FDA Update: May 2018

May 30, 2018

The Emerging Therapeutics team has been following some important actions taken by the U.S. Food and Drug Administration.

New Pill Bottle

New Indication for Bydureon

On April 2, 2018, Bydureon® (exenatide extended release - AstraZeneca) injectable suspension received approval from the FDA as adjunct therapy with basal insulin. It can be used along with insulin glargine to manage type 2 diabetes for adults whose blood sugar is not controlled by other medications. In the DURATION-7 clinical study, average hemoglobin A1c (HbA1c) levels decreased by more than one-half of a percentage point for patients adding Bydureon to their insulin glargine compared to patients using a placebo and insulin glargine. Some patients in each group also took metformin. Nearly one-third of Bydureon-treated participants achieved HbA1cs at or below 7%, but only 7% of those on placebo did. Bydureon is a glucagon-like peptide-1 (GLP-1) receptor agonist that may increase the risk of hypoglycemia when used with insulin. Labeling for it includes a boxed warning for patients who have medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2), because GLP-1 agonists may cause some types of thyroid tumors. Pancreatitis also is possible during its use. Prescribing information may be accessed here.

Second Indication Approved for Rubraca

Rubraca® (rucaparib – Clovis Oncology) was approved by the FDA for an additional indication on April 6, 2018. It now can be used as maintenance treatment for recurrences of epithelial ovarian, fallopian tube or primary peritoneal cancer for patients who are in a complete or partial response to platinum-based chemotherapy. At the same time, the FDA converted to full approval its original accelerated approval for ovarian cancer that has progressed despite at least two chemotherapy treatments and that has a deleterious BRAC genetic mutation as confirmed by an FDA-approved diagnostic test. Rubraca is an oral poly (ADP-ribose) polymerase (PARP) inhibitor that has recommended dosing of 600mg twice a day until the cancer worsens or the patient cannot take the drug any longer. It is available in 200mg, 250mg and 300mg tablets. Prescribing information is here

Opdivo-Yervoy Combination Approved

Bristol-Myers Squibb announced on April 16, 2018, that the FDA had approved two of its monoclonal antibody drugs to be used in combination for patients who have previously untreated advanced renal cell carcinoma (RCC). Opdivo® (nivolumab) is a programmed death receptor-1 (PD-1) blocker that also has numerous indications to treat melanoma and several other cancer types. Yervoy® (ipilimumab), which blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4), has previous indications for melanoma. Together, they increase T-cell activity to improve anti-tumor effects against advanced RCC. In the CheckMate-214 clinical trial, 41.6% of patients using Opdivo plus Yervoy had an objective response (OR) as compared to 26.5% of patients using Sutent® (sunitinib). Objective response means that tumor size decreased by a specified amount of size for a predetermined amount of time. Sutent currently is a standard of care for the initial treatment of advanced RCC. Fewer serious adverse events were reported among patients treated with Opdivo/Yervoy than the Sutent-treated participants, as well. Recommended dosing is 3mg/Kg of Opdivo infused intravenously (IV) over 30 minutes followed by a 1mg/Kg IV infusion of Yervoy over 90 minutes. Treatments using both drugs are given once every three weeks up to four times. Then, Yervoy is discontinued and Opdivo is administered as 240mg once every two weeks or 480mg once every four weeks. Patients can stay on Opdivo therapy until they no longer tolerate its side effects or it stops working. Yervoy has a boxed warning about the possibility it may cause severe immune-related reactions that potentially could involve the intestines, liver, nerves, skin and other organs. Full prescribing information for both drugs can be accessed here.

Crysvita Approved to Treat X-linked Hypophosphatemia

On April 17, 2018, the FDA approved an Ultragenyx drug, Crysvita® (burosumab-twza,) to treat X-linked hypophosphatemia (XLH) for adults and pediatric patients at least one year old. XLH is a rare inherited disease that causes low phosphorous levels in the blood. Symptoms can include rickets (weak bones), bone and tooth pain, shortness and hearing loss. Recommended initial pediatric dosing is 0.8mg/Kg (rounded to the nearest 10mg) as a subcutaneous (SC) injection once every two weeks. For adults, the dose is 1mg/Kg (rounded to the nearest 10mg) once every four weeks. The single-dose upper limit for both children and adults is 90mg. Ultragenyx plans to launch Crysvita on May 1, 2018. It will be available through a limited network of specialty pharmacies that includes Accredo. Complete prescribing information is available here

Generic Approved for Zavesca

Amerigen Pharmaceuticals received FDA approval on April 17, 2018, for miglustat capsules, the first generic for Actelion’s Zavesca®. An inhibitor of the enzyme glucosylceramide synthase, miglustat is taken one to three times daily by patients who have type 1 Gaucher disease. Approximately 6,000 patients in the U.S. have the genetic condition, which causes the accumulation of fat molecules in the spleen, liver, bone marrow and other parts of the body. Miglustat use is limited because it can cause severe diarrhea and weight loss. Amerigen has not yet announced its launch or pricing plans, although the generic has been added to Express Script’s drug file. According to information from Actelion, sales of Zavesca amounted to nearly $107 million in 2016. Since Zavesca is on Express Scripts’ specialty drug list, the generic will be included as well.

Tavalisse Approved for Chronic Immune Thrombocytopenia

On April 17, 2018, the (FDA approved Rigel Pharmaceutical’s Tavalisse™ (fostamatinib disodium hexahydrate), a drug to treat thrombocytopenia in adult patients who have chronic immune thrombocytopenia (ITP) and who have had an insufficient response to a previous treatment. The recommended initial dose is 100mg taken orally twice daily. After four weeks, the dose can be increased to 150mg twice daily, if needed, to achieve a target platelet count of at least 50 x 109/L as necessary to reduce the risk of bleeding. Rigel is planning on making Tavalisse available in late May 2018 through a limited network of specialty pharmacies that does not include Accredo. Pricing plans have not yet been announced. Complete prescribing information is available here.

Tagrisso Receives New Indication

Under FDA’s priority review and breakthrough therapy programs, AstraZeneca’s Tagrisso® (osimertinib) tablets was given a new indication on April 18, 2018. It was approved for first-line treatment of patients who have epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Before beginning treatment, patients will be verified -- through an FDA-approved diagnostic test -- to have exon 19 deletions or exon 21 L858R mutations. Tagrisso is a tyrosine kinase inhibitor (TKI) that blocks the activity of both EGFR-sensitizing and EGFR T790M-resistance mutations. It is taken as one daily 80mg dose. When compared in a clinical trial to two other TKIs, Iressa® (gefitinib - AstraZeneca) and Tarceva® (erlotinib - Genentech), that also are used for initial therapy of EGFR-mutated NSCLC, Tagrisso produced better results. The average length of progression-free survival (PFS) for patients using Tagrisso was nearly twice as long as for patients using one of the other drugs (18.9 months vs. 10.2 months. A higher percentage of Tagrisso-treated patients had an OR, as well; and their responses lasted an average of 17.6 months as opposed to 9.6 months for those using a comparator drug. For complete prescribing information, please click here.

Olysio Discontinued

Due to a significant drop in sales, Janssen Therapeutics is withdrawing Olysio® (simeprevir) from the U.S. market. Olysio is a protease inhibitor that was FDA approved in 2013 for use in combination with other antiviral drugs to treat hepatitis C. The subsequent approval and widespread adoption of more effective drugs that have less complicated dosing effectively has made Olysio obsolete. Its marketing will end on May 25, 2018; but supplies may be exhausted before then. Patients using it should assure with their doctors that they have enough Olysio to finish the complete 12-week course of therapy.

New Formulation for Akynzeo

The FDA approved as a new drug an intravenous (IV) formulation of Helsinn Healthcare’s Akynzeo® (fosnetupitant 235mg/palonosetron 0.25mg) single-dose vials on April 19, 2018. A combination of two anti-nausea agents, it is administered along with dexamethasone to prevent cancer chemotherapy (chemo)-induced nausea and vomiting (CINV). Palonosetron, first approved as Aloxi® injection in 2008, is a serotonin-3 (5-HT3) receptor antagonist. It prevents CINV during the acute phase, which is within the first 24 hours after chemo is started. Fosnetupitant dissociates into netupitant, a drug in the substance P/neurokinin 1 (NK1) receptor antagonist class. It also prevents acute CINV, but it continues working for up to five days to prevent delayed phase CINV, as well. Akynzeo also is available as oral capsules. Recommended dosage for the IV form is one vial mixed with 50mL of fluid and given over one-half hour before the start of each chemo treatment. It will be launched in May, but pricing for the new form has not yet been released. Prescribing information is here.

Jynarque Approved to Treat Rapidly Progressing Autosomal Dominant Polycystic Kidney Disease

On April 23, 2018, the FDA approved Otsuka Pharmaceutical’s Jynarque™ (tolvaptan) tablets to slow the decline in kidney function for adults who are at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). An inherited condition, ADPKD, which affects about 140,000 Americans, involves the development and enlargement of cysts in the kidneys. It leads to end-stage renal disease, dialysis and/or kidney transplants. Jynarque, the first drug approved to treat it, will be taken orally twice a day. Recommended initial dosing is 45mg each morning and 15mg eight hours later. Doses are increased weekly to 60mg/30mg and then to a maintenance dose of 90mg/30mg. Jynarque will be available to patients in late May, but its distribution will be limited through a risk evaluation and mitigation (REMS) program because it may cause liver damage. Accredo will not have access to Jynarque. Prescribing information is here.

Kmyriah Receives New Indication

Kymriah™ (tisagenlecleucel) suspension for IV infusion was FDA approved on April 30, 2018, to treat adults who have large B-cell lymphoma that has relapsed or recurred despite being treated two or more times. Specifically, it now is indicated to treat high grade B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) and DLBCL arising from follicular lymphoma (FL). Kite Pharma’s Yescarta™ (axicabtagene ciloleucel) was approved last October with similar indications. Novartis plans to set the wholesale acquisition cost (WAC) for the adult dose of Kymriah at $373,000, the same as Yescarta’s list price and about $100,000 lower than the WAC for Kymriah’s acute lymphoblastic leukemia (ALL) indication. A chimeric antigen receptor T cell (CAR-T) therapy, Kymriah originally was approved on Aug. 30, 2017, for treating patients under the age of 25 years who have B-cell ALL that has relapsed at least two times or that no longer responds to standard treatments. It is administered as a one-time infusion at a certified treatment center that has staff members trained to give it and to recognize its possible side effects. Adverse events, such as acute kidney injury, bleeding episodes, encephalopathy; and/or cytokine release syndrome (CRS), which is an overreaction to T-cell activation, may be associated with Kymriah infusions. Because some may be fatal, labeling carries a boxed warning and Kymriah also has a risk evaluation and mitigation strategy (REMS). Revised prescribing information is here.

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