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P T. 2017;42(9): 554-561,593

Drug and Device News September 2017

NEW DRUG APPROVALS

Vyxeos for Poor-Prognosis Acute Myeloid Leukemia

The FDA has approved a combination of daunorubicin and cytarabine (Vyxeos, Jazz Pharmaceuticals) to treat adults with two types of acute myeloid leukemia (AML): newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

T-AML occurs as a complication of chemo therapy or radiation in approximately 8% to 10% of patients treated for cancer within an average of five years after treatment. AML-MRC is characterized by a history of certain blood disorders and other significant mutations within cancer cells. Patients with t-AML or AML-MRC have very low life expectancies.

The safety and efficacy of daunorubicin/cytarabine were studied in 309 patients with newly diagnosed t-AML or AML-MRC who were randomized to receive the combination or separately administered daunorubicin and cytarabine. Patients who received the combination had median overall survival of 9.56 months versus 5.95 months for the separate drugs.

The Vyxeos prescribing information includes a boxed warning not to interchange the medication with other daunorubicin-and/or cytarabine-containing products.

The FDA had granted this application priority review, breakthrough therapy, and orphan drug designations.

Source: FDA, August 3, 2017

Idhifa for Relapsed or Refractory Acute Myeloid Leukemia

Enasidenib (Idhifa, Celgene Corporation) has secured FDA approval for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML) who have specific mutations in the IDH2 gene. A new companion diagnostic, the RealTime IDH2 Assay (Abbott Laboratories), is used to detect these mutations in blood or bone marrow samples.

Enasidenib, an isocitrate dehydrogenase- 2 inhibitor, works by blocking several enzymes that promote cell growth. Its efficacy was studied in a single- arm trial of 199 patients with relapsed or refractory AML with IDH2 mutations. With a minimum of six months of treatment, 19% of patients experienced complete remission for a median 8.2 months, and 4% of patients experienced complete remission with partial hematologic recovery for a median 9.6 months. Of 157 patients who required transfusions of blood or platelets due to AML at the start of the study, 34% no longer required transfusions after treatment with enasidenib.

The prescribing information for enasidenib includes a boxed warning that differentiation syndrome can occur and can be fatal if not treated.

Idhifa was granted priority review and orphan drug designations.

Source: FDA, August 1, 2017

Vosevi for HCV

The FDA has approved a fixed-dose, single-tablet regimen of sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg (Vosevi, Gilead Sciences) for the retreatment of chronic hepatitis C virus (HCV) infection. The drug is indicated in adults without cirrhosis or with mild cirrhosis who have HCV genotype 1, 2, 3, 4, 5, or 6 and were previously treated with an NS5A inhibitor-containing regimen, or who have HCV genotype 1a or 3 and were previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor.

Vosevi contains the previously approved drugs sofosbuvir and velpatasvir and a new drug, voxilaprevir. Its approval was supported by data from the POLARIS-1 and POLARIS-4 studies evaluating 12 weeks of treatment in these patient populations. Across the two studies, 340 of the 353 patients treated with Vosevi (96%) achieved the primary endpoint of a sustained viral response (an undetectable viral load) 12 weeks after completing therapy.

Sources: Gilead Sciences and FDA, July 18, 2017

Nerlynx to Reduce Risk of Breast Cancer Recurrence

Neratinib (Nerlynx, Puma Biotechnology, Inc.) has received FDA approval as the first extended adjuvant therapy for early-stage, HER2-positive breast cancer. To lower the risk of recurrent cancer, it is indicated for adults who have previously been treated with a regimen that includes trastuzumab (Herceptin, Genentech).

HER2-positive breast cancers are aggressive and can spread to other parts of the body, making adjuvant therapy important. Approximately 15% of patients with breast cancer have HER2-positive tumors.

Neratinib is a kinase inhibitor that works by blocking several enzymes that promote cell growth. Its safety and efficacy were studied in a randomized trial of 2,840 patients with early-stage, HER2- positive breast cancer who completed treatment with trastuzumab within the previous two years. The study measured the amount of time after the start of the trial that it took for the cancer to come back or for death to occur from any cause (invasive disease-free survival). After two years, 94.2% of patients treated with neratinib had not experienced cancer recurrence or death compared with 91.9% of patients receiving placebo.

Source: FDA, July 17, 2017

Tremfya for Plaque Psoriasis

The FDA has approved guselkumab (Tremfya, Janssen Biotech) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Guselkumab is the first approved biologic therapy that selectively blocks only interleukin (IL)-23, a cytokine that plays a key role in plaque psoriasis.

Guselkumab is administered as a 100-mg subcutaneous injection every eight weeks, following two starter doses at weeks 0 and 4. In clinical studies, patients receiving guselkumab experienced significant improvement in skin clearance and greater improvement in symptoms of plaque psoriasis, including itch, pain, stinging, burning, and skin tightness, when compared with placebo at week 16. The guselkumab clinical development program included more than 2,000 patients in the phase 3 VOYAGE 1, VOYAGE 2, and NAVIGATE studies.

Source: Janssen Biotech, July 13, 2017

Endari for Sickle Cell Disease

Endari (L-glutamine oral powder, Emmaus Medical Inc.) has won FDA approval for patients 5 years of age and older with sickle cell disease to reduce severe complications associated with the blood disorder. It is the first new treatment for the disease in almost 20 years.

L-glutamine oral powder’s safety and efficacy were studied in a randomized 48-week trial of patients 5 to 58 years of age with sickle cell disease who had two or more painful crises within the 12 months prior to trial enrollment. Patients treated with L-glutamine oral powder experienced fewer hospital visits for pain treated with a parenterally administered narcotic or ketorolac (sickle cell crises), on average, compared with patients who received a placebo (median three versus four); fewer hospitalizations for sickle cell pain (median two versus three); and fewer days in the hospital (median 6.5 days versus 11 days).

Source: FDA, July 7, 2017

Generic Approvals

Prasugrel Tablets

Mylan Pharmaceuticals has received FDA approval to market 5-mg and 10-mg prasugrel tablets, the first generic version of Effient (Eli Lilly). Prasugrel is a P2Y12 platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in certain patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention.

Source: FDA, July 12, 2017

Phentermine Hydrochloride ODT

Zydus Pharmaceuticals has received approval to market phentermine hydrochloride orally disintegrating tablets, 15 mg, 30 mg, and 37.5 mg. This is the first generic version of Suprenza (Akrimax Pharmaceuticals), an appetite suppressant indicated for use as a short-term adjunct in a weight-loss regimen, along with exercise, behavioral modification, and caloric restriction.

Source: FDA, June 28, 2017

Paroxetine Capsules

The FDA has approved Actavis Laboratories’ marketing application for paroxetine capsules 7.5 mg, the first generic form of Brisdelle (Noven Therapeutics). Paroxetine is a selective serotonin reuptake inhibitor used to treat moderate-to-severe vasomotor symptoms associated with menopause.

Source: FDA, June 20, 2017

NEW INDICATIONS

Imbruvica for Chronic GVHD

Ibrutinib (Imbruvica, Pharmacyclics LLC) has secured a new indication that makes it the first FDA-approved therapy for the treatment of chronic graft versus host disease (cGVHD).

The indication includes treatment of adults with cGVHD after failure of one or more treatments. Ibrutinib’s efficacy and safety were studied in a single-arm trial of 42 patients with cGVHD whose symptoms persisted despite standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% of patients had two or more organs affected by cGVHD. In the trial, 67% of patients experienced improvements in their cGVHD symptoms. In 48% of patients in the trial, the improvement of symptoms lasted for up to five months or longer.

Ibrutinib is a kinase inhibitor. The FDA granted this indication priority review, breakthrough therapy, and orphan drug designations.

Source: FDA, August 2, 2017

Nivolumab for More Colorectal Cancers

The FDA has approved a ninth indication for nivolumab injection for intravenous use (Opdivo, Bristol-Myers Squibb). The new indication allows the treatment of patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

This indication received accelerated approval based on patients’ overall response rate (ORR) and duration of response in CheckMate-142, a phase 2, open-label, single-arm study evaluating nivolumab in patients with locally determined dMMR or MSI-H mCRC whose disease had progressed during or after treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy or who were intolerant to such treatment. In patients who received prior treatment with those medications, nivolumab demonstrated an ORR of 28% (a 1.9% complete response rate and a 26% partial response rate). Among all enrolled patients, 32% responded to treatment with nivolumab (a 2.7% complete response rate and a 30% partial response rate). The median duration of response was not reached in either group.

Source: Bristol-Myers Squibb, August 1, 2017

Vectibix CRC Use Refined

Panitumumab (Vectibix, Amgen) is now FDA-approved to treat metastatic colo rectal cancer (mCRC) in patients with wild-type RAS as first-line therapy in combination with FOLFOX and as monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. Panitumumab is the first fully human monoclonal anti-epidermal growth factor receptor antibody approved by the FDA for this patient population.

Wild-type RAS in this indication includes both KRAS and NRAS as determined by a new FDA-approved test. The multigene, next-generation-sequencingbased test was approved to identify the RAS mutation status of a patient’s tumor and to help identify patients who are more likely to benefit from treatment with panitumumab, which has demonstrated a significant overall survival benefit to patients whose mCRC does not have RAS mutations.

Source: Amgen, June 29, 2017

Orencia for Psoriatic Arthritis

Abatacept (Orencia, Bristol-Myers Squibb) has received FDA approval for the treatment of adults with active psoriatic arthritis (PsA).

Abatacept is a selective T-cell costimulation modulator. The costimulation blockade of abatacept inhibits T-cell activation and the resulting cascade of events that contribute to inflammation. T-cell activation is involved in the pathogenesis of PsA.

The approval was based on results from two randomized, double-blind, placebocontrolled trials in which abatacept improved (or reduced) disease activity in both tumor necrosis factor (TNF)-naïve and exposed patients with high disease activity, many tender and swollen joints, and a disease duration of more than seven years.

Abatacept is available in intravenous and subcutaneous injection formulations. It should not be administered concomitantly with TNF antagonists, and is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra. Abatacept is also approved to treat adult RA and juvenile idiopathic arthritis.

Source: Bristol-Myers Squibb, July 6, 2017

Fycompa as Epilepsy Monotherapy

The FDA has approved perampanel CIII (Fycompa, Eisai Inc.) as monotherapy for the treatment of partial-onset seizures (POS) with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older. The medication was previously approved for adjunctive use for POS and primary generalized tonic-clonic seizures in epilepsy patients in that age group.

Fycompa was initially approved for adjunctive use in POS in 2012. Based on a regulatory pathway outlined by the FDA in 2016, Fycompa’s approval as monotherapy was extrapolated based on comparable exposures to those obtained with adjunctive use in clinical trials for the treatment of POS.

Source: Eisai Inc., July 26, 2017

NEW FORMULATIONS

Self-Injectable Benlysta for Lupus

The FDA has approved a subcutaneous (SC) formulation of belimumab (Benlysta, GlaxoSmithKline) for the treatment of adults with active, autoantibody- positive systemic lupus erythematosus (SLE) who are receiving standard therapy. The approval marks the first SC self-injection treatment option for patients with SLE.

After training from their health care provider, patients will be able to administer the medicine as a once-weekly injection of 200 mg, from either a single-dose prefilled syringe or from a single-dose autoinjector. The existing intravenous (IV) formulation of Benlysta, approved in 2011, is administered by health care professionals to patients as a weight-based dose of 10 mg/kg, via a one-hour infusion in a hospital or clinic setting every four weeks (following an initial loading phase given on days 0, 14, and 28).

Benlysta, a BLyS-specific inhibitor, is a human monoclonal antibody that binds to soluble BLyS. Benlysta does not bind B cells directly. By binding BLyS, Benlysta inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

Source: GlaxoSmithKline, July 21, 2017

FDA REVIEW ACTIVITIES

Priority Review Designations

Abemaciclib for Breast Cancer

The FDA has accepted for filing with priority review the new drug application for abemaciclib (Eli Lilly), a cyclin-dependent kinase (CDK) 4 and 6 inhibitor. Lilly is seeking two indications: monotherapy for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer who had prior endocrine therapy and chemotherapy for metastatic disease; and in combination with fulvestrant in women with HR+, HER2− advanced breast cancer whose disease progressed following endocrine therapy.

Abemaciclib is an investigational oral cell-cycle inhibitor designed to block the growth of cancer cells by specifically inhibiting CDK4 and CDK6.

This submission is based on the MONARCH 1 and MONARCH 2 studies, which evaluated the efficacy and safety of abemaciclib as monotherapy and combined with fulvestrant, respectively. In addition to the clinical trials evaluating abemaciclib in breast cancer, a phase 3 trial of abemaciclib in lung cancer is under way.

Source: Eli Lilly, July 10, 2017

Alecensa for ALK+ Lung Cancer

The FDA has accepted Genentech’s supplemental new drug application and granted priority review for the kinase inhibitor alectinib (Alecensa) as first-line treatment for people with anaplastic lymphoma kinase-positive, locally advanced, or metastatic non–small-cell lung cancer. Alectinib is currently approved for patients who have progressed on, or are intolerant to, crizotinib.

The submission is based on results from phase 3 studies that found alectinib reduced the risk of worsening disease by more than half compared with the current standard of care and lowered by more than 80% the risk of tumors spreading to or growing in the brain.

The FDA will make a decision on approval by November 30, 2017.

Source: Genentech, August 3, 2017

Xarelto for Recurrent VTE

The FDA has granted priority review to Janssen Research & Development for a supplemental new drug application (sNDA) for rivaroxaban (Xarelto). The sNDA would allow Xarelto to include a 10-mg, once-daily dose for reducing the risk of venous thromboembolism (VTE) after at least six months of standard anticoagulant therapy.

Once anticoagulant therapy is stopped, VTE recurs in up to 10% of people during the first year and up to 20% within three years. This application is based on data from the EINSTEIN CHOICE study, which found rivaroxaban 10 mg reduced the risk of recurrent VTE by 74% and rivaroxaban 20 mg by 66%, compared with aspirin, with comparable rates of major bleeding.

This accelerated review advances the FDA’s Prescription Drug User Fee Act target date to October 28, 2017.

Source: Janssen Research & Development, June 28, 2017

Sprycel for Chronic Myeloid Leukemia

The FDA has accepted a supplemental new drug application for dasatinib (Sprycel, Bristol-Myers Squibb) for priority review. The application includes an indication for dasatinib to treat children with Philadelphia chromosome-positive (Ph+) chronic phase chronic myeloid leukemia (CP-CML), as well as for a formulation as powder for oral suspension.

The application includes data from an ongoing phase 2, open-label, nonrandomized trial studying dasatinib in pediatric patients with CP-CML who have not responded to imatinib and in pediatric patients newly diagnosed with CP-CML.

Sprycel was first approved in 2006 for the treatment of adults with Ph+ CP-CML who did not respond to prior therapy including imatinib. Sprycel is also approved for adults with Ph+ acute lymphoblastic leukemia who have not responded to previous therapy and for adults with newly diagnosed Ph+ CP-CML.

The application has an action date of November 9, 2017.

Source: Bristol-Myers Squibb, July 10, 2017

Fast-Track Designations

VT-1598 for Valley Fever

Viamet Pharmaceuticals has received a fast-track designation for VT-1598, a novel oral agent for the treatment of coccidioidomycosis, also known as Valley fever.

Valley fever is an invasive respiratory fungal infection found largely in areas of California, Arizona, Texas, New Mexico, Mexico, and Central and South America. The infection mainly causes flu-like symptoms, but each year approximately 5% to 10% of the patients develop chronic pulmonary or potentially fatal disseminated disease.

VT-1598 is an orally available inhibitor of fungal cytochrome P450 51 that has demonstrated high potency against a range of pathogens. Viamet believes that it may avoid the side effects that limit the use of current oral antifungal therapies, such as liver toxicity and drug–drug interactions.

Source: Viamet Pharmaceuticals, July 13, 2017

Hepatitis Delta Virus Treatment

The FDA has granted a fast-track designation to Eiger BioPharmaceuticals for pegylated interferon lambda 1a (Lambda) as a treatment for chronic hepatitis delta virus (HDV) infection. One of the most severe forms of viral hepatitis, HDV occurs only as a coinfection in people with hepatitis B infection. HDV leads to more severe liver disease than HBV alone, including accelerated liver fibrosis, liver cancer, and liver failure.

Lambda has been administered in HBV/HCV clinical trials involving more than 3,000 patients. It stimulates an immune response, targeting type III interferon (IFN) receptors, which are distinct from the type I IFN receptors targeted by IFN alfa. Type III receptors are highly expressed on hepatocytes, with limited expression on hematopoietic and central nervous system cells, which may reduce off-target effects and improve tolerability.

Eiger licensed worldwide rights to Lambda from Bristol-Myers Squibb in April 2016.

Source: Eiger BioPharmaceuticals, July 27, 2017

Vaccine for UTIs

The FDA has granted fast-track status to Sequoia Sciences’ novel investigational vaccine designed to treat recurrent urinary tract infections (UTIs) caused by multidrug-resistant bacteria. About 3 million U.S. adults develop UTIs every year; an estimated half of those are caused by antibiotic-resistant bacteria. The vaccine is designed to create an immune response preventing bacteria from colonizing the urinary tract. In a recently completed clinical trial in women, the vaccine was well tolerated and generated a strong immune response.

Source: Sequoia Sciences, July 26, 2017

SB-318 and SB-913 for MPS I and MPS II

Sangamo Therapeutics, Inc., has received a fast-track designation for SB-318 and SB-913, in vivo genome-editing product candidates for the treatment of mucopolysaccharidosis (MPS) types I and II. MPS I and MPS II are genetic mutations that interfere with the enzymes that break down glycosaminoglycans, sugar carbohydrates within the cells. In people with MPS, the enzymes are missing or malfunctioning. In time, the glycosaminoglycans collect in cells, blood, and connective tissues, causing permanent damage to physical abilities, organ and system functioning, and mental development.

SB-318 and SB-913 previously received orphan drug and rare pediatric disease designations from the FDA. Phase 1/2 clinical trials are screening patients for enrollment.

Source: Sangamo Therapeutics, July 13, 2017

Orphan Drug Designations

MNK-1411 for Duchenne MD

Mallinckrodt has received orphan drug status for MNK-1411 (cosyntropin injection), a long-acting formulation for the treatment of Duchenne muscular dystrophy (DMD). In DMD, a genetic disorder that primarily affects boys, a protein that helps keep muscle cells intact is absent, leading to muscle degeneration and weakness.

MNK-1411, which is approved and marketed outside of the U.S. for certain autoimmune and inflammatory conditions, was fast-tracked by the FDA in August 2016. Mallinckrodt has completed a phase 1 study for MNK-1411 in healthy volunteers. The phase 2 trial is slated to begin later this year.

Source: Mallinckrodt, July 12, 2017

Vaccine DSP-7888 for MDS

The FDA has granted an orphan drug designation for DSP-7888 (Boston Bio-medical), an investigational cancer peptide vaccine. The vaccine is a first-in-class compound aimed at preventing myelodysplastic syndrome (MDS), a group of blood disorders characterized by abnormal development of bone marrow blood cells. Approximately 10,000 to 15,000 people are diagnosed with MDS in the U.S. annually, and an estimated one-third can develop acute myeloid leukemia.

The vaccine contains peptides that activate Wilms’ tumor gene 1–specific cytotoxic T lymphocytes and helper T cells, which may improve efficacy compared with a killer peptide treatment regimen alone.

DSP-7888 is being investigated in three monotherapy phase 1 and 2 studies and in combination with bevacizumab in a phase 2 study of patients with recurrent or progressive glioblastoma. Early clinical data have shown signs of clinical activity and indicate that DSP-7888 was well tolerated.

Source: Boston Biomedical, July 10, 2017

ALLN-177 for Primary Hyperoxaluria

Allena Pharmaceuticals, Inc., has received an orphan drug designation for the investigational product ALLN-177, an oral formulation of oxalate decarboxylase. The first-in-class compound is being developed to treat patients with primary hyperoxaluria (PH), a genetic metabolic disorder in which the liver overproduces oxalate.

PH can lead to kidney stone disease, kidney damage, and kidney failure. There are no FDA-approved therapies for the disorder, and in the most severe cases, patients may need liver and/or kidney transplants.

ALLN-177 is an oral, nonabsorbed enzyme that works in the gastro intestinal tract, where it can degrade both dietary and endogenously produced oxalate. Preclinical data from animal studies demonstrated oxalate decarboxylase significantly reduced urinary and plasma oxalate.

Source: Allena, July 13, 2017

PRN1008 for Pemphigus Vulgaris

The FDA has granted an orphan drug designation to Principia Biopharma, Inc., for PRN1008, a therapy to treat pemphigus vulgaris, a potentially life-threatening autoimmune skin disorder that affects approximately 40,000 U.S. patients.

Pemphigus vulgaris is caused by auto-antibodies that break the bond between the skin cells, leading to inflammation, skin blisters, and mouth and genital ulcers. It is traditionally treated with high doses of corticosteroids, often with a steroid-sparing immunosuppressant drug.

PRN1008 is an oral, reversible covalent inhibitor of Bruton’s tyrosine kinase (BTK), a component of B-cell signaling. PRN1008 has an antibody-like specificity for BTK, which can impact the immune cascade in immunological disorders. The reversible covalent bonding allows that effect to turn off and on quickly as needed, potentially delivering a safer profile. PRN1008 also has the potential to significantly reduce prednisone use and its related risks.

Principia Biopharma is conducting a phase 2 trial to evaluate the safety and efficacy of PRN1008.

Source: Principia Biopharma, July 11, 2017

Entrectinib for NTRK Fusion-Positive Solid Tumors

The FDA has granted an orphan drug designation to entrectinib (Ignyta) for treatment of NTRK fusion-positive solid tumors. NTRK fusions are molecular alterations that occur in a broad variety of adult and pediatric solid tumor types.

Entrectinib is an investigational tyrosine kinase inhibitor targeting tumors that harbor NTRK1/2/3, ROS1, or ALK gene fusions. It is the only TRK inhibitor with clinically demonstrated activity against primary and metastatic central nervous system disease across a range of tumor types and molecular targets. It has not shown undesirable off-target activity.

A global, multicenter, open-label phase 2 clinical trial is under way.

Source: Ignyta, July 10, 2017

SOBI003 for MPS IIIA

Swedish Orphan Biovitrum AB (Sobi) has been granted an orphan drug designation for SOBI003, a chemically modified human recombinant sulfamidase for treatment of mucopolysaccharidosis type IIIA (MPS IIIA). One in 100,000 children is born with the inherited metabolic disorder, which is characterized by severe and progressive developmental delay, motor retardation, and eventually dementia. Very few patients survive into adulthood.

In MPS IIIA, the body cannot break down long chains of sugar molecules called heparan sulfate, which then accumulate in lysosomes. SOBI003 is an enzyme replacement therapy that reduces heparan sulfate storage materials in affected cells. SOBI003 is taken up by cells and transported into the lysosomal compartment, where heparan sulfate is degraded.

The first clinical trials with SOBI003 are expected to begin in 2018.

Source: Swedish Orphan Biovitrum, July 5, 2017

Haegarda to Prevent HAE Attacks

The FDA has granted CSL Behring seven years of orphan drug exclusivity for Haegarda (C1 esterase inhibitor subcutaneous [human]), the first subcutaneous treatment option for prevention of hereditary angioedema (HAE) attacks. Twice-weekly subcutaneous administration builds and maintains a steady-state level of functional C1-INH activity and eliminates the need for venous access, including ports. In placebo-comparison studies, Haegarda (which received FDA approval in June) reduced the number of HAE attacks by a median of 95% and the use of rescue medication by a median of greater than 99%.

Source: CSL Behring, June 22, 2017

Gilteritinib for Acute Myeloid Leukemia

Astellas Pharma, Inc., has received an orphan drug designation for gilteritinib in patients with acute myeloid leukemia (AML). Gilteritinib is a receptor tyrosine kinase inhibitor that acts against two common types of mutations involved in the growth of cancer cells that are seen in up to one-third of patients with AML. Astellas is investigating gilteritinib in AML through phase 3 trials.

Source: Astellas Pharma, July 20, 2017

New or Revised Applications

SUN-101/eFlow for COPD

The FDA has accepted Sunovion’s resubmission of the new drug application for SUN-101/eFlow (glycopyrrolate) for maintenance treatment of airflow obstruction in moderate-to-very-severe chronic obstructive pulmonary disease (COPD). The resubmission addresses points raised in the FDA’s complete response letter to Sunovion.

SUN-101 is a long-acting muscarinic antagonist bronchodilator delivered via the proprietary investigational eFlow closed-system nebulizer (PARI Pharma GmbH). The application for SUN-101/eFlow is supported by clinical trial data that demonstrated a statistically significant change from baseline versus placebo in morning pre-dose trough forced expiratory volume in one second. Sunovion was not required by the FDA to conduct any additional clinical studies prior to resubmitting the application.

The FDA has set a Prescription Drug User Fee Act action date of December 15, 2017.

Source: Sunovion, June 30, 2017

Latuda for Bipolar Depression In Children and Adolescents

Sunovion has submitted a supplemental new drug application for the expanded use of lurasidone (Latuda) as mono therapy in children and adolescents (10 to 17 years of age) with major depressive episodes associated with bipolar I disorder. Lurasidone is currently indicated as monotherapy for adults with bipolar depression and adjunctive therapy with lithium or valproate in adults and adolescents (13 to 17 years of age) with schizophrenia.

Bipolar disorder is the fourth leading cause of disability among children and adolescents worldwide, and affects approximately 1.7% of children and adolescents in the United States. Roughly half of adults with bipolar disorder experience their first symptoms during adolescence. Symptoms of bipolar disorder in children and adolescents can be severe and may cause suicidal thoughts.

The application is supported by data from a six-week, phase 3 clinical study of 347 children and adolescents with bipolar depression. Lurasidone was associated with statistically significant and clinically meaningful improvement in depressive symptoms compared with placebo and was generally well tolerated, with few effects on weight and metabolic parameters.

Source: Sunovion, June 30, 2017

Binimetinib and Encorafenib For Advanced Melanoma

Array BioPharma has submitted two new drug applications for binimetinib and encorafenib as combination treatment for patients with BRAF-mutant advanced, unresectable, or metastatic melanoma. About 200,000 new cases of melanoma are diagnosed worldwide each year, approximately half of which have BRAF mutations. Only about 20% of people survive for at least five years following a diagnosis with late-stage disease. Binimetinib is a late-stage small-molecule MEK inhibitor and encorafenib is a late-stage small-molecule BRAF inhibitor. Both target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK).

The applications are supported by data from the pivotal phase 3 COLUMBUS study. In part 1 of the study, COMBO450 (binimetinib 45 mg/encorafenib 450 mg) significantly extended progression-free survival (PFS) in patients with advanced BRAF-mutant melanoma (14.9 months, compared with 7.3 months with vemurafenib 960 mg). In part 2, binimetinib 45 mg plus encorafenib 300 mg (COMBO300) was compared with encorafenib 300 mg. Topline results showed median PFS was 12.9 months, compared to 9.2 months for patients treated with encorafenib alone.

Source: Array BioPharma, July 5, 2017

Xeljanz for Ulcerative Colitis

The FDA has accepted a supplemental new drug application for tofacitinib citrate (Xeljanz, Pfizer), an investigational oral treatment for adults with moderately to severely active ulcerative colitis. If approved, it will be the first oral Janus kinase inhibitor available as a therapeutic option for those patients.

The submission included data from three phase 3 studies from the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis global clinical development program (OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain) evaluating the safety and efficacy of tofacitinib, and OCTAVE Open, the open-label long-term extension study of tofacitinib in patients who completed or who had treatment failure in OCTAVE Sustain or were non-responders in OCTAVE Induction 1 or 2.

The anticipated Prescription Drug User Fee Act action date is March 2018.

Source: Pfizer, July 13, 2017

Mirabegron for Overactive Bladder

Astellas has submitted a supplemental new drug application for the use of mirabegron (Myrbetriq) in combination with solifenacin succinate (VESIcare) for the treatment of overactive bladder (OAB).

The application is based on data from more than 5,000 patients with OAB in the global phase 3 SYNERGY I, SYNERGY II, and BESIDE studies, which evaluated combination therapy with mirabegron and solifenacin succinate compared with each drug as monotherapy and placebo.

Sourc: Astellas Pharma, Inc., June 29, 2017

Lenvatinib for Hepatocellular Carcinoma

Eisai, Inc., submitted a supplemental new drug application to the FDA for the first-line use of lenvatinib (Lenvima), a multiple-receptor tyrosine kinase inhibitor, to treat hepatocellular carcinoma (HCC). The submission is based on positive results of the international, multicenter phase 3 REFLECT trial, in which lenvatinib was the first systemic therapy to show noninferior overall survival versus sorafenib in previously untreated patients with unresectable HCC. Lenvatinib also demonstrated statistically significant and clinically meaningful improvements in progression-free survival, time to progression, and objective response rate.

Source: Eisai, Inc., July 25, 2017

Erenumab for Migraine

The FDA has accepted the biologics license application for erenumab (Aimovig) for the prevention of migraine. If approved, erenumab is expected to be the first fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor, specifically designed to prevent migraine in patients experiencing four or more migraine days per month.

The application for erenumab is supported by data from phase 2 and phase 3 clinical studies in more than 2,600 patients. Erenumab significantly reduced the number of migraine-affected days, acute medication overuse, and disability compared with placebo.

The FDA has set a Prescription Drug User Fee Act target action date of May 17, 2018. Erenumab will be jointly marketed in the U.S. by Amgen and Novartis.

Source: Novartis, July 20, 2017

Yonsa for Prostate Cancer

The FDA has accepted Churchill Pharmaceuticals’ new drug application for abiraterone acetate (Yonsa) ultramicrosize tablets. The submission was based primarily on the final results of the STAAR Study, a randomized, open-label trial in 53 men. The study compared Yonsa 500 mg plus methylprednisolone 4 mg to Zytiga (abiraterone acetate) 1,000 mg plus prednisone 5 mg. More than 90% of patients treated with Yonsa achieved absolute testosterone levels of less than 1 ng/dL at each time point. Yonsa ultramicrosize tablets also have double the bioavailability of the comparator formulation of abiraterone acetate.

Under the Prescription Drug User Fee Act, the FDA has set a target date of March 19, 2018, to complete its review.

Source: Churchill Pharmaceuticals, July 20, 2017

Complete Response Letters

Dextenza for Ocular Pain

Ocular Therapeutix has received a complete response letter (CRL) from the FDA regarding its resubmission of a new drug application for dexamethasone insert (Dextenza).

Dextenza delivers dexamethasone without preservatives to the ocular surface to relieve eye pain for up to 30 days after ophthalmic surgery. Following treatment, Dextenza resorbs and exits the nasolacrimal system without need for removal.

The CRL refers to deficiencies in manufacturing processes and analytical testing identified during a pre-approval inspection of the Ocular Therapeutix manufacturing facility in May 2017. The CRL did not identify any efficacy or safety concerns with respect to the clinical data provided in the application nor any need for additional clinical trials. The company is evaluating the CRL’s requirements and plans to work closely with the FDA to satisfy them.

Source: Ocular Therapeutix, July 11, 2017

Osteoporosis Drug Evenity

The FDA has issued a complete response letter on the biologics license application for romosozumab (tentatively branded as Evenity), a treatment for post-menopausal women with osteoporosis being developed by Amgen and UCB. The FDA asked that efficacy and safety data from the phase 3, active-comparator ARCH study be integrated into the application. The resubmission of the application will also include the efficacy and safety data from the BRIDGE study, the phase 3 trial evaluating Evenity in men with osteoporosis, which the FDA has also requested.

Source: Amgen, July 16, 2017

DRUG SAFETY ISSUES

Compounded Drug Harms Eyes

The use of a compounded drug by doctors in Dallas left some patients with significant vision problems, the FDA says.

The FDA investigated reports from April and June that at least 43 patients were administered intravitreal injections of a drug containing the steroid triamcinolone and the anti-infective moxifloxacin compounded by Guardian Pharmacy Services in Dallas. The product was injected at the end of cataract surgery at two Dallas surgical centers. The injections were meant to provide post-operative prophylaxis for ocular inflammation and endophthalmitis so the patient would not need post-operative eye drops. Over several months, patients developed such symptoms as blurred or decreased vision, poor night vision, loss of color perception, photophobia, glare, halos, flashing lights, ocular discomfort, pain, loss of balance, headaches, and/or nausea. Examinations showed macular edema, followed in some cases by retinal degeneration. While symptoms have reportedly improved in some patients, a number still have a significant reduction in best-corrected visual acuity and visual fields.

Source: FDA, July 28, 2017

Opana ER Off the Market

Endo International PLC has removed the opioid pain reliever Opana ER (oxymorphone hydrochloride extended release) from the market because of abuse problems. An FDA advisory panel had determined that the risks of the long-acting opioid painkiller outweigh its benefits.

The FDA approved Opana ER in 2006. Because the drug was being abused, a reformulated version was introduced in 2012. The rate of abuse for the nasal spray form of the drug fell, but rates of intravenous abuse soared.

Endo said it “continues to believe in the safety, efficacy, and favorable benefit–risk profile of Opana ER … when used as intended,” but it acceded to the FDA’s June 2017 withdrawal request,

Sources: Reuters and Endo, July 6, 2017

Cantrell Recalls Sterile Drugs

Cantrell Drug Company is voluntarily recalling all lots of unexpired sterile drug products due to lack of sterility assurance. The products were distributed to health care facilities nationwide (except for Connecticut, Hawaii, South Carolina, and Vermont). Administration of a drug product intended to be sterile that is not sterile could result in serious infections that may be life-threatening.

The affected products include all unexpired lots distributed from February 16, 2017, to July 19, 2017; they would be packaged in a syringe or intravenous bag.

Source: FDA, July 25, 2017

DEVICE APPROVALS

Neonatal MRI Device

The FDA has cleared the first magnetic resonance imaging (MRI) device specifically for neonatal brain and head imaging in neonatal intensive care units (NICUs).

The Embrace Neonatal MRI System (Aspect Imaging Ltd.), designed specifically for imaging of the neonatal head, may be used on neonates with a head circumference up to 38 cm and weight between 1 and 4.5 kg. The system has a temperature-controlled incubator placed directly into the MRI system, minimizing movement of the baby. If urgent access to the baby is necessary during the imaging process, the baby can typically be removed from the system in less than 30 seconds.

The Embrace Neonatal MRI System can be placed in a NICU because it does not require a safety zone or a radiofrequency shielded room. Since the system is fully enclosed, medical device implants in close proximity to the system are not required to be “MR Conditional” or “MR Safe.”

To avoid putting vulnerable patients at risk, the efficacy of the system was demonstrated primarily based on nonclinical testing, including images of phantoms simulating an infant brain that were determined to be of sufficient quality for diagnostic use by an independent board-certified radiologist. The safety of the Embrace Neonatal MRI System was demonstrated through performance testing, including a review of electrical and mechanical safety measures.

The Embrace Neonatal MRI System was reviewed through the premarket clearance (510[k]) pathway.

Source: FDA, July 20, 2017

DEVICE SAFETY

Fujifilm Recalls Duodenoscopes

Fujifilm has recalled all ED-530XT duodenoscopes to institute design changes. Fujifilm issued an “urgent medical device correction and removal” notification informing customers that changes to the devices would include replacement of the forceps elevator mechanism and its O-ring seal, replacement of the distal end cap, and new operation manuals. The FDA has cleared the updated design and labeling for the ED-530XT.

The FDA issued a safety communication in February 2015 noting that the complex design of duodenoscopes may impede effective reprocessing—a detailed, multistep process to clean and disinfect or sterilize 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 and show with a high degree of assurance that their reprocessing instructions, when followed correctly, effectively clean and disinfect the duodenoscopes.

Fujifilm customers should continue to use the manual reprocessing procedures outlined by the FDA in December 23, 2015, for Model ED-530XT duodenoscopes.

In January, Fuji told the FDA that it planned to remove older “legacy” duodenoscope models (the ED-250XL5, ED-250XT5, ED-450XL5, and ED-450XT5) based on the limited number currently in use. Fuji said it would replace the 250/450 duodenoscope models with the ED-530XT model, in addition to necessary accessories, at no cost.

Sources: FDA, July 21, 2017, and January 13, 2017

Penumbra Recall

Penumbra, Inc., is recalling the Penumbra 3D revascularization device because there is a risk of the delivery wire breaking or separating during use. Fractured pieces of the wire could be left inside the patient’s brain bloodstream, and this (or attempts made to retrieve the fractured pieces) can worsen the stroke. The Penumbra 3D revascularization device is intended to restore blood flow or remove thrombus within a blood vessel in the brain during an acute ischemic stroke in patients who are ineligible for or fail intravenous tissue plasminogen activator therapy.

Source: FDA, July 21, 2017