eChapter 69 (Part 1): The Goodman & Gilman Year in Review: 2013 New and Noteworthy FDA Approvals

The FDA approved 40 new drugs and biologics of note in 2013. Twenty-two are pharmacologically similar to others already marketed and 10 are newly licensed biologics (see part 2 of this series). The remainder represent eight first-in-class agents indicated for the management of cancer, diabetes, hepatitis C infection, hypercholesterolemia, multiple sclerosis, and pulmonary hypertension (Table 69-1). Three drugs, ibrutinib (IMBRUVICA) for lymphoma (Table 69-1), obinutuzumab (GAZYVA) for chronic lymphocytic leukemia (see part 2 of this series), and sofosbuvir (SOVALDI) for hepatitis C infection (Table 69-1), were the first drugs to be approved under FDA's "breakthrough therapy" designation.1 Established in 2012, FDA reserves breakthrough designations for drugs exhibiting superior efficacy against serious diseases.

Among previously approved drugs, one product, pertuzumab (PERJETA), became the first FDA-approved neoadjuvant treatment for breast cancer.2 Neoadjuvant treatments are given as a first step to shrink a tumor before the main treatment (usually surgery) is given. Another new product, clinolipid (see part 2 of this series) was granted a priority review to help alleviate the long-standing national shortage of parenteral lipid emulsions that are used as a source of essential fatty acids for patients requiring intravenous feeding.3 Three prescription products were switched to over-the-counter status in 2013: oxybutynin (OXYTROL FOR WOMEN),4 levonorgestrel (PLAN B ONE-STEP),5 and triamcinolone acetonide (NASACORT ALLERGY 24 HR).6

Also in 2013, five diagnostic tests to guide optimization of targeted drug therapies were licensed:

• Abbott RealTime HCV Genotype II: a blood test that differentiates between seven hepatitis C genotypes (1, 1a, 1b, 2, 3, 4, and 5) was licensed to aide in determining the optimal approach to treating chronic hepatitis C infections.7

• EGFR Mutation Test: was licensed as a companion diagnostic test for erlotinib (TARCEVA) to detect exon 19 deletions and exon 21 L858R substitution mutations of the epidermal growth factor receptor (EGFR) gene.8

• FerriScan (licensed as a magnetic resonance imaging test for measuring liver iron concentration): was approved as a companion diagnostic for desferasirox (EXJADE) therapy in patients with non-transfusion-dependent thalassemia to help select appropriate candidates for therapy and to aide in the timing of the discontinuance of therapy.9

• THxID BRAF: was licensed as a companion diagnostic for trametinib (MEKINIST; Table 69-1) and dabrafenib (TAFINLAR; Table 69-2) to determine if a patient's melanoma cells have the V600E or V600K BRAF gene mutation.10

• Xpert MTB/RIF Assay: was licensed as the first rapid (2-hour) test to detect Mycobacterium tuberculosis bacteria and simultaneously determine their susceptibility to rifampin.11

First-In-Class New Drug Monographs

Ibrutinib (IMBRUVICA) is an irreversible inhibitor of Bruton's tyrosine kinase (BTK). BTK is a member of the Tec family of cytoplasmic tyrosine kinases and is also known as agammaglobulinemia tyrosine kinase (ATK) and B-cell progenitor kinase (BPK).16, 17, 18, 19, 20 BTK is essential for B-cell receptor (BCR) signaling17-18,21 and its inhibition by ibrutinib is associated with reductions in malignant B-cell proliferation, survival, migration, and substrate adhesion22-23 (see Figure 69-1, B Cell Receptor Signaling Basics).24 Based on response rate and the median duration of response (66% and 17.5 months, respectively) among 111 patients treated for a median duration of 8.3 months, ibrutinib received accelerated approval from FDA as a "breakthrough" therapy for mantle cell lymphoma.17, 20, 23, 25, 26 Despite documentation of the development of resistance, ibrutinib may prove to be beneficial for other B-cell malignancies and regimens employing ibrutinib in combination with other antineoplastic agents that are under investigation.17 The main side effects identified for ibrutinib are abdominal pain, anemia, anorexia, bruising, constipation, edema, diarrhea, dyspnea, fatigue, infection, musculoskeletal pain, nausea, neutropenia, rash, thrombocytopenia, and vomiting. Other clinically significant adverse effects of ibrutinib are lymphocytosis and renal failure. The recommended dose of ibrutinib is 560 mg taken by mouth once daily, adjusted on the basis of tolerability and graded toxicities. Patients receiving ibrutinib should remain well hydrated and undergo periodic blood cell counts and renal function monitoring. Ibrutinib is metabolized by CYP3A and 2D6 and is excreted through the feces. Dosage modification is necessary in the presence of CYP3A inducers or inhibitors. The structure of ibrutinib is shown in Figure 69-2.

Radium Ra-223 dichloride (XOFIGO) is the first alpha particle-emitting isotope to be licensed by the FDA. It is indicated for the treatment of bone metastases in patients with resistant prostate cancer and is only appropriate for administration in clinical settings licensed to safely handle nuclear pharmaceuticals.27 Radium Ra-223 dichloride is administered by injection as a series of 50 kilobecquerel (kBq)/kg doses given every 4 weeks for 6 doses. The becquerel (Bq) unit is the International System of measurement for radioactivity and is defined as the quantity of material in which one nucleus decays per second. Fifty thousand becquerel (50 kBq) is equivalent to 1.35 microcurie (μCi). XOFIGO is supplied in 6 mL single-use vials with a total radioactivity of 6,000 kBq as measured on the reference date. The product has a half-life of 11.4 days and a 28-day shelf-life. A decay correction factor must be used to calculate the volume to be administered for each injection. Radium-223 is a calcium ion mimetic that forms complexes with hydroxyapatite in areas of high bone turnover, such as at or near sites of bone metastases.28 The high linear energy transfer of the emitted alpha particles (2 protons and 2 neutrons) leads to double-strand DNA breaks in adjacent cells that arrest tumor growth.28 The alpha particle penetration from radium-223 dichloride is limited to less than 10 cell diameters, which in turn limits the damage to surrounding healthy tissues.27, 29 FDA approval of radium-223 dichloride was based on a single clinical trial of 809 men with symptomatic castration-resistant prostate cancer that had spread to bones but not to other organs. In this study, a survival benefit of approximately 3 months was demonstrated.27 After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone, bone marrow, and intestines.28 Bone marrow suppression is the main complication of therapy and hematologic evaluation of patients must be performed at baseline and prior to every dose. Patients who are sexually active should be advised to use condoms and their female partners should use a reliable method of contraception for a minimum of six months after completing treatment. Following IV administration, radium-223 dichloride is rapidly redistributed to bone and intestines. Elimination of radium-223 dichloride is through fecal elimination and radioactive decay to stable lead-207. Gastrointestinal side effects are common and patients should be advised to follow good hygiene practices during therapy and throughout the first week following discontinuation of therapy.

Riociguat (ADEMPAS) is the first soluble guanylate cyclase (sGC) stimulator to win FDA approval. sGC is the receptor for nitric oxide (NO) and a cardiopulmonary system enzyme that catalyzes the synthesis of cyclic guanosine monophosphate (cGMP).30 The sGC-cGMP pathway is involved in the regulation of vascular tone (see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Figure 36.13), proliferation, fibrosis, and inflammation.31 Riociguat is a potent vasodilator that acts through complementary mechanisms to both stabilize endogenous NO-sGC binding and also to activate sGC through a NO-independent binding site. Riociguat is indicated for the treatment of pulmonary arterial hypertension (PAH) and also to improve exercise tolerance in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It is not recommended for patients with veno-occlusive disease. Riociguat received priority FDA approval on the basis of two pivotal, phase III efficacy trials (the Pulmonary Arterial Hypertension sGC Stimulator Trial [PATENT-1]32 and the Chronic Thromboembolic Pulmonary Hypertension sGC Stimulator Trial [CHEST-1]33), demonstrating that 3 or 4 months of continuous therapy is associated with modest improvements in walking distance and relevant hemodynamic parameters (i.e., systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance, and cardiac output). Ongoing extension phases of these trials (PATENT-234 and CHEST-235) are investigating the long-term safety and efficacy of riociguat for the two approved indications. Riociguat is classified by FDA as Pregnancy Category X and is only available to females under a restricted distribution (REMS) program.36 Other adverse effects associated with riociguat include anemia, bleeding, constipation, diarrhea, dizziness, dyspepsia/gastritis, headache, hypotension, gastroesophageal reflux, ischemia, nausea, peripheral edema, and vomiting. Concomitant administration with other drugs affecting the nitric oxide-sGC-cGMP pathway, including nitric oxide donors (e.g., glyceryl trinitrate, isosorbide dinitrate, amyl nitrate, others) and phosphodiesterase inhibitors (e.g., vardenafil), is strongly contraindicated due to the risk of syncope and life-threatening hypotension.31 Riociguat is metabolized to an intermediate metabolite, M1, through CYPs 1A1, 3A4, 3A5, 2C8, and 2J2. It is eliminated through urine and feces with a terminal half-life of 7-12 hours. Riociguat is a substrate for the membrane transport proteins P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and both riociguat and M1 are strong inhibitors of CYP1A1. Therefore, prescribing vigilance is required to avoid the consequences of significant drug-drug interactions with other therapies that affect these metabolic systems.31 Riociguat is administered orally in three divided doses per day, and separated by at least one hour from antacids. The starting dose is 1.5-3 mg/day with a gradual titration to the maximum tolerated dose, not to exceed 7.5 mg daily in non-smokers. Riociguat is not recommended for patients with severe renal or hepatic dysfunction. The structure of riociguat is shown in Figure 69-3.

Sofosbuvir (SOVALDI) is a nucleotide analog prodrug that undergoes intracellular metabolism to the pharmacologically active uridine analog triphosphate (GS-461203) and the predominant circulating metabolite GS-331007 (inactive).37 Renal clearance is the major elimination pathway for GS331007 and the median terminal half-lives of sofosbuvir and GS-331007 are 0.4 and 27 hours, respectively. Sofosbuvir is indicated for the treatment of chronic hepatitis C virus (HCV) infections in combination with ribavirin or ribavirin plus pegylated interferon. The active moiety, GS-461203, is an inhibitor of the NS5B RNA-dependent RNA polymerase, an enzyme that is essential for HCV replication. Sofosbuvir is substituted into HCV RNA by the polymerase and results in premature chain termination of the nascent viral genome. Sofosbuvir has antiviral activity against all HCV genotypes, but the rapid development of resistance (notably S282T, L159F, and V321A) makes monotherapy inadvisable.38 The recommended dose of sofosbuvir is 400 mg once daily for 12-48 weeks depending on viral genotype and patient status. Sofosbuvir is a substrate of P-gp and BCRP and should not be co-administered with St. John's wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampin, rifapentine, or tipranavir/ritonavir. Common adverse effects of sofosbuvir in combination with ribavirin or ribavirin/interferon are anemia, fatigue, headache, insomnia, and nausea. Although sofosbuvir is classified as FDA Pregnancy Category B, extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients during combination therapy with ribavirin (classified as FDA Pregnancy Category X); two non-hormonal methods of contraception are recommended. The efficacy of sofosbuvir was evaluated in six Phase 3 trials: five in a total of 1,724 HCV mono-infected subjects with genotypes 1 through 6 and one in 223 HCV/HIV-1 co-infected subjects with HCV genotypes 1, 2, or 3.37 Each study used combination therapy with ribavirin (genotypes 2 or 3 or HIV co-infection) or ribavirin/peginterferon alfa 2a (genotypes 1, 4, 5, or 6). Sustained virologic response (SVR), defined as HCV RNA below the lower limit of quantification (LLOQ) 12 weeks after the end of treatment, was the primary endpoint for each study. The percentage of subjects with a SVR associated with each study is shown in Table 69-2. The chemical structure of sofosbuvir is shown in Figure 69-4. For additional information on antiviral drug combinations currently in clinical trials for chronic hepatitis C infection see Tse39 and Manns.40