eChapter 2016 (Part 1): The Goodman & Gilman Year in Review: New and Noteworthy FDA Approvals

In 2016 the U.S. Food and Drug Administration (FDA) approved 22 new drugs and granted 32 noteworthy biologic licenses. Among the 22 new drugs are:

• Six pharmacological "firsts" (Table P1-1);

• Three diagnostic imaging agents for use with PET scans (fluciclovine F-18,¹ gallium Ga-68 dotatate,² and rubidium chloride Rb-82)³;

• Three previously unapproved marketed drugs (see Part 2);

• Two entities previously regulated only as a dietary supplements (see Part 2); and

• Eight additional new molecular entities that are pharmacologically similar to previously approved drugs (see Part 2).

The 32 noteworthy biologics approved in 2016 are described in Part 3 of this series. Among them are:

• 12 new authorizations expanding the clinical uses for biologics that are already on the market in the United States (see Tables P1-2 and P1-3);

• Six first-to-market monoclonal antibodies;

• Three biosimilars;

• Three recombinant coagulation factors;

• Three new influenza vaccines;

• One new oral vaccine for travelers (cholera);

• One previously marketed biologic approved for a new indication (daclizumab for multiple sclerosis);

• A new immune globulin concentrate formulated for subcutaneous administration (notable for being the 12^th SC IgG formulation to be marketed in the United States);

• A new fibrin patch; and

• A cellular sheet of chondrocytes for autologous implantation (MACI).

In 2016 FDA authorized 19 new cancer therapies,⁴ approved 39 therapies for rare (orphan) conditions,⁵ and designated 16 drugs as therapy breakthroughs.^6,7 Throughout this series, orphan, breakthrough, and cancer therapy designations are notated by the symbols †, $, and #, respectively, and biologics are notated by the symbol ¶. Table P1-2 lists the 15 marketed drugs and biologics that gained supplemental approval for an orphan indication in 2016. Among the breakthrough therapy drug approvals are two first-in-class small molecule drugs (pimavanserin, a selective serotonin 5-HT_2A receptor reverse agonist, and venetoclax^#, a B-cell lymphoma-2 [BCL-2] protein inhibitor) (Table P1-1); nine established drugs designated as breakthrough therapies for 13 serious disease states (Table P1-3); and two new monoclonal antibodies (atezolizumab^# and olaratumab^#) for cancer (see Part 3). Established in 2012, breakthrough designations are reserved for drugs exhibiting superior efficacy against serious diseases.⁸ In the first four years of the program, a total of 59 breakthrough therapies were approved.⁹

Companion diagnostic tests were licensed in 2016 in conjunction with FDA approval of venetoclax^# (see Table P1-1) and rucaparib^# (see Part 2). In 2016, a third test was licensed to help detect the subset of patients with metastatic non-small cell lung cancer who qualify as candidates for therapy with erlotinib^# (Tarceva)^10-11 and a fourth new test (Xpert Carba-R Assay) was licensed as an infection control aid for the in-house detection of genetic markers associated with carbapenem antibiotic resistance.¹² Companion diagnostic tests are intended to aid prescribers in selecting targeted therapies for individual patients and to reduce the risks associated with exposures to suboptimal therapies. The new Vysis CLL FISH Probe Kit¹³ detects the 17p depletion required to qualify patients for venetoclax^# therapy; the new FoundationFocus CDxBRCA assay¹³ quantitatively tests for the BRCA1 and BRCA2 alterations that qualify patients for therapy with rucaparib^#14 (see part 2 of this series); and the cobas EGFR Mutation Test v2¹⁵ tests for epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations that qualify patients with metastatic non-small cell lung cancer for treatment with erlotinib^#.^10,11

FDA announced the agency's intent to regulate laboratory-developed diagnostic tests in 2014, staring with companion tests, and extending to the next generation sequencing tests (tests that sequence large segments of a person's genome).^16,17,18,19 The timely development of these tests is necessary for continued forward progress on the National Institute of Health's Precision Medicine Initiative.^19,20 In support of the initiative, FDA guidance documents were drafted and regulatory oversight of laboratory tests as "medical devices" was initially expected to be phased in over a decade.^19,21-22 However, after failing to reach consensus with stakeholders, in late 2016 FDA announced an indefinite postponement of the planned oversight.²³ As a consequence of this decision, the broader Precision Medicine Initiative may also be delayed or derailed.²⁴ For now, a list of cleared or approved companion diagnostic tests remains available from FDA online at www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm301431.htm.¹³

In addition to small-molecule, biologic, and companion test approvals, 10 notable medical devices also were cleared for marketing in 2016 (Table P1-4). Among them is the first "artificial pancreas."¹²⁶ Other 2016 FDA accomplishments are summarized in Part 2 of this series. Additional biologic drug approvals are covered in Part 3. Brief "first-in-class" and new "targeted-diagnostic" monographs follow in Table P1- 1 below.

First-In-Class New Drug Monographs

(Note: In reference to the drug monographs below, lists of drugs that are known to be P-glycoprotein and cytochrome P450 enzyme inducers and inhibitors can be found in: Preissner S, Kroll K, Dunkel M, et al. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan; 38 (Database issue): D237-43. doi: 10.1093/nar/gkp970. The searchable database is available at: bioinformatics.charite.de/transformer/.)³⁹

Defibrotide (Defitelio)²⁵ is a thrombolytic agent that also has anti-inflammatory and anti-ischemic activities.^25,40 It acts by increasing prostaglandin I2 (prostacyclin), prostaglandin E2, and the activities of tissue plasminogen activator (tPA) and thrombomodulin, and also by decreasing von Willebrand factor (vWF) and the activity of tissue plasminogen activator inhibitor (TPAI).^25,26,40 Defibrotide is indicated for the treatment of hepatic veno-occlusive disease in patients with with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Untreated hepatic veno-occlusive disease is associated with a high rate of mortality and defibrotide is proven to improve survival in patients who develop multi-organ failure associated with the disease. In this setting, defibrotide is thought to restore thrombo-fibrinolytic balance through the stabilization of endothelial cells (by reducing endothelial-cell activation) and by protecting endothelial cells from further damage.⁴¹ The survival benefit was demonstrated in a phase 3 clinical trial in which defibrotide was associated with a 23% survival benefit (over historical controls) at post-transplant day 100.⁴¹ Defibrotide has been licensed as an orphan drug since 1985 (for thrombotic thrombocytopenic purpura). Orphan drug status for treatment and prevention of hepatic veno-occlusive disease was granted in 2003 and 2007, respectively. Chemically, defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. The dose for hepatic veno-occlusive disease is 6.25 mg/kg IV every 6 hours for a minimum of 21 days and a maximum of 60 days. The main side effect of defibrotide is bleeding; concomitant administration with anticoagulants, platelet inhibitors, and other thrombolytic agents is contraindicated due to increased risk of bleeding. Supportive care is the recommended management for defibrotide-associated bleeding as there is no reversal agent. Other unwanted effects include hypotension, hypersensitivity reactions (including anaphylaxis and angioedema), and hyperuricemia. At an incremental cost calculated to be $47,736 per quality-adjusted life-year gained, a recent cost-impact analysis concluded that defibrotide is highly cost-effective for the treatment of hematopoietic stem-cell transplants.⁴²

Eteplirsen (Exondys 51)²⁸ is classified as an antisense oligonucleotide (AON) and is a phosphorodiamidate morpholino oligomer (PMO) sequence targeted to a portion of exon 51 on dystrophin pre-messenger ribonucleic acid.⁴³ PMOs are synthetic molecules in which the five-membered ribofuranosyl rings with negatively charged phosphate linkages found in natural DNA and RNA are replaced by a six-membered morpholino rings with uncharged phosphorodiamidate linkages.⁴⁴ The chemical structure of eteplirsen is shown in Figure P1-1. Etepilresen is indicated for the subset of patients with Duchenne muscular dystrophy who have a gene mutation that causes the production of nonfunctional dystrophin, a protein necessary to maintain the integrity of muscle cell membranes.²⁸ By forcing the exclusion of exon 51 from dystrophin mRNA, eteplirsen works by increasing the production of partially functional (truncated) dystrophin proteins.^28,43 It is estimated that only 13–14% of patients with Duchenne muscular dystrophy have disease that is amenable to exon 51 skipping.⁴⁵ Granted orphan drug status in 2007, eteplirsen is the first drug to receive FDA-approval for the treatment of Duchenne muscular dystrophy and it is the first-to-market "exon skipper." Eteplirsen is administered as a weekly 30-mg/kg IV infusion. Unwanted effects reported with its administration have included vertigo, contact dermatitis, arthralgia, ecchymosis, rash, infection, and vomiting. Eteplirsen approval was based on the detection of a tiny increase in dystrophin levels (averaging 0.93% of normal) over the baseline value of 0.08% of normal amounts from biopsies of untreated Duchenne muscles.⁴⁵ Evidence of functional improvement during 36 months of open-label eteplirsen administration points to a slower decline in walking ability than age-matched historical controls.⁴⁶ A 75-m difference in 6-minute walk tests was detected by 24 months, and a statistically significant difference of 151 m was detected by 36 months.⁴⁶ In addition, fewer eteplirsen-treated patients lost ambulation during the observation period than untreated, matched historical controls.⁴⁶

Lifitegrast (Xiidra)³⁰ is a lymphocyte function-associated antigen-1 (LFA-1) antagonist indicated for dry eye disease (keratoconjunctivitis sicca). LFA-1 is a cell surface protein found on leukocytes. Lifitegrast binds to LFA-1 and blocks its interaction with intercellular adhesion molecule-1 (ICAM-1). Through this mechanism, lifitegrast may inhibit T-cell adhesion to ICAM-1 and subsequent secretion of inflammatory cytokines.⁴⁷ Lifitegrast efficacy was demonstrated on the basis of a statistically significant (p = 0.0007) improvement in subject-reported eye dryness scores among 706 subjects on day 84 compared with baseline and relative to placebo.⁴⁸ On a 100-point visual analog scale, the magnitude of the treatment effect difference measured 7.16 points.⁴⁸ Except for eye dryness scores, the mean changes from baseline to day 14 and to day 84, separately, were similar between treatment groups for ocular discomfort, itching, foreign body sensation, eye discomfort, burning/stinging, photophobia, and pain.⁴⁸ Lifitegrast is packaged in single-use containers and formulated as a unpreserved sterile ophthalmic solution for twice daily administration. Contact lenses must be removed prior to, and must not be reinserted for 15 minutes after, the administration of lifitegrast. Common side effects are dysgeusia and reduced visual acuity. Less common are headache; redness, itching, and irritation of the eyes; tearing; sinusitis; and ocular discharge. The chemical structure of lifitegrast is shown in Figure P1-2.

Nusinersen (Spinraza)³² is an intrathecally administered survival motor neuron-2 (SMN2)-directed antisense oligonucleotide (AON) designed to treat spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. In contrast to natural DNA and RNA, the 2'-hydroxy groups of the ribofuranosyl rings of nusinersen are replaced with 2'-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages. These substitutions allow nusinersen to target a specific sequence in the intron downstream of exon 7 and increase production of functional SMN protein by increasing exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts.³² Through this mechanism, nusinersen was purposefully engineered to compensate for the genetic defect associated with spinal muscular atrophy.⁵⁰ The dose of nusinersen is 12 mg intrathecally administered on days 0, 14, 28, and 58 and then once every 4 months thereafter. Nusinersen is associated with thrombocytopenia, coagulation abnormalities, and renal toxicity, so it is recommended to measure and assess platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and a quantitative spot urine protein test at baseline, and prior to each dose. Other unwanted effects associated with nusinersen include antibody formation, headache, back pain, infection, constipation, nasal congestion, growth inhibition, and hyponatremia. Nusinersen was granted orphan drug status in 2011. FDA approval was based on the results of a controlled trial in infantile-onset SMA patients and on open-label uncontrolled trials in patients who had, or were likely to develop, SMA.⁵¹ Nusinersen administration is correlated with the following: some patients achieving motor milestones such as the ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so; some patients maintaining milestones at ages when they would be expected to be lost; and some patients surviving to unexpected ages. Overall the findings appear to support the early initiation of treatment with nusinersen.

Pimavanserin^$ (Nuplazid)³⁴ acts as an inverse agonist for serotonin 5-HT_2A receptors to lower their basal activity.⁵² Pre-frontal cortex 5-HT_2A receptors are recognized as a mediator of hallucinogenic activity.^53,54 Pimavanserin is 40 times more selective for 5-HT_2A receptors than for 5HT_2C receptors and has low affinity for sigma-1 receptors.^34,55 Pimavanserin exhibits no significant affinity for calcium channels or 5-HT_2B, dopaminergic, muscarinic, histaminic, or adrenergic receptors.^34,55 Pimavanserin is classified as an atypical antipsychotic and is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease. Its selectivity for 5-HT_2A makes it unlikely to impede motor function in patients with Parkinson's disease psychosis.^52,56 Like other atypical antipsychotics, pimavanserin is labeled with warnings related to QT prolongation and an increased risk of death in elderly patients with dementia-related psychosis. The usual dose of pimavanserin is 34 mg daily. The drug is metabolized to an active metabolite (AC-279) through cytochrome P450 enzymes (CYP3A4, CYP3A5, and others) so dosage reductions are recommended when pimavanserin is co-administered with strong CYP3A4 inducers. Other unwanted effects reported in placebo-controlled trials with the use of pimavanserin were: visual, auditory, tactile, or somatic hallucinations (5% vs. 3%); confusion (6% vs. 3%); peripheral edema (7% vs. 2%); and nausea (7% vs. 4%). Evidence for the efficacy of pimavanserin include reaching the phase 3 clinical trial primary endpoint of a meaningful reduction in the Scale for Assessment of Positive Symptoms as adjusted for Parkinson's Disease score (mean reduction of 37% from baseline compared with 14% for placebo), as well as reductions in other measures related to hallucinations and delusions, and also measures indicative of less burden on caregivers.⁵⁷ The chemical structure of pimavanserin is shown in Figure P1-3 and the stepwise story of its discovery and development has been published by Hacksell and colleagues.⁵²

Venetoclax^$ (Venclexta)³⁶ is classified as a orally active biologic response modifier and a signal transduction inhibitor.^37,59 Venetoclax is a selective inhibitor of B-cell lymphoma-2 (BCL-2) protein and is a BH-3 mimetic.^59,60,61 B-cell lymphoma-2 protein is oncogenic because it is antiapoptotic.⁶² Its overproduction is associated with increased tumor cell survival and chemotherapy resistance.^37,59 Venetoclax is indicated for the management of chronic lymphocytic leukemia (CLL) in patients with a 17p deletion. 17p testing is indicated prior to initiating therapy with venetoclax using the FDA-approved companion test kit (Vysis CLL FISH Probe Kit).¹³ The initial daily dose of venetoclax is 20 mg, and the dose is titrated up over 5 weeks to 400 mg daily. At this dose in an early clinical trial, the response to venetoclax was reported to be 79% and the 15-month progression-free survival rate was 69%.⁶³ On the basis of these and other efficacy results, FDA granted breakthrough therapy status to venetoclax.⁶² Guidelines for tumor lysis syndrome prophylaxis (consisting of hydration and allopurinol) and dose reductions for hematologic and nonhematologic toxicities are included in the drug labeling. Venetoclax is a CYP3A4/5 and P-glycoprotein (P-gp) substrate associated with clinically significant drug-drug interactions. Venetoclax is also an inhibitor of breast cancer resistance protein (BCRP), and a weak OATP1B1 inhibitor. Guidelines for minimizing the risk during unavoidable co-administration of interacting drugs are provided in the product labeling. Exposure to venetoclax is associated with fetal toxicity and male infertility. An effective form of contraception is necessary prior to starting therapy and for at least 30 days after stopping the treatment. For men, pretreatment sperm banking is suggested. Other unwanted effects of venetoclax include GI intolerance, cough, fatigue, hyperkalemia, hyperphosphatemia, peripheral edema, fever, and headache. Severe back pain, kidney toxicity, and hyperuracemia also may occur. Venetoclax has been licensed as an orphan drug for CLL since 2012. In 2016, designation as an orphan drug was extended to acute myeloid leukemia and multiple myeloma. The chemical structure of venetoclax is shown in Figure P1-4, and the story of its discovery and development has been described by Cang.⁶² Strategies designed to overcome possible acquired resistance to venetoclax have been explored.⁶⁴

2016 Novel Diagnostic Agent Approvals

Fluciclovine F-18 (Axumin)^1,66 is a radiolabeled synthetic analog of the amino acid L-leucine. The chemical structure of fluciclovine F-18 is shown in Figure P1-5. It is a diagnostic adjunct indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence. The use of Axumin to localize sites suspicious for prostate cancer recurrence is based on the principle that radiolabeled fluciclovine is transported across cell membranes by amino acid transporters (such as LAT-1 and ASCT2) that are upregulated in cancer cells,⁶⁷ causing fluciclovine F-18 to accumulate to higher levels in cancer cells compared to normal cells. PET imaging is used to find these areas of abnormal accumulation. Since fluciclovine F-18 accumulation may occur with other types of cancer and with benign prostatic hypertrophy, and because detection accuracy using AXUMIN is at least partially correlated to serum PSA values, fluciclovine F-18 use is usually an adjunct to the histopathological evaluation of suspected recurrence sites. In addition to FDA approval, fluciclovine F-18 is designated as an orphan drug for the diagnosis of gliomas. To minimize radiation exposure, handling of Axumin in health care settings requires the use of personal protective equipment (waterproof gloves), effective shielding, and other safety measures. The storage and disposal of the radiolabeled product must comply with regulatory requirements for radioactive materials.

Gallium Ga-68 dotatate (Netspot)^2,69 is a β-1 emitting radionuclide for use with positron emission tomography (PET). It is indicated for the detection of somatostatin receptor positive neuroendocrine tumors. These are rare, benign or malignant tumors that develop in the hormone-producing cells of the stomach, intestines, pancreas, lungs, and other locations. Gallium Ga-68 dotatate has been in use in the United States as an orphan drug since 2013. Dotatate, (DOTA-0-Tyr3-Octreotate) is a cyclic 8-amino-acid peptide with a covalently bound chelator. Its chemical structure is shown in Figure P1-6. Gallium-radiolabeled dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 receptors. The abnormal uptake of Netspot during a PET scan correlates to the density of overexpressed receptors in somatostatin receptor positive tumors. However, Netspot is not specific to neuroendocrine tumors and its uptake is seen in other tumor types, other pathologic conditions, or as a normal physiological variant. Histopathological confirmation of abnormal findings should be considered. The use of specialized equipment (i.e., an Eckert & Ziegler GalliaPharm Germanium 68/Gallium 68 [Ge 68/Ga 68] generator) is required to prepare Netspot for injection prior to administration. To minimize radiation exposure, handling of Netspot in health care settings requires the use of personal protective equipment (waterproof gloves), effective shielding, and other safety measures.

Rubidium chloride Rb-82 generator (Ruby-Fill)³ is a radionuclide generator system used to produce a patient-specific dose of Rb-82 for use with positron emission tomography (PET) to evaluate regional myocardial perfusion in patients with suspected or proven coronary artery disease. Rb-82 is a medical isotope with a half-life of only 75 seconds. The isotope exhibits biochemical behavior analogous to potassium and is rapidly taken up by heart muscle cells in proportion to blood flow. Rb-82 is generated from strontium 82 adsorbed on stannic oxide in a lead-shielded column that provides a means for obtaining sterile non-pyrogenic solutions of rubidium Rb-82 chloride for injection. Ruby-Fill is the second Rb-82 generator to be marketed in the United States. The first, Cardiogen-82, was FDA approved in 1989. Cardiogen-82 was the subject of a recall in 2011 due to unintended strontium (Sr) exposures. It was re-cleared for marketing in 2012 with a new FDA requirement for a black box warning for the drug class aimed at minimizing untended ⁸²Sr and ⁸⁵Sr exposures. In addition, the receipt, transfer, possession, storage, and disposal of rubidium generators are subject to radioactive material regulations and licensing requirements. To minimize radiation exposure, handling of Ruby-Fill in health care settings requires the use of personal protective equipment (waterproof gloves), effective shielding, and other safety measures.