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P T. 2019;44(2): 30-37, 68

Drug and Device News February 2019


Sprycel for Newly Diagnosed Ph + ALL in Pediatric Patients

The FDA has approved dasatinib (Sprycel, Bristol-Myers Squibb) in combination with chemotherapy for pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. It is the first and only second-generation tyrosine kinase inhibitor for this condition.

Dasatinib was continually administered to 106 patients aged <18 years old starting at trial day 15 of induction chemotherapy. Cohort 1 evaluated efficacy in 78 patients treated with dasatinib 60 mg/m2 daily for up to two years in combination with a backbone chemotherapy regimen of the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol. Patients considered high-risk, based on minimal residual disease (MRD), also received stem cell transplants.

Results showed that all patients achieved complete remission. Those with MRD ≥ 0.05% at day 78 were eligible for hematopoietic stem cell transplantation (HSCT) in first remission.

The most common adverse reactions included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. Serious adverse reactions involved pleural effusion (10%).

Dasatinib was first approved in 2017 for the treatment of pediatric patients with Ph+ chronic myeloid leukemia.

Source:, January 2, 2019

Herzuma, a Herceptin Biosimilar

The FDA has approved trastuzumab-pkrb (Herzuma, Celltrion/Teva Pharmaceutical Industries Ltd.), a HER2/neu receptor antagonist biosimilar to trastuzumab (Herceptin, Genentech) used in the treatment of breast cancer.

The FDA approval is based on a review of a comprehensive data package including foundational analytical similarity data, nonclinical data, clinical pharmacology, immunogenicity, clinical efficacy, and safety data. The clinical development program demonstrated that there were no clinically meaningful differences in purity, potency, and safety between trastuzumabpkrb and trastuzumab for the treatment of HER2-overexpressing breast cancer for the approved indications.

A boxed warning states that treatment with trastuzumab may be associated with cardiomyopathy, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity.

Celltrion and Teva entered into an exclusive partnership in October 2016 to commercialize Herzuma in the U.S. and Canada.

Source: Celltrion Inc. and Teva Pharmaceutical Industries Ltd., December 15, 2018

Xospata for Some Cases of AML

Gilteritinib tablets (Xospata, Astellas Pharma) have received FDA approval for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML) with an FLT3-gene mutation. Between one-quarter and one-third of patients with AML have an FLT3 mutation, which is associated with a highly aggressive form of the disease and a higher risk of relapse.

The efficacy of gilteritinib was studied in a clinical trial of 138 patients with relapsed or refractory AML and a confirmed FLT3 mutation. Twenty-one percent achieved complete remission, or complete remission with partial hematologic recovery (no evidence of disease and partial recovery of blood counts) after treatment with gilteritinib.

Among the common side effects reported by subjects were myalgia/ arthralgia, fatigue, and elevated liver transaminase. Health care providers should monitor patients for posterior reversible encephalopathy syndrome, prolonged QT interval, and pancreatitis. Rare cases of differentiation syndrome have been seen in patients taking gilteritinib. Women who are pregnant or breastfeeding should not take gilteritinib as it may harm the developing fetus or newborn baby.

The FDA also approved an expanded indication for a companion diagnostic for use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect the FLT3 mutation in patients with AML.

The FDA granted gilteritinib fast track, priority review, and orphan drug designations.

Source: FDA., November 28, 2018

Truxima, a Rituxan Biosimilar

The FDA has approved rituximab-abbs (Truxima, Celltrion), the first biosimilar to rituximab (Rituxan, Genentech), for adults with CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL). Rituximab-abbs is the first biosimilar approved in the U.S. for the treatment of NHL.

Rituximab-abbs is indicated for the treatment of adults with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy; and non-progressing (including stable disease), low-grade, CD20- positive, B-cell NHL as a single agent, after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.

The approval is based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data demonstrating that rituximab-abbs is a biosimilar to rituximab. Rituximab-abbs was approved as a biosimilar, not as an interchangeable product.

The most common side effects are infusion reactions, fever, lymphopenia, chills, infection, and asthenia. Like rituximab (approved in 1997), rituximab-abbs has a boxed warning about increased risks of fatal infusion reactions, and severe skin and mouth reactions, some with fatal outcomes; hepatitis B virus reactivation that may cause serious liver problems, including liver failure, and death; and progressive multifocal leukoencephalopathy. This product must be dispensed with a patient medication guide.

Source: FDA., November 28, 2018

Firdapse for Lambert-Eaton Myasthenic Syndrome

Amifampridine tablets (Firdapse, Catalyst Pharmaceuticals) have been approved by the FDA for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. This rare autoimmune disorder affects the connection between nerves and muscles.

Around three in one million individuals worldwide are believed to have LEMS. Patients suffer from significant weakness and fatigue that often causes great difficulties with daily activities. LEMS may be associated with other autoimmune diseases but typically occurs in patients with cancer, such as small-cell lung cancer.

In two clinical trials, patients receiving amifampridine experienced a greater benefit than those taking placebo. The most common side effects reported were paresthesia, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension, and muscle spasms. In addition, seizures have been observed in patients with no history of seizures.

The FDA granted amifampridine priority review, breakthrough therapy, and orphan drug designations.

Source: FDA., November 28, 2018

Vitrakvi to Treat Tumors With NTRK Gene Fusions

The FDA has given accelerated approval to larotrectinib (Vitrakvi, Loxo Oncology) to treat solid tumors with a neurotrophic receptor tyrosine kinase-(NTRK) gene fusion. Larotrectinib is indicated for adult and pediatric patients who have tumors with an NTRK-gene fusion without a known acquired resistance mutation; that are metastatic or where surgical resection is likely to result in severe morbidity; and that have no satisfactory alternative treatments or that have progressed following treatment.

The approval is part of a shift toward treating cancers based on tumor genetics rather than site of origin. NTRK genes, which encode for TRK proteins, can become fused to other genes, resulting in growth signals that support tumor growth. NTRK fusions are rare, but they occur in cancers arising in many parts of the body. Prior to this approval, there had been no treatment for cancers that frequently express this mutation, such as mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma, and infantile fibrosarcoma.

In three clinical trials that included 55 pediatric and adult patients, larotrectinib demonstrated a 75% overall response rate across different types of solid tumors, with 73% of responses lasting at least six months and 39% lasting a year or more. Common side effects included fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting, and increased aspartate transaminase and alanine transaminase.

The FDA granted this application priority review, breakthrough therapy, and orphan drug designations. As larotrectinib received accelerated approval, further clinical trials are required to confirm its clinical benefit.

Source: FDA., November 26, 2018

Daurismo for AML

The FDA has approved glasdegib (Daurismo, Pfizer Inc.), a once-daily oral medicine for the treatment of newly diagnosed AML in adults 75 years of age or older or who have comorbidities that preclude intensive induction chemotherapy.

Glasdegib is the first FDA-approved Hedgehog pathway inhibitor for AML. The Hedgehog signaling pathway plays an essential role in the development of the human embryo. In adults, it is believed that abnormal activation of this pathway contributes to the development and persistence of cancer stem cells.

The standard of care for people with AML is intensive chemotherapy, but for many older patients and those with certain health conditions, intensive treatment is not an option. Glasdegib is taken in combination with low-dose cytarabine (LDAC), which is a type of chemotherapy.

In a randomized clinical trial, the median overall survival was 8.3 months for patients treated with glasdegib plus LDAC compared with 4.3 months for patients treated with LDAC alone. The most commonly reported adverse events included anemia, fatigue, hemorrhage, febrile neutropenia, muscle pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

Source: Pfizer Inc.., November 21, 2018

Gamifant for Primary Hemophagocytic Lymphohistiocytosis

Emapalumab-lzsg (Gamifant, Novimmune SA) has secured FDA approval for the treatment of pediatric (newborn and above) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy. It is the first FDA approval of a drug made specifically for this rare condition.

In HLH, overactive immune cells release molecules that lead to inflammation and organ damage. Primary or “familial” HLH is inherited; symptoms usually develop within the first months or years of life.

In a clinical trial of 27 pediatric patients (median age, one year), 63% experienced a response and 70% were able to proceed to stem cell transplant. Common side effects included infections, hypertension, infusion-related reactions, low potassium, and fever.

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

Source: FDA., November 20, 2018

Generic Drug Approvals

Bismuth Subsalicylate Chewable Tablets, Metronidazole Tablets, and Tetracycline Hydrochloride Capsules

The FDA has approved the sale of 262.4-mg bismuth subsalicylate chewable tablets USP, 250-mg metronidazole tablets USP, and 500-mg tetracycline hydrochloride capsules USP by Ailex Pharmaceuticals, LLC. This is the first generic version of HELIDAC Therapy (Casper Pharma LLC), which is indicated for the eradication of Helicobacter pylori in patients with H. pylori infection and duodenal ulcer disease (active or with a history of duodenal ulcer).

Source: FDA., November 30, 2018

Colchicine Capsules

Par Pharmaceutical, Inc. has received FDA approval to market 0.6-mg colchicine capsules, the first generic version of Mitigare capsules (Hikma Pharmaceuticals), which are indicated for the prophylaxis of gout flares in adults.

Source: FDA., November 29, 2018

Dexmedetomidine Hydrochloride Injection

Fresenius Kabi USA, LLC, has secured the FDA’s permission to market dexmedetomidine hydrochloride in a 0.9% sodium chloride injection, 80 mcg/20 mL, 200 mcg/50 mL, and 400 mcg/100 mL (4 mcg/mL), single-dose containers. This is the first generic version of these formulations of Precedex (Hospira), which is indicated for the sedation of non-intubated patients prior to and/or during surgical and other procedures.

Source: FDA., November 29, 2018

Aminocaproic Acid Tablets

The FDA has approved the sale of 500-mg and 1,000-mg aminocaproic acid tablets, USP, by Sunny Pharmtech Inc. This is the first generic version of Amicar (Clover Pharmaceuticals), which is indicated for enhancing hemostasis when fibrinolysis contributes to bleeding.

Source: FDA., November 27, 2018

Oxycodone Hydrochloride/ Acetaminophen Oral Solution

The FDA has approved the sale of oxycodone hydrochloride and acetaminophen oral solution, 10 mg/300 mg per 5 mL, by Mikart, Inc. This is the first generic version of Roxicet (WestWard Pharmaceuticals), which is indicated for the management of pain that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Source: FDA., November 27, 2018

Buprenorphine Transdermal System

Watson Laboratories, Inc. has received approval to market the buprenorphine transdermal system, 5 mcg/hour, 10 mcg/ hour, 15 mcg/hour, and 20 mcg/hour. This is the first generic version of Butrans (Purdue Pharma LP), which is indicated for the management of pain that is severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are insufficient.

Source: FDA., November 20, 2018

Dyclonine Hydrochloride Topical Solution

The FDA has approved the sale of Novocol Healthcare’s dyclonine hydrochloride topical solution, 0.5% and 1%, under the brand name DycloPro. This is the first generic version of Dyclone (AstraZeneca), which is indicated for anesthetizing accessible mucous membranes prior to various endoscopic procedures.

Source: FDA., November 20, 2018

Docosanol Cream, 10%

Actavis Laboratories FL, Inc. has received FDA approval for the sale of over-the-counter docosanol cream, 10%. This is the first generic version of Abreva, 10% (GlaxoSmithKline), which is indicated for cold sores and fever blisters on the face or lips.

Source: FDA., November 19, 2018


Cabometyx for Patients With Aggressive Liver Cancer

Exelixis received FDA approval for cabozantonib (Cabometyx) for patients with hepatocellular carcinoma (HCC) who have previously received Nexavar (sorafenib, Bayer).

Cabozantonib’s new indication is an important treatment advance for patients with HCC, an aggressive liver cancer. There are limited treatment options available, particularly once the disease has progressed with sorafenib treatment.

The FDA granted approval based on results from a phase 3 clinical trial of cabozantinib versus placebo for patients with HCC who had previously received sorafenib.

Patients administered cabozantinib had significantly improved rates of overall survival and progression-free survival versus patients receiving placebo. Also, those treated with cabozantinib were more likely to achieve partial response or stable disease versus those receiving placebo. Common serious adverse events included palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea. Treatment-related grade 5 adverse events, which occurred in six patients, were hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome.

Cabozantinib was previously approved for patients with advanced renal cell carcinoma.

Source:, January 15, 2019

Oxtellar XR As Monotherapy in Partial-Onset Seizures

The FDA has expanded the indication for oral, once-daily, extended-release oxcarbazepine (Oxtellar XR, Supernus Pharmaceuticals, Inc.) to include monotherapy as well as adjunctive therapy in the treatment of partial-onset seizures in adults and in children 6 to 17 years of age. The product is available in 150-mg, 300-mg, and 600-mg extended-release tablets.

Source: Supernus Pharmaceuticals., Inc., December 14, 2018

Tecentriq, Avastin, and Chemo For Initial Treatment of NSCLC

The FDA has approved atezolizumab (Tecentriq, Genentech), in combination with bevacizumab (Avastin, Genentech), paclitaxel, and carboplatin (chemotherapy), for the first-line treatment of people with metastatic nonsquamous non–small-cell lung cancer (NSCLC) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

This approval is based on results from the phase 3 IMpower150 study, which showed that this combination significantly improved overall survival (OS) compared to bevacizumab and chemotherapy (median OS, 19.2 vs. 14.7 months) in the intention-to-treat, wild-type population. The safety profile of the combination was consistent with that observed in previous studies.

Genentech is working with the FDA on post-marketing commitments to better understand and characterize the potential effects of atezolizumab-related antidrug antibodies and neutralizing antibodies across all studies.

Atezolizumab is also approved for people with metastatic NSCLC with disease progression during or following platinum-containing chemotherapy, who have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK genetic alterations.

Source: Genentech., December 6, 2018

Venclexta for AML

The FDA has granted accelerated approval to venetoclax tablets (Venclexta, AbbVie/Genentech) in combination with a hypomethylating agent (azacitidine or decitabine) or low-dose cytarabine (LDAC) for newly diagnosed AML in adults aged 75 years or older or who have comorbidities that preclude intensive induction chemotherapy.

The approval is based on two open-label, non-randomized trials in this patient population. M14-358 evaluated venetoclax in combination with azacitidine (n = 67) or decitabine (n = 13), and M14-387 evaluated venetoclax and LDAC (n = 61). Efficacy was established based on the rate of complete remission (CR) and duration of CR.

In M14-358, the use of venetoclax with azacitidine resulted in a CR rate of 37%, and the median time in remission was 5.5 months. For venetoclax with decitabine, the CR rate was 54%, with a median observed time in remission of 4.7 months. In M14-387, patients taking venetoclax with LDAC achieved a CR rate of 21%, and the median observed time in remission was six months.

Serious adverse reactions were reported in 75% of patients using venetoclax with azacitidine, in 85% of patients using venetoclax and decitabine, and in 95% of patients using venetoclax with LDAC. The most common serious adverse effects of these regimens were a low white-blood-cell count with fever, pneumonia, bacteria in the blood, inflammation of the tissue under the skin, device-related infection, diarrhea, fatigue, bleeding, localized infection, multiple organ dysfunction syndrome, and respiratory failure.

Continued approval of this new indication for venetoclax (an oral B-cell lymphoma-2 inhibitor) may be contingent upon verification and description of clinical benefit in confirmatory trials.

Sources: AbbVie. and Genentech, November 21, 2018


Tolsura for Fungal Infections

The FDA has approved a new formulation of itraconazole capsules (Tolsura, Mayne Pharma Group Ltd.) for the treatment of some systemic fungal infections in adults.

Tolsura is indicated for blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis) and aspergillosis (pulmonary and extrapulmonary, in patients who are intolerant of or refractory to amphotericin B therapy). These serious infections most commonly occur in vulnerable or immunocompromised patients—for example, those with a history of cancer, transplants, human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS), or chronic rheumatic disorders—and are often associated with high mortality rates or long-term health issues.

This formulation of itraconazole incorporates Mayne Pharma’s proprietary SUBA (SUper-BioAvailable) technology to improve the bioavailability of poorly soluble drugs. Tolsura has been shown in clinical studies to have increased bio-availability and significantly reduced variability compared to conventional oral itraconazole capsules.

The product has a boxed warning related to the risks of congestive heart failure and certain drug interactions.

Source: Mayne Pharma Group Ltd.., December 11, 2018

Dextenza for Eye Pain After Surgery

Dextenza (dexamethasone ophthalmic insert, Ocular Therapeutix) has become the first FDA-approved, single-administration insert for eye pain after ophthalmic surgery. The single 0.4-mg dose is released over 30 days and does not require removal as it is resorbable.

The preservative-free product offers an alternative to the current, complex eye-drop regimen, which necessitates administering up to 70 topical steroid drops. Compliance with eye-drop use after ophthalmic surgery has proved challenging for patients.

In two randomized, phase 3 clinical trials, patients who received dexamethasone ophthalmic insert following cataract surgery showed a statistically significant improvement in pain. The most common ocular adverse reactions were anterior chamber inflammation including iritis and iridocyclitis, increased intraocular pressure, reduced visual acuity, eye pain, cystoid macular edema, corneal edema, and conjunctival hyperemia. The most common non-ocular adverse event was headache.

The drug is contraindicated in patients with active corneal, conjunctival, or canalicular infections; mycobacterial infections; fungal diseases of the eye; and dacryocystitis. For any persistent corneal ulceration, fungal invasion must be considered and a fungal culture should be taken when appropriate.

Source: Ocular Therapeutics., December 3, 2018

ACTPen for Actemra

The FDA has approved the ACTPen 162 mg/0.9 mL, a single-dose, prefilled autoinjector for tocilizumab (Actemra, Genentech), as an additional formulation for adults with moderate-to-severe, active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs, and for adults with giant cell arteritis. Caregivers can also use the ACTPen to inject patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis.

Approval is based on data from two studies which showed that single-dose subcutaneous administration of 162 mg of tocilizumab with ACTPen was bio-equivalent to administration with the currently marketed prefilled syringe, and that the intended users of ACTPen were successful in performing the tasks required to administer doses of tocilizumab. Adverse events associated with tocilizumab in both studies were consistent with the medicine’s established safety profile.

Source: Genentech., November 26, 2018


Breakthrough Therapy Status

NRX-101 for Suicidal Bipolar Depression

NeuroRx has received a breakthrough therapy designation for NRX-101, which would be the first oral treatment for severe bipolar depression with acute suicidal ideation and behavior after initial stabilization with ketamine or other effective therapy. Each year, more than 25,000 patients lose their lives to severe bipolar depression.

NRX-101 is a fixed-dose combination of D-cycloserine (DCS), an NMDA antagonist, and lurasidone, which has 5-HT2a receptor antagonist activity. Currently approved antidepressants primarily raise serotonin levels, but DCS raises levels of the neurotransmitters glutamate and glutamine. Thus, NRX-101 may represent a new class of antidepressants that could reduce suicidal thoughts; serotonin-based antidepressants are associated with an increased suicide risk suicide in vulnerable populations.

The designation is partly based on study results from STABIL-B, which evaluated the clinical effect of NRX-101 compared with lurasidone. Data indicate the drug was well tolerated in participants.

Source: NeuroRx, Inc.., November 13, 2018

Fast-Track Designations

ACE-083 for Charcot-Marie-Tooth Disease

Acceleron Pharma Inc. was granted a fast-track designation for ACE-083, a muscle agent for the treatment of patients with Charcot-Marie-Tooth disease (CMT).

CMT is the most common inherited neurologic disease, estimated to affect more than 125,000 people in the U.S. Clinical manifestations include muscle weakness in the lower legs. There are no FDA-approved therapies.

ACE-083, a locally acting therapeutic candidate based on the naturally occurring protein follistatin, uses the myostatin+ approach to inhibit multiple TGF-beta superfamily ligands. It is designed to have a concentrated effect on the targeted muscles where it is administered, maximizing growth and strength.

ACE-083 is being evaluated in two phase 2 trials: one in CMT and one in facioscapulohumeral muscular dystrophy. To date, results have shown that patients treated with ACE-083 experience robust increases in muscle volume.

Source: Acceleron Pharma Inc.., November 28, 2018

HTD1801 for Nonalcoholic Steatohepatitis

HighTide Therapeutics Inc. has received a fast-track designation for HTD1801 for the treatment of patients with nonalcoholic steatohepatitis (NASH).

NASH, a form of nonalcoholic fatty liver disease, is a chronic, complex illness characterized by hepatitis and liver-cell damage that can lead to cirrhosis and liver cancer. There are no approved therapies for this condition.

HTD1801, a multifunctional oral therapeutic, was designed to address the complex nature of NASH, especially for patients with comorbid diabetes and/or dyslipidemia. HighTide has completed a first-in-human study of HTD1801 in healthy volunteers. A U.S. multicenter, phase 2 trial in adults with NASH is scheduled to begin enrollment in the near future.

Source: HighTide Therapeutics Inc., November 27, 2018

Priority Review Status

Tecentriq for Small-Cell Lung Cancer

The FDA has accepted a supplemental biologics license application and granted priority review for atezolizumab (Tecentriq, Genentech) in combination with carboplatin and etoposide for the initial treatment of people with extensive-stage small-cell lung cancer. The agency is expected to decide on approval by March 18, 2019.

Atezolizumab is a monoclonal antibody designed to inhibit programmed death ligand-1, which may enable the reactivation of T cells.

The new application is based on results from the phase 3 IMpower133 study evaluating atezolizumab in combination with chemotherapy (carboplatin and etoposide) versus chemotherapy alone in chemotherapy-naïve patients with extensive-stage small-cell lung cancer. Atezolizumab plus chemotherapy versus chemotherapy alone extended overall survival (12.3 vs. 10.3 months) and progression-free survival at one year (12.6% vs. 5.4%). The safety profile for the combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified.

Source: Genentech, December 5, 2018

Quizartinib for AML

The FDA has granted a priority review designation for quizartinib (Daiichi Sankyo) for the treatment of adults who have relapsed or refractory FLT3-ITD AML.

AML, an aggressive blood and bone marrow cancer, causes uncontrolled growth and accumulation of malignant white blood cells. The five-year survival rate is approximately 26%. FLT3 mutations are one of the most common genetic abnormalities in AML, and FLT3-ITD is the most common FLT3 mutation, affecting around one in four patients. Patients with FLT3-ITD AML have a poor prognosis.

The application is based on results from QuANTUM-R, the first phase 3 study to show that an FLT3 inhibitor prolonged overall survival as an oral single agent versus chemotherapy in patients with relapsed or refractory FLT3-ITD AML.

Source: Daiichi Sankyo, November 21, 2018

Orphan Drug Designations

INT41 for Huntington’s Disease

The FDA has given an orphan drug designation to INT41 (Vybion Inc.) for Huntington’s disease, a fatal neurodegenerative illness marked by progressive decline in motor and cognitive function.

INT41 is an intrabody delivered with a recombinant adeno-associated virus (AAV). Intrabodies are small antibody formats that can function within the cell when delivered by appropriate means, such as an AAV. Certain AAV serotypes are neurotropic and provide a delivery approach that has been used for multiple neurologic diseases. Work on animal models and mechanism of action has been completed for INT41.

Source: Vybion Inc., December 3, 2018

OBI-888 for Pancreatic Cancer

OBI Pharma, Inc. has received an orphan drug designation for OBI-888 for the treatment of pancreatic cancer.

Pancreatic cancer has a survival rate of only 8.5% at five years. Treatment options are limited to surgical resection for patients with early stages of the disease, but this asymptomatic illness is often undiagnosed or misdiagnosed until the advanced stages.

OBI-888 is a first-in-class monoclonal antibody immunotherapy targeting Globo H, a glycolipid antigen expressed in up to 15 epithelial cancers. OBI-888 induces tumor-killing via antibody-dependent, cell-mediated cytotoxicity; antibody-dependent, cell-mediated phagocytosis; and complement-dependent cytotoxicity.

In preclinical xenograft animal models in pancreatic, colon, lung, and breast tumors, OBI-888 demonstrated tumor shrinkage at various doses. It was well tolerated in subjects, with no adverse effects found in all doses tested.

Source: OBI Pharma, November 21, 2018

PLN-74809 for Primary Sclerosing Cholangitis

The FDA has granted orphan drug status to Pliant Therapeutic’s antifibrotic compound PLN-74809 for the treatment of primary sclerosing cholangitis (PSC).

PSC is a chronic and progressive liver disorder of unknown origin that frequently occurs in the setting of inflammatory bowel disease. It is characterized by inflammation and eventual fibrosis of the liver and its bile ducts. More than 50% of patients require a liver transplantation within 10 to 15 years of diagnosis. There are no approved therapies.

PLN-74809 targets the fibrotic process in the liver cells and bile ducts, potentially slowing progression of the disease. In preclinical studies, PLN-74809 modulated fibrotic tissue-specific integrins that selectively block the activation of TGF-beta, preventing the growth of fibrotic tissue within the lung and liver.

Source: Pliant Therapeutics, November 20, 2018

Complete Response Letter

Reformulation of Roxicodone

The FDA has sent a complete response letter to SpecGx LLC (a subsidiary of Mallinckrodt PLC) relating to its new drug application (NDA) for an abuse-deterrent, immediate-release reformulation of oxycodone hydrochloride tablets. Roxicodone has been formulated for the management of pain that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

The agency “provided guidance regarding areas of further evaluation necessary to resubmit the NDA for further review and potential approval of the drug, which was designed with properties to deter intravenous and intranasal abuse,” Mallinckrodt said. The company expressed disappointment, but said it will meet with the FDA and “continue to pursue a pathway to try to gain approval of the drug.”

Source: Mallinckrodt PLC, December 12, 2018


Chinese Plant Targeted in Valsartan Impurity Probe

The FDA has issued a warning letter to Zhejiang Huahai Pharmaceutical Co. Ltd. (ZHP) in Linhai, Taizhou Zhejiang, China, manufacturer of the active pharmaceutical ingredient (API) in valsartan that is the focus of an ongoing investigation into probable cancer-causing impurities in some common heart medicines.

The letter outlines manufacturing violations at ZHP’s Chuannan facility, including impurity control, change control, and cross-contamination from one manufacturing process line to another. The agency is still looking into the root cause of the impurity.

The ZHP facility manufactures APIs including valsartan, a drug in the angio-tensin II receptor blocker (ARB) class that is used to treat high blood pressure and heart failure. On September 28, the FDA also put this facility on import alert, stopping all APIs made there, as well as finished drug products made using its APIs, from legally entering the U.S.

The FDA announced recalls of valsartan beginning in July because of the presence of N-Nitrosodimethylamine (NDMA) in APIs supplied by ZHP. Subsequent international investigations were expanded to include all manufacturers of APIs and finished drugs in the ARB class, and have resulted in additional recalls of valsartan, irbesartan, and losartan-containing products found to contain NDMA and N-Nitrosodiethylamine— both of which are known animal and suspected human carcinogens.

Source: FDA, December 11, 2018

Lemtrada and Strokes

Rare but serious cases of stroke and tears in the lining of head and neck arteries have occurred in patients with multiple sclerosis (MS) shortly after they received alemtuzumab (Lemtrada, Genzyme). As a result, the FDA has added a new warning about these risks to the prescribing information in the drug label and to the patient medication guide. The agency has also added the risk of stroke to the existing boxed warning.

Alemtuzumab is also approved under the brand name Campath (Genzyme) to treat B-cell chronic lymphocytic leukemia. The Campath drug label will also be updated to include these risks in the adverse reactions section under post-marketing experience.

Since the FDA’s 2014 approval of alemtuzumab to treat relapsing forms of MS, the agency has identified 13 worldwide cases of ischemic and hemorrhagic stroke or arterial dissection that occurred shortly after the patient received alemtuzumab. One patient who suffered a hemorrhagic stroke died. Symptoms were reported within one day of receiving alemtuzumab by 12 patients and after three days by one patient. This analysis includes only reports submitted to the FDA.

Health care professionals should advise patients at every infusion of alemtuzumab to seek immediate emergency medical attention if they experience symptoms of ischemic or hemorrhagic stroke or cervicocephalic arterial dissection.

Source: FDA, November 29, 2018

Idhifa and Differentiation Syndrome

The FDA warns that signs and symptoms of life-threatening differentiation syndrome are going unrecognized in patients receiving enasidenib (Idhifa, Celgene) for acute myeloid leukemia (AML).

In the clinical trial conducted for enasidenib’s approval, at least 14% of patients experienced differentiation syndrome. A more recent systematic analysis by the FDA identified a differentiation syndrome incidence of 19%; 5% of the cases were fatal. Celgene’s safety report for May 1 to July 31, 2018, included five deaths associated with differentiation syndrome in patients taking enasidenib.

The drug’s prescribing information and patient medication guide already contain a warning about differentiation syndrome, but the FDA is reminding health care professionals and patients about the need for early recognition and aggressive management, including corticosteroids. Differentiation syndrome has occurred as early as 10 days and up to five months after starting enasidenib.

Health care professionals should describe to patients differentiation syndrome symptoms, including fever, cough, shortness of breath, swelling of arms and legs, swelling around the neck, groin, or underarm, fast weight gain of more than 10 pounds within a week, bone pain, dizziness, or lightheadedness.

Enasidenib was approved in 2017 for AML in patients with an isocitrate dehydrogenase- 2 genetic mutation whose disease has returned or has not improved after treatment with other chemotherapy medicines. The drug blocks several enzymes that promote abnormal white-blood- cell growth.

Source: FDA, November 29, 2018

MS May Worsen Sharply After Discontinuing Gilenya

When patients stop taking fingolimod (Gilenya, Novartis), MS can become much worse than it was before the medicine was started or while it was being taken. This increase in severity is rare but can result in permanent disability. The FDA has added a new warning about the risk to the prescribing information and the patient medication guide.

Between 2010, when fingolimod was approved to treat relapsing MS, and 2018, the FDA identified 35 cases of severely increased disability accompanied by the presence on magnetic resonance imaging scans of multiple new lesions that occurred two to 24 weeks after stopping fingolimod. Most patients experienced this worsening in the first 12 weeks after stopping the drug. The increase in dis-ability was more severe than that occurring in typical MS relapses, and in cases where the baseline disability was known, it appeared unrelated to the patients’ prior disease state. Seventeen patients had partial recovery, eight experienced permanent disability or no recovery, and six eventually returned to the same level of disability they had before or during fingolimod treatment.

Health care professionals should inform patients before starting treatment about the potential risk of a severe increase in disability after stopping this drug. Upon stopping fingolimod, patients should be carefully observed for evidence of exacerbation of their MS symptoms.

Source: FDA, November 20, 2018

Implanted Pumps and Intrathecal Pain Drugs

Serious complications can occur when implanted pumps are used to deliver medications that have not been approved for the purpose into the spinal fluid to treat or manage pain. Complications may include dosing errors, pump failure, opioid withdrawal, infection, pain, fever, vomiting, muscle spasms, cognitive changes, weakness, and cardiac or respiratory distress.

Implanted pumps are surgically inserted under the skin and connected to an implanted catheter to deliver medicines. They treat diseases, conditions, and pain by delivering medicine into the body, including the spinal fluid or intrathecal space. The pump requires periodic refilling with medication by a health care provider. Intrathecal delivery of medication with an implanted pump is generally reserved for patients who are inadequately managed by other pain treatments.

FDA-approved labeling (Instructions for Use) identifies medicines that have been evaluated for compatibility with the pump, including Infumorph (West-Ward Pharmaceuticals) and Prialt (TerSera Therapeutics). However, not all pumps are approved for use with Prialt. Drugs that are approved for intrathecal administration must meet additional safety standards over those administered in other ways because the spinal cord and brain tissue are highly sensitive to preservatives or infectious organisms such as bacteria or viruses, which can cause serious complications.

The FDA found that some patients are being treated with medications that are not approved (including compounded medicines, and hydromorphone, bupivacaine, fentanyl, and clonidine) for use with intrathecal implanted pumps. Pump failure occurs more frequently with such medicines, which may contain preservatives or have other characteristics that can damage the tubing or lead to corrosion of the mechanism.

Source: FDA, November 14, 2018


World-First Device Treats Pre-mature Babies, Newborns With Heart Openings

Each year, almost 12,000 underweight babies are born in the U.S. with a heart opening requiring medical intervention. The FDA has now approved a ground-breaking device to treat patent ductus arteriosus (PDA) that can be implanted in babies weighing as little as two pounds.

Abbott’s Amplatzer Piccolo Occluder, which is smaller than a pea, offers hope to premature infants and newborns who may not respond to medical management and are a high risk for heart surgery.

PDA is a common congenital heart defect in premature babies. A potentially life-threatening opening between two blood vessels leading from the heart, it is present in the developing fetus and allows the mother’s blood to circulate throughout the fetus’ body. Usually, the PDA closes naturally before birth but in premature babies, it can fail to close, leading to breathing difficulties.

The Amplatzer Piccolo is a self-expanding, wire mesh device that can be inserted through the aortic or pulmonary artery. The physician inserts it through a small incision in the leg, guiding it through vessels to the heart, where it seals the opening. The device can also be retrieved and reinserted for optimal placement.

The FDA’s approval was based partly on results from the pivotal ADO II AS trial. The trial enrolled 50 patients with a PDA who were older than 3 days at eight centers across the U.S. The safety and efficacy of the device is further supported by additional data from a continued access protocol with 150 more patients.

Source:, January 14, 2019

Mobile App for Opioid Recovery

The FDA has cleared a medical mobile app to increase retention in outpatient programs for opioid use disorder (OUD). Pear Therapeutics’ ReSET-O is a cognitive behavioral therapy for use in addition to outpatient treatment under the care of a health care professional, in conjunction with buprenorphine treatment and contingency management.

Sometimes, patients find their commitment to staying in treatment wanes. Medical devices, including apps, can play an important role in helping them comply with treatment regimens. Providing patients with OUD with more options and proper support to address treatment challenges is key to helping them succeed.

ReSET-O can be downloaded to mobile devices after patients receive a prescription. It is intended to be used while they are participating in an outpatient OUD treatment program, and can also serve as a training, monitoring, and reminder tool for health care providers.

There is no evidence that ReSET-O decreases illicit drug use or improves abstinence in patients with OUD. Clinical study data did not indicate any side effects associated with the program used in the trial. Adverse events were typical of patients with OUD: cardiovascular disease, gastrointestinal diseases, human immunodeficiency virus, hepatitis C, nutrition-related diseases, risk of over-dose, depression, mania, and suicidal behavior, ideation, and attempts.

The app is not intended to be used as a stand-alone therapy, a substitute for medication, or for non-native English speakers.

Source: FDA, December 10, 2018

Spiration Valve System To Treat Emphysema

The FDA has approved the Spiration Valve System (Olympus Medical Systems Group) for severe emphysema.

Approval was based on EMPROVE trial data showing that patients treated with Spiration benefited from statistically significant and clinically meaningful improvements in lung function and quality of life compared to standard-of-care medical management. Also, the system offers a favorable risk–benefit profile with a short procedure time. Serious adverse events included chronic obstructive pulmonary disease exacerbations, pneumothorax, pneumonia, and death.

The umbrella-shaped Spiration Valve, which is placed in targeted airways in the lung during a short procedure, improves breathing by blocking the airflow to the diseased portion of the lung. The therapy leads to volume reduction in the treated area, allowing healthier tissue to function better.

The FDA granted the device breakthrough medical device and priority review status.

Source: Olympus Medical Systems Group, December 5, 2018

CMV Test for Newborns

The FDA has permitted marketing of the Alethia CMV Assay Test System (Meridian Bioscience, Inc.), a diagnostic test to detect cytomegalovirus (CMV) in newborns younger than 21 days. Most people show no signs or symptoms of infection, but CMV can cause serious health problems in those with weakened immune systems and for some newborns.

Alethia can detect CMV DNA from a saliva swab. Test results should be used only in conjunction with results from other diagnostic tests and clinical information.

Data from a prospective clinical study showed that 1,472 out of 1,475 newborn saliva samples were correctly identified by Alethia as negative for the presence of CMV DNA. Three negative samples were incorrectly identified as positive, and five samples were correctly identified as positive for CMV DNA. The FDA also reviewed data from 34 samples of archived specimens from babies known to be infected with CMV in which all the specimens were correctly identified as positive for the presence CMV DNA.

The test was reviewed through the de novo premarket review pathway.

Source: FDA, November 30, 2018

GammaCore to Prevent Cluster Headaches

ElectroCore, Inc. has received 510(k) clearance to expand its label for gammaCore non-invasive, vagus nerve-stimulator (nVNS) therapy to include adjunctive use for the preventive treatment of cluster headaches in adults. It is the first device or drug to be approved for the prevention of cluster headaches.

In the PREVA pivotal study, intention-to- treat patients receiving standard-of-care and gammaCore during the randomized phase had a greater reduction from baseline (−5.9) in the number of cluster attacks per week than those receiving only standard-of-care alone (−2.1). Also, 40% of patients receiving gammaCore and standard-of-care experienced a 50% or greater reduction in weekly attacks, versus 8.3% of patients receiving standard-of- care alone.

To prevent cluster headaches, adults should self-administer two treatments daily, which consist of three consecutive two-minute stimulations. The first treatment should be applied within one hour of waking and the second applied 7 to 10 hours later.

GammaCore is available by prescription only.

Source: electroCore, Inc., November 28, 2018.