multicenter, open-label, phase IIb trial in which 61 patients received 200 mg/m2 of melphalan followed by transplant. The ORR was 95 percent, and the CR rate was 31 percent. The drug has a boxed warning for severe bone marrow suppression, hypersensitivity, and leukemogenicity.

Obinutuzumab: Under the Priority Review program, the FDA approved obinutuzumab in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen. Approval was based on results from the phase III GADOLIN trial, in which adding obinutuzumab to bendamustine led to longer PFS.