3
Specialty Pharmacy Continuum • May/June 2020
CLINICAL
Newly approved drugs, gene therapy spark hope
‘An Exciting Time’ to Manage Sickle Cell Disease Sickle cell disease (SCD) affects approximately 100,000 people living in the United States—double the number of people who have cystic fibrosis and hemophilia combined, according to the CDC. For nearly 20 years, the hematologic disorder had only one treatment option: hydroxyurea. In the last three years, three new drugs have been approved for SCD, offering the community new hope. The FDA approved two of these drugs at the end of 2019. “It is truly an exciting time to be patients,” said Deepa caring for SCD patients,
From 1989 through 1993, an average of
75,000 hospitalizations due to SCD occurred in the United States, costing approximately
$475 million.
Manwani, MD, the director of pediatric hematology at the Children’s Hospital at Montefiore, in New York City. “With more treatment options available and in clinical trials, there is great optimism and hope.” SCD describes a spectrum of disorders, among which sickle cell anemia is the most common. A disease that primarily occurs in people of African and Afro-Caribbean descent, SCD also affects the Latin(x) community, the second largest population in which SCD predominates. SCD also affects people of Middle Eastern, Asian and Mediterranean heritage, according to the American Society of Hematology. Until recently, hydroxyurea remained the sole treatment for SCD. Approved in 1998 to treat SCD in adults, the myelosuppressive agent originally was developed as an antineoplastic and is used to treat malignancies such as leukemia, ovarian cancer and melanoma. Doctors prescribe hydroxyurea to reduce the occurrence of acute painful episodes, also known as sickle cell crises, a condition caused by irregularly shaped red blood cells aggregating and collecting in blood vessels. Hydroxyurea reduces these painful episodes, which usually require hospitalization, by 50%. While decreasing
hospitalizations helps improve overall quality of life while containing health care systems’ costs, a 50% reduction is not enough, according to John J. Strouse, MD, PhD, an associate professor in at Duke the Department of Pediatrics Pedia Medicine, in DurUniversity School of Med ham, N.C. “Many people sstill have emergency department visits and hospitalizations for pain when th they are taking hydroxyurea.” hydroxyur Common Comm side effects include ne neutropenia, elevated liver enzymes, bone marrow suppression, anorexia, anorexia gastrointestinal tina disturbances such as nausea s and vomiting, and infertility. ity However, Dr. Strouse said patients tend to tolerate tolerat the drug relatively well. Newer drugs dru on the market give physicians g additional tools to additi add to t their treatment arsenal. Despite their potential to improve quality of life for patients with SCD, only time can elucidate the full impact of these noncurative therapies, as long-term outcomes associated with novel therapies have not been studied, Dr. Manwani explained. In 2017, a branded formulation of L-glutamine (Endari, Emmaus Medical) became the first SCD drug approved in nearly 20 years in 2017, but clinicians have met the drug’s release with mixed reviews. “I think many of us in the SCD community were surprised about Endari’s approval, given some concerns about the data,” Dr. Strouse said. Among these are an unclear mechanism of action and data demonstrating moderate effectiveness at best. Moreover, some patients find its twicedaily dosing and powder formulation less convenient than swallowing a hydroxyurea pill once a day. L-glutamine also must be taken with food and drink—a feature that creates a barrier for some patients, said Stephanie Guarino, MD, a clinical director of the sickle cell program at Christiana Care’s Center for Special Health Care Needs in Wilmington, Del.
In the fall 2019, the FDA approved crizanlizumab-tmca (Adakveo, Novartis) to treat occlusive crises in patients with SCD aged 16 years and older. The P-selectin blocker prevents platelets, red blood cells and leukocytes from interacting with P-selectin glycoprotein ligand-1 on endothelial cells and platelets. Interfering with the activity of these blood components reduces painful episodes and hospital admissions. Crizanlizumab-tmca can be administered either as monotherapy or concomitantly with hydroxyurea. Common side effects include nausea, pain in the back and joints, and fever. On Nov. 25, 2019, the FDA approved another drug for SCD—only 10 days after crizanlizumab-tmca’s approval. Voxelotor (Oxbryta, Global Blood Therapeutics) inhibits the polymerization of hemoglobin S, an abnormal form of hemoglobin that causes erythrocytes to sickle. Indi-
drug costs as creating financial barriers that require a tremendous effort for providers to obtain the insurance authorizations and gain buy-in from hospital committees. She remains optimistic that the benefits these new drugs offer in terms of quality of care and cost will outweigh some of the financial hurdles. Federal interventions such as 340B pricing similar to that offered at federally funded hemophilia treatment centers could help ease some of the payor burden.
Gene Therapy Promising Gene therapy offers some hope to patients who have SCD. According to ClinicalTrials.gov, there are 18 studies on gene therapy for sickle cell either enrolling, actively recruiting or active. Among these are therapies exploring single infusions of CD34+ bone marrow and other CD34+ agents. Another therapy targets BCL11A, a gene that suppresses SCD-
‘Many people still have emergency department visits and hospitalizations for pain when they are taking hydroxyurea.’ —John J. Strouse, MD, PhD cated for patients aged 12 years and older, the oral drug is dosed once daily without regard to food. Like crizanlizumabtmca, it can be taken as monotherapy or adjunctively with hydroxyurea. Headache; gastrointestinal disturbances such as abdominal pain, diarrhea and nausea; and rash, pyrexia and fatigue are among the most common side effects. The drug also requires dose adjustments in patients who have severe hepatic impairment. Despite the new treatment options, Dr. Strouse does not foresee these new drugs replacing hydroxyurea, given its nearly 20-year history of data, high degree of patient tolerance, and affordability. He anticipates that novel treatments will serve either as options for patients who are unable to tolerate hydroxyurea or as adjunctive therapy. As with many new drugs, cost is a potential hurdle. At roughly $1,200 per 30-day supply, L-glutamine is the least expensive of the three drugs. Crizanlizumab-tmca requires weight-based dosing. Drug costs are estimated to be approximately $2,500 per vial, not including outpatient clinic use and administration fees. Heavier patients may need up to four vials per treatment. The monthly cost for voxelotor is $10,417. Hydroxyurea costs roughly $1,200 per year on the high end. Dr. Guarino foresees these high-dollar
resistant fetal hemoglobin. According to George Daley, MD, the dean of the faculty of medicine at Harvard Medical School in Cambridge, Mass., newborns express a special form of hemoglobin called fetal hemoglobin. Because fetal hemoglobin does not sickle, babies born with SCD rarely exhibit symptoms initially. However, around the 6-month mark of life, babies stop producing fetal hemoglobin and start producing adult beta globin, due to BCL11A expression. “The data suggest that blocking BCL11A expression might stop cells from sickling,” Dr. Daley said. (Some patients who carry the SCD mutation also have one or more genetic variants for hereditary persistence of fetal hemoglobin [HPFH]. SCD patients who have HPFH were found to have drastically reduced levels of BCL11A and very mild SCD.) Cost may continue to challenge patients, payors and health care systems alike, but experts agree that better outcomes and potential curative therapies on the horizon offer the SCD community an unprecedented amount of hope. —Frieda Wiley, PharmD Dr. Manwani reported financial relationships with Forma Therapeutics, GBT, Novartis, and Pfizer. Dr. Strouse reported research support from Takeda.
