Editor’s Summary: In the current edition of Medness Plus, Esha Sehanobish highlights FDA’s approvals of EYELEA (aflibercept) to treat age-related macular degeneration and the first generic version of Epipen. We also focus on a news about the FDA approval of Xerava that exemplifies the importance of public-private partnerships in addressing global health threats and the challenge of antibiotic resistance. In the clinical trials section, Teva & Regeneron’s Fasinumab hits osteoarthritis goals for phase 3. Also making news is FDA declining to approve Akcea Therapeutics and Ionis Pharmaceuticals’ drug Waylivra (volanesorsen). This drug could have been potential treatment for a genetic disease that causes fat accumulation in the blood called familial chylomicronemia syndrome (FCS). This edition also features the news about the first ever drug ever drug approved by FDA for a rare eye disease. Read on to know which one it is.- Abhi Dey
FDA approves EYLEA (aflibercept) injection sBLA in wet age-related macular degeneration
Regeneron Pharmaceuticals, Inc (NASDAQ: REGN) recently announced that the US food and drug administration (FDA) approved a supplemental Biologics License Application (sBLA) for EYLEA (aflibercept) injection in patients with wet age-related macular degeneration (wet AMD) [1]. Based on the definition generated by FDA, BLA or biologics license application is mostly a request for permission to introduce or deliver for introduction, a biologics product into interstate commerce (21 CFR 601.2) [2]. BLA is regulated under 21 CFR 600-680. It could be submitted by any legal person who is involved in the manufacture or any applicant for a license who is responsible for the established standards of the product.
Regeneron’s supplemental biologics licence application for #EYLEA gains #FDA approval https://t.co/OjJAdHMJkb @Regeneron @EPM_Magazine #sBLA #wetAMD pic.twitter.com/8NOlLEjAHa
— Euro Pharma Mag (@EPM_Magazine) August 25, 2018
The sBLA was released based of the second-year data from the Phase 3 VIEW 1 and 2 trials in which the patients with wet AMD were treated with a modified 12-week dosage schedule which includes doses given at least every 12 weeks and then additional doses as and when required. EYLEA injection has been implicated in treating patients with Neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME) and diabetic retinopathy in patients with DME. A vascular endothelial growth factor (VEGF) inhibitor is the formulation used for the EYLEA (aflibercept) injection. This inhibitor is considered to block VEGF-A and placental growth factor (PLGF) thus blocking the growth of new blood vessels and decrease the ability of the fluid to pass through the blood vessels. EYLEA is a market leading, FDA approved anti-VEGF treatment that has been approved in the US after an extensive body of research. Along with the approval, a safety information list has already been issued for the safe use of the injection. EYLEA and other intravitreal injections have been associated with retinal detachments and endophthalmitis, hence proper techniques must be applied during the administration of the injections. Intraocular pressure increase has also been reported within 60 minutes of the injection usage. Other adverse effects (≥ 5%) reported in patients receiving EYLEA were eye pain, cataract, conjunctival hemorrhage, vitreous detachment and floaters.
“We are pleased that the FDA has approved an updated label for EYLEA,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron. “Providing information to retinal physicians about the visual outcomes with a modified 12-week dosing schedule will help physicians make the most informed choices in treating patients suffering from wet age-related macular degeneration.”
FDA approves the first generic version of EpiPen
FDA recently approved the first generic version of EpiPen and EpiPen Jr (epinephrine) auto-injector as products from Teva Pharmaceuticals in 0.3 mg and 0.15 mg strengths. The approval is for emergency treatment of allergic reactions including the life-threatening ones such as anaphylaxis in adult and pediatric patients who weigh more than 33 pounds [3].
Mylan’s EpiPen now has its first FDA-approved generic rival #tictocnews https://t.co/rMZFN0mh8Q pic.twitter.com/ohiKHZGZub
— TicToc by Bloomberg (@tictoc) August 29, 2018
Anaphylaxis is an emergency condition arising out of life-threatening allergies to food, insect bites/stings etc. which could be fatal. It is common in Americans affecting approximately one in 50 and those who were already affected by Anaphylaxis once, tend to be at risk for another. Therefore, they should always have an epinephrine dose at hand. EpiPen automatically injects a dose of epinephrine to a person’s thigh to halt the allergic reaction at once. When EpiPen is administered intramuscularly or subcutaneously, it has a faster onset and a short duration of action. Its mode of action involves reducing the swelling in the airway and increasing the blood flow in the veins. A few such auto-injector products have already been approved by FDA, including EpiPen, Auvi-Q and Adrenaclick. There are some “authorized generic” versions of Adrenaclick and EpiPen that are marketed without the brand names. It is usually made under the brand name’s existing new drug application using the same process, formulation and manufacturing facilities as used by the brand name manufacturer. Sometimes the reason for this is to make the drug available at a lower cost. In this case, the Epinephrine auto-injector is available as a combination product consisting of the drug (epinephrine) and the auto-injector. The development of such combination products is much more difficult than the typical drug and is maintained by strict supervision from the FDA. For this one, the FDA has published three drafts or final guidances since 2009 related to the development of generic epinephrine auto-injectors. Some of the more common adverse effects include weakness, dizziness, sweating, headache, vomiting, anxiety and/or respiratory disorders. Patients with heart diseases may feel chest pain after EpiPen administration in which case they should get immediate medical help. Epinephrine should not be injected into the vein, buttock, fingers, hands or feet.
“This approval means patients living with severe allergies who require constant access to life-saving epinephrine should have a lower-cost option, as well as another approved product to help protect against potential drug shortages,” FDA Commissioner Scott Gottlieb, M.D., said in the announcement. “This approval means patients living with severe allergies who require constant access to life-saving epinephrine should have a lower-cost option, as well as another approved product to help protect against potential drug shortages.
From Visually.
FDA approves the first drug for a rare eye disease called neurotrophic keratitis
FDA recently approved the Oxervate, a product of an Italian firm, Dompe. This eye drop has been approved for treating neurotrophic keratitis, a rare type of eye disease. It is the first drug to be approved for the treatment of this eye disease that affects the cornea [4].
https://t.co/aaxAdHPAqm
FDA approval of Oxervate#eyedro ps #ophthalmicsolution firstinclass recombinant human nerve growth factor with potential to completely heal rare #neurotrophickeratitis #excimerlaser #exotropia #extraocularmuscles, #eyelids #farsightedness #floaters #fovea pic.twitter.com/JnEHNjt2WD— OphthalmologySurgery (@SurgeryClinical) August 23, 2018
The approval was based on safety and efficacy studies that were carried out amongst 151 patients with neurotrophic keratitis. There were two, eight-week, randomized controlled multi-center, double-masked studies that were conducted for Oxervate, a topical eye drop containing cenegermin. The first one included patients affected in one eye and the second study involved those that were affected in both the eyes. All eye drops in both the groups were given six times daily for eight weeks. In the first study, there were three groups, one who received Oxervate, the second received a different concentration of cenegermin and the third received one without it. In the second study out of the two groups, one was treated with Oxervate and the other with an eye drop that did not contain cenegermin. In both these studies, complete corneal healing was reported in 70 percent of the patients treated with Oxervate compared to 28 percent treated without cenegermin, the active ingredient of Oxervate. The most common adverse effects in patients treated with Oxervate include eye inflammation and pain, increased lacrimation i.e. watery eyes and ocular hyperemia (enlarged blood vessels in the white of the eyes). This eye drop was granted Orphan drug status which provides a basis for further development of drugs for rare diseases. It was granted Priority Review designation under which FDA takes action within six months of application filing where the agency determines the safety and effectiveness of the drug if it is approved.
“While the prevalence of neurotrophic keratitis is low, the impact of this serious condition on an individual patient can be devastating,” said Wiley Chambers, M.D., an ophthalmologist in the FDA’s Center for Drug Evaluation and Research. “In the past, it has often been necessary to turn to surgical interventions; these treatments are usually only palliative in this disease. Today’s approval provides a novel topical treatment and a major advance that offers complete corneal healing for many of these patients.”
FDA approves XERAVATM (eravacycline) for the treatment of complicated intra-abdominal infections (CIAI)
Tetraphase Pharmaceuticals Inc. (NASDAQ: TTPH), a biopharmaceutical company focused on the development and commercialization of novel antibiotics to treat multiple drug resistance, recently announced that FDA had approved XERAVA for the treatment of CIAI [5]. The drug was investigated as a part of the IGNITE (Investigating Gram-negative Infections Treated with Eravacycline) Phase 3 trials. XERAVA achieved high clinical cure rates in patients and was also well-tolerated in general.
.@US_FDA approved XERAVA, a new @BARDA-supported antibiotic that can be used to enhance #HealthSecurity, protect patients from certain multi-drug resistant infections. pic.twitter.com/HIfE5VUZmZ
— ASPR (@PHEgov) August 28, 2018
The company’s IGNITE Phase 3 trial was divided into two parts. In the first part, patients with CIAI who received twice-daily intravenous (IV) eravacycline, met the primary end-point as they achieved statistical non-inferiority of clinical response to ertapenem and was also well-tolerated. In the second phase 3 trial, those with CIAI and treated with twice-daily IV eravacycline, met the primary endpoint where it reached statistical non-inferiority of clinical response compared to meropenem and was also well-tolerated. Intra-abdominal infection is an amalgamation of several different disease processes and can be classified as complicated and uncomplicated based on the extent of the infection. For example, the complicated intra-abdominal infections extend beyond the source organ to the peritoneal space because of the damage to the GI tract. CIAI is caused by gram-positive and anaerobic bacteria and gram-negative aerobic ones. The most common manifestations of the CIAI include peritonitis, appendicitis, stomach or intestinal perforations, cholecystitis and intra-abdominal abscess. XERAVA is a tetracycline antibacterial drug that has been approved for complicated intra-abdominal infections in patients who are 18 years or older. Since this drug was approved in the backdrop of the ever-growing problem of drug resistance, the use of XERAVA has been restricted to treat and prevent infections that are strongly suspected or proven to be caused by susceptible bacteria. The most common adverse effects include nausea, infusion-site reactions and vomiting.
“The approval of XERAVA is an extraordinary achievement, one for which we thank the patients who have participated in our clinical studies, study investigators and physicians as well as our dedicated employees,” said Guy Macdonald, President and Chief Executive Officer of Tetraphase. “We are thrilled to have received FDA approval, and a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in Europe all within the same quarter. Each milestone is a significant accomplishment on its own and achieving both underscores the potential for Tetraphase and the medical need for XERAVA.”
From Visually.
FDA rejects the rare-disease (FCS) drug WAYLIVRA (volanesorsen)
Ionis Pharmaceuticals (NASDAQ: IONS) and its subsidiary Akcea Therapeutics (NASDAQ: AKCA) recently announced that FDA issued a rejection for their rare-disease drug WAYLIVRA (volanesorsen) [6]. They received a Complete Response Letter from the Division of Metabolism and Endocrinology products of the FDA that involved updates about the drug.
A betting man may have placed a pretty strong wager on the @US_FDA ‘s approval of Akcea Therapeutics’ Waylivra, a treatment for the rare lipid disorder familial chylomicronemia syndrome. https://t.co/VEJSseYAsl pic.twitter.com/5NlWYBXJhr
— BioSpace (@biospace) August 28, 2018
FCS or Familial chylomicronemia syndrome is a hereditary and very rare disease that leads to chronic complications because of permanent organ damage and potentially fatal acute pancreatitis. One of the significant manifestations of FCS is an increase in the levels of triglycerides. WAYLIVRA, is a part of Ionis’s antisense technology and is designed to reduce the ApoC-III production. ApoC-III is a liver protein that plays an integral part in the regulation of plasma triglycerides thus also affecting other metabolic parameters. Based on the Phase 3 APPROACH trial, the largest ever conducted for patients with FCS, there was a reduction in triglycerides by 77%. A reduction in triglycerides is in fact considered as a goal for the treatment of FCS by The Endocrine Society. The adverse effects of the study were injection site reactions and reductions in platelet levels. The real reason for the rejection by FDA has not yet been released by Ionis pharmaceuticals and Akcea Therapeutics which is surprising, considering the fact that positive reviews were obtained from the studies.
“We are extremely disappointed with the FDA’s decision. FCS is an ultra-rare and debilitating disease. Our disappointment extends to the patient and physician community who currently do not have a treatment available to them. We continue to feel strongly that WAYLIVRA demonstrates a favorable benefit/risk profile in people with FCS as was reflected in the positive outcome from our Advisory Committee hearing in May. We will continue to work with the FDA to confirm the path forward,” said Paula Soteropoulos, chief executive officer of Akcea Therapeutics.
Regeneron and Teva pharmaceuticals announce positive phase 3 Fasinumab results in patients with hip or knee pain from osteoarthritis
Teva Pharmaceuticals Industries Ltd. (NYSE and TASE: TEVA) and Regeneron Pharmaceuticals Inc. (NASDAQ: REGN) recently announced positive topline Phase 3 results for treatment with Fasinumab for patients with hip or knee pain caused from osteoarthritis [7]. The Phase 3 trial was a randomized, double-blind, placebo-controlled study of Fasinumab in patients with pain in knee and hip from osteoarthritis. Co-primary and secondary endpoints were achieved at week 16, based on the primary efficacy analysis. Patients treated with Fasinumab experienced significantly less pain and improved functional ability when compared to the those that who were placebo-treated.
Regeneron and Teva announced positive topline results from a Phase 3 trial for fasinumab, an investigational treatment for patients with chronic pain associated with #osteoarthritis of the knee or hip. https://t.co/xv8oVGTiqu
— ClinicalPainAdvisor (@ClinicalPainAdv) August 24, 2018
Fasinumab is known to target nerve growth factor (NGF), a protein that is essential in the regulation of pain signaling. NGF levels are elevated in synovial fluids of patients with chronic pain conditions. Fasinumab is an investigational therapy invented by Regeneron using the company’s VelocImmune technology to yield optimized fully-human antibodies. The Phase 3 trial is a part of a larger 52 weeks trial of active treatment, that has been designed to determine the efficacy, safety and tolerability of Fasinumab in patients with chronic hip and knee pain caused due to osteoarthritis. 85% of this sub-study patients had osteoarthritis of the knee. The safety data that was presented at 16 weeks was essentially the interim and preliminary data. The primary safety analysis, scheduled to be a part of a larger long-term trial, will occur at 72 weeks which involves 52 weeks of active treatment and 20 weeks of follow up. The independent data monitoring committee, earlier this year, had suggested the discontinued use of the two higher doses (3mg every four weeks and 6mg every eight weeks). The more recent study involved doses of Fasinumab at 1mg every four or eight weeks and was compared to the placebo. Based on the preliminary studies it was concluded that Fasinumab was generally well-tolerated at week 16 and the adverse effects were like those observed in previous Fasinumab trials. At the first endpoint, the discontinuation of the treatment due to adverse effects was 6% for placebo group patients and 5% for the Fasinumab 1mg every eight-week group patients and 6% for 1mg every four-week group patients. The companies have agreed to report further results at an upcoming medical congress.
“We are encouraged by these data and look forward to advancing our pivotal Phase 3 Fasinumab program in patients with osteoarthritis of the knee or hip, who currently have very limited therapeutic choices to treat their chronic pain, other than with non-steriodal anti-inflammatory drugs or opioids,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron.
From Visually.
Reference:
- http://files.shareholder.com/downloads/REGN/6371609214x0x983465/426107E7-1C67-40D4-B2E0-7D00808BB9CD/REGN_News_2018_8_17_General_Releases.pdf.
- https://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicsLicenseApplicationsBLAProcess/.
- https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM617173.htm?utm_campaign=08162018_PR_FDA%20approves%20first%20generic%20version%20of%20EpiPen&utm_medium=email&utm_source=Eloqua.
- https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm618047.htm.
- https://ir.tphase.com/news-releases/news-release-details/tetraphase-pharmaceuticals-announces-fda-approval-xeravatm.
- http://ir.ionispharma.com/news-releases/news-release-details/akcea-and-ionis-receive-complete-response-letter-waylivra-fda.
- http://files.shareholder.com/downloads/REGN/6371609214x0x983455/93E83348-21CF-4D27-A135-94891912FABC/REGN_News_2018_8_16_General_Releases.pdf.
About the Author:
Esha Sehanobish
She is presently a Postdoctoral research fellow at Albert Einstein college of medicine, NY and works on characterization of enzymes that could act as potential therapeutic targets against tuberculosis. She is an enzymologist with a doctoral degree from the University of Central Florida in 2016. She loves using her communication skills to raise awareness about the importance of science in general by using social media. When she is not doing “science”, she loves designing and painting as a way of expressing ones thoughts through graphics and color.
Editor and Blog Design
Abhi graduated from the Molecular Biophysics Unit of IISc (Bangalore, India) in 2011. As a Biomedical Scientist, he has worked with all three life-forms in his 13-year research career, viz., particulate, unicellular and multicellular. He is currently an Assistant Scientist at Emory University (Atlanta, GA) studying mechanisms of tumor recurrence in kids with brain tumors. As a postdoctoral fellow, he was the recipient of two Young Investigator Awards from Alex Lemonade Stand Foundation (Philadelphia, PA) and Rockland Immunochemicals. His current research has been funded by Northwestern Mutual Foundation (Milwaukee, WI), CURE Childhood Cancer Foundation (Atlanta, GA) and American Association for Cancer Research (AACR). When he is not on the bench you will find him spending time with his family or exploring the world through traveling and blogging.
Cover image: (Cell Image Library)This confocal micrograph shows the detailed structure of the retina from a one-month-old mouse. The retina is the photoreceptive organ of the eye. It is composed of layers of neuronal cells that capture and transmit the light information, converting it into electrical signals that the brain can interpret. Fluorescent markers have been used to highlight different classes of these cells within the retina. Green staining highlights glial cells, which act as neuronal supporting cells and produce myelin, the protective conductive layer that surrounds the axons of the neurons. The red fluorescently labelled protein marks astrocytes, star-shaped glial cells that provide nutrients to developing neurons and regulate neuronal activity. The blue fluorescence marks cell nuclei. This image was created as part of a study to examine the stress observed in the retina as a result of oxygen deprivation. These studies are helping scientists to understand why premature babies develop retinal disease when born too early. 2011 Wellcome Images Award winner.
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