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P T. 2018;43(4): 194-201, 246

Drug and Device News April 2018

NEW DRUG APPROVALS

Erleada for Prostate Cancer

Apalutamide (Erleada, Janssen) has become the first FDA-approved treatment for nonmetastatic castration-resistant prostate cancer (CRPC). The approval was the first to use the endpoint of metastasis-free survival (MFS), measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment.

Apalutamide works by blocking the effect of androgens on the tumor. Its safety and efficacy were determined in a randomized clinical trial of 1,207 patients with nonmetastatic CRPC. All received either apalutamide or placebo and were also treated with hormone therapy, either gonadotropin-releasing hormone analogue therapy or surgical castration. The median MFS for patients taking apalutamide was 40.5 months compared with 16.2 months for patients taking placebo.

Common side effects of apalutamide include fatigue, hypertension, rash, diarrhea, nausea, arthralgia, falls, hot flush, decreased appetite, fractures, and peripheral edema. Severe side effects of apalutamide include falls, fractures, and seizures.

Source: FDA, February 14, 2018

Symdeko for Cystic Fibrosis

The FDA has approved a new combination of tezacaftor and ivacaftor (Symdeko, Vertex Pharmaceuticals, Inc.) to treat the underlying cause of cystic fibrosis (CF) in patients 12 years of age and older. The drug is indicated for people who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or who have at least one mutation responsive to tezacaftor/ivacaftor.

Two phase 3 studies, EVOLVE and EXPAND, enrolled approximately 750 CF patients 12 years of age and older with two copies of the F508del mutation or with one F508del mutation and one mutation that results in residual CFTR function. Across both studies, patients treated with Symdeko experienced statistically significant and clinically meaningful improvements in lung function and other measures of disease, with a favorable safety profile. The most common adverse events, regardless of treatment group, included infective pulmonary exacerbation and cough. The first data from the ongoing EXTEND rollover study show that the lung function improvements and the safety and tolerability profiles seen in EVOLVE and EXPAND were sustained for up to 48 total weeks of Symdeko treatment.

Source: Vertex Pharmaceuticals, February 12, 2018

Three-Drug Biktarvy for HIV

The FDA has approved Biktarvy (Gilead Sciences, Inc.), a once-daily, single-tablet regimen for the treatment of human immunodeficiency virus 1 (HIV-1) infection that includes 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. Bictegravir is a novel, unboosted integrase strand transfer inhibitor, while emtricitabine and tenofovir alafenamide (marketed as Descovy by Gilead) provide a dual nucleoside reverse transcriptase inhibitor backbone.

Biktarvy is indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral therapy (ART) history or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ART regimen for at least three months with no history of treatment failure and no known substitutions associated with resistance to Biktarvy’s components.

The medication does not require a dosage adjustment in patients with an estimated creatinine clearance of at least 30 mL per minute, does not require HLA-B*5701 testing, has no food intake requirements, and has no baseline viral load or CD4 count restrictions. It has a boxed warning regarding the risk of post-treatment acute exacerbation of hepatitis B.

The approval was supported by data from four ongoing phase 3 studies: two in treatment-naïve HIV-1 infected adults and two in virologically suppressed adults. The triple therapy met its primary objective of noninferiority at 48 weeks across all four studies in a diverse population of 2,415 participants. No participants failed with treatment-emergent virological resistance, no patients discontinued due to renal adverse events, and no cases of proximal renal tubulopathy or Fanconi syndrome were reported. The most common adverse reactions were diarrhea, nausea, and headache.

Source: Gilead Sciences, February 7, 2018

Apadaz for Acute Pain

The FDA has approved an immediate-release combination of acetaminophen and the prodrug benzhydrocodone (Apadaz, KemPharm, Inc.) for the short-term management (14 days or less) of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Apadaz contains 6.67 mg benzhydrocodone hydrochloride (a prodrug of hydrocodone equivalent to 7.5 mg hydrocodone bitartrate) and 325 mg acetaminophen. The prodrug consists of hydrocodone plus benzoic acid. The Drug Enforcement Administration intends to list Apadaz as a Schedule II controlled substance; the clinical program did not demonstrate abuse-deterrence by current standards.

KemPharm believes Apadaz is unique among prescription opioids in that it contains a prodrug that is chemically inert on its own. When it is ingested, enzymes in the gastrointestinal tract cleave the ligand from the prodrug (benzhydrocodone) and release the parent drug (hydrocodone) so it can exert its therapeutic effect.

The approval via the 505(b)(2) pathway was based in part on pharmacokinetic studies with Vicoprofen (hydrocodone bitartrate and ibuprofen, AbbVie [discontinued]), Ultracet (tramadol hydrochloride and acetaminophen, Janssen), and Norco (hydrocodone bitartrate and acetaminophen, Allergan) in which Apadaz demonstrated that it is expected to result in therapeutic effects equivalent to currently approved immediate-release hydrocodone/acetaminophen combination products when administered orally as intended.

Source: Apadaz, February 23, 2018

Generic Approvals

Glatiramer Acetate Injection

The FDA has granted approval to Glatopa (glatiramer acetate injection, Sandoz) 40 mg/mL, a generic version of Teva Pharmaceuticals’ Copaxone 40 mg/mL, for the treatment of patients with relapsing forms of multiple sclerosis. The three-times-weekly injection is supplied in a 1-mL prefilled syringe and was deemed by the FDA to be bioequivalent and, therefore, therapeutically equivalent, to the reference drug. Glatopa was developed under a collaboration agreement between Momenta Pharmaceuticals, Inc., and Sandoz and is produced in the U.S.

Sources: FDA, February 12, 2018; and Sandoz, February 13, 2018

Remifentanil Hydrochloride

Fresenius Kabi USA has been authorized to market remifentanil hydrochloride for injection (1 mg/vial, 2 mg/vial, and 5 mg/vial). It is the generic version of Ultiva injection (Mylan).

Remifentanil, an intravenous opioid agonist, is indicated as an analgesic agent for administration during induction and maintenance of general anesthesia for inpatient and outpatient procedures; for continuation of analgesia in the immediate postoperative period in adult patients; and as an analgesic component of monitored anesthesia care in adult patients.

Source: FDA, January 16, 2018

Potassium Chloride ER Tablets

Paddock LLC has received approval for a generic version of potassium chloride extended-release (ER) tablets (K-Tab, AbbVie) in 10 MEQ (750 mg) and 20 MEQ (1,500 mg) strengths. The drug is indicated for treatment of hypokalemia with or without metabolic alkalosis, digitalis intoxication, and hypokalemic periodic paralysis. It is also indicated for prevention of hypokalemia in at-risk patients, such as those on digitalis or who have significant cardiac arrhythmias.

Source: FDA, January 12, 2018

NEW INDICATIONS

Imfinzi to Reduce Risk of Lung Cancer Progression

The FDA has approved a new indication for durvalumab (Imfinzi, Astra-Zeneca)—treating patients with unresectable stage III non–small-cell lung cancer (NSCLC) whose cancer has not progressed after treatment with chemoradiation. Durvalumab becomes the first treatment approved to reduce the risk of cancer progression in these patients.

By targeting the programmed death-1/ programmed death ligand-1 pathway, durvalumab may help the body’s immune system attack cancer cells. Durvalumab was granted accelerated approval in 2017 for the treatment of certain patients with locally advanced or metastatic bladder cancer.

The latest approval was based on a randomized trial of 713 patients whose cancer had not progressed after completing chemotherapy and radiation. Median progression-free survival was 16.8 months for durvalumab compared with 5.6 months for placebo. In addition, AstraZeneca has agreed to a post-marketing commitment to provide additional information from its study to the FDA about overall survival with durvalumab after chemotherapy and radiation.

Common side effects of durvalumab in patients with stage III unresectable NSCLC include cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. Serious risks include immune-mediated side effects, such as pneumonitis, hepatitis, colitis, endocrinopathies, and nephritis. Other serious side effects include infection and infusion-related reactions.

Source: FDA, February 16, 2018

Verzenio for More Breast Cancer

Abemaciclib (Verzenio, Eli Lilly and Co.) has received FDA approval for use in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer.

This approval was based on results from the phase 3, randomized, double-blind, placebo-controlled MONARCH 3 trial, in which 493 postmenopausal women with HR+, HER2− advanced breast cancer who had no prior systemic treatment received initial endocrine-based therapy. Abemaciclib dosed orally at 150 mg twice daily on a continuous schedule with an AI, compared with placebo plus an AI, demonstrated median progression-free survival of 28.2 months versus 14.8 months, an objective response rate of 55.4% versus 40.2%, and a median duration of response of 27.4 months versus 17.5 months.

The most common adverse reactions in the MONARCH 1, 2, and 3 trials were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

In September 2017, the FDA approved abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, for two indications in HR+, HER2− advanced or metastatic breast cancer with disease progression following endocrine therapy: in combination with fulvestrant (Faslodex, AstraZeneca) for women and as monotherapy for adults after chemotherapy.

Source: Eli Lilly and Co., February 26, 2018

Zomacton for Adult GHD

The FDA has approved somatropin for injection (Zomacton, Ferring Pharmaceuticals) 5 mg and 10 mg recombinant human growth hormone (GH) for replacement of GH in adults with growth hormone deficiency (GHD).

Adult GHD occurs in one or two adults per 100,000. It can be a continuation of childhood-onset GHD or can occur in adulthood, primarily from trauma, surgery, or radiation to the head. Zomacton is also indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

Source: Ferring Pharmaceuticals, January 31, 2018

NEW FORMULATIONS

Osmolex ER for Parkinson’s

The FDA has approved an amantadine extended-release tablet (Osmolex ER, Osmotica Pharmaceutical) for the treatment of Parkinson’s disease and for the treatment of adults’ drug-induced extra-pyramidal reactions, which are side effects of many common medications. It is available in 129-mg, 193-mg, and 258-mg strengths.

The proprietary formula contains a combination of immediate-release and extended-release amantadine utilizing Osmotica’s patented Osmodex technology. The tablet is taken once daily in the morning, releasing amantadine throughout the day.

Source: Osmotica, February 19, 2018

Dexycu After Cataract Surgery

Dexamethasone intraocular suspension (Dexycu, Icon Bioscience, Inc.) has received FDA approval for use as a long-acting treatment for inflammation associated with cataract surgery.

Under the current standard of care for inflammation associated with the surgery, patients (many of them elderly) must self-administer medicated eye drops several times daily for weeks. Dexycu, given as a single 5-mcL injection at the end of surgery, employs Icon Bioscience’s Verisome technology to dispense a biodegradable extended-release formulation of dexamethasone into the posterior chamber of the eye. This can help eliminate patient noncompliance and dosing errors.

Source: Icon Bioscience, February 12, 2018

LABELING UPDATE

Cosentyx for Scalp Psoriasis

The FDA has approved a label update for secukinumab (Cosentyx, Novartis) that includes data on clearing moderate-to-severe scalp psoriasis, a difficult-to-treat condition that affects half of psoriasis patients.

The update is based on results of a phase 3, randomized, double-blind, placebo-controlled study of the efficacy and safety of 300 mg secukinumab in 102 patients with moderate-to-severe scalp psoriasis. At week 12, the proportions of patients achieving an Investigator’s Global Assessment modified 2011 scalp-only score of 0 or 1 (clear or almost clear) were 56.9% and 5.9% for the secukinumab and placebo groups, respectively.

Secukinumab is an interleukin-17A antagonist approved to treat moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.

Source: Novartis, February 6, 2018

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

SAGE-217 for Major Depressive Disorder

The FDA has granted a breakthrough therapy designation to SAGE-217 (Sage Therapeutics) for the treatment of major depressive disorder (MDD).

The decision was based primarily on results from the phase 2 trial of SAGE-217 in patients with moderate-to-severe MDD, which found a statistically significant mean reduction in the Hamilton Rating Scale for Depression (HAM-D) score from baseline at day 15 compared with placebo. The researchers also observed statistically significant improvements in the HAM-D score compared with placebo by the morning following the first dose through week 4. The effects remained numerically greater than placebo through the end of follow-up at week 6.

SAGE-217 is a next-generation positive allosteric modulator that targets synaptic and extrasynaptic gamma-aminobutyric acid (GABA) receptors and has a pharmacokinetic profile intended for daily oral dosing. The GABA system is the major inhibitory signaling pathway of the brain and central nervous system (CNS) and contributes significantly to regulating CNS function.

SAGE-217 is also being developed for treatment of other affective disorders, Parkinson’s disease, and sleep disorders.

Source: Sage Therapeutics, February 7, 2018

PF-04965842 for Atopic Dermatitis

Pfizer has received a breakthrough designation for the once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 for the treatment of patients with moderate-to-severe atopic dermatitis (AD).

PF-04965842 is an oral small molecule. Inhibition of JAK1 is thought to modulate multiple cytokines involved in the pathophysiology of AD, including interleukin (IL)-4, IL-13, IL-31, and interferon gamma.

Source: Pfizer, February 14, 2018

Priority Review Designations

Rituxan for Pemphigus Vulgaris

The FDA has accepted Genentech’s supplemental biologics license application and granted priority review for the use of rituximab (Rituxan) for the treatment of pemphigus vulgaris (PV), a life-threatening autoimmune condition characterized by progressive painful blistering of the skin and mucous membranes.

PV, the most common condition in a group of autoimmune disorders collectively called pemphigus, affects 30,000 to 40,000 people in the United States. Approved treatment options are limited.

The submission is based on data from a randomized trial comparing rituximab plus a tapering regimen of low-dose oral corticosteroid (CS) with a standard dose of CS alone as a first-line treatment in patients with newly diagnosed moderate-to-severe pemphigus. Results showed that rituximab improved PV remission rates and the frequency of successful tapering and/or cessation of CS therapy. Another phase 3 study in PV is being conducted to evaluate rituximab plus a tapering regimen of CS compared with mycophenolate mofetil (Cellcept, Genentech).

Source: Genentech, February 14, 2018

Blincyto for ALL

The first-ever application for a minimal residual disease (MRD)-positive indication has been granted priority review by the FDA. Amgen submitted a supplemental biologics license application for blinatumomab (Blincyto) for the treatment of patients with MRD-positive B-cell precursor acute lymphoblastic leukemia (ALL).

MRD refers to the presence of a small amount of detectible cancer cells that remain in the patient after treatment. After remission, MRD is the strongest prognostic factor for relapse in ALL. However, up to half of patients remain MRD-positive after induction treatments. There are no approved therapies for MRD-positive ALL.

Blinatumomab is the first and only approved bispecific CD19-directed CD3 T-cell engager (BiTE) immunotherapy. It is also the first bispecific antibody construct from Amgen’s BiTE platform, which helps the body’s immune system target cancer cells and represents a new area of oncology research.

The submission includes results from the phase 2 BLAST study evaluating patients with B-cell precursor ALL and persistent or recurrent MRD after at least three cycles of intensive chemotherapy.

Source: Amgen, February 14, 2018

Tafenoquine for Malaria

The FDA has granted 60 Degrees Pharmaceuticals (60P) a priority review designation for tafenoquine for the prevention of malaria in adults.

In January, 60P received a fast-track designation for the use of tafenoquine to prevent malaria in adults traveling to areas where the disease is prevalent. Malaria poses a significant risk to employees of nongovernmental organizations, vacationers, industrial and business workers, and military forces. Malaria cases among travelers returning to the U.S. are trending upwards, with 84% of those infected requiring hospitalization. In 2015, there were 212 million clinical cases worldwide, with an estimated 429,000 malaria-caused deaths.

In 2014, 60P entered into a cooperative research and development agreement with the U.S. Army Medical Materiel Development Activity to develop tafenoquine, which was discovered at the Walter Reed Army Institute of Research. Because malaria is the top infectious disease threat to U.S. service members overseas, the military maintains a robust antimalarial drug development effort through internal research and commercial partnerships.

Tafenoquine has a convenient weekly dosing regimen, which will encourage adherence. An analysis of five clinical trials concluded that tafenoquine appeared to be safe and well tolerated when the anticipated clinical regimen was administered.

Source: 60 Degrees Pharmaceuticals, February 8, 2018

Fast-Track Designations

PF614 for Chronic Pain

Ensysce Biosciences has received a fast-track designation for PF614, which is used to manage moderate-to-severe chronic pain when an around-the-clock analgesic is needed for an extended period.

PF614 is an extended-release oxycodone prodrug designed with a two-step enzyme activation process that has abuse-deterrent properties. A recently completed phase 1 trial comparing a single oral dose of PF614 with oxycodone (Oxycontin, Purdue Pharma) in healthy volunteers demonstrated the safety and the extended-release characteristics of this prodrug approach to opioid delivery.

Unlike other opioid technologies, Ensysce prodrugs do not require an elaborate formulation to confer parenteral and nasal abuse deterrence, the manufacturer says. While all abuse-deterrent formulations have been able to reduce some forms of abuse, they still contain substantial quantities of bioavailable opioids that can be extracted and abused by all routes of administration. In contrast, PF614 is inactive until it is metabolized in the small intestine after oral administration.

Source: Ensysce Biosciences, January 29, 2018

Amphora for Chlamydia

Evofem Biosciences, Inc., has been granted a fast-track designation for Amphora (L-lactic acid, citric acid, and potassium bitartrate) vaginal gel for the prevention of urogenital chlamydia.

Chlamydia is the most commonly reported sexually transmitted infection in the United States, with cases on the rise by 4.7% between 2015 and 2016 alone. While treatment with antibiotics is effective, repeat infection is common. Multiple chlamydial infections increase a woman’s risk of serious reproductive health complications, including pelvic inflammatory disease and ectopic pregnancy.

The clinical development program for Amphora includes an ongoing placebo-controlled phase 2b/3 study to evaluate its efficacy in preventing urogenital acquisition of Chlamydia trachomatis (primary endpoint) and Neisseria gonorrhea (secondary endpoint) in women when applied up to one hour prior to vaginal intercourse.

Evofem is also developing Amphora as an on-demand, nonhormonal vaginal contraceptive. Data from a phase 3 trial are expected in 2019.

Source: Evofem Biosciences, Inc., February 21, 2018

Orphan Drug Designations

GNbAC1 for Polyneuropathy

GeNeuro has received an orphan drug designation for GNbAC1, a monoclonal antibody for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP).

CIDP is a rare autoimmune disorder of the peripheral nervous system. Current long-term therapy is often limited by side effects, and one-third of patients are refractory to existing treatments.

GNbAC1 is designed to neutralize a pathogenic, viral envelope protein found in approximately half of CIDP patients that impairs the integrity of Schwann cells, which maintain the myelin sheath around peripheral nerves. The protein is thought to be a causal factor in several diseases, including multiple sclerosis, type-1 diabetes, and CIDP. GNbAC1 may reduce local inflammation and restore remyelination.

Source: GeNeuro, February 22, 2018

ARO-AAT for Rare Liver Disease

The FDA has granted an orphan drug designation to ARO-AAT (Arrowhead Pharmaceuticals), a second-generation investigational medicine for the treatment of a rare genetic liver disease associated with alpha-1 antitrypsin deficiency. Arrowhead filed a clinical trial application in December 2017 requesting regulatory permission to begin first-in-human studies of ARO-AAT.

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. RNA interference, or RNAi, is a mechanism in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing, triggering the mechanism to induce rapid, deep, and durable knockdown of target genes.

Source: Arrowhead Pharmaceuticals, February 15, 2018

Selumetinib for NF1

AstraZeneca and Merck have been granted an orphan drug designation for selumetinib, a MEK 1/2 inhibitor, for the treatment of neurofibromatosis type 1 (NF1).

NF1 is an incurable genetic condition that affects one in 3,000 births. The highly variable symptoms include skin, nervous system, and skeletal manifestations. NF1 can also cause secondary complications, including learning difficulties, visual impairment, pain, disfigurement, twisting and curvature of the spine, high blood pressure, and epilepsy. Plexiform neurofibromas (PNs), tumors that arise from nerve fascicles and tend to grow along the length of the nerve, occur in approximately 20% to 50% of NF1 patients, causing pain, motor dysfunction, and disfigurement. People with NF1 also have a higher risk of other cancers, including malignant brain and peripheral nerve sheath tumors, and leukemia. Symptoms begin during early childhood with varying degrees of severity and can reduce life expectancy by up to 15 years. There is no cure, and treatment options are limited.

Mutations in the NF1 gene may result in dysregulation in RAS/RAF/MEK/ERK signaling, which can cause cells to grow, divide, and copy themselves in an uncontrolled manner. Selumetinib inhibits the MEK enzyme in this pathway, potentially inhibiting tumor growth.

Selumetinib in NF1 is being studied in the phase 1/2 SPRINT trial in pediatric patients with symptomatic NF1-related PNs. Phase 2 trial results are expected later in 2018.

Source: AstraZeneca and Merck, February 15, 2018

YS-ON-001 for Pancreatic Cancer

The FDA has granted an orphan drug designation for YS-ON-001 (Yisheng Biopharma) for the treatment of pancreatic cancer.

YS-ON-001 is a clinical-stage immuno-oncology biologic product with a unique immunomodulating mechanism and a broad spectrum of antitumor activity. It has multiple modes of action, such as induction of antitumor cytokines, activation of natural killer cells, regulation of macrophage polarization, and suppression of regulatory T cells.

The manufacturer says the biologic has potential to become a monotherapeutic agent or to be combined with standard-of-care chemotherapies, targeted therapies, and checkpoint inhibitors or with other emerging immunotherapies that produce additive or synergistic treatment effects.

Source: Yisheng Biopharma, February 26, 2018

GDC-0084 for Glioblastoma Multiforme

The FDA has granted orphan drug status to Kazia Therapeutics for GDC-0084, an investigational drug for the treatment of glioblastoma multiforme, the most common and most aggressive form of primary brain cancer.

More than 130,000 patients worldwide are diagnosed with glioblastoma multiforme each year. The prognosis is poor, with a median survival of 12 to 15 months with best available care. Existing drug treatments are largely ineffective in almost two-thirds of patients.

GDC-0084 was licensed from Genentech in late 2016 after demonstrating favorable results in a phase 1 study of patients with advanced brain cancer. Kazia will be starting an international phase 2 study at centers in the United States, with initial data available in 2019.

Source: Kazia Therapeutics, February 23, 2018

IaIp for Necrotizing Enterocolitis

Prometic Life Sciences, Inc., has received an orphan drug designation for inter-alpha inhibitor proteins (IaIp) for the treatment of necrotizing enterocolitis (NEC).

NEC is the most common acquired gastrointestinal disease diagnosed in premature neonates and one of the leading causes of death in neonatal intensive care units. The cause of NEC is not well understood but may involve bacteria, injury to the bowel lining, inadequate oxygen supply to the bowel, and an abnormal immune response. Infants who undergo related surgery are typically hospitalized 60 days longer than other premature infants.

IaIp are endogenous proteins that control excessive inflammatory responses to toxins, infectious organisms, and tissue and organ damage. An inverse correlation between IaIp levels in plasma and disease severity and mortality has been demonstrated in humans with sepsis. In a gold-standard animal model proven to emulate NEC in humans, the supplementation of IaIp significantly increased the survival rate.

IaIp are rapidly consumed and cleared from circulation during severe sepsis, as evidenced by the significantly lower plasma levels of IaIp in newborns suffering from NEC. There is also strong scientific evidence that IaIp play a key role in modulating systemic inflammation. Systemic IaIp administration to restore plasma levels may reduce inflammation and tissue injury.

Source: Prometic Life Sciences, February 15, 2018

Riluzole Oral Film for ALS

The FDA has granted an orphan drug designation to riluzole oral soluble film (OSF) (Aquestive Therapeutics, Inc.) for the treatment of amyotrophic lateral sclerosis (ALS).

Patients with ALS, a debilitating neurodegenerative disease, often find swallowing difficult or impossible. Riluzole OSF was designed to dissolve instantly in the mouth without water.

Riluzole OSF is in late-stage clinical development, with a rollout planned for the second half of 2019.

Source: Aquestive Therapeutics, January 31, 2018

DP1038 for Acromegaly

Dauntless Pharmaceuticals, Inc., has received an orphan drug designation for DP1038 (octreotide acetate), an intranasal treatment for acromegaly.

Acromegaly is most often caused by a benign pituitary adenoma and is characterized by clinical features including enlargement of the hands and feet, facial changes, hypertension, diabetes mellitus, and cardiomyopathy. Octreotide, a somatostatin analogue that suppresses excessive growth hormone production from pituitary adenomas, is the mainstay of medical management of acromegaly.

In a phase 1 clinical study of healthy volunteers, DP1038 demonstrated an excellent safety and pharmacokinetic profile as well as on-target pharmacological effects.

Source: Dauntless Pharmaceuticals, January 30, 2018

Rare Pediatric Disease Designation

A002 for Achromatopsia

The FDA has granted a rare pediatric disease designation to MeiraGTx for AAV2/8-hCARp.hCNGB3 (A002), an investigational adeno-associated virus (AAV) gene therapy for achromatopsia due to mutations in the CNGB3 gene. Achromatopsia is an inherited eye disorder that severely limits sight and causes extreme light sensitivity, involuntary eye movement, and complete color blindness. There are no effective treatments.

A002 is delivered via a subretinal injection to cover the central region of the retina, including the fovea, where the majority of cones are located.

An open-label, multicenter, phase 1/2 dose escalation trial is currently treating patients in the highest of three dose cohorts. The primary endpoint is to determine the safety of the treatment.

Source: MeiraGTx, February 1, 2018

Complete Response Letter

Novartis Fluticasone Propionate/Salmeterol

Novartis has received a complete response letter from the FDA asking for more data on its generic formulation of fluticasone propionate/salmeterol (Advair, GlaxoSmithKline). Novartis says it is “highly unlikely” its generic will launch this year. This is the third generic formulation of fluticasone propionate/ salmeterol to be turned away by the FDA.

Source: FiercePharma, February 8, 2018

DRUG SAFETY ISSUES

Boxed Warning for Ocaliva

The FDA is adding a boxed warning to obeticholic acid (Ocaliva, Intercept Pharmaceuticals, Inc.) in an effort to prevent incorrect dosing of the liver-disease medication in patients with moderate-to-severe primary biliary cholangitis (PBC). Obeticholic acid has been incorrectly dosed daily instead of weekly in some of these patients, increasing the risk of serious liver injury.

The agency is clarifying the recommendations for screening, dosing, monitoring, and managing PBC patients with moderate-to-severe liver disease taking obeticholic acid. The boxed warning will highlight this information. The FDA is also requiring a medication guide for patients.

Obeticholic acid increases bile flow from the liver and suppresses bile acid production in the liver, reducing the liver’s exposure to toxic levels of bile acids. Progressive PBC can lead to liver failure or death. Treatment of PBC with obeticholic acid may delay or prevent progression of the disease.

The obeticholic acid dosing regimen is based on calculating a Child–Pugh score in PBC patients with suspected liver cirrhosis before treatment to determine their specific classification and starting dosage. Health care professionals (HCPs) should routinely monitor all patients for biochemical response, tolerability, and PBC progression, and re-evaluate Child–Pugh classification to determine if dosage adjustment is needed. HCPs should also educate patients and caregivers on the symptoms of worsening liver function.

Source: FDA, February 1, 2018

Clarithromycin and the Heart

Health care professionals (HCPs) should think twice before prescribing the antibiotic clarithromycin to patients with heart disease because of a potential increased risk of heart problems or death that can occur years later, the FDA warns. The recommendation is based on the agency’s review of a 10-year follow-up study of patients with coronary heart disease from a large clinical trial that first uncovered this issue.

The FDA has added a warning to the drug label about this increased risk of death in patients with heart disease, and it is advising prescribers to consider using other antibiotics in such patients. It has added the study results to clarithromycin drug labels.

HCPs should weigh the benefits and risks of clarithromycin before prescribing it to any patient, particularly those with heart disease—even for short periods. HCPs should advise patients with heart disease of the signs and symptoms of cardiovascular problems, regardless of the medical condition for which clarithromycin is prescribed.

Source: FDA, February 22, 2018

Gericare Eye Wash Recall

Kareway Products, Inc., is voluntarily recalling 60,000 units of Gericare Eye Wash, Sterile Eye Irrigation Solution, due to potential microbial contamination that compromises sterility. The product is used to clean, refresh, and soothe eyes for daily use or for emergency eye cleansing by flushing foreign material. It is packaged in 4-fluid-ounce bottles. The affected product, Lot #86041601, has an expiration date of September 2019. Kareway is arranging for the return or disposal of the recalled product.

Source: FDA, February 2, 2018

DEVICE APPROVALS

Blood Test for Concussions

The FDA has permitted marketing of the Banyan Brain Trauma Indicator (Banyan Biomarkers, Inc.), the first blood test to evaluate mild traumatic brain injury (mTBI), commonly called concussion, in adults.

Most patients with a suspected head injury are examined using the 15-point Glasgow Coma Scale, followed by a computed tomography (CT) scan to detect intracranial lesions that may require treatment. However, most patients evaluated for mTBI do not have detectable intracranial lesions after having a CT scan. A blood test for concussion will help health care professionals determine the need for a CT scan in patients suspected of having mTBI and help prevent unnecessary neuroimaging and associated radiation exposure.

The proteins UCH-L1 and GFAP are released from the brain into the blood after a head injury; the Brain Trauma Indicator measures these protein levels within 12 hours of the trauma. Levels of these proteins can help predict which patients may have intracranial lesions visible by CT scan and which won’t. Test results can be available within three to four hours.

The FDA evaluated data from a multicenter prospective study of 1,947 blood samples from adults with suspected mTBI and compared the blood test results with CT scan results. The Brain Trauma Indicator predicted the presence of intracranial lesions on a CT scan 97.5% of the time and their absence 99.6% of the time.

The Brain Trauma Indicator was reviewed under the FDA’s de novo pre-market review pathway.

Source: FDA, February 14, 2018

Stroke Warning Software

New clinical decision-support software may help speed treatment for a potential stroke. The FDA has permitted marketing of Viz.AI Contact (Viz.AI), a computer-aided triage application that uses an artificial intelligence algorithm to analyze computed tomography (CT) images for indicators associated with a stroke. Such algorithms can help providers identify the most appropriate treatment plan for a disease or condition.

Viz.AI Contact is designed to send a text notification to a neurovascular specialist if a suspected large vessel blockage has been identified. The algorithm will automatically notify the specialist while the first-line provider is conducting a standard review of the images, potentially involving the specialist sooner than the usual standard of care in which patients wait for a radiologist to review CT images and notify a neurovascular specialist. The notification can be sent to a mobile device, but the specialist still needs to review the images on a clinical workstation.

The Viz.AI Contact application is intended to be used by neurovascular specialists. It is limited to analysis of imaging data, should not replace a full patient evaluation, and should not be the sole justification for a diagnosis.

The company submitted a retrospective study of 300 CT images that assessed the independent performance of the image analysis algorithm and notification functionality of the Viz.AI Contact app against the performance of two trained neuroradiologists for the detection of large vessel blockages in the brain. Real-world evidence was used with a clinical study to demonstrate that the application could notify a neurovascular specialist sooner in cases where a blockage was suspected.

Source: FDA, February 13, 2018

Mobile Insulin Dosing System

The FDA has cleared Glooko’s Mobile Insulin Dosing System (MIDS) for the titration of long-acting insulin in type-2 diabetes patients. MIDS is the first insulin titration application accessible through a unified diabetes management platform, which provides a complete program for diabetes management.

The system includes access to patients’ blood glucose (BG) data directly from their glucose meters so that they don’t have to manually enter the numbers and so that health care providers (HCPs) can access accurate data. MIDS analyzes a patient’s fasting BG levels and recommends insulin dose adjustments based on the HCP’s preconfigured treatment plan and/or published clinical guidelines so patients can quickly and easily reach their optimal insulin dose. MIDS includes customizable in-app reminders to check fasting BG and to take insulin.

Source: Glooko, February 14, 2018

Smart Watch for Epilepsy

The Embrace smart watch (Empatica, Inc.) has received FDA clearance for use by patients with epilepsy. Embrace uses advanced machine learning to monitor for “grand mal” or “generalized tonic-clonic” seizures and sends an alert to summon caregivers for help. It also analyzes sleep, rest, and physical activity.

In a multisite clinical study, 135 patients with epilepsy were admitted to top-level IV epilepsy monitoring units for continuous monitoring with video-electroencephalography (EEG) while simultaneously wearing the device. From these patients, 6,530 hours of data were recorded over 272 days, including 40 generalized tonic-clonic seizures. Embrace’s algorithm detected 100% of the seizures, which were clinically labeled by at least two out of three independent epileptologists who examined the video-EEG data without seeing any of the Embrace data.

The smart watch measures multiple indicators of a seizure. It uses electrodermal activity, a signal used by stress researchers to quantify physiological changes related to sympathetic nervous system activity. More than 40% of generalized tonic-clonic seizures are not reported, but Embrace’s high sensitivity makes seizure reporting easier and more accurate.

Source: Empatica, February 5, 2018

Clot Retrieval Device for Stroke

The FDA has cleared the use of the Trevo clot retrieval device (Concentric Medical, Inc.) to treat certain stroke patients up to 24 hours after symptom onset, expanding the device indication to more patients. The device is cleared for use as an initial therapy for an acute ischemic stroke to reduce paralysis, speech difficulties, and other stroke disabilities and only as an addition to treatment with tissue plasminogen activator (t-PA).

The Trevo device was first cleared by the FDA in 2012 to remove a blood clot and restore blood flow in stroke patients who could not receive or did not respond to t-PA. In 2016, the FDA allowed expanded marketing of the device for certain patients in addition to treatment with t-PA if used within six hours of the onset of symptoms.

Trevo is inserted through a catheter up into the blood vessel to the site of the blood clot. When the shaped section at the end of the device is expanded (up to 3 to 6 mm in diameter), it grips the clot, allowing the physician to pull it back through the blood vessel along with the device for removal through a catheter or sheath.

The FDA evaluated data from a clinical trial comparing 107 patients treated with the Trevo device and medical management with 99 patients who had only medical management. About 48% of patients treated with the Trevo device were functionally independent (ranging from no symptoms to slight disability) three months after their stroke compared with 13% of patients who were not treated with the Trevo device.

Risks associated with using the Trevo device include a failure to retrieve the blood clot, embolization to new territories in the brain, arterial dissections and vascular perforations, and access site complications at the femoral artery entry point.

Source: FDA, February 15, 2018

QuickVue Flu Test

The FDA has granted 510(k) clearance to the QuickVue Influenza A+B assay (Quidel Corporation) for the rapid, differential detection of influenza types A and B.

In a clinical study, the test, using nasal swab and nasopharyngeal swab specimens from symptomatic patients, met the FDA’s reclassification criteria for Class II Rapid Influenza Diagnostic Tests. The test (waived under the Clinical Laboratory Improvement Amendments) returns results in approximately 10 minutes.

Source: Quidel Corporation, February 13, 2018

Accula Flu Test

The Accula Flu A/Flu B test (Mesa Biotech, Inc.) has received 510(k) clearance and a Clinical Laboratory Improvement Amendments waiver from the FDA. The test cassette is used on Mesa’s polymerase chain reaction testing platform designed for point-of-care infectious disease diagnosis. It provides a qualitative result in approximately 30 minutes using samples collected with a nasal swab. The test will be marketed by Sekisui Diagnostics under the Silaris brand.

Source: Mesa Biotech, February 7, 2018

DEVICE SAFETY ISSUES

Pentax Duodenoscopes

Pentax is recalling all ED-3490TK duodenoscopes to replace the forceps elevator mechanism, O-ring seal, and distal end cap, and to update the operation manual to recommend annual maintenance. The design changes are intended to reduce the potential for leakage of patient fluids into the closed elevator channel and under the distal cap. The FDA has cleared the updated design and labeling for the device.

The complex design of duodenoscopes may impede effective reprocessing—the detailed, multistep process of cleaning, disinfecting, and sterilizing reusable devices. The FDA has been working with duodenoscope manufacturers as they modify and validate their reprocessing instructions to enhance the safety margin of their devices. The agency is closely monitoring the association between reprocessed endoscopes and the transmission of infectious agents.

Source: FDA, February 8, 2018

Extracorporeal Photopheresis

The FDA is evaluating reports of venous thromboembolism (VTE) in patients who received autologous immune cell therapy with the Cellex Photopheresis System (Therakos, Inc.).

Since 2012, the FDA has received seven reports of pulmonary embolism (PE) during or soon after treatment with the device (mean, 1.2 days). Two reports involved fatalities, although the link between the PE and death cannot be made with certainty. Four PE events (including the fatalities) occurred in patients undergoing treatment for graft-versus-host disease (GVHD). The FDA also received two reports noting the diagnosis of deep vein thrombosis (DVT) in an extremity during or soon after GVHD treatment. Although allogeneic transplant patients who develop GVHD are at increased risk for VTE, the FDA says the timing of the events suggests that this therapy may increase that risk.

Cellex is an extracorporeal photopheresis (ECP) system approved for use in the ultraviolet-A irradiation of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma that is unresponsive to other forms of treatment.

The FDA recommends that providers alert patients, clinical staff, and technicians involved in ECP procedures of the signs and symptoms of PE and DVT; refer to device labeling regarding considerations for anticoagulation use with this system; and report VTE events related to ECP procedures that come to their attention.

Source: FDA, February 2, 2018

OTHER DEVICE NEWS

VIVO for Wound Closure

Adhesys Medical, Inc., has been granted an expedited access pathway designation for VIVO, a surgical sealant proposed as an adjunct to standard closure techniques in gastrointestinal procedures to reduce intestinal leakage, a life-threatening postoperative complication affecting up to 20% of patients. The manufacturer calls it “a unique technology platform” with an “unparalled” combination of features comprising bonding strength, fast sealing, and flexibility.

Source: Adhesys Medical, February 1, 2018