The Year in FDA Approvals

Here, we review recent therapies approved by the U.S. Food and Drug Administration for the treatment of red blood cell and iron disorders, including two new treatments for sickle cell disease.

Ferric maltol

On July 25, 2019, oral ferric maltol was approved for the treatment of iron deficiency in adults.

Ferric maltol is a non-salt formulation of ferric iron that provides an alternative to salt based oral iron therapies and carries fewer gastrointestinal side effects than are typically observed with salt-based therapies.

The approval was based on a review of data from the AEGIS-H2H study, in which oral ferric maltol was found to be noninferior to intravenous iron therapy in improving hemoglobin levels, without requiring hospital-based administration, in patients with iron-deficiency anemia.

The proportion of patients who discontinued treatment during previous studies due to adverse events (AEs) was 4.6%, and the most common AE leading to discontinuation of ferric maltol in these studies was abdominal pain (1.7% of patients).

According to the FDA’s prescribing information, ferric maltol should be administered as 30 mg twice daily, taken 1 hour before or 2 hours after a meal. The duration of treatment depends on the severity of iron deficiency, but generally at least 12 weeks of treatment is required.


On November 8, 2019, luspatercept-aamt was granted FDA approval for the treatment of anemia that requires 2 or more red blood cell transfusions over 8 weeks in adults with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). The approval was limited to patients with these subtypes of MDS who have either not responded to an erythropoiesis-stimulating agent (ESA), previously responded to an ESA but lost response, or are unlikely to respond to ESA therapy because of a high serum erythropoietin level (>200 U/L).

Approval was based on results from the MEDALIST trial, which enrolled 229 patients with very low–, low-, or intermediate-risk MDS-RS that was transfusiondependent.

Participants in the trial were randomized 2:1 to luspatercept-aamt or placebo. All patients received supportive care, including red blood cell transfusions.

The primary endpoint of the study was the proportion of patients who were transfusion independent during any 8-week period between weeks 1 and 24 of treatment.

Of the 153 patients in the luspatercept-aamt group, 58 were transfusion-independent (37.9%; 95% CI 30.2-46.1), compared with 10 patients who received placebo (13.2%; 95% CI 6.5-22.9), yielding a treatment difference of 24.6% (p<0.0001).

The most common adverse reactions to luspatercept-aamt, occurring in >10% of patients, included fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and hypersensitivity.


On November 15, 2019, the FDA approved crizanlizumab-tmca to reduce the frequency of vaso-occlusive crisis in patients aged 16 and older with sickle cell disease (SCD). The agent is a monoclonal antibody targeted against the P-selectin glycoprotein that is expressed on activated endothelial cells and platelets.

“[Crizanlizumab-tcma] is the first targeted therapy approved for SCD, specifically inhibiting selectin, a substance that contributes to cells sticking together and leads to vaso-occlusive crisis,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the agency’s Center for Drug Evaluation and Research. “Vaso-occlusive crisis can be extremely painful and is a frequent reason for emergency department visits and hospitalization for patients with SCD,” he said.

The approval was based on results from a randomized clinical trial of 198 patients with SCD and a history of vaso-occlusive crisis. Participants received either placebo or crizanlizumab tmca at one of two doses (2.5 mg/kg or 5.0 mg/kg). Those receiving the higher crizanlizumab-tmca dose experienced an average of 1.63 pain episodes per year and 35% had no episodes. Patients in the placebo group averaged 2.98 annual pain episodes and 17% had no episodes. Treatment with crizanlizumab-tmca also delayed the time to first vaso-occlusive crisis after the start of treatment, from 1.4 months to 4.1 months.

AEs associated with crizanlizumab-tmca included back pain, fever, arthralgia, and nausea. The FDA advises health care professionals to monitor patients for infusion-related reactions and discontinue the drug for severe reactions. Patients should also be monitored for interference with automated platelet counts or platelet clumping.


On November 20, 2019, givosiran was approved for the treatment of adults with acute hepatic porphyria (AHP), a rare disease that affects approximately 5 to 10 people per 100,000 in the U.S. The disease is characterized by painful neurovisceral attacks, with or without cutaneous manifestations, which often require hospitalization, supportive care, and narcotics to manage. Givosiran downregulates levels of the enzyme amino levulinic acid synthase (ALAS), which, when induced, leads to AHP crises.

One drug, hemin for injection, is approved to ameliorate recurrent porphyria attacks in women, but the potential for iron overload and the fact that it is not routinely stocked in hospital pharmacies make its use challenging.

In the pivotal ENVISION study, 94 patients with AHP were randomized to receive either once-monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo to determine givosiran’s effect on reducing the rate of porphyria attacks that require hospitalization, an urgent health care visit, or intravenous hemin administration at home. Over 6 months, the rate of attacks in the givosiran-treated group was 1.9, compared with 6.5 in the placebo group. In addition, givosiran treatment led to dramatic decreases in biomarkers of AHP (urinary deltaaminolevulinic acid and porphobilinogen).

Givosiran’s manufacturer has committed to a postmarketing analysis in pediatric patients ages 12 to 17.


On November 25, 2019, the FDA approved voxelotor, a once-daily oral therapy that modulates hemoglobin affinity for oxygen by binding to hemoglobin S and stabilizing it, to treat patients with SCD aged 12 and older. Voxelotor inhibits hemoglobin (Hb) polymerization, reduces sickling, and improves red blood cell survival.

This approval was based on results from the phase III HOPE trial, in which 274 patients were randomized to receive either:

  • voxelotor 1,500 mg (n=90)
  • voxelotor 900 mg (n=92)
  • placebo (n=92)

The median age of participants was 24 years (range = 12-64) and baseline Hb range was 5.5 to 10.5 g/dL. Approximately 65% of enrolled patients were taking hydroxyurea at the time of enrollment; those on stable hydroxyurea doses continued therapy throughout the trial.

The primary endpoint of the study was Hb response rate, defined as an increase of >1 g/dL from baseline to week 24. For voxelotor, the response rate was 51% (n=46/90) compared with 6.5% (n=6/92) for the placebo group (p<0.0001). In the arm receiving voxelotor 1,500 mg, the mean changes for Hb, indirect bilirubin, and reticulocyte count were 1.14 g/dL, –29.08%, and –19.93% respectively, compared with -0.08 g/dL, –3.16%, and 4.54% in the placebo group.

Common AEs (occurring in >10% of patients) included headache, diarrhea, abdominal pain, nausea, rash, fatigue, and pyrexia. The recommended starting dosage is 1,500 mg orally once daily.