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P T. 2019;44(6): 324-328, 331-336

Drug and Device News June 2019

NEW DRUG APPROVALS

Duaklir Pressair for COPD

The FDA has approved aclidinium bromide/formoterol fumarate (Duaklir Pressair, Circassia Pharmaceuticals Inc.) for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

This fixed-dose combination of the long-acting muscarinic antagonist aclidinium and the long-acting beta agonist formoterol is administered twice daily via the preloaded, breath-actuated Pressair, a multidose dry-powder inhaler.

The approval relied on several studies, including the phase 3 AMPLIFY. The trial compared inhaled Duaklir Pressair to its individual components (aclidinium and formoterol) and to inhaled tiotropium (Spiriva Handihaler, Boehringer Ingelheim) in 1,583 patients with moderate-to-very-severe symptomatic COPD. At week 24, Duaklir Pressair significantly improved lung function versus aclidinium, as measured by the change from baseline in forced expiratory volume in one second (FEV1) one-hour post-dose. Also, it significantly increased lung function versus formoterol as measured by change from baseline in pre-dose morning (trough) FEV1. And it significantly improved overall early-morning symptom severity scores versus tiotropium.

The most common adverse events were COPD exacerbations, nasopharyngitis, and headache.

Source: Circassia Pharmaceuticals Inc., April 17, 2019

Balversa for Bladder Cancer

The FDA has granted accelerated approval to erdafitinib (Balversa, Janssen Pharmaceutical) for adults with advanced or metastatic bladder cancer, with fibroblast growth factor (FGFR) genetic alterations FGFR3 or FGFR2, that has progressed during or after prior chemotherapy.

Bladder cancer is the sixth most common cancer in the U.S. Alterations in FGFR are present in approximately 20% of patients with recurrent and refractory bladder cancer.

Erdafitinib’s efficacy was studied in a clinical trial of 87 patients who had locally advanced or metastatic bladder cancer, with FGFR3/FGFR2 alterations, that had progressed after chemotherapy. The overall response rate was 32.2%, and response lasted for an average of approximately 5.5 months. Responses were seen in patients who had previously not responded to anti–programmed-death (PD)-1 or PD ligand-1 therapy.

Common side effects included increased phosphate levels, mouth sores, tiredness, change in kidney function, diarrhea, dry mouth, nails separating from the bed or poor nail formation, change in liver function, low sodium levels, decreased appetite, change in sense of taste, anemia, dry skin, dry eyes, and hair loss. Erdafitinib can cause serious eye problems. Women who are pregnant or breastfeeding should not take erdafitinib. The drug must be dispensed with a patient medication guide.

The FDA gave erdafitinib a breakthrough therapy designation. As the drug received accelerated approval, further clinical trials are required to confirm its clinical benefit.

The FDA also approved the thera-screen FGFR RGQ RT-PCR Kit (QIAGEN Manchester, Ltd.) for use as a companion diagnostic with erdafitinib for this indication.

Source: FDA, April 12, 2019

Evenity for Osteoporosis

Romosozumab-aqqg (Evenity, Amgen) has been approved by the FDA to treat osteoporosis in postmenopausal women at high risk of fracture. This includes women who have had previous osteoporotic fractures, and those with multiple risk factors for fracture or who have failed or are intolerant to other osteoporosis therapies.

Romosozumab-aqqg is a monoclonal antibody that blocks the effects of sclerostin and increases new bone formation. As the bone-forming effect subsides after 12 doses, additional doses should not be used. If further osteoporosis therapy is required, patients should begin a treatment that reduces bone disintegration.

Romosozumab-aqqg’s safety and efficacy were shown in two clinical trials involving more than 11,000 women with postmenopausal osteoporosis. In the first trial, one year of treatment with romosozumab-aqqg lowered the risk of new vertebral fractures by 73% compared with placebo. In the second trial, one year of romosozumab-aqqg followed by one year of alendronate reduced the new vertebral-fracture risk by 50% compared with two years of alendronate alone. Romosozumab-aqqg followed by alendronate also reduced nonvertebral-fracture risk compared with alendronate alone.

Romosozumab-aqqg increased the risk of cardiovascular death, heart attack, and stroke in the alendronate trial, but not in the placebo trial. The drug has a boxed warning about the potential increase in heart attack risk, stroke, and cardiovascular death, and should not be used in patients who have had a heart attack or stroke within the previous year.

Source: FDA, April 9, 2019

Once-Daily Dovato for HIV-1

The FDA has approved dolutegravir/lamivudine (Dovato, ViiV Healthcare), a complete, once-daily, single-tablet regimen to treat human immunodeficiency virus type 1 (HIV-1) infection in adults with no prior antiretroviral treatment and no known resistance to its two key components.

This is the first FDA-approved two-drug, fixed-dose, complete regimen for HIV-infected adults who have never received treatment. The current standard of care for treatment-naïve patients is a three-drug regimen. A two-drug regimen eliminates the additional toxicity and potential drug interactions from a third drug.

The approval is based on results of GEMINI 1 and GEMINI 2, phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority studies involving more than 1,400 adults with HIV-1. At week 48, dolutegravir/lamivudine demonstrated noninferiority when compared to a three-drug regimen of dolutegravir, emtricitabine, and tenofovir in treatmentnaïve adults.

Dovato includes 50 mg of dolutegravir, an integrase strand transfer inhibitor, and 300 mg of lamivudine, a nucleoside analogue reverse transcriptase inhibitor. ViiV Healthcare markets the drugs separately as Tivicay and Epivir, respectively.

A boxed warning cautions that patients infected with both HIV and hepatitis B virus (HBV) should use additional treatment for HBV or consider a different drug regimen. Patients with HIV and HBV who take products containing lamivudine have developed HBV variants associated with resistance to lamivudine and could have severe liver problems, including liver failure, when they stop taking drugs containing lamivudine.

Dolutegravir/lamivudine is not recommended in patients with a creatinine clearance of less than 50 mL/min or in patients with severe hepatic impairment. The most common adverse reactions in study participants were headache, diarrhea, nausea, insomnia, and fatigue.

Sources: Viiv Healthcare and FDA, April 8, 2019

Asceniv for Primary Humoral Immunodeficiency Disease

The FDA has approved immune globulin intravenous, human–slra, 10% liquid, previously known as RI-002 (Asceniv, ADMA Biologics, Inc.) to treat primary humoral immunodeficiency (PI) disease in adults and adolescents aged 12 to 17 years.

The plasma-derived, polyclonal, intravenous immune globulin, which contains polyclonal antibodies, is used by the immune system to neutralize microbes, such as bacteria and viruses, and to prevent infection and disease.

A pivotal phase 3 clinical study enrolled 59 PI patients at nine U.S. sites who received regular infusions over one year. The primary endpoint evaluated the rate of serious bacterial infections (SBIs) in patients treated with the drug. During the 12-month study period, there were no SBIs.

The drug has a boxed warning about potential thrombosis and renal dysfunction or failure. The most common adverse reactions were headache, sinusitis, diarrhea, viral gastro-enteritis, nasopharyngitis, upper respiratory tract infection, bronchitis, and nausea.

Source: ADMA Biologics, April 1, 2019

Generic Approvals

Naloxone Hydrochloride Nasal Spray

The FDA has approved marketing of the first generic naloxone hydrochloride nasal spray by Teva Pharmaceuticals USA Inc. The spray, a life-saving medication that can stop or reverse the effects of an opioid overdose, has been available as Narcan (Adapt Pharma). The agency plans to prioritize the review of additional generic-drug applications for products intended to treat opioid overdose, along with facilitating an over-the-counter naloxone product.

On average, according to the Centers for Disease Control and Prevention, more than 130 Americans die every day from overdoses involving opioids. If naloxone nasal spray is administered quickly, it can counter overdose effects, usually within minutes. The person administering naloxone nasal spray should immediately seek further medical attention on the patient’s behalf.

Naloxone nasal spray does not require assembly and delivers a consistent, measured dose when used as directed. The product can be used in adults or children and is easily administered by anyone. The drug is sprayed into one nostril while the patient is lying on his or her back and can be repeated if necessary. Using naloxone nasal spray in opioid-dependent patients may result in severe opioid withdrawal.

Although this is the first generic naloxone nasal spray approved for use in a community setting by individuals without medical training, generic injectable naloxone products have been available for years in health care settings. The FDA also previously approved a brand-name naloxone nasal spray and an autoinjector for use by individuals with no medical training.

Source: FDA, April 19, 2019

Aliskiren Tablets

Anchen Pharmaceuticals, Inc. has received FDA permission to market aliskiren tablets, 150 mg and 300 mg, the first generic versions of those formulations of Tekturna tablets (Noden Pharma). Aliskiren is indicated to treat hypertension in adults.

Source: FDA, March 22, 2019

Naftifine Hydrochloride Gel, 1%

The FDA has approved the marketing of naftifine hydrochloride gel, 1%, by Tolmar, Inc. This is the first generic version of the gel marketed as Naftin (Sebela Ireland Ltd.) for the topical treatment of tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum, T. mentagrophytes, T. tonsurans, and Epidermophyton floccosum.

Source: FDA, March 20, 2019

Pyridostigmine Bromide Syrup

Novitium Pharma has secured approval from the FDA to market pyridostigmine bromide syrup, 60 mg/5 mL. It is the first generic form of Mestinon syrup, marketed by Bausch, in this strength. The drug is used to improve muscle strength in patients with myasthenia gravis.

Source: FDA, March 8, 2019

Fulvestrant Injection

The FDA has given Amneal Pharmaceuticals Company GmbH approval to produce fulvestrant injection, 250 mg/5 mL (50 mg/mL), the first generic form of Faslodex (AstraZeneca). Fulvestrant is used to treat HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy, and HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy.

Faslodex had global sales of approximately $1 billion in 2018, according to AstraZeneca, accounting for 5% of the company’s product sales.

Sources: FDA, March 4, 2019; Astra-Zeneca, February 14, 2019

NEW INDICATIONS

Keytruda, Inlyta as First-Line Treatment for Kidney Cancer

The FDA has approved pembrolizumab (Keytruda, Merck) in combination with axitinib (Inlyta, Pfizer) for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

The approval was based on data from the prespecified interim analysis of the randomized, open-label, phase 3 KEYNOTE-426 trial in 861 patients who had not received systemic therapy for advanced RCC. For the pembrolizumab–axitinib combination, compared with sunitinib (Sutent, Pfizer), the estimated 12-month overall survival was 90% versus 78%; median progression-free survival was 15.1 months versus 11.1 months; and objective response rate was 59% versus 36%. Results were consistent across prespecified subgroups, risk categories, and programmed cell death ligand-1 tumor-expression status.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Pembrolizumab can also cause severe or life-threatening infusion-related reactions.

Source: Merck, April 22, 2019

Keytruda Expansion for NSCLC

The FDA has expanded the use of pembrolizumab (Keytruda, Merck) as monotherapy in patients with non–small-cell lung cancer (NSCLC). Now, pembrolizumab is indicated for the first-line treatment of patients with stage 3 NSCLC who are not candidates for surgical resection or definitive chemoradiation, or who have metastatic NSCLC, and whose tumors express programmed cell death ligand-1 (PD-L1) with no estimated glomerular filtration rate or anaplastic lymphoma kinase genomic tumor aberrations. PD-L1 expression (a tumor proportion score [TPS] of at least 1%) is to be determined by an FDA-approved test.

In the phase 3, randomized, open-label, active-controlled KEYNOTE-042 trial, 1,274 patients received pembrolizumab or one of two chemotherapy regimens: pemetrexed plus carboplatin or paclitaxel plus carboplatin. Pembrolizumab monotherapy demonstrated a statistically significant improvement in median overall survival (OS) compared with chemotherapy alone in patients with a TPS of at least 1% (OS, 16.7 vs. 12.1 months). In patients whose tumors expressed PD-L1 with a TPS of at least 50%, the OS benefit for pembrolizumab increased to 20.0 months versus 12.2 months.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Pembrolizumab can also cause severe or life-threatening infusion-related reactions.

Source: Merck, April 11, 2019

Ibrance for Male Breast Cancer

The FDA has extended the indication for palbociclib capsules (Ibrance, Pfizer) in combination with specific endocrine therapies to include men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced or metastatic breast cancer.

Breast cancer is rare in males; an estimated 2,670 cases, < 1% of all breast cancer, are expected in 2019. Most breast tumors in men express hormone receptors. Men are more likely to be diagnosed at an older age and with more advanced disease.

Palbociclib, a kinase inhibitor, was approved in 2015. It is approved in combination with an aromatase inhibitor as the first hormonal-based therapy in postmenopausal women and in men, or with fulvestrant in patients whose disease has progressed following hormonal therapy. Pfizer provided the results of an analysis of real-world data from electronic health records as additional supportive data to characterize palbociclib use in combination with endocrine therapy (aromatase inhibitor or fulvestrant) in male patients with breast cancer, based on observed tumor responses.

The most common side effects in patients taking palbociclib are infections, leukopenia, fatigue, nausea, stomatitis, anemia, hair loss, diarrhea, and thrombocytopenia.

Source: FDA, April 4, 2019

NEW FORMULATION

Avaclyr for Herpetic Keratitis

The FDA has approved acyclovir ophthalmic ointment, 3% (Avaclyr, Fera Pharmaceuticals) for the treatment of herpetic keratitis. Acyclovir is the gold-standard treatment in herpes virus infections; the new product provides this therapy in an ophthalmic dosage form.

In herpetic keratitis, herpes simplex virus (HSV) infects the cornea. The infection usually heals without damaging the eye, but more severe infections can lead to scarring of the cornea or blindness. HSV keratitis is a major cause of blindness worldwide.

Acyclovir is an HSV nucleoside analog DNA polymerase inhibitor. It is indicated in the treatment of acute herpetic keratitis (dendritic ulcers) in patients with HSV-1 and HSV-2 infections. The most common adverse reactions in trials were eye pain (stinging), punctate keratitis, and follicular conjunctivitis.

Source: Fera Pharmaceuticals, April 1, 2019

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

Inebilizumab for Neuromyelitis Optica Spectrum Disorder

The FDA has granted a breakthrough therapy designation for Viela Bio’s anti-CD19 monoclonal antibody inebilizumab as monotherapy for neuromyelitis optica spectrum disorder (NMOSD).

NMOSD is a recently proposed unifying term for neuromyelitis optica (NMO, also known as Devic’s disease) and related syndromes. It is a relapsing, neuroinflammatory autoimmune disease in which the body’s immune system attacks healthy cells, most commonly in the optic nerves and spinal cord. NMOSD can cause severe muscle weakness and paralysis, loss of vision, respiratory failure, problems with bowel and bladder function, and neuropathic pain. There is no cure or approved treatment.

Approximately 80% of patients have autoantibodies to the water channel protein aquaporin-4 (AQP4). These AQP4-immunoglobulin G autoantibodies are thought to be produced by plasmablasts and plasma cells and bind primarily to astrocytes in the central nervous system; this is believed to trigger NMOSD attacks. Inebilizumab is a humanized monoclonal antibody designed to bind with high affinity to CD19 and deplete a broad range of B cells, including autoantibody-secreting plasmablasts and CD19-expressing plasma cells. After binding to CD19, these cells are rapidly depleted from the circulation.

The designation is based on results from the largest monotherapy study ever conducted in NMOSD. Patients were randomized to receive two intravenous doses of inebilizumab monotherapy or placebo and followed for 6.5 months. An open-label study is ongoing, with patients receiving an inebilizumab infusion every six months.

Source: Viela Bio, April 18, 2019

Selumetinib for NF1

AstraZeneca and Merck have been granted a breakthrough therapy designation for the MEK 1/2 inhibitor selumetinib. The designation is for the treatment of pediatric patients aged 3 years and older with neurofibromatosis type 1 (NF1) symptomatic and/or progressive, inoperable plexiform neurofibromas (PNs).

NF1 is an incurable genetic condition that affects one in 3,000 to 4,000 people. Symptoms begin in early childhood, vary in severity, and can reduce life expectancy by up to 15 years. Caused by a mutation in the NF1 gene, it is associated with many symptoms, including cutaneous neurofibromas and skin pigmentation. In up to 50% of patients, tumors develop on the nerve sheaths (plexiform neurofibromas), which can cause pain, motor dysfunction, airway dysfunction, bowel/bladder dysfunction, and disfigurement, and may transform into malignant peripheral nerve-sheath tumors. Patients can also experience other complications.

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

The designation is based on phase 2 data from the SPRINT trial, which evaluated selumetinib as an oral monotherapy in pediatric patients. Selumetinib is being assessed as a monotherapy and in combination with other treatments in ongoing trials.

Source: AstraZeneca and Merck, April 1, 2019

PRM-151 for Idiopathic Pulmonary Fibrosis

The FDA has given a breakthrough designation to Promedior for PRM-151, an antifibrotic immunomodulator to treat idiopathic pulmonary fibrosis (IPF).

IPF is characterized by fibrosis and the scarring of lung tissue. Patients most often suffer from progressive shortness of breath, particularly with exertion; chronic cough; fatigue and weakness; and chest discomfort. Currently approved drugs slow but do not halt disease progression, and the only curative therapy is lung transplant. Median survival is three to five years after diagnosis.

PRM-151 is a recombinant form of the endogenous human innate immunity protein pentraxin-2, which is specifically active at the site of tissue damage. PRM-151 acts as a macrophage polarization factor to prevent and potentially reverse fibrosis.

The designation was partly based on a phase 2, randomized, double-blind trial of PRM-151 versus placebo. Most patients also received either pirfenidone or nintedanib. Patients treated with PRM-151 versus placebo every four weeks exhibited a change in forced vital capacity percentage of predicted value (−2.5% vs. −4.8%), and a change in six-minute walk distance (−0.5 m vs.−31.8 m). The short monthly infusion of PRM-151 was well tolerated.

Source: Promedior, March 26, 2019

Fast-Track Designations

Annamycin for Relapsed or Refractory Acute Myeloid Leukemia

Moleculin Biotech, Inc. has received a fast-track designation for annamycin for the treatment of relapsed or refractory acute myeloid leukemia (AML).

Annamycin is in separate phase 1/2 trials in the U.S. and Europe for the treatment of AML. The company recently announced positive interim top-line data.

Source: Moleculin Biotech, April 18, 2019

APR-246 for MDS

Aprea Therapeutics’ APR-246 has received fast-track and orphan drug designations for the treatment of patients with myelodysplastic syndromes (MDS) with a TP53 mutation.

MDS represents a spectrum of hematopoietic stem-cell malignancies in which bone marrow fails to produce enough healthy blood cells. Approximately 30% to 40% of patients with MDS progress to acute myeloid leukemia (AML); mutation of the p53 tumor suppressor protein is thought to contribute to disease progression.

TP53 is the most frequently mutated gene in human cancer, occurring in approximately 50% of all tumors. These mutations (found in approximately 20% of patients with MDS and AML) are often associated with resistance to anticancer drugs and poor overall survival.

APR-246 has been shown to reactivate mutant and inactivated p53 protein by restoring wild-type TP53 conformation and function, inducing programmed cell death in cancer cells. The drug has demonstrated preclinical antitumor activity in a wide variety of solid and hematological tumors, including MDS, AML, and ovarian cancer. It has also shown strong synergy with other anticancer agents.

A phase 1/2 clinical program has been completed, demonstrating APR-246’s favorable safety profile, biological activity, and clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.

Source: Aprea Therapeutics, April 16, 2019

Tebentafusp for Metastatic Uveal Melanoma

Tebentafusp (IMCgp100) has received a fast track designation for the treatment of patients who are HLA-A*0201-positive with previously untreated, metastatic uveal melanoma (mUM).

The poor prognosis in mUM has changed little in decades. Tebentafusp (Immunocore Ltd.) is a novel, bi-specific biologic T-cell redirection therapy that specifically targets the melanoma-associated antigen gp100. The pivotal, randomized IMCgp100–202 study is comparing tebentafusp with investigator’s choice (dacarbazine, ipilimumab, or pembrolizumab) in HLA-A*0201-positive adults with previously untreated mUM. The primary endpoint is overall survival.

Source: Immunocore Ltd., April 3, 2019

RVT-801 for Farber Disease

Enzyvant has been granted rare pediatric disease and fast-track designations for RVT-801, an enzyme-replacement therapy in preclinical development for Farber disease.

Farber disease is rare but thought to be significantly underdiagnosed, with patients often misdiagnosed with juvenile idiopathic arthritis. The disease is caused by mutations in the ASAH1 gene, resulting in the deficiency of acid ceramidase, a critical lysosomal enzyme. This deficiency leads to the accumulation of ceramide in cells, with proinflammatory and proapoptotic effects.

Patients with Farber disease typically present with joint contractures or arthritis, subcutaneous nodules, and/or a weak or hoarse voice. More severe symptoms can include impaired cognitive development because of brain involvement, as well as impacts on the lungs, liver, and bones. Disease onset usually occurs in early childhood.

RVT-801, a recombinant form of human acid ceramidase, is being developed as a potential enzyme-replacement therapy for acid ceramidase deficiency manifesting as Farber disease. In a mouse model of Farber disease, RVT-801 was shown to be biologically active, reducing the accumulation of ceramides and related inflammation in tissues.

Source: Enzyvant, March 21, 2019

Nalmefene for Opioid Overdose

The FDA has granted a fast-track designation to nalmefene hydrochloride injection, Purdue Pharma’s opioid antagonist for the emergency treatment of known or suspected opioid overdose.

Nalmefene has a longer duration of effect than naloxone, also an opioid antagonist, which could make nalmefene injection an important alternative for the treatment of opioid overdose.

Purdue says it will work to advance this option with the commitment of not profiting from future sales of the drug. The company is exploring options to ensure that nalmefene is developed for and accessible to the people who need it most.

Source: Purdue Pharma, March 13, 2019

Priority Review Status

Brolucizumab for Wet AMD

The FDA has accepted Novartis’ biologics license application for brolucizumab (RTH258) for the treatment of neovascular age-related macular degeneration (nAMD) or wet age-related macular degeneration (AMD). Novartis used a priority review voucher to expedite FDA review. If brolucizumab is approved, Novartis anticipates launching it by the end of 2019.

Estimates suggest that by 2020, up to 1.75 million people in the U.S. will be living with wet AMD, a leading cause of blindness. In nAMD, abnormal blood vessels form beneath the macula, the area of the retina responsible for sharp, central vision. These blood vessels are fragile and leak fluid, disrupting the normal retinal architecture and ultimately damaging the macula.

As a humanized, single-chain antibody fragment, brolucizumab offers small-size, enhanced tissue penetration, and rapid clearance from systemic circulation. In preclinical studies, brolucizumab inhibited activation of VEGF receptors. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema, and improve vision in patients with chorioretinal vascular diseases.

The application is primarily based on phase 3 data from two prospective, randomized, double-masked, multicenter studies comparing brolucizumab with aflibercept. The mean change in best-corrected visual acuity from baseline to week 48 for brolucizumab versus aflibercept was 6.6 letters versus 6.8 letters in the first study, and 6.9 letters versus 7.6 letters in the second study. Significantly fewer brolucizumab patients showed disease activity, intraretinal fluid, and/or subretinal fluid compared with aflibercept patients.

Source: Novartis, April 15, 2019

Orphan Drug Designations

Nanatinostat for Cancers Associated With EBV

The FDA has granted orphan drug designations to Viracta for nanatinostat, in combination with the antiviral valganciclovir, for the treatment of post-transplant lymphoproliferative disorder, plasmablastic lymphoma, and angioimmunoblastic T-cell lymphoma.

Approximately 95% of adults are infected with Epstein-Barr virus (EBV). Infections are commonly asymptomatic or associated with mononucleosis. Following infection, the virus remains latent in a small subset of lymphatic cells for the rest of the patient’s life. Cells containing the latent virus are increasingly susceptible to malignant transformation. Immunocompromised patients are at increased risk of developing EBV lymphomas. EBV is also associated with some solid tumors.

Nanatinostat (VRx-3996), an oral histone deacetylase inhibitor, is being evaluated in an ongoing phase 1b/2 clinical study. Nanatinostat is designed to activate EBV genes that have been epigenetically suppressed. In combination with valganciclovir, cancer cells that harbor the virus will be selectively killed. Viracta says this approach has the potential to become the first targeted, orally administered epigenetic therapy for EBV-associated cancers.

Source: Viracta Therapeutics, April 16, 2019

Hyleukin-7 for Idiopathic CD4+ Lymphocytopenia

The FDA has granted an orphan drug designation to NeoImmuneTech, Inc. for Hyleukin-7, a T-cell amplifier in development for the treatment of idiopathic CD4+ lymphocytopenia (ICL).

Patients with ICL have persistently low CD4+ T-lymphocyte counts without human immunodeficiency virus infection or any other cause of immunodeficiency. They frequently suffer from severe and recurrent opportunistic infections and are at high risk for certain types of cancer. No specific treatment for ICL exists.

Hyleukin-7 (rhIL-7-hyFc, NT-I7), an immuno-oncology (I-O) agent, is a T-cell growth factor composed of a covalently linked homodimer of engineered interleukin-7 (IL-7) molecule, biologically fused with the proprietary long-acting platform hyFc. IL-7 is known to be a critical factor for T-cell homeostasis, increasing both the number and functionality of T cells. Hyleukin-7 amplifies and reinvigorates persistent T-cell immunity in the treatment of patients with cancer and lymphopenia, providing unique opportunities for I-O combination strategies.

In a phase 1 trial in healthy subjects and in multiple ongoing dose-escalation trials in cancer patients, Hyleukin-7 showed a well-tolerated safety profile and dose-dependent increases of CD4+ and CD8+ T-lymphocyte counts.

Source: NeoImmuneTech, Inc., April 16, 2019

Tinostamustine for T-cell Prolymphocytic Leukemia

The FDA has granted orphan drug status to tinostamustine (Imbrium Therapeutics), a potentially first-in-class alkylating deacetylase inhibiting molecule, for the treatment of T-cell prolymphocytic leukemia (T-PLL).

T-PLL is an extremely aggressive T-cell leukemia characterized by the out-of-control growth of mature T-cells. Because of its rarity, T-PLL can be misdiagnosed, resulting in poor patient outcomes. Median survival is about one year. The disease typically progresses rapidly and does not respond well to standard multiagent chemotherapy. Most patients present with hepatosplenomegaly and generalized lymphadenopathy, often with skin infiltration, anemia, and thrombocytopenia. T-PLL affects older adults and is more common in men than in women.

Tinostamustine (EDO-S101) is a novel multi-action therapy in phase 2 clinical development for a range of rare and difficult-to-treat blood cancers and advanced solid tumors. Preclinical studies have shown that tinostamustine could improve access to the DNA strands within cancer cells, break them, and counteract damage repair. Data suggest that these complementary and simultaneous modes of action have the potential to overcome resistance toward some other cancer treatments.

Source: Imbrium Therapeutics, March 28, 2019

Complete Response Letters

Gimoti for Diabetic Gastroparesis

The FDA has sent Evoke Pharma, Inc. a complete response letter regarding its application to produce a nasal spray formulation of metoclopramide (Gimoti) for the relief of symptoms associated with acute and recurrent diabetic gastroparesis.

The letter provides recommendations to address two remaining approvability issues, related to clinical pharmacology and product/device quality, in the resubmitted application. The agency did not request any new clinical data or raise any safety concerns. Evoke believes it can address the issues.

Gimoti, the first non-oral drug treatment for symptoms associated with acute and recurrent diabetic gastroparesis in adult women, would represent the first significant advancement in gastroparesis treatment in 40 years.

Source: Evoke Pharma, Inc., April 2, 2019

Rizaport for Acute Migraines

IntelGenx Corp. has received a complete response letter from the FDA regarding its resubmitted application for Rizaport VersaFilm for the treatment of acute migraines.

The FDA cited issues related to the chemistry, manufacturing, and controls section of the application. The agency requested additional information but no new bioequivalence study. IntelGenx said it believes the recommendations are manageable and it remains committed to working closely with the FDA.

Source: IntelGenx Technologies Corp., April 2, 2019

Citizen Petition

Braeburn Contests Sublocade’s Orphan Status

Braeburn Inc. has filed a citizen petition calling for the FDA to revoke the orphan drug designation for Indivior’s Sublocade (buprenorphine extended-release injection) for the treatment of opioid use disorder (OUD). The petition asks the FDA to refuse to honor a seven-year orphan drug exclusivity period for Sublocade, which would likely prevent the approval of any other OUD buprenorphine product until the end of 2024.

In December 2018, the FDA tentatively approved Braeburn’s buprenorphine extended-release injection (Brixadi) for the treatment of moderate-to-severe OUD. The agency concluded that Brixadi met the standards for approval but wasn’t eligible for marketing in the U.S. because of exclusivity considerations.

In its petition, Braeburn notes that orphan drugs are intended to treat rare conditions with small, underserved patient populations, but OUD affects more than 2 million Americans. In 1994, the FDA granted orphan status to Indivior’s Subutex (buprenorphine sublingual tablets) under a rarely used provision that allows such designations if more than 200,000 Americans are affected but there is “no reasonable expectation” of recovering development and marketing costs.

According to Braeburn, the FDA “grand fathered” the Subutex designation to Sublocade, without revisiting the 1994 data or considering Sublocade’s current eligibility as an orphan drug in a vastly changed market.

Sources: Braeburn Inc., April 9, 2019, and December 23, 2018

DRUG SAFETY ISSUES

Addyi and Alcohol

The FDA has loosened its ban on alcohol use among women taking flibanserin (Addyi, Sprout Pharmaceuticals), but the drug’s manufacturer is appealing for label changes that would ease restrictions even further.

Flibanserin was approved in 2015 to treat acquired, generalized hypoactive sexual-desire disorder in premenopausal women. Data reviewed prior to approval included cases of severe hypotension and syncope when flibanserin and alcohol were taken together. As a result, a boxed warning states that women taking flibanserin must avoid alcohol. An FDA-mandated risk evaluation and mitigation strategy (REMS) requires that healthcare professionals who prescribe flibanserin and pharmacies dispensing the drug must be certified with the REMS program, and that patients must be counseled about the risk of hypotension and syncope. The FDA also required Sprout to further study the interaction between flibanserin and alcohol.

Based on post-marketing studies, the FDA found that flibanserin’s labeling should be changed to clarify that alcohol does not have to be avoided completely. Sections with the boxed warning, contraindications, warnings and precautions, and adverse reactions are being updated to reflect that women should stop drinking alcohol at least two hours before taking flibanserin at bedtime or should forego their flibanserin dose that evening. Women should not consume alcohol at least until the morning after taking flibanserin at bedtime.

The FDA ordered the labeling change because they could not reach an agreement with Sprout, which continued to request the removal of the boxed warning and the contraindication about alcohol. The FDA said this was unacceptable.

Sprout argues that new flibanserin alcohol-interaction studies demonstrated no syncope or orthostatic hypotension that required medical attention. However, according to the FDA, in the post-marketing trial required by the agency among women who took flibanserin and drank alcohol simultaneously, critical blood pressure measurements were missing or delayed.

Through a standard appeals process, Sprout is continuing discussions with the FDA about the labeling—including what Sprout views as the now-inconsistent REMS program.

Sources: FDA, April 11, 2019; Sprout Pharmceuticals, April 12, 2019

Don’t End Opioids Abruptly

The FDA has received reports of serious harm in patients who are physically dependent on opioid pain medications when these are discontinued suddenly or the dose is decreased rapidly. In response, the agency is requiring changes to the prescribing information (intended for use in the outpatient setting) that will expand guidance on safely decreasing or discontinuing opioid pain medications in physically dependent patients.

Rapid discontinuation can result in uncontrolled pain or withdrawal symptoms. These symptoms can lead patients to seek other sources of opioid pain medications, which could be confused with seeking drugs for abuse. Patients may attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. A too-rapid cessation of opioid pain medication can also lead to psychological distress and suicide.

Health care professionals (HCPs) should not abruptly discontinue opioids in physically dependent patients. When an HCP and a patient agree to taper the drug, a variety of factors should be considered, including dose, duration of treatment, type of pain being treated, and the patient’s physical and psychological status. No standard opioid-tapering schedule is suitable for all patients. HCPs should create a patient-specific plan to gradually taper the dose and ensure ongoing monitoring and support, as needed, to avoid serious withdrawal symptoms, worsening of the patient’s pain, or psychological distress.

The FDA is focused on striking the right balance between reducing the new-addictions rate by decreasing excessive exposure to opioids through rational prescribing and maintaing appropriate access to treatment for patients living with serious pain.

Physical dependence differs from addiction, which also involves behaviors, thoughts, and feelings, such as a strong desire to take the drug; difficulty in controlling drug use; persisting in drug use despite harmful consequences; and giving drug use a higher priority than other activities and obligations.

Source: FDA, April 9, 2010

Impurity-Free ARBs

As extensive recalls caused by nitrosamine impurities pushed angiotensin II receptor blockers (ARBs) toward shortage, the FDA released a list of 40 ARBs deemed free of contaminants based on its own testing, evaluation of manufacturing processes, and information from manufacturers and international regulators. The agency expects this list of contaminant-free ARBs to grow.

By mid-April, the FDA had reported the recall of approximately 1,000 lots of valsartan, losartan, and irbesartan products used to treat high blood pressure and heart failure.

Valsartan products are already in short supply. With losartan supplies tightening, the FDA said it was “not objecting to temporary distribution of specific lots of losartan that contain impurities above the interim acceptable intake limit, for a short period of time.” The benefits from access to the drugs outweigh the low, increased cancer risk over the time it should take for impurity-free losartan to reach the market. The FDA expects many companies to be able to manufacture losartan without impurities and replenish the U.S. supply in approximately six months.

The maximum possible exposure to nitrosamines in ARB medicines appears to be small, the agency said.

The FDA has informed manufacturers about factors that can contribute to the formation of nitrosamine impurities during manufacturing, and steps they should take to ensure these impurities are not present in ARBs in the future.

The agency has also listed products on the market that remain under evaluation but can still be distributed.

Sources: FDA, April 4 and April 19, 2019

DEVICE APPROVALS

TransPyloric Shuttle for Obesity

The FDA has approved the TransPyloric Shuttle Device (BAROnova, Inc.), a nonsurgical weight-loss option for obese adults with a body mass index of 35 to 40 kg/m2, or 30 to 34.9 kg/m2 with obesity-related comorbid conditions. The device can be used for up to 12 months while patients undergo lifestyle modification counseling to help them develop and maintain healthier habits.

The TransPyloric Shuttle (TPS) is delivered and retrieved endoscopically, relying on its mechanical structure to maintain its shape so it can remain in the stomach, as opposed to traditional, inflatable intragastric balloons. The TPS is the size of a small peach (approximately 5.6 cm in diameter) and up to 90% smaller than the fluid-filled balloons. In the stomach, it is designed to slow the passage of food so patients feel full sooner and stay full longer. The 12-month treatment duration is twice as long as the intragastric balloons, which could enable patients to achieve more durable lifestyle changes and health benefits.

Approval was based on the pivotal ENDObesity II trial, a randomized, double-blind, sham-controlled study of 302 patients. Patients treated with TPS had lost, on average, 3.4 times more weight than patients in the control group (9.5% vs. 2.8%) at the 12-month follow up. Approximately 67% of people treated with TPS lost 5% or more of their body weight, and 40% lost 10% or more of their weight. Improvements in blood pressure and other cardiometabolic risk factors, as well as quality of life, were also observed with TPS treatment.

The most common adverse events were gastrointestinal, such as stomach pain, nausea, vomiting, and dyspepsia.

Source: BAROnova, Inc., April 23, 2019

Nerve Stimulation for ADHD

The FDA has permitted the marketing of the first medical device to treat attention-deficit/hyperactivity disorder (ADHD). NeuroSigma’s prescription-only Monarch external trigeminal nerve stimulation system (eTNS) is indicated for patients aged 7 to 12 years who are not taking prescription ADHD medication. It is the first nondrug treatment for ADHD to receive FDA marketing authorization.

Monarch eTNS is intended for home use during periods of sleep under the supervision of a caregiver. The cell-phone-sized device generates a low-level electrical pulse and connects via a wire to a small patch that adheres to the patient’s forehead, and should feel like a tingling sensation on the skin. The system delivers the electrical stimulation to the branches of the trigeminal nerve, which sends therapeutic signals to those parts of the brain that are thought to be involved in ADHD. While the exact mechanism of eTNS is not known, neuroimaging studies show that eTNS increases activity in the brain regions that are important in regulating attention, emotion, and behavior.

The efficacy of Monarch eTNS was shown in a clinical trial among 62 children comparing eTNS as monotherapy to a placebo device, used each night for four weeks. The primary endpoint was improvement on a clinician-administered ADHD Rating Scale (ADHD-RS). At the end of week 4, the average ADHD-RS score in the active group decreased significantly from 34.1 points at baseline to 23.4 points, compared with a decrease from 33.7 to 27.5 points in the placebo group. Trials suggest that a response to eTNS may take up to four weeks to become evident.

The most common side effects observed with eTNS were drowsiness, increased appetite, trouble sleeping, teeth clenching, headache, and fatigue.

The Monarch eTNS should not be used in children under 7 years of age or in patients with an active implantable pacemaker, active implantable neurostimulators, or body-worn devices such as insulin pumps. The system should not be used in the presence of magnetic resonance imaging scanners or cell phones.

The FDA reviewed the Monarch eTNS through the de novo premarket review pathway.

Source: FDA, April 19, 2019

Early Sepsis Indicator

The Early Sepsis Indicator (Beckman Coulter Diagnostics) has received FDA 510(k) clearance. The first-of-its-kind, hematology-based cellular biomarker is designed to help emergency department (ED) physicians identify patients with sepsis or at increased risk of developing sepsis at an early stage.

Findings from the pivotal clinical trial showed that the company’s monocyte distribution-width biomarker best discriminated sepsis from all other conditions when combined with the current standard of care.

Early Sepsis Indicator (ESI) results are automatically reported as part of a routine complete blood count with differential for adult ED patients. A positive result signals a higher probability of sepsis, enabling physicians to initiate lifesaving treatments faster. A negative reading indicates a lower probability of sepsis. Compared to reviewing white blood-cell count alone, the ESI reinforces clinicians’ suspicion of sepsis by 43% and, together with clinical signs and symptoms, improves their confidence by 63% in helping to rule out sepsis.

Source: Beckman Coulter Diagnostics, April 18, 2019

Therox for Heart Attacks

The FDA has granted TherOx, Inc. premarket approval for its SuperSaturated Oxygen (SSO2) Therapy. The Therapy offers interventional cardiologists the first FDA-approved treatment beyond percutaneous coronary intervention (PCI) to significantly reduce muscle damage in heart-attack patients.

SSO2 Therapy is indicated for patients who experience the most serious kind of heart attack, left anterior descending ST-elevation myocardial infarction, treated within six hours of symptom onset. Administered immediately after the coronary artery has been successfully opened by PCI (angioplasty and stenting), SSO2 Therapy delivers hyperbaric levels of oxygen directly to the ischemic heart muscle. A small catheter carries a onetime, 60-minute infusion of the patient’s super-oxygenated blood to the targeted area. This helps reduce capillary swelling to restore blood flow to the surrounding tissue and decrease the infarct size.

Even after angioplasty with stenting, many heart-attack patients suffer irreversible damage to the heart muscle. In multiple, randomized, prospective clinical trials, SSO2 Therapy has been shown to consistently and safely reduce infarct size in patients with anterior acute myocardial infarction and thereby improve outcomes. A pivotal, randomized controlled trial demonstrated a 26% relative reduction in infarct size compared to PCI alone. Additional trial data show left ventricular stability at 30 days, with no deleterious enlargement.

Source: TherOx, Inc., April 4, 2019

Cryotherapy Device for Menstrual Bleeding

The FDA has approved the Cerene Cryotherapy Device (Channel Medsystems) as a new approach to treating heavy menstrual bleeding.

The device delivers cryotherapy to freeze the uterus lining and significantly reduce future menstrual bleeding. The procedure does not require general anesthesia and can be performed in the gynecologist’s office. In contrast, heat-based endometrial ablation is more often used with general anesthesia in hospitals or surgery centers.

The pivotal CLARITY study included 242 women. At 12 months, the reduction in menstrual bleeding exceeded treatment goals. Patients’ median pain score ranged from 0 to 2 (on a 0–10 numeric scale) across eight periprocedural time points, with no subjects requiring general anesthesia. Hysteroscopy performed 12 months after the procedure demonstrated an accessible uterine cavity in 98.7% of 223 available participants.

Cerene is indicated for endometrial cryoablation in premenopausal women with heavy menstrual bleeding resulting from benign causes for whom child bearing has been completed.

Source: Channel Medsystems, April 2, 2019

DEVICE SAFETY

FDA Tightens Staple Oversight

The FDA is taking steps to ensure the safety and proper use of surgical staples.

In March, the agency reported that an analysis of medical device reports, involving surgical staplers for internal use and implantable surgical staples, showed that more than 32,000 malfunctions were linked to more than 9,000 serious injuries and 366 patient deaths from January 1, 2011 to March 31, 2018.

The FDA has now proposed reclassifying surgical staplers for internal use from class I (low risk) to class II (moderate risk) medical devices with special controls. Currently, manufacturers of surgical staplers for internal use are not required to submit a premarket notification to the FDA. Reclassifiying the staplers as class II devices would allow the agency to require premarket review and enable it to establish special controls, such as mandatory performance testing of mechanical features and demonstrating usability and labeling comprehension.

The agency has also issued draft guidance to help manufacturers ensure that their labeling provides adequate information for use, including hazards, contraindications, and other facts, to help practitioners use the device safely and for its intended purpose.

Source: FDA, April 23, 2019

Surgical Mesh Barred for Pelvic Organ Prolapse

The FDA has ordered manufacturers of all remaining surgical mesh products that are indicated for the transvaginal repair of pelvic organ prolapse (POP) to cease the sale and distribution of their products in the U.S. immediately.

The agency has determined that Boston Scientific and Coloplast have not demonstrated reasonable assurance of safety and effectiveness for these devices. This is the premarket review standard that has applied since 2016 when the agency reclassified the devices as class III (high risk). For the devices to stay on the market, the agency required evidence that they worked better than surgery without the use of mesh to repair POP. That evidence was lacking, the FDA said.

Surgical mesh has been used since the 1950s to repair abdominal hernias. In the 1970s, gynecologists began implanting the mesh for abdominal repair of POP and, in the 1990s, for transvaginal repair of POP. In 2002, the first mesh device for transvaginal POP repair was cleared for use as a class II (moderate-risk) device.

In new reviews, however, the agency determined that manufacturers had failed to provide an adequate assessment of the long-term safety of the devices and failed to demonstrate an acceptable long-term benefit compared with transvaginal surgical tissue repair without the use of mesh (native tissue repair).

Boston Scientific markets the Uphold LITE Vaginal Support System and the Xenform Soft Tissue Repair System, and Coloplast sells Restorelle DirectFix Anterior. Both firms must continue the follow-up of patients who are enrolled in post-market surveillance studies.

In recent years, the FDA had seen a significant increase in the number of reported adverse events associated with the use of surgical mesh for transvaginal POP repair. As a result, the agency had taken a series of escalating actions regarding this use.

Source: FDA, April 16, 2019

FDA Troubled by New Data On Tainted Duodenoscopes

Even after the thorough cleaning known as “reprocessing,” up to 5.4% of duodenoscopes in studies tested positive for “high-concern” bacteria such as Escherichia coli or Staphylococcus aureus, the FDA says. Also, up to 3.6% tested positive for low-to-moderate-concern organisms that also indicate reprocessing failure.

When the studies were designed, the FDA expected to see a total contamination rate for any type of organism of less than 1%, or as close to zero as possible.

In 2015, the agency ordered the three U.S. manufacturers of duodenoscopes—Olympus, Fujifilm, and Pentax—to conduct studies that included sampling and culturing reprocessed duodenoscopes in clinical use. In December of that year, based on preliminary findings, the agency announced a 3% contamination rate for “high-concern” organisms. The new results update those findings: high-concern bacteria are more often associated with disease.

Based on these interim results, the percentage of contaminated samples shows the need for improvements, say the FDA. Further analyses are under way and the agency is exploring additional steps, such as the sterilization of duodenoscopes in addition to meticulous cleaning; new scope designs that could reduce the risk of contamination; and disposable duodenoscopes that would eliminate the need for reprocessing.

An individual’s risk of acquiring infection from an inadequately reprocessed medical device remains relatively low, given the large number of such devices in use. The number of medical device reports associated with infections peaked in 2015 at 250, and has declined by 62% to fewer than 100 per year in 2017 and 2018. However, the FDA has also received reports of three U.S. patient deaths in 2018 that were related to infections associated with duodenoscopes.

Source: FDA, April 12, 2019

Inova Genetic Tests

The FDA has issued a warning letter to Inova Genomics Laboratory of Falls Church, Virginia, for illegally marketing certain genetic tests that have not been reviewed by the agency for safety and effectiveness.

The tests claim to predict patients’ responses to specific antidepressants, opioids, cancer treatments, anesthesia, and diabetes medications based on genetic variants. Selecting or changing one’s drug treatment in response to the test results could lead to potentially serious health consequences for patients. The FDA is unaware of any data establishing that Inova’s tests can help patients or health care providers make appropriate treatment decisions for the listed drugs.

Source: FDA, April 4, 2019

Medtronic Cybersecurity Risk

Medtronic has disclosed a potential cybersecurity risk in several implantable cardiac devices, including defibrillators and resynchronization therapy hardware. The risk was discovered in the Conexus radio frequency wireless telemetry protocol, which transmits unencrypted data to program the devices or gather information from the implants.

According to Medtronic, these vulnerabilities could enable unauthorized users to access or change the settings on implantable devices, at-home monitors, or programmers in the clinic. The company said there have been no reports of a related cyberattack or privacy breach, or any harm to patients.

The affected devices include Amplia, Claria, Compia, Concerto, Consulta, and Viva CRT-D devices; Evera, Maximo II, Mirro, Nayamed ND, Primo, Protecta, Secura, Virtuoso, and Visia implantable defibrillators; and some CareLink monitors and programmers. Medtronic’s pacemakers do not use Conexus telemetry.

Medtronic and the FDA recommended that the devices continue to be used, as the benefits of remote monitoring—earlier detection of arrhythmias, fewer hospital visits, and improved survival rates—outweigh the risks of cyberattack. To exploit the vulnerabilities, attackers would need specialized knowledge of medical devices, wireless telemetry, and electrophysiology. In addition, device activation times are limited outside the hospital/clinic, vary by patient, and would be hard to predict by unauthorized users.

The FDA stated that reprogramming or updating the devices is not required at present.

Sources: FierceBiotech, March 26, 2019; Medtronic, March 21, 2019