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P T. 2017;42(12): 726-732, 763

Drug and Device News December 2017

NEW DRUG APPROVALS

Yescarta for Lymphoma

Axicabtagene ciloleucel (Yescarta, Gilead Sciences) has become the first FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of adults with relapsed or refractory large B-cell lymphoma who have undergone two or more lines of systemic therapy. The indication includes diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for patients with primary central nervous system lymphoma.

In CAR-T therapy for hematologic cancer, a patient’s own T cells are engineered, on a person-by-person basis, to seek and destroy cancer cells.

The approval of Yescarta, a CD19-directed genetically modified autologous T-cell immunotherapy, is supported by data from the ZUMA-1 trial. In this study, the overall response rate of patients treated with a single infusion of Yescarta (n = 101) was 72%, including 51% who were in complete remission. At a median follow-up of 7.9 months, patients in complete remission had not reached the estimated median duration of response. Thirteen percent of patients experienced grade 3 or higher cytokine release syndrome (CRS), and 31% experienced neurological toxicities; some cases were fatal.

Yescarta has a boxed warning regarding the risks of CRS and neurological toxicities. The FDA approved a risk evaluation and mitigation strategy (REMS) for Yescarta that will educate health care professionals about its risks. Kite, the Gilead subsidiary that developed the treatment, expects to certify 70 to 90 U.S. centers to provide the therapy under the REMS. The U.S. list price of Yescarta is $373,000.

Source: Gilead, October 19, 2017

Calquence for Mantle Cell Lymphoma

The FDA has granted accelerated approval to acalabrutinib (Calquence, AstraZeneca) for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy. Mantle cell lymphoma is a rare, fast-growing type of non-Hodgkin’s lymphoma that has usually spread to the lymph nodes, bone marrow, and other organs by the time it is diagnosed.

Acalabrutinib is a kinase inhibitor that blocks an enzyme needed by the cancer to multiply and spread. In a single-arm trial that included 124 patients with mantle cell lymphoma who had received at least one prior treatment, 81% had a complete (40%) or partial (41%) response. Because acalabrutinib received accelerated approval, further study is required (and under way) to verify its anticipated clinical benefits.

Common side effects of acalabrutinib include headache, diarrhea, bruising, fatigue, myalgia, anemia, thrombocytopenia, and neutropenia. Serious side effects include hemorrhage, infections, and atrial fibrillation. Second primary malignancies have occurred in some patients.

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

Source: FDA, October 31, 2017

Shingrix Shingles Vaccine

The FDA has approved zoster vaccine recombinant, adjuvanted (Shingrix, GlaxoSmithKline), a non-live, recombinant subunit vaccine given intramuscularly in two doses for the prevention of herpes zoster (shingles) in adults 50 years of age and older.

The risk and severity of shingles increase with age as the immune system weakens. Shingrix combines an antigen, glycoprotein E, and an adjuvant system, AS01B, intended to generate a strong and long-lasting immune response. Its approval was based on phase 3 clinical trials evaluating its efficacy, safety, and immunogenicity in more than 38,000 people. In a pooled analysis, Shingrix demonstrated efficacy of more than 90%, sustained over a follow-up period of four years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) has recommended that Shingrix be used instead of Zostavax (Merck) for shingles prevention and that adults who previously received Zostavax should now receive Shingrix. The ACIP also lowered its recommended age threshold for vaccination from 60 years of age to 50 years of age. The CDC director and the Department of Health and Human Services must review and approve the ACIP recommendations.

Sources: GlaxoSmithKline, October 20 and 25, 2017

Zilretta for Arthritic Knee Pain

Flexion Therapeutics has received FDA approval for triamcinolone acetonide extended-release injectable suspension (Zilretta), the first extended-release, intra-articular injection for osteoarthritis (OA) knee pain.

Zilretta employs proprietary microsphere technology combining triamcinolone acetonide, a commonly administered, short-acting corticosteroid, with a poly(lactic-co-glycolic acid) matrix. The nonopioid medication provides pain relief over 12 weeks and is not intended for repeat administration.

The approval was based on a phase 3, randomized, double-blind clinical trial that enrolled patients at 37 centers worldwide. A total of 484 patients who received Zilretta 32 mg, placebo, or immediate-release triamcinolone acetonide 40 mg were followed for up to 24 weeks. Compared with placebo, Zilretta demonstrated a statistically significant reduction from baseline at week 12 in the weekly mean of average daily pain intensity scores as assessed by a 0–10 rating scale.

Zilretta’s label also includes results from a double-blind, randomized, parallel-group trial that examined blood glucose concentrations in patients with type-2 diabetes. The trial demonstrated that Zilretta may avoid the disruptive blood glucose spikes that can be seen with corticosteroid use in patients coping with both knee OA and type-2 diabetes.

Sources: Flexion Therapeutics, Inc., October 6, 2017; and Zilretta prescribing information, October 2017

Generic Approval

Glatiramer Acetate Injection

The FDA has approved two formulations of Mylan’s glatiramer acetate injection—40 mg/mL for three-times-a-week injection and 20 mg/mL for once-daily injection. These generic versions of Copaxone (Teva) are indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). The 40-mg/mL formulation had not been available previously as a generic.

Copaxone is the most prescribed treatment for relapsing forms of MS in the United States, with brand sales for the 20-mg/mL dose of approximately $700 million and for the 40-mg/mL dose of approximately $3.64 billion for the 12 months ending July 31, 2017, according to QuintilesIMS.

Source: Mylan, October 3, 2017

NEW INDICATIONS

Simponi Aria for PsA, AS

Golimumab (Simponi Aria, Janssen Biotech, Inc.) has received FDA approval for the treatment of adults with active psoriatic arthritis (PsA) or active ankylosing spondylitis (AS). Golimumab, a fully human anti-tumor necrosis factor-alpha therapy administered via a 30-minute infusion, first received FDA approval in 2013 for the treatment of moderately to severely active rheumatoid arthritis.

The new approvals are based on two large-scale, pivotal phase 3 studies.

In the GO-VIBRANT (PsA) study, 75% of patients receiving golimumab, compared with 22% of patients receiving placebo, achieved at least a 20% improvement in the American College of Rheumatology response at week 14. Treatment with golimumab resulted in the inhibition of the progression of structural joint damage and improvement in physical function associated with PsA at week 24.

In the GO-ALIVE (AS) study, 73% of patients receiving golimumab, compared with 26% of patients receiving placebo, achieved at least a 20% improvement in the Assessment of Spondyloarthritis International Society criteria at week 16.

Source: Janssen, October 20, 2017

Stelara for Adolescent Psoriasis

The FDA has approved an expanded indication for ustekinumab (Stelara, Janssen Biotech, Inc.) for the treatment of patients 12 years of age or older with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

The approval is based on a phase 3 study of the efficacy and safety of subcutaneous administration of ustekinumab in patients in this age group. At least two-thirds of patients receiving ustekinumab were responders at the week 12 primary endpoint after doses at weeks 0 and 4, defined by achieving a Physician’s Global Assessment score of 0 or 1. Safety findings were consistent with those in adults.

Ustekinumab is a fully human interleukin (IL)-12 and IL-23 antagonist administered subcutaneously at weeks 0 and 4, then every 12 weeks thereafter. It is also indicated under certain circumstances for the treatment of patients 18 years of age and older with psoriatic arthritis and Crohn’s disease.

Source: Janssen, October 13, 2017

Rivaroxaban VTE Dosing

Janssen has received FDA approval for the 10-mg once-daily dosing of rivaroxaban (Xarelto) for reducing the continued risk of recurrent venous thromboembolism (VTE) after patients complete at least six months of initial anticoagulation therapy. This approval is based on the Einstein Choice trial, in which the factor Xa inhibitor demonstrated superior efficacy in reducing the continued risk of recurrent VTE with major bleeding rates similar to aspirin.

The rivaroxaban prescribing information has been amended to instruct prescribers to begin patient treatment with 15 mg, dosed twice daily, for the first 21 days after a VTE occurrence. On day 22 through at least day 180, the daily dose decreases to 20 mg once daily. After at least 180 days, physicians can prescribe 10 mg once daily for patients at continued risk for DVT and/or PE.

If anticoagulation therapy is stopped, up to 20% of patients will have a recurrent VTE within three years.

Source: Janssen, October 30, 2017

NEW FORMULATIONS

Larger Alunbrig Tablets

The FDA has approved a 180-mg brigatinib tablet (Alunbrig, Takeda) that allows once-daily dosing with a single pill rather than six.

Brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non–small-cell lung cancer who have progressed on or are intolerant to crizotinib (Xalkori, Pfizer). Initially, it was available only in 30-mg tablets; patients had to take three pills daily (for the first seven days) followed, if tolerated, by six pills daily. With the approval of a 180-mg tablet, brigatinib became the only ALK inhibitor available as a once-a-day pill that can be taken with or without food.

Source: Takeda, October 3, 2017

Easier-to-Use Bydureon

A new formulation of extended-release exenatide—an injectable suspension called Bydureon BCise (AstraZeneca) in an improved once-weekly, single-dose autoinjector—has received FDA approval for adults with type-2 diabetes whose blood sugar remains uncontrolled on one or more oral medicines in addition to diet and exercise.

Unlike other glucagon-like peptide-1 receptor agonists, Bydureon BCise has a continuous-release microsphere delivery system designed to provide consistent therapeutic levels of exenatide to help patients reach and maintain steady state. Across two clinical trials, average hemoglobin A1c reductions of up to 1.4% and average weight loss of up to 3.1 pounds were achieved when used as monotherapy or as an add-on to metformin, a sulfonylurea, a thiazolidinedione, or any combination of two of these oral antidiabetic medicines at 28 weeks.

Bydureon BCise will be available in the U.S. in the first quarter of 2018. Bydureon Pen will also remain available. They should not be used to treat type-1 diabetes or diabetic ketoacidosis.

Source: AstraZeneca, October 23, 2017

Intravenous Varubi

An intravenous (IV) formulation of rolapitant (Varubi, Tesaro, Inc.) has won FDA approval to help prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy, including but not limited to highly emetogenic chemotherapy. Rolapitant IV is indicated in combination with other antiemetic agents in adults.

Delayed nausea and vomiting can occur 25 to 120 hours following chemotherapy. Rolapitant is a highly selective, competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV). With a plasma half-life of about seven days, a single dose of rolapitant, as part of an antiemetic regimen, significantly improved complete response rates in the delayed phase of CINV.

Results from three phase 3 trials of rolapitant oral tablets demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy. In addition, patients who received rolapitant reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. Results from a bioequivalence trial demonstrated comparability of the IV and oral formulations of rolapitant.

Source: Tesaro, October 25, 2017

Extended-Release Lyrica

The FDA has approved extended-release pregabalin tablets (Lyrica CR, Pfizer, Inc.) as once-daily therapy for the management of neuropathic pain associated with diabetic peripheral neuropathy (pDPN) and the management of post-herpetic neuralgia (PHN). Lyrica CR did not receive approval for the management of fibromyalgia.

The efficacy and safety of the new formulation were established by a randomized, placebo-controlled trial in 801 PHN patients that included a six-week, single-blind, dose optimization phase followed by a 13-week double-blind phase. In the study, 73.6% of patients in the extended-release pregabalin group achieved at least 50% improvement in pain intensity compared with 54.6% in the placebo group. Because both pDPN and PHN are peripheral neuropathic pain conditions, the PHN data was supportive of both indications.

Source: Pfizer, Inc., October 12, 2017

Ingrezza 80-mg Capsules

An 80-mg valbenazine capsule (Ingrezza, Neurocrine Biosciences) has received FDA approval for the treatment of adults with tardive dyskinesia. Valbenazine, a selective vesicular monoamine transporter 2 inhibitor, was approved by the FDA in April 2017 as a 40-mg capsule. The typical daily dose is 80 mg, meaning patients would need to take only one capsule of the new strength each day.

Source: Neurocrine Biosciences, October 5, 2017

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

Tagrisso for EGFR-Mutant NSCLC

The FDA has granted breakthrough therapy designation for osimertinib (Tagrisso, AstraZeneca) for the first-line treatment of patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non–small-cell lung cancer (NSCLC).

The designation is based on the phase 3 FLAURA trial of osimertinib versus standard-of-care EGFR tyrosine kinase inhibitor (TKI) therapy in previously untreated patients with locally advanced or metastatic EGFR mutation-positive NSCLC. Median progression-free survival was 18.9 months for osimertinib and 10.2 months for EGFR-TKIs (erlotinib or gefitinib [Iressa, AstraZeneca]). Improvements were seen in all prespecified subgroups, including patients with and without brain metastases.

In September 2017, the National Comprehensive Cancer Network guidelines were updated to include the use of osimertinib in the first-line treatment of patients with locally advanced or metastatic EGFR mutation-positive NSCLC. Tagrisso is approved in the U.S. as second-line treatment for patients with advanced NSCLC who progress following treatment with an EGFR-TKI due to the EGFR T790M resistance mutation.

Source: AstraZeneca, October 9, 2017

Valoctocogene Roxaparvovec For Hemophilia A

Valoctocogene roxaparvovec (formerly BMN 270, BioMarin Pharmaceutical, Inc.) has secured an FDA breakthrough therapy designation as a treatment for hemophilia A based on data from an ongoing phase 1/2 study.

The investigational therapy inserts a corrected copy of a defective gene into a vector containing a DNA sequence coding for factor VIII, a clotting protein. The cells use the information to build functional factor VIII.

The global phase 3 program includes two studies with valoctocogene roxaparvovec, one with a 4e13-vg/kg dose and one with a 6e13-vg/kg dose. The studies will each likely include approximately 40 patients.

Valoctocogene roxaparvovec has also received an FDA orphan drug designation for the treatment of hemophilia A.

Source: BioMarin Pharmaceutical, Inc., October 26, 2017

DAS181 for Lower Respiratory Infection

The FDA has granted breakthrough therapy status to Ansun BioPharma’s first-in-class experimental compound DAS181 for the treatment of lower respiratory tract parainfluenza virus (PIV) infection in immunocompromised patients.

DAS181 utilizes a host-directed approach to block respiratory viruses by cleaving sialic acid receptors located in the human respiratory tract that are bound by most of the major respiratory viruses. DAS181 makes it difficult for viruses that rely on sialic acid receptors for entry to develop resistance; little to no resistance has been observed in multiple clinical studies. In addition to PIV, DAS181 has demonstrated activity against influenza virus, metapneumo-virus, and human enterovirus-68.

Ansun recently completed a phase 2 study of DAS181 and is planning a phase 3 study. DAS181 has also received a fast-track designation for this indication.

Source: Ansun BioPharma, October 10, 2017

Cemiplimab for Squamous Cell Carcinoma

Cemiplimab (REGN2810, Regeneron Pharmaceuticals/Sanofi) has received an FDA breakthrough therapy designation for the treatment of adults with metastatic or locally advanced and unresectable cutaneous squamous cell carcinoma (CSCC). Cemiplimab is an investigational human monoclonal antibody targeting programmed death-1.

Although CSCC has a good prognosis when caught early, it can prove difficult to treat in its advanced stages. It is responsible for the most deaths among nonmelanoma skin cancer patients.

Regeneron and Sanofi previously reported positive preliminary results for cemiplimab from two expansion cohorts involving 26 advanced CSCC patients from a phase 1 study. EMPOWERCSCC 1, a phase 2, potentially pivotal, single-arm, open-label clinical trial of cemiplimab, is enrolling patients.

Sources: Regeneron and Sanofi, September 8, 2017

Priority Review Designations

Elagolix for Endometriosis

AbbVie has received a priority review designation for elagolix, an investigational, orally administered gonadotropin-releasing hormone (GnRH) that would be the first new oral management option for endometriosis-associated pain in more than a decade.

Elagolix blocks endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration results in readily reversible, dose-dependent inhibition of luteinizing hormone and follicle-stimulating hormone secretion, reducing production of estradiol and progesterone. The safety and efficacy of elagolix were evaluated in nearly 1,700 women with moderate-to-severe endometriosis-associated pain.

AbbVie expects the Prescription Drug User Fee Act date will be in the second quarter of 2018.

Source: AbbVie, October 27, 2017

Perjeta for Early Breast Cancer

The FDA has accepted Genentech’s supplemental biologics license application and granted priority review for pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy for adjuvant treatment of HER2-positive early breast cancer. This combination is already approved for patients with metastatic HER2-positive breast cancer who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

The application is based on the APHINITY study, which evaluated the efficacy and safety of the triple combination compared to trastuzumab and chemotherapy as adjuvant therapy in 4,805 people with operable HER2-positive early breast cancer.

The FDA is expected to make a decision by January 28, 2018.

Source: Genentech, September 29, 2017

Lynparza for Metastatic Breast Cancer

The FDA has granted priority review to a supplemental new drug application for olaparib tablets (Lynparza, AstraZeneca/Merck) for patients with germline BRCA-mutated, HER2-negative metastatic breast cancer who have been treated previously with chemotherapy.

This submission, which marks the third U.S. indication sought for the poly(ADP-ribose) polymerase inhibitor, is based on positive results from the phase 3 OlympiAD trial. Olaparib is indicated for certain patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and is being tested in a range of tumor types, including breast, prostate, and pancreatic cancers.

The Prescription Drug User Fee Act date is in the first quarter of 2018.

Sources: AstraZeneca and Merck, October 18, 2017

Opdivo for Resected Melanoma

The FDA has accepted for priority review the supplemental biologics license application for nivolumab (Opdivo, Bristol-Myers Squibb) to treat melanoma patients who are at high risk of recurrence following complete surgical resection.

The application is based on the ongoing phase 3 CheckMate-238 study, which evaluated nivolumab (a programmed death-1 immune checkpoint inhibitor) in patients who have undergone complete resection of stage IIIb/c or stage IV melanoma. Nivolumab 3 mg/kg met the primary endpoint by significantly reducing the risk of recurrence compared with ipilimumab (Yervoy, Bristol-Myers Squibb) 10 mg/kg, which is FDA-approved for stage III adjuvant melanoma.

Source: Bristol-Myers Squibb, October 16, 2017

Fast-Track Designations

PBI-4050 for IPF

The FDA has granted a fast-track designation to PBI-4050 (ProMetic) for idiopathic pulmonary fibrosis (IPF).

IPF is a chronic, ultimately fatal disease in which normal tissue is replaced by fibrotic scar tissue, leading to inflammation that causes vital organs to lose their function. The five-year mortality rate ranges from 50% to 70%.

PBI-4050 is an orally active drug candidate with excellent safety and efficacy profiles confirmed in several in vivo experiments. The proof-of-concept data generated to date confirm the antifibrotic activity of PBI-4050 in several key organs, including the kidneys, heart, lungs, and liver.

Source: ProMetic Life Sciences, Inc., October 25, 2017

MIV-711 for Osteoarthritis

MIV-711 (Medivir AB) has received an FDA fast-track designation for the treatment of osteoarthritis.

MIV-711 is a potent and selective inhibitor of cathepsin K, the principal protease involved in breaking down collagen in bone and cartilage. It is being developed as a disease-modifying osteoarthritis drug (DMOAD) to slow or reverse the progressive degeneration of joints. No DMOADs are currently approved.

Source: Medivir, October 24, 2017

Mino-Lok for Catheter Infections

Citius Pharmaceuticals, Inc., has received an FDA fast-track designation for Mino-Lok, a catheter lock solution that has entered phase 3 trials as an adjunctive treatment for catheter-related bloodstream infection (CRBSI).

There are no approved therapies to salvage infected central venous catheters. CRBSIs are responsible for mortality rates up to 25% and contribute to significant morbidities.

Source: Citius Pharmaceuticals, Inc., October 31, 2017

HTX-011 for Postoperative Pain

Heron Therapeutics, Inc., has been granted a fast-track designation for HTX-011, the first long-acting, extended-release formulation of bupivacaine designed to address both postoperative pain and inflammation in a single administration at the surgical site. In phase 2 clinical studies, HTX-011 demonstrated superiority over placebo and bupivacaine, the current standard of care, in all surgical models evaluated and significantly reduced the need for opioids following surgery. Heron has initiated the HTX-011 phase 3 program and expects to file a new drug application in 2018.

Source: Heron Therapeutics, October 26, 2017

ALZ-801 for Alzheimer’s Disease

ALZ-801 (Alzheon, Inc.) has received a fast-track designation from the FDA to treat Alzheimer’s disease (AD). ALZ-801 is a novel, oral antiamyloid medication, an optimized prodrug of tramiprosate, which has shown promising results. Clinical data for ALZ-801 and tramiprosate suggest long-term efficacy in AD patients with the APOE4 genotype, along with a favorable safety profile.

The initial phase 3 program for ALZ-801 will focus on patients with the homozygous APOE4/4 genotype at the mild stage of AD, with potential for future expansion. No approved drugs target the underlying pathology or slow the progressive cognitive and functional decline of AD.

Source: Alzheon, Inc., October 24, 2017

Orphan Drug Designations

Valbenazine for Tourette Syndrome

The FDA has granted orphan drug status to valbenazine (Ingrezza, Neurocrine Biosciences), a novel selective vesicular monoamine transporter 2, for the treatment of pediatric patients with Tourette syndrome. Valbenazine is indicated in the U.S. for adults with tardive dyskinesia.

Tourette syndrome is a neurological disorder characterized by rapid, nonrhythmic stereotyped motor tics, such as grimacing, head jerks, and extremity movements, and by vocal tics that include grunting, throat clearing, and repeating words and phrases. The average age of onset is 6 years.

Source: Neurocrine Biosciences, Inc., October 23, 2017

MM-121 for Certain NSCLC Cases

MM-121 (seribantumab, Merrimack) has been granted an FDA orphan drug designation for the treatment of heregulin-positive non–small-cell lung cancer.

MM-121 is a fully human monoclonal antibody designed to block tumor survival signals and enhance the antitumor effect of combination therapies by targeting the cell surface receptor HER3 in patients with high expression of the biomarker heregulin. Heregulin-positive cancer cells are characterized by their ability to escape the effects of targeted, cytotoxic, and antiendocrine therapies. MM-121 is being evaluated in the phase 2 SHERLOC study in combination with docetaxel versus docetaxel alone.

Merrimack will also evaluate MM-121 (added to standard of care) in the phase 2 SHERBOC trial in patients with heregulin-positive, hormone-receptor–positive, HER2-negative metastatic breast cancer.

Source: Merrimack Pharmaceuticals, Inc., October 30, 2017

SYNB1618 for Phenylketonuria

SYNB1618 (Synlogic), a preclinical-stage drug candidate for the treatment of phenylketonuria (PKU), has received an FDA orphan drug designation.

PKU is an inborn error of metabolism caused by a mutation in the gene that breaks down the amino acid phenylalanine (Phe). Phe accumulation in the blood and brain can lead to neurocognitive abnormalities. Current management of PKU involves strict dietary protein restriction with the consumption of Phe-free protein supplements. Orally administered SYNB1618 is designed to complement the missing function in patients with PKU by providing alternative metabolic pathways to consume Phe.

Source: Synlogic, October 24, 2017

H3B-6527 for Liver Cancer

The FDA has granted H3 Biomedicine an orphan drug designation for H3B-6527 for the treatment of patients with hepatocellular carcinoma (HCC), the most common form of liver cancer in adults.

H3B-6527 is a selective, orally bioavailable, and potent inhibitor of fibroblast growth factor receptor 4 (FGFR4). Aberrant signaling through the FGF19–FGFR4 axis has been shown to drive tumor development and dependency in preclinical models of HCC. H3B-6527 has shown sustained tumor regression in several preclinical models of HCC where FGF19-FGFR4 signaling is aberrantly activated. H3B-6527 is currently in phase 1 clinical trials.

Source: H3 Biomedicine, October 10, 2017

KD025 for Chronic GVHD

The FDA has granted an orphan drug designation to KD025, Kadmon Holdings’ Rho-associated coiled-coil kinase inhibitor, for the treatment of chronic graft-versus-host disease (cGVHD). KD025 is being studied in an ongoing phase 2 trial in adults with steroid-dependent or steroid-refractory cGVHD and active disease. In a preliminary analysis of data from the lowest-dose cohort, KD025 200 mg daily demonstrated clinically meaningful responses, with no drug-related serious adverse events.

Source: Kadmon Holdings, October 6, 2017

Lixivaptan for Certain Kidney Patients

Palladio Biosciences has received an orphan drug designation for lixivaptan, developed to treat autosomal dominant polycystic kidney disease (ADPKD).

ADPKD, a genetic disease that affects thousands of U.S. residents, is marked by uncontrolled growth of fluid-filled cysts in the kidney that can each grow as large as a football. Lixivaptan is a potent, selective vasopressin V2 receptor antagonist. This mechanism of action has been shown to delay the progression of the autosomal dominant form of PKD.

Source: Palladio Biosciences, October 4, 2017

Complete Response Letter

Ataluren for Duchenne MD

The FDA has issued a complete response letter for ataluren (PTC Therapeutics), an investigational medication for Duchenne muscular dystrophy (DMD) that targets nonsense mutation dystrophinopathies.

The FDA indicated that evidence of effectiveness from one or more additional adequate, well-controlled clinical trials will be necessary to provide substantial evidence of effectiveness. The company said it strongly disagreed with the FDA decision and would file a formal dispute resolution request.

Ataluren is a protein restoration therapy designed to enable the formation of a functioning protein (in this case, dystrophin) in patients with genetic disorders caused by a nonsense mutation. Primarily affecting males, DMD is a rare and fatal genetic disorder that results in progressive muscle weakness from early childhood and leads to premature death in the mid-20s due to heart and respiratory failure.

Source: PTC Therapeutics, October 25, 2017

More Data Sought on Dsuvia

The FDA has declined to approve sufentanil sublingual tablets, 30 mcg (Dsuvia, AcelRx Pharmaceuticals) for moderate-to-severe acute pain until it receives additional information.

AcelRx received an FDA complete response letter with two main recommendations: the collection of additional data on at least 50 patients to assess the safety of Dsuvia dosed at the maximum amount described in the labeling, and changes in the directions for use, validated through a human-factors study, to address potential use-related errors in administration of the tablet with the noninvasive, single-dose applicator. The company termed the FDA’s requests “manageable.”

Sufentanil is an opioid marketed for intravenous (IV) and epidural anesthesia and analgesia. However, its use has been limited due to the short duration of action with IV delivery. The sufentanil pharmacokinetic profile when delivered sublingually potentially avoids the high peak plasma levels and short duration of action seen with IV administration.

Source: AcelRx Pharmaceuticals, October 12, 2017

DEVICE APPROVALS

OptiScanner Glucose Monitor

The FDA has granted 510(k) clearance for use of the OptiScanner 5000 Glucose Monitoring System (OptiScan Biomedical Corporation) in surgical intensive care unit (SICU) patients. The OptiScanner 5000 is a first-of-its-kind, automated, bedside glucose monitoring system that provides physicians with critical information to manage patient glucose levels. The system has alarms to alert clinicians to hyperglycemia and hypoglycemia.

The clearance by the FDA was based on results from OptiScan’s pivotal, multicenter clinical trial in 160 SICU patients comparing the accuracy of the OptiScanner 5000 with industry-standard glucose measurement in the ICU. Results demonstrated the OptiScanner 5000 to be safe and accurate.

Source: OptiScan Biomedical Corporation, October 18, 2017

Magnetom Terra 7T MRI

The FDA has given 510(k) clearance to the Magnetom Terra (Siemens Medical Solutions, Inc.), a magnetic resonance imaging (MRI) device with a magnetic field strength of 7 teslas (7T)—more than double the static magnetic field strength previously available for U.S. clinical use. The added field strength allows for better visualization of smaller structures and subtle pathologies that may improve disease diagnosis.

The FDA reviewed sample clinical images and the safety of the radio-frequency subsystem through computational modeling, simulations, and rigorous experimental validation. Siemens provided data from a comparative study of 35 healthy patients that compared images of the patients using the 7T device and images using a 3T device. Board-certified radiologists reviewed the images and confirmed that the images from the 7T device were of diagnostic quality and, in some cases, better than images from the 3T.

The Magnetom Terra is for patients who weigh more than 66 pounds. It is limited to examinations of the head, arms, and legs.

Source: FDA, October 12, 2017

Medtronic Intellis for Pain Relief

The Intellis platform (Medtronic PLC) for the management of certain types of chronic intractable pain has received FDA approval.

Intellis was designed to overcome limitations with current spinal cord stimulation (SCS) systems, such as battery performance; its battery can be fully recharged from empty to full in approximately one hour. Intellis can also power the Evolve workflow, which standardizes guidance and balances high-dose and low-dose therapy settings. The Intellis platform can record and track patient activity 24/7 and is managed on the Samsung Galaxy Tab S2 tablet interface.

Medtronic neurostimulation therapy for chronic intractable pain uses a medical device placed under a patient’s skin to deliver mild electrical impulses through a lead implanted in the epidural space to block pain signals from going to the brain. SCS is a nonopioid therapy that is clinically proven and cost-effective for treating chronic pain.

Source: Medtronic, September 18, 2017

Remedē for Sleep Apnea

The FDA has approved the implantable Remedē System (Respicardia, Inc.) for patients who have been diagnosed with moderate-to-severe central sleep apnea.

The Remedē System is comprised of a battery pack surgically placed under the skin in the upper chest area and small, thin wires that are inserted into the blood vessels in the chest near the phrenic nerve, which stimulates breathing. The system monitors the patient’s respiratory signals during sleep and stimulates the nerve to move the diaphragm and restore normal breathing.

The FDA evaluated data from 141 patients to assess the effectiveness of the Remedē System in reducing the apnea hypopnea index (AHI), a measure of the frequency and severity of apnea episodes. After six months, AHI was reduced by 50% or more in 51% of patients with an active Remedē System. AHI was reduced by 11% in patients without an active Remedē System implanted.

Source: FDA, October 6, 2017

Medacta Shoulder Systems

Medacta International has received FDA clearance for the Anatomic Shoulder and Reverse Shoulder components of its modular Medacta Shoulder System.

The system features wide-ranging sizes, adjustable offset, and innovative configurations and is supported by Medacta’s Clinical Excellence Program. The system is part of a multicenter, post-marketing, prospective, open clinical study that will collect clinical and radiological outcomes for the next 10 years.

Source: Medacta International, October 26, 2017

DEVICE SAFETY ISSUES

Magellan Lead Test Warning

The FDA has sent a warning letter to Magellan Diagnostics alleging violations of federal law, including marketing significantly modified versions of two of its blood lead testing systems without FDA clearance and failing to submit reports to the FDA after customers complained of discrepancies in blood lead test results.

In May 2017, the FDA said using Magellan’s LeadCare test systems on blood drawn from the vein may provide falsely low results. The agency launched an investigation, which included an inspection (May 10 to June 29) of Magellan’s facility. FDA investigators observed numerous violations, including failure to submit medical device reports to the FDA regarding discrepancies in test results. In addition, Magellan altered two of its blood lead testing systems after they were already FDA-cleared but did not report these changes to the FDA for review and evaluation.

Magellan’s parent company, Meridian Bioscience, Inc., said Magellan “has initiated prompt and comprehensive quality system remediation activities.” The companies said that they are committed to “ensuring all aspects of the system are in full compliance,” that they “take this very seriously,” and that they are addressing the issue “with the highest sense of urgency.”

Sources: FDA and Meridian, October 23, 2017