FDA Update: June 2019

Jun 18, 2019

Express Scripts Office of Clinical Evaluation and Policy tracks some recent updates to the drug pipeline.

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First Vaccine for Dengue Fever FDA Approved

Under Priority Review, Dengvaxia® (dengue tetravalent vaccine, live) was approved by the FDA on May 1, 2019. For use only in areas where dengue fever is endemic, such as Guam and Puerto Rico, it protects children and adolescents ages nine to 16 from all four dengue viruses. An individual’s first experience with dengue fever, which is spread by mosquitoes, may produce only mild effects or none at all. Subsequent infections, however, may cause severe symptoms that can include bleeding (dengue hemorrhagic fever), breathing problems, confusion and unrelenting vomiting. Dengvaxia is administered -- only to patients who have a documented history of or who test positive for prior dengue infections -- as three injections at six-month intervals. In trials, it blocked dengue infections for about three-fourths of vaccinated patients. The FDA awarded Dengvaxia a Tropical Disease Priority Review Voucher as part of their program to encourage development of new drugs and biological products for prevention and treatment of neglected tropical diseases. Its manufacturer, Sanofi, can use the voucher to get faster review for a future product or sell to another company. Prescribing information may be found here.

AstraZeneca’s Qternmet XR Approved for Diabetes

Qternmet® XR (dapagliflozin/saxagliptin/metformin) received approval from the FDA on May 2, 2019. The combination of a selective sodium‑glucose cotransporter-2 (SGLT-2) inhibitor, a dipeptidyl peptidase‑4 (DPP‑4) inhibitor and extended-release metformin is indicated to treat adults who have type 2 diabetes, who currently are taking metformin and who need additional glycemic control despite diet limitations and exercise. Qternmet XR will be taken once a day in the morning along with breakfast or a snack. All medications that contain metformin have a boxed warning that taking it may cause lactic acidosis, the buildup of excessive acid in the blood. Prescribing information is here.

Tibsovo Approved for a New Subset of Patients Who Have Acute Myeloid Leukemia

Originally approved by the FDA to treat adults whose acute myeloid leukemia (AML) has returned or become resistant to previous treatment, Tibsovo® (ivosidenib – Agios Pharmaceuticals), was awarded a new indication on May 2, 2019. Newly diagnosed patients who are at least 75 years old or who cannot tolerate intensive induction chemotherapy (chemo) for AML now are candidates for its use. Patients also must test positive for a mutation in isocitrate dehydrogenase-1 (IDH1) enzymes. Normally, IDH1 helps to break down fats from food, regulate glucose levels and protect against oxidative stress. Mutated IDH1 converts normal substances into 2-hydroxyglutarate (2-HG), which promotes cancer cell formation. Approximately 6% to 10% of patients who have AML also have IDH1 mutations. By blocking the production of 2-HG, Tibsovo decreases the creation of AML cells. It is taken as 500mg (two 250mg tablets) once a day along with a low-fat meal or snack. Its label has a boxed warning because nearly one-fifth of patients using it in clinical trials developed differentiation syndrome, a potentially fatal condition caused by very fast production of immature myeloid cells in bone marrow. Other possible results from its use include QT interval prolongation and Guillain-Barre syndrome, so patients need close monitoring during treatment. The new indication was granted through the Real-Time Oncology Review (RTOR), an FDA pilot program that accelerates approvals by allowing the FDA to begin analyzing clinical trial results as soon as they are available, but before their formal submission. Its approval also was under Priority Review (the FDA’s plan to approve drugs in six months or less). Full prescribing information is here.

Vyndaqel/Vyndamax Approved for Transthyretin-Mediated Amyloidosis Cardiomyopathy

The FDA approved Vyndaqel® (tafamidis meglumine) capsules and Vyndamax (tafamidis) capsules on May 3, 2019. They are the first drugs approved in the U.S. to treat cardiomyopathy (CM) caused by transthyretin-mediated amyloidosis (ATTR), a rare heart condition. Accumulations of malformed proteins (amyloid fibrils) in the hearts of patients who have ATTR-CM cause enlargement and thickening of the heart, which eventually leads to heart failure and death. Tafamidis helps to prevent the formation of amyloid fibrils by stabilizing transthyretin (TTR), a transport protein in blood and cerebrospinal fluid. Recommended daily dosing is 80mg (four capsules) of Vyndaqel or 61mg (one capsule) of Vyndamax, which was developed to increase convenience for patients. The two formulations are not interchangeable, however. Vyndaqel was launched in May 2019, and Vyndamax is expected to be available later in the year. The annual wholesale acquisition cost (WAC) is reported to be $225,000. Prescribing information for both drugs is here.

New Indication for Kadcyla

Genentech’s Kadcyla® (ado-trastuzumab emtansine) got an additional FDA approval on May 3, 2019. It now can be used to treat patients who still have residual invasive human epidermal growth factor receptor 2 positive (HER2+) early breast cancer after treatment with a taxane agent (such as paclitaxel) and Herceptin® (trastuzumab) followed by surgery. Drug treatment before surgery is known as neoadjuvant therapy; afterward, it is called adjuvant therapy. Previously, Kadcyla was approved only for HER2+ breast cancer that had metastasized following taxane/Herceptin treatment. A monoclonal antibody/drug conjugate, Kadcyla’s approval as adjuvant treatment was based on results of the KATHERINE study. After three years, 88.3% of study patients who were treated with Kadcyla were alive and free from a return of invasive breast cancer as opposed to 77.0% of patients who used Herceptin. The FDA approved the new indication under two of its pilot programs – RTOR and Assessment Aid, a standardized template for data delivery. Both programs accelerate the approval process. In addition, it has an FDA Breakthrough Therapy Designation (BTD), which also speeds up the development and review of medicines intended to treat serious or life-threatening diseases. Kadcyla’s extended indication was approved in about three months versus the usual six or 10 month timeframe. For adjuvant therapy of early HER2+ breast cancer, it is given as a 30-minute intravenous (IV) infusion at 3.6mg/kg once every three weeks for 14 treatments. Kadcyla is not interchangeable with any other trastuzumab product. A boxed warning concerns the possibility of embryo, heart or liver damage that it may cause. Complete prescribing information is available here.

Sorilux Approved for Adolescent Psoriasis

Mayne Pharma Group has announced that on May 6, 2019, the FDA approved its 0.005% calcipotriene foam product, Sorilux®, to treat plaque psoriasis for patients between 12 years and 18 years of age. First approved in 2010, Sorilux previously was indicated only for patients at least 18 years old. According to the National Psoriasis Foundation (NPF), approximately 8 million patients in the U.S. have psoriasis, with many patients initially diagnosed between 15 years and 25 years of age. Calcipotriene is a vitamin D analog that is believed to decrease the production of psoriasis cells. Directions are to rub a thin layer of the foam into areas of affected skin twice a day, avoiding the face and mucous membranes. Sorilux should not be used around open flames or people who are smoking because the propellant it uses is flammable. Its complete prescribing information is here.

Generic Approved for Cuprimine

Amerigen Pharmaceuticals Limited received approval from the FDA on May 7, 2018, for penicillamine capsules, 250mg. The first generic for Bausch Health’s Cuprimine®, penicillamine is a chelator that binds excess copper in the blood of patients who have Wilson’s disease. A hereditary condition, Wilson’s disease affects about 30,000 Americans. Patients who have it cannot process copper correctly into bile. Too much copper in the blood eventually damages the brain, eyes, kidneys and liver. Penicillamine also has indications to reduce cysteine elimination for patients who have cystinuria and to decrease disease activity for patients who have rheumatoid arthritis (RA) that is resistant to other treatments. Dosing depends on the condition being treated as well as on its severity. Amounts above 500mg/day should be divided into two doses. Penicillamine should be taken at least one hour before or two hours after food, milk and any other drugs or supplements. It has a number of possibly serious side effects, including kidney damage, myasthenia gravis and several types of blood abnormalities. Patients using it as maintenance therapy should be monitored closely once a month, following twice weekly lab testing for the first month of treatment and twice monthly testing for the next five months. Pricing and a launch date are uncertain. According to IQVIA, U.S. Cuprimine sales in 2018 amounted to approximately $127 million. Amerigen’s penicillamine is not interchangeable with either Meda Pharmaceutical’s Depen® Titratable tablets, 250mg or Mylan’s D-PENAMINE tablets, 125mg.

Generic Launched for Tarceva

On May 10, 2019, Mylan introduced to the U.S. market the first generics for Tarceva® (erlotinib - Genentech) tablets, 25mg, 100mg and 150mg. It is used, along with gemcitabine, for initial treatment of advanced, unresectable or metastatic pancreatic cancer. It has a second indication for maintenance or subsequent-line therapy for patients who have metastatic non-small cell lung cancer (NSCLC) that tests positive for epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations and that has progressed following at least one prior chemo regimen. For pancreatic cancer, the once-daily recommended dose is 100mg; for NSCLC, the dose is 150mg. IQVIA estimates that sales of Tarceva were about $212 million in the U.S. for the 12-month period ending on March 31, 2019.

Delzicol Generic Available in the U.S.

A generic for Delzicol® (mesalamine – Allergan) delayed-release capsules, 400mg, was introduced in the United States on May 10, 2019, by Teva Pharmaceutical Industries. It is a type of salicylic acid that acts locally in the intestines to treat ulcerative colitis (UC) for patients five years of age and older. It also is indicated to maintain UC remission for adults. Several other brand and generic mesalamine drugs are FDA approved, but Teva’s generic is substitutable only for Delzicol. Its price and exclusivity status are not yet known. For the 12 months that ended on Feb. 28, 2019, IQVIA set U.S. sales of Delzicol at about $130 million.

Cyramza Gains New Indication

Eli Lilly’s Cyramza® (ramucirumab) was given an additional FDA approval on May 10, 2019. Its new indication is as monotherapy for patients who have hepatocellular carcinoma (HCC), who have alpha-fetoprotein (AFP) levels of 400ng/mL or higher and who already have been treated with Nexavar® (sorafenib – Bayer HealthCare). Produced by HCC, AFP is a biological marker that can identify patients appropriate for treatment with Cyramza and also track its effectiveness in restricting disease progression. The American Cancer Society (ACS) estimates about 42,000 new cases of liver cancer will be diagnosed in the U.S. this year. AFP is high for roughly 40% of patients who have advanced HCC, and they have few treatment options. Cyramza is a targeted therapy that inhibits vascular endothelial growth factor receptor 2 (VEGFR2). It works by blocking the formation of new blood vessels, which are needed for tumor growth and survival. To treat HCC, the recommended dose is 8mg/kg once every two weeks as a one-hour IV infusion. In addition to the new indication, the FDA is allowing Lilly to remove a previously required boxed warning about possibly increased risks of hemorrhaging, gastrointestinal (GI) perforation and reduced wound healing for patients receiving Cyramza. Its full prescribing information may be found here.

Bavencio and Inlyta Combination Indicated to Treat Kidney Cancer

FDA approval was granted on May 14, 2019, to EMD Serono (a division of Merck) and Pfizer for combination use of their drugs, Bavencio® (avelumab) injection and Inlyta® (axitinib) tablets, as first-line therapy to treat advanced renal cell carcinoma (RCC). Around 74,000 new cases of kidney cancer will be diagnosed in the U.S., this year, with the majority being RCC. An estimated 20% to 30% of new RCC will not be discovered until it is in advanced stages, which have an average five-year survival rate of 12%. Bavencio, a human programmed death receptor-1 (PD-1)-blocking antibody, enhances the immune system’s ability to destroy cancer cells. It has additional approvals as monotherapy to treat metastatic Merkel cell carcinoma (MCC) and metastatic urothelial (bladder) carcinoma. For RCC, recommended dosing is an 800mg IV infusion once every two weeks. Previously indicated only as second-line therapy for RCC, Inlyta is a tyrosine kinase inhibitor (TKI). It blocks VEGF receptors to reduce the formation of new blood vessels needed by tumors to grow and survive. Inlyta is taken orally twice a day at 12-hour intervals. In the phase III clinical trial that lead to the approval, average progression-free survival (PFS) was 13.8 months for patients treated with Bavencio and Inlyta compared to 8.4 months for those taking Sutent® (sunitinib), a current standard treatment for RCC.

Revised prescribing information for Bavencio is here. Inlyta’s prescribing information is available here.

Venclexta and Gazyva Combination Given New Indications

FDA approval was granted on May 16, 2019, for the combination use of AbbVie’s Venclexta® (venetoclax) and Genentech’s Gazyva® (obinutuzumab) to treat people with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In the phase III clinical trial that lead to the approval, fixed 12-month treatment with Venclexta plus Gazyva significantly reduced the risk of disease progression or death by 67% compared to a current standard of care. Gazyva is a CD20-directed monoclonal antibody that targets cancer cells both directly and along with the body’s immune system. Venclexta inhibits B-cell lymphoma-2 (BCL-2), a protein that may interfere with apoptosis (the self-destruction process) in cancer cells. Both drugs have indications for other types of cancer.

Revised prescribing information for Venclexta is here. Gazyva’s prescribing information is here.

Fragmin Approved for Use in Children

On May 16, 2019, the FDA approved the use of Fragmin® (dalteparin sodium) injection to reduce the recurrence of symptomatic venous thromboembolism (VTE) in pediatric patients one month of age and older. VTE can include deep vein thrombosis (blood clots in the deep veins of the leg) and pulmonary embolism (blood clots in the lungs). Fragmin, a type of heparin, was initially approved by the FDA in 1994 for use as an anticoagulant in adults. Full prescribing information can be found here.

Expanded Indication for Gattex

Takeda Pharmaceuticals received a new indication for Gattex® (teduglutide) on May 17, 2019. It is a glucagon-like peptide-2 (GLP-2) analog that improves intestinal absorption in patients who have short bowel syndrome (SBS) and who are dependent on parenteral support. SBS can occur after extensive resection of the bowel due to Crohn’s disease, ischemia (lack of blood flow) or other conditions. Patients with SBS often suffer from malnutrition, severe diarrhea, dehydration and fatigue. Treatment typically consists of nutritional support -- including parenteral nutrition -- and/or IV fluids. Previously restricted to adult patients, Gattex now can be used for children as young as one year of age. The recommended dose for both adults and pediatric patients is 0.05mg/kg once daily by subcutaneous (SC) injection. To ensure that benefits of treatment outweigh its risks, Gattex has a Risk Evaluation and Mitigation Strategy (REMS) that includes a communication plan to inform healthcare providers and patents about risks of developing cancer and polyps (growths) in the intestine, obstructions in the intestine, gallbladder disease and biliary tract and pancreatic disease. Prescribing information is here.

FDA Approves Midazolam Nasal Spray

Nayzilam® (midazolam) nasal spray, a new dosage form for the C-IV benzodiazepine, was FDA approved on May 17, 2019. It is indicated for use as an acute treatment for patients age 12 years and older who have epilepsy and who experience seizure clusters and/or acute repetitive seizures that are different from their usual seizure patterns. The single-dose spray devices, which contain 5mg of midazolam, are intended for immediate use by caregivers when the unusual seizures start. If a second dose is needed, it should be given in the other nostril about 10 minutes after the first spray. No more than two doses should be used for any one episode, and no more than five seizure clusters should be treated with it in any one month. Nayzilam should not be given more often than every three days. It will be dispensed in packages of two sprayers with a Medication Guide and clear instructions for administration. Presently, midazolam is available only in oral syrup and injectable forms. All midazolam products have a boxed warning cautioning about concurrent use with opioids, which increases the risks of sedation, respiratory depression and death. It also is contraindicated for use in patients who have narrow-angle glaucoma. The manufacturer, UCB, has not announced its plans for pricing or launch. Please see prescribing information here.

Zolgensma Approved for Spinal Muscular Atrophy

On May 24, 2019, the FDA approved Zolgensma® (onasemnogene abeparvovec-xioi – AveXis). It is a gene therapy that contains a normal copy of the human survival motor neuron 1 (SMN1) gene for patients who have spinal muscular atrophy (SMA) due to bi-allelic mutations in the SMN1 gene. At a dose determined by the patient’s weight, it will be given as one 60-minute IV infusion. The wholesale acquisition cost (WAC) of Zolgensma is $2,125,000, which can be paid over time through various payer agreements. AveXis plans to market it in the first part of June, 2019. A boxed warning on its labeling cautions that Zolgensma may cause damage the liver, so liver function must be monitored before and for at least three months after treatment. Prescribing information is here.

Piqray Approved to Treat Certain Breast Cancers

The FDA approved Piqray® (alpelisib – Novartis) on May 24, 2019. To be used along with AstraZeneca’s Faslodex® (fulvestrant), Piqray is a kinase inhibitor indicated to treat patients who have advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer that has mutations in phosphoinositide 3-kinase C (PI3KC). The two-drug combination will be second-line therapy when endocrine-based therapy is failing. Piqray’s recommended dose is 300mg (two 150mg tablets) once a day along with Faslodex 500mg intramuscularly (IM) on the first day of each 28-day cycle after one injection each on days 1 and 15 of the first cycle. Qiagen’s therascreen® PIK3CA RGQ PCR companion diagnostic test was approved by the FDA at the same time. Although other PI3K inhibitors have been FDA approved, Piqray is the first to be indicated specifically for HR+/HER2- advanced breast cancer with a PIK3CA mutation. Click here for full prescribing information.

Extended FDA Approval for Jakafi

On May 24, 2019, the FDA granted approval to Jakafi® (ruxolitinib – Incyte Corp.) tablets for treating acute graft-versus-host disease (aGvHD). It is the first drug indicated to treat patients who are at least 12 years old and who have aGvHD that has not responded to treatment with corticosteroids. Between 35% and 50% of patients who receive a stem cell transplant from a donor develop the potentially life-threatening condition in which immune cells in the donated tissue (the graft) attack organs and tissues of the transplant recipient (the host). Approximately one-half of patients who have aGvHD do not respond to standard treatment with immunosuppression and a corticosteroid, such as methylprednisolone. Acute steroid-resistant aGvHD has a one-year survival rate of only about 30%. To treat it, 5mg of Jakafi will be taken twice daily. A Janus Associated Kinase (JAK) inhibitor that specifically targets JAK1 and JAK2 receptors involved in regulating blood and immune function, it has previous approvals for myelofibrosis and polycythemia vera (rare blood cancers that involve overactivity of JAK signaling pathways). The new indication was approved with both Breakthrough Therapy and Priority Review designations. Jakafi also is an orphan drug for treating aGvHD. Its revised prescribing information is here.

Vraylar Gains New Indication

On May 28, 2019, Allergan and Geodon Richter were given FDA approval for Vraylar® (cariprazine) capsules to treat adults who have depressive episodes that are associated with bipolar I disorder. An atypical antipsychotic drug, Vraylar now is FDA approved to treat all phases (depressive, manic and mixed) of bipolar I disorder. It also has an indication for schizophrenia. For the new indication, recommended dosing is either 1.5mg or 3mg daily. All atypical antipsychotics are required to carry a boxed warning against using them for elderly or pediatric/adolescent/young adult patients. They may increase the risk of death for seniors and promote suicidal feelings or actions for younger patients. Full prescribing information is here.

New Indication for Revlimid

Celgene’s Revlimid® (lenalidomide) capsules was FDA approved on May 28, 2019, for the treatment of two indolent (slowly progressing) non-Hodgkin’s lymphomas, which together represent about 30% of U.S. lymphoma cases. Along with Rituxan® (rituximab – Genentech), it is indicated to treat adult patients who have follicular lymphoma (FL) or marginal zone lymphoma (MZL) that no longer responds to chemo or that recurs after chemo. The treatment protocol is on 28-day cycles that include 20mg of Revlimid once a day for the first 21 days of each cycle and 375mg/m2 of Rituxan once a week for the first cycle followed by once a month for the rest of therapy. Treatments continue for up to 12 cycles if the patient can tolerate them. In the pivotal clinical trial, average PFS was nearly three times as long for patients treated with the two-drug combination versus patients receiving Rituxan and a placebo (39.4 months versus 14.1 months). Revlimid also is indicated as monotherapy for mantle cell lymphoma and transfusion-dependent anemia. In combination with dexamethasone, it treats multiple myeloma. However, it has significant risks of causing severe side effects, including blood cell abnormalities and deformity or death of a fetus. Therefore, it is available only through limited distribution under a risk evaluation and mitigation strategy (REMS). Revlimid’s updated prescribing information is here.

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