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Drug and Device News July 2017

NEW DRUG APPROVALS

Kevzara for Rheumatoid Arthritis

The FDA has approved sarilumab (Kevzara, Regeneron/Sanofi) for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have shown an inadequate response to or are intolerant of one or more disease-modifying antirheumatic drugs, such as methotrexate. Sarilumab is a human monoclonal antibody that binds to the interleukin-6 receptor (IL-6R), thereby inhibiting IL-6R–mediated signaling. IL-6 is a cytokine that can contribute to the inflammation associated with RA.

The U.S. wholesale acquisition cost (WAC) of sarilumab is $39,000 per year, which is approximately 30% lower than the WAC for the two most widely used tumor necrosis factor-alpha inhibitors, according to the manufacturers.

Source: Regeneron, May 22, 2017

Radicava for ALS

Edaravone (Radicava, Mitsubishi Tanabe Pharma America) has secured FDA approval for the treatment of patients with amyotrophic lateral sclerosis (ALS). In the United States, the only other approved ALS medication, generic riluzole, modestly slows disease progression in some patients.

Edaravone is expected to be available in the U.S. by August. The manufacturer has priced the treatment at $1,086 per infusion. If taken annually for 12 months (13 cycles), according to the dosing and administration included on the label, the total cost before government discount would be $145,524.

Source: Mitsubishi Tanabe, May 5, 2017

Generic Approvals or Launches

Atomoxetine Capsules

The FDA has approved the first generic atomoxetine (Strattera, Eli Lilly) to treat attention-deficit/hyperactivity disorder in pediatric and adult patients. Apotex Inc., Teva Pharmaceuticals USA, Aurobindo Pharma, and Glenmark Pharmaceuticals received permission to market atomoxetine in multiple strengths. According to IMS Health sales data for the 12 months ending with April 2017, Strattera capsules achieved annual sales of approximately $1.1 billion.

The labeling includes a boxed warning regarding an increased risk of suicidal ideation in children and adolescents. Other important warnings include a risk of severe liver damage and the potential for serious cardiovascular events.

Sources: FDA and Glenmark, May 31, 2017

Quetiapine Fumarate Tablets

The FDA has approved the first generic equivalents of Seroquel XR tablets (quetiapine fumarate, AstraZeneca). Pharmadex (with partner TruPharma), Par Pharmaceutical, Inc., IntelliPharmaCeutics Corp., and Lupid Ltd. now have FDA permission to market 50-mg, 150-mg, 200-mg, 300-mg, and 400-mg tablets, while Accord Healthcare, Inc., can sell 150-mg, 200-mg, and 300-mg tablets. According to IMS Health data, U.S. sales of Seroquel XR and generic equivalents were approximately $1.34 billion for the 12 months ending December 31, 2016.

Seroquel XR is a once-daily tablet indicated for the treatment of schizophrenia; acute depressive episodes in bipolar disorder; and acute manic or mixed episodes in bipolar disorder alone or with lithium or divalproex; and for adjunctive therapy with antidepressants for patients with major depressive disorder.

Sources: FDA, May 9, 2017, Pharmadex, May 16, 2017, and Lupid Ltd., May 18, 2017

Clofarabine Injection

Abon Pharmaceuticals has received final FDA approval for its abbreviated new drug application for clofarabine injection 20 mg/20 mL in a single-use vial. This is the first generic equivalent of Clolar (Genzyme), which is indicated for the treatment of patients 1–21 years of age with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.

Sources: FDA, May 9, 2017, and Abon Pharmaceuticals, May 16, 2017

Acamprosate Calcium Tablets

Zydus Cadila has received approval from the FDA to market acamprosate calcium delayed-release tablets, 333 mg. This medication is used for the maintenance of abstinence from alcohol in patients with alcohol dependence.

Source: Zydus Cadila, May 27, 2017

Olmesartan Medoxomil Tablets

Glenmark Pharmaceuticals has been granted approval by the FDA for olmesartan medoxomil tablets, 5 mg, 20 mg, and 40 mg—a generic version of Benicar tablets (Daiichi Sankyo). Benicar is indicated for the treatment of hypertensive patients.

Source: Glenmark, May 26, 2017

Memantine Tablets

Strides Shasun has received FDA approval to market memantine hydrochloride tablets USP, 5 mg and 10 mg, which are indicated for patients with moderate-to-severe Alzheimer’s-type dementia.

Source: Strides Shasun, May 24, 2017

Aripiprazole Tablets

The FDA has approved the marketing of aripiprazole by Orchid Pharma in 2-mg, 5-mg, 10-mg, 20-mg, and 30-mg tablets. Aripiprazole is indicated for the treatment of patients with schizophrenia; for acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder; for adjunctive therapy with antidepressants for the treatment of major depressive disorder; and for the treatment of irritability associated with autistic disorder.

Source: Orchid Pharma, May 24, 2017

Cyproheptadine Tablets

Zydus Cadila has received FDA approval to market cyproheptadine hydrochloride tablets USP, 4 mg. The drug is an antihistamine used to relieve allergy symptoms, including watery eyes, running nose, itching eyes or nose, sneezing, hives, and itching.

Source: Zydus Cadila, May 23, 2017

Levocetirizine Oral Solution

Lannett Company has received FDA approval for levocetirizine dihydrochloride oral solution, 2.5 mg/5.0 mL (0.5 mg/mL)—the therapeutic equivalent of Xyzal (UCB). Levocetirizine oral solution is indicated for the relief of symptoms associated with perennial allergic rhinitis in children 6 months to 2 years of age and for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 months of age and older.

Source: Lannett Company, May 16, 2017

Extended-Release Metformin Tablets

Teva Pharmaceutical Industries has announced the U.S. launch of generic Glumetza (metformin extended-release tablets), 500 mg and 1,000 mg. Metformin extended-release tablets are used with diet and exercise to help control high blood sugar in adults with type-2 diabetes mellitus. The product is not for patients with type-1 diabetes or diabetic ketoacidosis.

Source: Teva, May 15, 2017

Fenofibric Acid Delayed-Release Capsules

Alembic Pharmaceuticals has received FDA approval for its fenofibric acid delayed-release capsules, 45 mg and 135 mg, which are therapeutically equivalent to Trilipix delayed-release capsules (AbbVie). The drug is indicated as an adjunctive therapy to diet to reduce triglycerides in patients with severe hyper-triglyceridemia and to reduce elevated low-density lipoprotein-cholesterol, total cholesterol, triglycerides, and apolipo-protein B, and to increase high-density lipoprotein-cholesterol in patients with primary hypercholesterolemia or mixed dyslipidemia.

Source: Alembic Pharmaceuticals, May 15, 2017

Pindolol Tablets

ANI Pharmaceuticals has relaunched pindolol tablets, 5 mg and 10 mg, in the United States. The drug, a beta blocker, is used to treat patients with hypertension alone or with other antihypertensive agents, particularly with a thiazide-type diuretic.

Source: ANI Pharmaceuticals, May 9, 2017

NEW INDICATIONS

Keytruda for More Cancers

The FDA has approved new indications for the anti-programmed death-1 (PD-1) therapy pembrolizumab (Keytruda, Merck).

Pembrolizumab is now approved in combination with pemetrexed (Alimta, Eli Lilly) and carboplatin, a common chemotherapy regimen, for the first-line treatment of patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC), irrespective of programmed death ligand-1 (PD-L1) expression. Pembrolizumab is the only anti–PD-1 therapy approved in the first-line setting as both monotherapy and combination therapy for appropriate patients with metastatic NSCLC. Pembrolizumab is approved as monotherapy in the first-line setting for patients with metastatic NSCLC whose tumors have high PD-L1 expression, as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. Pembrolizumab as monotherapy is also indicated for the second-line or greater treatment of patients with metastatic NSCLC whose tumors express PD-L1, with disease progression during or after platinum-containing chemotherapy.

The FDA also added an indication for pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high or mismatch repair-deficient solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, or patients with colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab became the first cancer drug approved by the FDA based on a patient’s genetic traits, regardless of where in the body the disease originated. The approval marks a major step in so-called precision medicine, in which genetic biomarkers may determine the course of therapy rather than the type of cancer.

Source: Merck, May 10 and 23, 2017

Zykadia for Lung Cancer

The FDA has approved the expanded use of ceritinib (Zykadia, Novartis) to include the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive, as detected by an FDA-approved test. Ceritinib first received accelerated approval in 2014 for patients with ALK-positive metastatic NSCLC who had progressed on or were intolerant of crizotinib. In January 2017, the FDA granted ceritinib breakthrough therapy status for the first-line treatment of patients with ALK-positive metastatic NSCLC with metastases to the brain and a priority review designation for first-line ALK-positive metastatic NSCLC.

Source: Novartis, May 26, 2017

Actemra for Giant Cell Arteritis

The FDA has expanded the approved use of subcutaneous (SC) tocilizumab (Actemra, Roche) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy that is specific to this type of vasculitis. SC tocilizumab was previously approved for the treatment of patients with moderately to severely active rheumatoid arthritis (RA). Intravenous (IV) tocilizumab was previously approved for the treatment of patients with moderately to severely active RA, systemic juvenile idiopathic arthritis, or polyarticular juvenile idiopathic arthritis. IV administration is not approved for the treatment of patients with giant cell arteritis.

Source: FDA, May 22, 2017

Bavencio for Bladder Cancer

The FDA has approved avelumab injection (Bavencio, EMD Serono/Pfizer) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or after platinum-containing chemotherapy, or who experience disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Avelumab was previously granted accelerated approval for the treatment of patients 12 years of age and older with metastatic Merkel cell carcinoma.

Avelumab was designed to potentially engage both the adaptive and innate immune systems. By binding to programmed death ligand-1 (PD-L1), avelumab is thought to prevent tumor cells from using PD-L1 for protection against leukocytes, such as T cells, exposing them to antitumor responses.

Source: Pfizer, May 9, 2017

NEW FORMULATIONS

Isentress HD for HIV-1 Infection

The FDA has approved Isentress HD (Merck), a new 1,200-mg once-daily dose of the company’s integrase inhibitor raltegravir (Isentress), for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults and children. The drug is administered orally as two 600-mg film-coated tablets, with or without food, in combination with other antiretroviral agents. To qualify for treatment, pediatric patients must weigh at least 40 kg; the children may be treatment-naïve or have had their infection suppressed by an initial regimen of Isentress 400 mg twice daily. Approved in 2007, raltegravir was the first integrase inhibitor developed for the treatment of patients with HIV-1.

Source: Merck, May 30, 2017

Zerviate Solution For Ocular Itching

The FDA has approved Zerviate (cetirizine ophthalmic solution 0.24%, Nicox S.A.), the first topical ocular formulation of this well-known antihistamine, for the treatment of itching associated with allergic conjunctivitis. Cetirizine, the active ingredient in Zyrtec tablets (Johnson & Johnson), is a second-generation antihistamine that binds competitively to histamine receptor sites to reduce swelling, itching, and vasodilation.

Source: Nicox, May 31, 2017

FDA REVIEW ACTIVITIES

Priority Review Designations

Axicabtagene for Non-Hodgkin’s Lymphoma

The FDA has accepted for priority review the biologics license application for the chimeric antigen receptor T-cell therapy candidate axicabtagene ciloleucel (Kita Pharma). The submission follows positive results demonstrated with a single infusion of axicabtagene in the phase 2 ZUMA-1 trial in patients with refractory, aggressive non-Hodgkin’s lymphoma. The FDA has set a target action date of November 29, 2017.

Source: Kita Pharma, May 26, 2017

Opdivo for Liver Cancer

The FDA has accepted a supplemental biologics license application that seeks to extend the use of nivolumab (Opdivo, Bristol-Myers Squibb) to patients with hepatocellular carcinoma after prior sorafenib therapy. The application received priority review status with an action date of September 24, 2017.

In July 2014, nivolumab was the first programmed death-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world.

Source: Bristol-Myers Squibb, May 25, 2017

Copanlisib for Lymphoma

Copanlisib (Bayer) has received priority review status for the treatment of patients with relapsed or refractory follicular lymphoma who have received at least two prior therapies. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant inhibitory activity against PI3K-alpha and PI3K-delta isoforms. The efficacy and safety of copanlisib have not been established.

Source: Bayer, May 17, 2017

Fast-Track Designations

Tideglusib for Myotonic Dystrophy

The FDA has granted fast-track status to tideglusib (AMO Pharma) for the treatment of patients with DM1, the severe form of congenital myotonic dystrophy. Tideglusib is an investigational inhibitor of glycogen synthase kinase 3 beta that has demonstrated preclinical efficacy in transgenic models and the reversal of muscle-cell differentiation deficits in ex vivo tissue samples derived from patients with congenital DM1.

Source: AMO Pharma, May 30, 2017

CM4620 for Pancreatitis

CM4620 (CalciMedica, Inc.), an investigational calcium release-activated calcium channel inhibitor, has received fast-track status for the potential treatment of patients with acute pancreatitis, an inflammatory condition that is the leading cause of gastrointestinal hospitalizations. CM4620 inhibits the uncontrolled increase in intracellular calcium in pancreatic acinar cells, thereby preventing inappropriate digestive enzyme activation, acinar-cell dysfunction and death, or necrosis. Currently, no therapeutic agents are indicated for acute pancreatitis.

Source: CalciMedica, May 24, 2017

SB-525 for Hemophilia

The FDA has granted a fast-track designation to SB-525 (Sangamo Therapeutics/Pfizer), a clinical-stage complementary DNA (cDNA) gene-therapy candidate for patients with hemophilia A. SB-525 uses a recombinant adeno-associated virus to deliver a human factor VIII cDNA construct and a proprietary synthetic liver-specific promoter to the nucleus of liver cells with a single infusion. The single-treatment strategy is intended to provide continuous therapeutic expression of the factor VIII protein.

Source: Sangamo Therapeutics, May 16, 2017

AXS-05 for Alzheimer’s Agitation

Axsome Therapeutics has received a fast-track designation from the FDA for AXS-05 (bupropion/dextromethorphan) for the treatment of agitation in patients with Alzheimer’s disease. There are currently no approved treatments for this condition. Axsome previously received clearance to proceed with a phase 2/3 trial of AXS-05 for this indication.

Source: Axsome Therapeutics, May 9, 2017

Reolysin for Metastatic Breast Cancer

The FDA has granted fast-track status to Reolysin (Oncolytics Biotech), a proprietary variant of the reovirus, for the treatment of patients with metastatic breast cancer.

In April 2017, data from an open-label, randomized, phase 2 study that assessed the therapeutic combination of intravenously administered Reolysin plus the chemotherapy agent paclitaxel compared with paclitaxel alone in patients with advanced or metastatic breast cancer demonstrated a statistically significant increase in median overall survival for the combined treatment. Oncolytics Biotech is pursuing metastatic breast cancer as its primary focus for late-stage clinical testing of Reolysin.

Source: Oncolytics Biotech, May 8, 2017

Breakthrough Therapy Status

Givosiran for Hepatic Porphyria

Givosiran (Alnylam Pharmaceuticals), an investigational RNA interference (RNAi) therapeutic agent targeting aminolevulinic acid synthase 1, has been granted breakthrough therapy status for the prophylaxis of attacks in patients with acute hepatic porphyria. The treatment is administered via subcutaneous injection.

RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. Small interfering RNA, the molecules that mediate RNAi, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made.

Source: Alnylam Pharmaceuticals, May 31, 2017

Plazomicin for Drug-Resistant Infections

The FDA has granted breakthrough therapy status to plazomicin (Achaogen, Inc.), an antibacterial being developed for the treatment of patients with serious bacterial infections due to multidrug-resistant Enterobacteriaceae, including those that are carbapenem resistant. The phase 3 CARE trial provided clinical evidence to support the breakthrough therapy designation for plazomicin for the treatment of bloodstream infections caused by certain Enterobacteriaceae in patients with limited or no alternative treatment options. Achaogen plans to submit a new drug application for plazomicin in the second half of 2017.

Source: Achaogen, May 23, 2017

Ribaxamase for C. Difficile Infection

The FDA has granted breakthrough therapy status to ribaxamase (Synthetic Biologics) for the prevention of Clostridium difficile infection (CDI). Ribaxamase is a first-in-class oral enzyme designed to degrade certain intravenous beta-lactam antibiotics in the gastrointestinal tract and to maintain the natural balance of the gut microbiome for the prevention of CDI, pathogenic overgrowth, and the emergence of antimicrobial resistance. If approved, ribaxamase would be the first drug designed to prevent CDI by protecting the gut microbiome from antibiotic-mediated dysbiosis.

Source: Synthetic Biologics, May 11, 2017

Setmelanotide for Gene-Related Obesity

The FDA has expanded a previously granted breakthrough therapy designation (BTD) for setmelanotide (Rhythm), a melanocortin-4 receptor (MC4R) agonist, for the treatment of obesity associated with genetic defects upstream of the MC4R in the leptin–melanocortin pathway, which includes both pro-opiomelanocortin (POMC)- and leptin receptor-deficiency obesity. The FDA had previously granted the BTD to setmelanotide for the treatment of POMC-deficiency obesity.

Source: Rhythm, May 11, 2017

Vonapanitase for Arteriovenous Fistula Patency and Hemodialysis

Vonapanitase (Proteon Therapeutics) has received breakthrough therapy status from the FDA for increasing arteriovenous fistula secondary patency (i.e., survival of the fistula without abandonment) and for use for hemodialysis in patients receiving or expected to initiate hemodialysis. The breakthrough therapy designation was supported by data from the phase 3 PATENCY-1 trial, which evaluated vonapanitase in patients with chronic kidney disease undergoing surgical creation of a radiocephalic arteriovenous fistula. In that study, vonapanitase demonstrated clinically meaningful improvements in secondary patency and in use for hemodialysis, although it did not meet the primary endpoint of improving primary patency. Proteon expects to submit a biologics license application to the FDA in 2019.

Source: Proteon Therapeutics, May 10, 2017

Orphan Drug Designations

CK-2127107 for SMA

The FDA has granted orphan drug status to CK-2127107 (Cytokinetics/Astellas Pharma) for the potential treatment of patients with spinal muscular atrophy (SMA). CK-2127107, a next-generation fast skeletal muscle troponin activator, is being developed for the treatment of patients with SMA, chronic obstructive pulmonary disease, and certain other debilitating diseases and conditions associated with skeletal muscle weakness and/or fatigue.

Skeletal muscle contractility is driven by the sarcomere, a highly ordered cytoskeletal structure composed of several key proteins. Skeletal muscle myosin is the motor protein that converts chemical energy into mechanical force through its interaction with actin. A set of regulatory proteins, which includes tropomyosin and several types of troponin, make the actin–myosin interaction dependent on changes in intracellular calcium levels. CK-2127107, a skeletal muscle activator, slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers, which sensitizes the sarcomere to calcium, leading to an increase in skeletal muscle contractility.

Source: Cytokinetics, May 16, 2017

Larotrectinib for Solid Tumors

The FDA has granted orphan drug status to larotrectinib (Loxo Oncology) for the treatment of solid tumors with NTRK-fusion proteins. NTRK fusions are rare genetic abnormalities in various adult and pediatric solid tumors.

Larotrectinib is an oral selective drug in development for the treatment of patients with cancers that harbor abnormalities involving tropomyosin receptor kinases (TRKs). Research suggests that the NTRK genes that encode for TRKs can become abnormally fused to other genes, resulting in growth signals that can lead to cancer throughout the body. Larotrectinib has also been granted breakthrough therapy and rare pediatric disease designations by the FDA.

Source: Loxo Oncology, May 12, 2017

XmAb5871 for IgG4-Related Disease

XmAb5871 (Xencor, Inc.) has been granted an orphan drug designation by the FDA for the treatment of patients with immunoglobulin G4-related disease, a newly defined fibroinflammatory autoimmune disorder that is estimated to affect up to 40,000 people in the United States. XmAb5871 is a first-in-class monoclonal antibody that targets FcγRIIb, a receptor that inhibits B-cell function.

Source: Xencor, May 11, 2017

Complete Response Letters

SUN-101/eFlow for COPD

The FDA has issued a complete response letter (CRL) regarding the new drug application for SUN-101/eFlow (glycopyrrolate, Sunovion Pharmaceuticals) for the long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Sunovion did not reveal what prompted the CRL, saying only that it did not require the company to conduct additional clinical studies. If approved, SUN-101 would have been the first nebulized long-acting muscarinic antagonist indicated for the treatment of COPD in the United States.

Source: Sunovion, May 26, 2017

TX-004HR for Dyspareunia

The FDA has issued a complete response letter regarding the new drug application for TX-004HR (Therapeutics MD, Inc.), an investigational applicator-free estradiol vaginal soft-gel capsule for the treatment of moderate-to-severe vaginal pain during sexual intercourse (dyspareunia), a symptom of vulvar and vaginal atrophy due to menopause. The only approvability concern raised by the FDA was the lack of long-term endometrial safety data for TX-004HR beyond the 12 weeks studied in the pivotal phase 3 REJOICE trial.

Source: Therapeutics MD, May 8, 2017

New Applications

Tresiba Label Change

Novo Nordisk has submitted a supplemental new drug application to the FDA seeking to include data in the label for insulin degludec (Tresiba) from the DEVOTE trial. DEVOTE was a long-term, randomized, double-blind, event-driven trial conducted to confirm the cardiovascular safety of insulin degludec compared with insulin glargine U100 when added to standard of care in patients with type-2 diabetes. The study confirmed the results of the DEVOTE interim analysis submitted to the FDA in March 2015, on the basis of which insulin degludec was approved in the U.S. in September 2015.

Source: Novo Nordisk, May 27, 2017

Sutent for Recurrent Kidney Cancer

A supplemental new drug application for sunitinib (Sutent, Pfizer) has been accepted for filing by the FDA. If approved, the application would expand the indications for sunitinib to include use as an adjuvant treatment in adults at high risk of recurrent renal cell carcinoma (RCC) after nephrectomy.

Sunitinib, an oral multi-kinase inhibitor, is indicated for the treatment of patients with advanced RCC; gastrointestinal stromal tumors after disease progression during treatment with or intolerance of treatment with imatinib mesylate; and progressive well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease.

Source: Pfizer, May 31, 2017

Tildrakizumab for Plaque Psoriasis

Sun Pharmaceutical Industries has announced the FDA’s acceptance of a biologics license application for tildrakizumab for the treatment of patients with moderate-to-severe plaque psoriasis. Tildrakizumab is an investigational humanized anti-interleukin (IL)-23p19 monoclonal antibody designed to selectively block the cytokine IL-23, thereby helping to control the pathogenic cells responsible for the inflammatory process of psoriasis. The filing was submitted by Merck, Sun’s partner in this project.

Source: Sun Pharmaceutical Industries, May 24, 2017

Yonsa for Prostate Cancer

Churchill Pharmaceuticals has submitted a new drug application to the FDA for Yonsa, an ultramicrosize formulation of abiraterone acetate. Yonsa is a cytochrome P450-17 inhibitor for the treatment of patients with metastatic castration-resistant prostate cancer in combination with methylprednisolone. The submission was based primarily on the final results from the STAAR study, a randomized, open-label trial comparing Yonsa plus methylprednisolone with another abiraterone acetate (Zytiga) plus prednisone in patients with metastatic castration-resistant prostate cancer.

Source: Churchill Pharmaceuticals, May 23, 2017

Erenumab for Migraine

Amgen has submitted a biologics license application to the FDA for erenumab, a human monoclonal antibody, for the prevention of migraine. Erenumab acts by blocking the calcitonin gene-related peptide receptor. The application included data from pivotal studies involving patients with episodic and chronic migraine. If approved, erenumab will be marketed in the United States by Amgen and Novartis.

Source: Amgen, May 18, 2017

Ibalizumab for HIV-1 Infection

A biologics license application has been submitted to the FDA for ibalizumab (Theratechnologies/TaiMed Biologics) for the treatment of patients with multidrug-resistant human immunodeficiency virus-1 (HIV-1) infection. If approved, ibalizumab would be the first antiretroviral treatment with a new mechanism of action to be introduced in nearly 10 years and the only treatment that does not require daily dosing.

Ibalizumab is an investigational humanized monoclonal antibody. Unlike other antiretroviral agents, ibalizumab binds primarily to the second extracellular domain of the CD4+ T-cell receptor, away from major histocompatibility complex II molecule binding sites. It potentially prevents HIV from infecting CD4+ immune cells while preserving normal immunological function. Ibalizumab is active against HIV-1 that is resistant to all approved antiretroviral agents.

Source: Theratechnologies, May 4, 2017

DRUG SAFETY ISSUES

MS Drug Linked to Brain Infection

A patient in Germany treated with the new multiple sclerosis (MS) drug ocrelizumab (Ocrevus, Roche) has been diagnosed with progressive multifocal leuko-encephalopathy (PML), a potentially deadly brain infection, after switching from natalizumab (Tysabri, Biogen) following three years of treatment, according to Reuters. The patient received a single dose of ocrelizumab in February.

According to Roche, the case of PML was reported as a carryover from natalizumab by the patient’s attending physician. The patient had previously tested positive for John Cunningham virus, a common virus that is normally harmless but can lead to PML in MS patients with weakened immune systems.

Dozens of patients receiving treatment with natalizumab have been diagnosed with PML. Use of the drug was temporarily halted in 2005, but resumed after patients for whom the medication was effective demanded its return and regulators added restrictions to its use.

Source: Reuters, May 25, 2017

Canagliflozin and Risk of Leg and Foot Amputations

Based on new data from two large clinical trials, the FDA has concluded that the type-2 diabetes medication canagliflozin (Invokana, Invokamet, Invokamet XR, Janssen), a sodium-glucose cotransporter-2 inhibitor, is associated with an increased risk of leg and foot amputations. The agency is requiring new warnings to be added to the canagliflozin labels to describe this risk.

Final results from the CANVAS and CANVAS-R trials showed that leg and foot amputations occurred approximately twice as often in patients treated with canagliflozin compared with those given placebo. Amputations of the toe and the middle of the foot were the most common; however, amputations involving the leg, above and below the knee, also occurred.

Source: FDA, May 16, 2017

NSAIDs and Rapid Heart Risk

A study led by researchers at the University of Montreal has found that the risk of myocardial infarction (MI) associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can increase as early as one week after starting the medications. In a systematic review of Canadian and European health care databases, the authors observed that taking any dose of NSAIDs for one week, one month, or more than one month was associated with an increased risk of MI among 61,460 cases of acute MI.

With NSAID use for one to seven days, the probability of an increased risk of MI was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios were 1.24 (range, 0.91–1.82) for celecoxib; 1.48 (range, 1.00–2.26) for ibuprofen; 1.50 (range, 1.06–2.04) for diclofenac; 1.53 (range, 1.07–2.33) for naproxen; and 1.58 (range, 1.07–2.17) for rofecoxib.

Overall, NSAIDs exhibited a rapid onset of risk for MI during the first week of use, the authors concluded. The use of high doses of ibuprofen (greater than 1,200 mg a day), naproxen (greater than 750 mg a day), or rofecoxib (greater than 25 mg a day) for eight to 30 days was particularly harmful.

Source: BMJ, May 9, 2017

Gadolinium Retention Harmless?

An FDA review to date has not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). Health care professionals should continue to limit the use of GBCAs to circumstances in which additional information provided by the contrast agent is necessary and should assess the necessity of repetitive MRIs with GBCAs.

Source: FDA, May 22, 2017

CLINICAL TRIAL NEWS

Cyramza for Urothelial Cancer

A phase 3 study of ramucirumab (Cyramza, Lilly) has met its primary endpoint of progression-free survival, demonstrating a statistically significant improvement. The randomized, double-blind, placebo-controlled RANGE trial is evaluating ramucirumab in combination with docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease had progressed during or after platinum-based chemotherapy.

In the U.S., ramucirumab is approved for use as a single agent or in combination with paclitaxel as a treatment for patients with advanced or metastatic gastric or gastroesophageal junction adeno-carcinoma whose cancer has progressed during or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved for use in combination with docetaxel as a treatment for patients with metastatic non–small-cell lung cancer whose disease has progressed during or after platinum-based chemotherapy. In addition, it is approved for use with FOLFIRI as a treatment for patients with metastatic colorectal cancer whose cancer has progressed during or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Source: Lilly, May 31, 2017

Fremanezumab for Migraine

Teva Pharmaceutical Industries has announced positive results from a phase 3 study of fremanezumab, an investigational treatment for the prevention of migraine. In this chronic migraine study, patients treated with fremanezumab experienced statistically significant reductions in the number of monthly headache days of at least moderate severity compared with placebo (−2.5 days) during the 12-week period after the first dose, for both monthly (−4.6 days; P < 0.0001) and quarterly (−4.3 days; P < 0.0001) dosing regimens. Based on these results, Teva plans to submit a biologics license application to the FDA for fremanezumab later this year.

Source: Teva, May 31, 2017

Taltz for Psoriatic Arthritis

In a pivotal phase 3 trial, patients with psoriatic arthritis for whom standard-of-care treatments failed to provide lasting relief experienced significant reductions in symptoms, including joint tenderness and swelling, when they were treated with the biologic drug ixekizumab (Taltz, Lilly). A total of 314 patients received regular injections of either ixekizumab or placebo for 24 weeks. Treatment with ixekizumab resulted in 53.3% of the patients having at least a 20% reduction in the number of tender and swollen joints, significantly outperforming placebo (19.5%).

Ixekizumab, an injectable monoclonal antibody, is already commercially available for the treatment of psoriasis. It works by blocking the inflammatory substance interleukin-17.

Source: Lilly, May 24, 2017

Pennvax-GP Vaccine for HIV

The human immunodeficiency virus (HIV) vaccine Pennvax-GP has produced among the highest immune response rates (humoral and cellular) ever demonstrated in a human study by an HIV vaccine, according to a report from its developer, Inovio Pharmaceuticals. Pennvax-GP combines four HIV antigens (env A, env C, gag, and pol) to cover several global HIV strains and to generate both a humoral (antibody) and a cellular (T-cell) immune response to potentially prevent and treat HIV infection.

Among the patients receiving the Pennvax-GP vaccine and interleukin (IL)-12 via intradermal immunization, 27 of 28 (96%) demonstrated a cellular response, and 27 of 28 (96%) demonstrated an env-specific antibody response. Similarly, among evaluated patients receiving Pennvax-GP and IL-12 via intramuscular vaccination, 27 of 27 (100%) demonstrated a cellular response, and 19 of 21 (90%) demonstrated an env-specific antibody response.

Source: Inovio Pharmaceuticals, May 24, 2017

Ozanimod for MS

The phase 3 RADIANCE study of ozanimod (Celgene Corporation)—an oral selective sphingosine 1-phosphate-1 and -5 receptor modulator—has met its primary endpoint of reducing the annualized relapse rate (ARR) compared with weekly interferon beta-1a (Avonex) in 1,313 patients with relapsing multiple sclerosis after two years of treatment (the study’s primary endpoint). Both the 0.5-mg and 1.0-mg doses of ozanimod demonstrated significant reductions in the ARR. Celgene plans to submit a new drug application to the FDA before the end of 2017.

Source: Celgene, May 22, 2017

Tolvaptan for Kidney Disease

Positive top-line results have been reported from a phase 3, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan (Otsuka Pharmaceutical) in adults with autosomal dominant polycystic kidney disease (ADPKD). The efficacy and safety of 12 months of tolvaptan (45–120 mg a day) were evaluated compared with placebo in 1,370 adults (18 to 65 years of age) with ADPKD-induced chronic kidney disease between late stage II and early stage IV and not previously treated with tolvaptan.

The study’s primary endpoint was the change in the estimated glomerular filtration rate (eGFR) from pretreatment baseline levels to the posttreatment assessment. In patients receiving tolvaptan, the reduction in the eGFR was significantly less than in the patients treated receiving placebo (P < 0.0001). The difference observed in this study represented a 35% reduction in the loss of kidney function with tolvaptan compared with placebo during 12 months of treatment.

Tolvaptan is a selective vasopressin V2-receptor antagonist that reduces cyst-cell proliferation and fluid secretion, ultimately reducing cyst development.

Source: Otsuka, May 22, 2017

Inotersen for FAP

The phase 3 NEURO-TTR study of inotersen (Ionis Pharmaceuticals), a next-generation antisense drug, in patients with familial amyloid polyneuropathy (FAP) has met both primary endpoints. During the 15-month trial, patients treated with inotersen achieved statistically significant benefits compared with placebo in the modified Neuropathy Impairment Score + 7 and in the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (P < 0.0001 and P = 0.0006, respectively). Statistically significant differences were also observed for both endpoints at eight months.

FAP, also called hereditary transthyretin (TTR) amyloidosis with polyneuropathy, is a progressive, debilitating, and ultimately fatal genetic disease in which patients experience TTR buildup in major organs, including peripheral nerves, the heart, the intestinal tract, the kidneys, and the bladder. Patients with FAP primarily experience nerve damage throughout their bodies resulting in the progressive loss of motor functions, such as walking. As TTR accumulates in major organs, it progressively affects organ function and eventually leads to death.

Source: Ionis Pharmaceuticals, May 15, 2017

Tenapanor for IBS-C

Ardelyx, Inc., has reported positive findings from its T3MPO-1 trial, the first of two phase 3 studies evaluating tenapanor for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). Tenapanor is an investigational, minimally systemic, small-molecule sodium–hydrogen exchanger 3 inhibitor.

The T3MPO-1 study achieved statistical significance for the primary endpoint and for seven of eight secondary endpoints. The primary endpoint, the combined responder rate for six of 12 weeks, showed that a greater proportion of tenapanor-treated patients compared with placebo-treated patients (27.0% versus 18.7%, respectively; P = 0.02) had at least a 30% reduction in abdominal pain and an increase of one or more complete spontaneous bowel movements during the same week for at least six weeks of the 12-week treatment period.

Source: Ardelyx, May 12, 2017

Imfinzi for Lung Cancer

Positive results have been reported from the ongoing phase 3 PACIFIC trial, a randomized, double-blind, placebo-controlled evaluation of durvalumab (Imfinzi, AstraZeneca/MedImmune) as sequential treatment in patients with locally advanced, unresectable (stage III) non–small-cell lung cancer who have not progressed after standard platinum-based chemotherapy administered concurrently with radiation therapy. A planned interim analysis conducted by an independent data-monitoring committee concluded that the study had met a primary endpoint by showing statistically significant and clinically meaningful progression-free survival in patients treated with durvalumab compared with those given placebo.

Durvalumab, a human monoclonal antibody directed against programmed death ligand-1 (PD-L1), blocks PD-L1 interaction with programmed death-1 and CD80 proteins on T cells, countering the tumor’s immune-evading tactics and inducing an immune response.

On May 1, 2017, durvalumab received accelerated approval from the FDA for use in previously treated patients with advanced bladder cancer.

Source: AstraZeneca, May 12, 2017

Galcanezumab for Migraine

Galcanezumab (Lilly), an investigational treatment for the prevention of episodic and chronic migraine, has met the primary endpoint in three phase 3 trials, demonstrating statistically significant reductions in the number of monthly migraine headache days compared with placebo at both studied doses (120 mg and 240 mg). Based on these results, Lilly plans to submit a biologics license application to the FDA for galcanezumab in the second half of 2017.

Galcanezumab is a monoclonal antibody designed to bind to and inhibit the activity of calcitonin gene-related peptide, which is believed to play a role in migraine and cluster headache. It is an investigational, once-monthly, self-administered subcutaneous injection.

Source: Lilly, May 12, 2017

Sotagliflozin for Type-1 Diabetes

In the phase 3 inTandem1 trial, patients with type-1 diabetes treated with sotagliflozin (Lexicon Pharmaceuticals) experienced a mean reduction from baseline in body weight of 1.6 kg for the 200-mg dose and 2.7 kg for the 400-mg dose compared with a mean body weight gain of 0.8 kg for patients given placebo (P < 0.001 for both doses) after 24 weeks of treatment. Sustained effects on body weight were also seen at 52 weeks.

In addition, systolic blood pressure (SBP) in a subset of patients with baseline hypertension (SBP greater than or equal to 130 mm Hg) was reduced by 9.9 mm Hg and 11.0 mm Hg at week 12 in those treated with 200 mg and 400 mg of sotagliflozin, respectively, compared with a reduction of 4.4 mm Hg in those given placebo (P = 0.017 and P = 0.003 for the 200-mg and 400-mg doses, respectively).

Lexicon previously announced that both doses of sotagliflozin had achieved the trial’s primary endpoint of statistically significant reductions in hemoglobin A1c at 24 weeks in patients receiving a background of optimized insulin.

Sotagliflozin is a first-in-class oral dual inhibitor of two proteins responsible for glucose regulation: sodium-glucose cotransporter types 1 and 2.

Source: Lexicon Pharmaceuticals, May 11, 2017

Tecentriq for Urothelial Cancer

A phase 3 study of the monoclonal antibody atezolizumab (Tecentriq, Roche) in patients with locally advanced or metastatic urothelial cancer (mUC) did not meet its primary endpoint of improved overall survival compared with chemotherapy. The study evaluated the efficacy and safety of atezolizumab compared with vinflunine, paclitaxel, or docetaxel administered every three weeks in 931 patients with mUC who had progressed during or after a platinum-based regimen. According to Reuters, the study’s disappointing results have raised questions about whether regulators should scale back their approval of atezolizumab.

Sources: Roche and Reuters, May 10, 2017

Gimoti for Diabetic Gastroparesis

A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study compared the efficacy and safety of Gimoti (metoclopramide nasal spray, Evoke Pharma) with that of placebo in women with symptomatic diabetic gastroparesis and delayed gastric emptying. Eligible patients were randomly assigned to receive either Gimoti or placebo administered as a single nasal spray four times daily—30 minutes before meals and at bedtime—for four weeks. The study’s primary endpoint was the change in the total symptom score from baseline to week 4. The trial data were not statistically significant in the intent-to-treat group (N = 205; P = 0.881).

Source: Evoke Pharma, May 10, 2017

RGN-259 for Dry Eye

In data from the four-week, phase 2b/3, double-blind, placebo-controlled ARISE-1 trial, 317 patients with dry eye syndrome demonstrated that RGN-259 (RegeneRx Biopharmaceuticals/ReGenTree) significantly reduced ocular discomfort during and after exposure to a controlled adverse environment. In addition, RGN-259 significantly reduced total and inferior corneal fluorescein staining in a subgroup of patients with compromised baseline tear-film break-up time. The active ingredient in RGN-259 is thymosin beta 4.

A second phase 3 dry eye trial (ARISE-2), designed to reproduce the results seen in ARISE-1, is under way with more than 500 patients in the United States. The study is expected to be completed by the fall of 2017.

Source: ReGenTree, May 9, 2017

Laquinimod for MS

The phase 3 CONCERTO study of laquinimod (Teva Pharmaceutical Industries/Active Biotech) versus placebo in patients with relapsing-remitting multiple sclerosis (RRMS) failed to reach its primary endpoint: the time to confirmed disability progression (CDP) after at least three months of treatment (hazard ratio, 0.937; P = 0.7057). Secondary endpoints measuring the time to CDP at six and nine months also did not reach statistical significance. Teva and Active Biotech have no plans to pursue further development of the drug.

Laquinimod is an investigational, once-daily, oral, selective aryl hydrocarbon receptor activator that targets neurodegeneration and inflammation in patients with RRMS, primary progressive MS, or Huntington’s disease.

Source: Teva, May 5, 2017

DEVICE APPROVALS

MS Autoinjector App

The FDA has approved a supplemental biologics license application for myBETAapp and the Betaconnect Navigator (Bayer). With this software, relapsing-remitting multiple sclerosis patients using the electronic Betaconnect autoinjector to administer interferon beta-1b (Beta-seron) can use Bluetooth technology to connect their current autoinjector to the new myBETAapp on their mobile device or computer. Patients can choose to share their injection data with their doctor.

Source: Bayer, May 30, 2017

iGlucose Monitoring System

The FDA has cleared the iGlucose blood glucose monitoring system (Smart Meter, LLC) for marketing in the United States. The device is the first subscription-free glucose meter and diabetes health-management system to offer automatic transmission of diabetes information to a cloud-based, personalized Web portal while facilitating real-time mobile communication between the person with diabetes and those individuals in his or her designated “circle of care.”

The iGlucose system uses digital mobile phone technology, known as Global System for Mobile communication, to facilitate two-way communication between an individual’s iGlucose meter and the iGlucose Web portal. Mobile health solutions have been recognized to lower costs and hemoglobin A1c levels, according to the manufacturer.

Source: Smart Meter, May 15, 2017

LungVision Imaging System

Body Vision Medical has received FDA clearance to market LungVision, a new imaging system that allows physicians to visualize radiolucent lesions and track endobronchial tools in real time. The device’s synergistic imaging merges intraoperative fluoroscopy with preoperative high-resolution imaging, such as computed tomography.

Source: Body Vision Medical, May 15, 2017

NxStage System One For Home Hemodialysis

The FDA has cleared the NxStage System One hemodialysis system (NxStage Medical), the first portable device for home hemodialysis and home nocturnal hemodialysis. When patients combine the device with the NxStage PureFlow SL dialysis preparation system, they can use ordinary tap water to create dialysis fluid on site and on demand, according to the manufacturer.

Source: NxStage Medical, May 10, 2017

Resonate High-Voltage Devices

The FDA has given the green light to the Resonate family of implantable cardioverter defibrillator and cardiac resynchronization therapy defibrillator systems, marketed by Boston Scientific. The approval includes new features in the Resonate devices, such as Smart-CRT technology with multisite pacing capability for multielectrode pacing and compatibility with the HeartLogic Heart Failure Diagnostic Service to help physicians improve heart failure management.

Source: Boston Scientific, May 9, 2017

Exablate Neuro System For Essential Tremor

The FDA has approved the Exablate Neuro (Model 4000) system (Insightec) for use with 1.5-Tesla magnetic resonance imaging (MRI) in the noninvasive treatment of essential tremor in patients who have not responded to medications.

Exablate Neuro uses focused ultrasound waves to target and ablate the Vim nucleus of the thalamus with no surgical incisions or implants. The treatment is administered under MRI guidance for real-time treatment monitoring. In July 2016, the FDA approved Exablate Neuro for use with 3.0-Tesla MRI systems.

Source: Insightec, May 9, 2017

MagVita TMS Depression Therapy

The FDA has cleared the MagVita TMS therapy system (MagVenture, Inc.) for the transcranial magnetic stimulation (TMS) treatment of major depressive disorder in adults who have failed to receive satisfactory improvement from prior antidepressant medications in the current episode. The system first received FDA clearance for the treatment of major depressive disorder in 2015. The new FDA-cleared device caters specifically to smaller psychiatric practices that wish to become TMS providers but are unsure of the patient flow.

The MagVita TMS therapy system delivers magnetic pulses to stimulate nerve cells in the part of the brain that controls mood. The rapid change in the magnetic field induces a current, and if the current induced is of sufficient amplitude and duration, it will excite neurons, according to the manufacturer.

Source: MagVenture, May 8, 2017

DEVICE SAFETY ISSUES

26 Deaths Linked to HeartMate II Blood Pumps

Abbott Laboratories and the Thoratec Corporation have recalled the Heart-Mate II LVAS Pocket System Controller because of a risk of patient injury and/or death during backup controller exchange. The FDA has identified this as a Class I recall, the most serious type of recall. Nearly 29,000 devices have been pulled from the market nationwide.

Abbott and Thoratec received a total of 70 reports of incidents in which the controller malfunctioned after an exchange, including 26 deaths and 19 injuries. All of the deaths occurred when patients attempted to exchange controllers while away from the hospital.

Source: FDA, May 23, 2017

MedWatch Safety Alerts

The FDA has issued alerts for the following devices:

  • SPF PLUS-Mini and SPF XL IIB implantable spinal fusion stimulators by Zimmer Biomet: Class I recall because of potential for harmful chemicals. Higher-than-allowed levels of harmful chemicals may cause chronic infections, long-term hospitalization due to additional surgical procedures, paralysis, and death. Posted May 30, 2017.
  • LeadCare testing systems (with blood obtained from a vein) by Magellan Diagnostics: Class I recall issued for LeadCare Plus and Ultra Testing systems. Falsely lower test results may lead to improper patient management and treatment for lead exposure or poisoning. Updated May 25, 2017; originally posted May 17, 2017.
  • V60 Non-Invasive Ventilator by Respironics: Class I recall due to unexpected device shutdown, which may cause serious adverse health consequences, including death. Posted May 22, 2017.
  • Coronary catheters by Abbott: Recalled because of difficulty in removing balloon sheath. Potential risks associated with balloon inflation and deflation difficulties include air embolism, additional intervention, thrombosis, and myocardial infarction. Posted May 16, 2017.
  • HeartWare splice kit intended to repair driveline of its ventricular assist device: Recalled because interruption in electrical connection may cause the pump to stop, which may lead to serious adverse health consequences, including death. Posted May 5, 2017.
  • Ventricular assist device controller and DC adapter by Medtronic Mechanical Circulatory Support (formerly HeartWare Inc.): Class I recall of updated controller and power-management software. Loose connector may allow moisture to enter controller, causing corrosion, electrical issues, reduced speaker volume, and connection failures, which could cause serious adverse health consequences, including death. Posted May 4, 2017.
  • Wingman35 crossing catheters by ReFlow Medical: Recalled because of tip splitting or separation. Tip splitting has the potential to stop the device from functioning. Tip separation may require medical intervention to retrieve a separated segment or may occlude blood flow to organs. Posted May 3, 2017.
  • NavLock Tracker by Medtronic: Letter to health care providers regarding minor and serious patient injuries, including two patient deaths, after procedures that involved use of non-Medtronic instruments with Medtronic’s NavLock Tracker. Posted May 3, 2017.