Scientists Simplifying Science
Donate
Facebook Twitter Instagram Linkedin
Club SciWri header

Medness Plus

SHARE THIS

Editor’s Note: Esha Sehanobish is back with her second edition of Medness Plus. In this she covers the latest stories about several FDA approvals, including Shire’s CINRYZE targeting hereditary angioedema, first generic version of Suboxone to treat opioid dependence, continuation of clinical testing by Solid Biosciences treat Duchenne Muscular Dystrophy and Achaogen’s new drug targeting Urinary Tract Infections in adults. Also check out the clinical trial updates on Bluebird Bio’s promising gene therapy trials in Sickle Cell Disease and the reasons behind Teva’s closure on chronic headache prevention drug, Fremanezumab, in Phase III.

Also new from this edition is the widget from National Cancer Institute (NIH) to help you find easy-to-understand definitions of terms related to medicine. If you find a term in Medness Plus that is new for you, please type it in and click ‘search’. The results will be automatically displayed in the blog.- Abhi Dey

Food and Drug Administration (FDA) news

FDA approves the label extension for CINRYZE for prevention of attacks in hereditary angioedema pediatric patients


Shire plc. a biotech company that specializes in rare diseases recently announced the FDA approval of label expansion for CINRYZE (C1 esterase inhibitor {human}) to pediatric patients that experience attacks due to hereditary angioedema (HAE) [1]. HAE is a rare genetic disorder that is caused due to inadequate levels of C1 esterase inhibitor (C1-INH) in the plasma. It results in recurrent attacks of swelling or edema in different parts of the body such as face, feet, abdomen and can be excruciating and unbearable [2]. Some that affect the laryngeal tract could be fatal as it might lead to asphyxiation. C1-INH is the active substance in CINRYZE. The mechanism is to replace the deficient protein in the plasma and regulate the production of bradykinin release during the HAE attack. Based on the recent multicenter, single-blind study on 12 patients aged 7 to 11 with HAE, the tolerability and safety of CINRYZE in pediatric patients with HAE was found to be like that of the adolescent and adult patients. CINRYZE was already approved by FDA in 2008 but was known to be effective in HAE attacks only in adolescents and adults.

Image Description: Swollen right hand in a female patient during a hereditary angioedema attack. Source: Wikimedia Commons

In June 2017, FDA approved Haegarda (a C1 esterase inhibitor) to CSL Behring LLC against HAE attacks in adolescent and adult patients [3]. It needs a subcutaneous administration, whereas CINRYZE, needs to be administered twice a week by IV. With the present FDA approval, Shire now has the upper hand since its product caters to a broader range of HAE patients as far as age is concerned. “Symptoms of HAE often present in childhood with the average child experiencing their first HAE attack around the age of 10. With the FDA label expansion of CINRYZE, children as young as six years old living with HAE now have the first FDA approved treatment option available to help prevent attacks,” said Andreas Busch, Ph.D., Executive Vice President, Head of Research and Development at Shire.

FDA approves the first generic version of Suboxone sublingual film to treat opioid dependence


Over the last few years, the FDA has increased its effort to establish and generate improved treatments for opioid dependence. Very recently Mylan Technologies Inc. and Dr. Reddy’s Laboratories received the FDA approval to market a generic version of Suboxone sublingual (applied under the tongue) film to treat opioid dependence [4]. Suboxone (buprenorphine and naloxone) should be a part of a more comprehensive treatment which includes counseling and psychosocial support. This is the newest addition to the family of some already approved buprenorphine products such as Bunavail, Probuphine, Sublocade, etc.

Nature vs. Nurture: The Contributing Factors of Opioid Abuse

From Visually.

 

This approval will further strengthen the Medical-assisted treatment (MAT) which uses medication in combination with counseling and behavioral therapies to treat the opioid use disorder [5]. By using MAT with buprenorphine, there was a reduction in opioid withdrawal symptoms and the desire to use opioids without causing the irregularities of highs and lows associated with misuse or abuse of opioids. Once used in proper doses, the pleasurable effects of other opioids have been shown to reduce hence making the continued use less attractive. Adverse effects such as hypoesthesia (numbness), glossodynia (burning mouth) are experienced for these sublingual films. Hence it should only be prescribed by Drug Addiction Treatment Act (DATA)-certified prescribers and should also be further researched for better alternatives. But even though FDA has approved Suboxone, there are some complications before it enters the market. Indivior, the patent holder has put a restraining order forcing Dr. Reddy’s laboratory to cease its activities regarding the launch of the drug temporarily. Mylan on the other hand has already reached a settlement with Indivior by delaying the launch till 2023 [6]. “The FDA is taking new steps to advance the development of improved treatments for opioid use disorder and to make sure these medicines are accessible to the patients who need them. That includes promoting the development of better drugs, and facilitating market entry of generic versions of approved drugs to help ensure broader access,” said FDA Commissioner Scott Gottlieb, M.D.

FDA under pressure to withdraw Takeda’s gout drug, Uloric


FDA approved Uloric in 2009 as a once-daily oral prescription medication to treat hyperuricemia (excess of uric acid in blood) in adults suffering from gout [7]. It is known to act by inhibiting the enzyme xanthine oxidase that finally breaks down hypoxanthine to uric acid. The idea is to lower the serum uric acid in patients who had an increased level. At the concentrations used, the drug is not supposed to inhibit any other enzymes involved in purine and pyrimidine biosynthesis. Following this approval, the prescribing information was made to include that there was a higher rate of cardiovascular (CV) adverse effects that were noted in clinical trials for Uloric when compared with allopurinol. Early this year Takeda Pharmaceuticals, USA announced their phase 3b cardiovascular outcomes trial for Uloric. The trial was titled, “Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Comorbidities (CARES).” It was conducted to test the CV safety of Uloric compared to allopurinol in patients with gout. Based on the trial, Uloric met the primary endpoint of CARES [8]. When analyzing each of the components of major adverse cardiovascular events as secondary endpoints, the rate of cardiovascular deaths was found to be higher for Uloric than it was for allopurinol. No specific reason was attributed to this outcome.

Image Description: Symptoms of gout in human hand, (Publication Year: 1881). Fig 1. Man aged 69. Fig 2. Woman aged 84 Fig 3-6. Heberdden’s nodositics. Source: Wikimedia Commons

Since then, FDA has been under a lot of pressure to revoke this drug which has shown to have alarming cardiovascular effects without being extraordinarily beneficial. There has also been no evidence from the post-market trial of Uloric being more beneficial than Allopurinol in terms of reducing gout attacks. A petition from Public Citizen was recently sent to FDA requesting the same [9]. “The FDA almost certainly would have denied approval of febuxostat if data from this post-market trial had been available at the time of the initial submission. The only logical course of action to prevent further cardiovascular deaths is obvious: This medication must be removed from the U.S. market immediately,” Dr. Michael Carome, director of Public Citizen’s Health Research Group said.

 

FDA clears Solid Biosciences to resume the clinical testing of gene therapy for treating Duchenne muscular dystrophy


FDA has lifted the hold on Phase I/II clinical trial, IGNITE DMD, for the microdystropin gene transfer, SGT-001, that has an application in the treatment of Duchenne muscular dystrophy (DMD). This announcement was made very recently by Solid Biosciences (NASDAQ: SLDB) [10]. It comes at a time when Sarepta Therapeutics is ready to report its human clinical trial data from a treatment using the same approach. DMD is caused by mutations in the dystrophin gene that results in almost and sometimes complete absence of the dystrophin protein. SGT-001 is an adeno-associated viral (AAV) microdystrophin therapy. The protein thus encoded and expressed in the muscles helps in stabilizing associated protein systems. “Gene therapy has the potential to dramatically change the course of DMD and may offer long-term benefit for those who suffer from this devastating disease,” said Barry Byrne, M.D., Ph.D., Director, University of Florida Powell Gene Therapy Center and Professor, Pediatrics and Molecular Genetics & Microbiology at the University of Florida College of Medicine.

Image Description:  Histopathology of gastrocnemius muscle from patient who died of pseudohypertrophic muscular dystrophy, Duchenne type. Cross section of muscle shows extensive replacement of muscle fibers by adipose cells. Source: Wikimedia Commons

FDA had placed a hold on the trial in response to reports of serious adverse effects in case of the first patient dosed with SGT-001. The lab test revealed a reduction in platelets and complement activation. Later, the patient seemed to be clinically stable with standard medical care, a revised steroid system and a limited course of eculizumab. Since then, the company has satisfactorily responded to the queries of FDA and have resumed their activities for further clinical trials. They have also made a few changes to the protocol which includes the addition of IV glucocorticoids in the initial weeks after administration of SGT-001 and will also include enhanced monitoring measures for complement activation. Due to the hold, Solid Biosciences now expect initial data from IGNITE DMD in the second half of 2019.  “We believe SGT-001 has the potential to offer significant benefit to patients with DMD, regardless of their age or stage of disease,” said Ilan Ganot, Founder and Chief Executive Officer of Solid Biosciences. “We are pleased to have been able to provide the FDA with a comprehensive response resulting in the removal of the clinical hold so we can continue development of this important potential treatment.”

FDA approves Achaogen’s drug for treatment of complicated Urinary tract infection (UTI) in adults


ZEMDRI (plazomicin) from Achaogen was recently approved by FDA to be used in adults with complicated urinary tract infection (UTI) including pyelonephritis which has limited or no alternative treatment. Achaogen (NASDAQ: AKAO) is a biopharmaceutical company that specializes in the commercialization of antibacterial agents that target multidrug-resistant gram-negative bacteria [15]. ZEMDRI is an aminoglycoside that has been engineered to avoid being affected by aminoglycoside modifying enzymes which in most cases is the common resistance mechanism in Enterobacteriaceae, a bacteria known to cause complicated urinary tract infection. Infections that are caused by carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae have become very frequent these days, and ZEMDRI is known to retain its potency against these. Its mode of administration is through once daily intravenous infusion. “The approval of ZEMDRI marks a significant milestone for Achaogen, and we are excited to offer healthcare practitioners a new treatment option for patients with certain serious bacterial infections. ZEMDRI is designed to retain its potent activity in the face of certain difficult-to-treat MDR infections, including CRE and ESBL- producing Enterobacteriaceae,” said Blake Wise, Achaogen’s Chief Executive Officer.

Image Description: Urine cultured on Oxoid Brilliance UTI Agar plate. 1uL of urine spread onto agar surface. Top sample is from patient with clinical urinary tract infection (UTI). Bottom sample is a mixed culture. Source: Wikimedia Commons

But the approval comes with a boxed warning. Boxed warnings or “black box warnings” as it might be referred to at times, indicate warnings which can cause life-threatening risks and typically appear on the prescription drug’s label or in the literature describing it. In this case, the boxed warning will include potential for nephrotoxicity causing kidney damage. There will also be a mention of hearing loss and weakened muscle or paralysis caused by neuromuscular blockade. It may in some cases even harm fetus. Keeping this in mind, Achaogen will now work with hospital and clinicians to make the treatment available to people.

 

Pharma News and Drug Trials

Bluebird Bio’s new clinical data shows that gene therapy might help with sickle cell disorders

 

Bluebird Bio (NASDAQ: BLUE) recently presented data from their ongoing HGB-206 Phase 1 multicenter clinical study of LentiGlobin investigational gene therapy in patients who have severe sickle cell disease (SCD). The event was at the European Hematology Association meeting [11]. In 2015, FDA had granted Breakthrough Therapy designation to LentiGlobin for the treatment of transfusion-dependent patients with beta-thalassemia major [12]. This Breakthrough Therapy designation is given to speed up the review process of a candidate drug that has shown promise over the existing ones and could be used effectively to treat life-threatening diseases. This does not, however, change the standards for approval. Lentiglobin BB305 drug product was in fact designed to treat severe SCD and beta-thalassemia by introducing a functional human beta-globin gene into the patient’s own hematopoietic stem cell, ex vivo, and then put those cells back into the patients by autologous stem cell transplantation.

The studies dated back to 2014 showed that eight patients were treated using Bluebird’s new therapy. The first patient treated in October 2014 showed successful response to the treatment and did not require any transfusions for three months after the treatment and no requirement for hospitalization with SCD- related complications. The other seven patients did not show similar response, and thus further improvements were needed for LentiGlobin to be a more persistent form of treatment. Since then they have made manufacturing and gene-therapy related advancements in the system. As sickle cell disease is related to abnormal red blood cells, Bluebird was aiming at 30% “anti-sickling,” healthy hemoglobin. Based on a recent trial that included four patients, a median of 39% was reached after three months. At this point, Bluebird Bio is the only company that has reached clinical trials with respect to producing data on gene modifications. Further improvement on the treatment is essential with more evidence related to the efficient functioning of the system.

Teva pharmaceutical’s cluster headache drug, falters at the Phase III clinical trial


Teva Pharmaceuticals (NYSA: TEVA) announced recently that it was stopping the clinical trial of its chronic cluster headache prevention drug fremanezumab, at the Phase III stage. The main reason for the decision was that the drug did not reduce the average number of the cluster headache attacks in a 12-week treatment period [13]. Along with the chronic cluster headache study, there was an episodic cluster headache study and a long-term safety study which were a part of the ENFORCE Phase III clinical development program. The chronic cluster headache study included three hundred patients and the drug was tested both intravenously and subcutaneously. Though this study ended with disappointing results, its effectivity against episodic cluster headache will continue to be tested. There was no concern with the safety of the drug as stated by the company.

4 Phases of a Migraine

From Visually.

 

Fremanezumab is a monoclonal antibody that is currently being reviewed by FDA and the European Medicines Agency (EMA) as a drug, targeting calcitonin gene-related peptide ligand, CGRP [14]. This method of blocking CGRP as a mode of reducing and preventing pain has already been utilized by other competing pharmaceutical companies. Last month saw the FDA approval for Amgen’s CGRP inhibitor, erenumab, that is injected once a month to patients suffering from migraine. “While we are disappointed with this outcome, we remain optimistic that fremanezumab could have clinical benefits in additional conditions, beyond migraine,” said Tushar Shah, senior vice president, head of global specialty clinical development at Teva.

 

 

Reference:

[1] Shire Newsroom, June 2018. https://www.shire.com/en/newsroom/2018/june/7rr5re.
[2] Cicardi M, Bork K, Caballero T, et al, on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012; 67(2):147-157.
[3] FDA news release, FDA approves first subcutaneous C1 Esterase Inhibitor to treat rare genetic disease, June 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm564332.htm.
[4] FDA new release, FDA approves first generic versions of Suboxone sublingual film, which may increase access to treatment for opioid dependence, June 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm610807.htm.
[5] Information about Medication-Assisted treatment. https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm600092.htm.
[6] The source for this information is: https://www.pharmamanufacturing.com/industrynews/2018/fda-approves-first-generic-suboxone/.
[7] The source of this information is: https://www.pharmacytimes.com/publications/issue/2009/2009-06/rxproductprofileuloric-0609.
[8] Takeda, news release, Takeda Announces Results from Uloric® (febuxostat) Cardiovascular Outcomes Trial in Patients with Gout and Cardiovascular Disease, March 2018. https://www.takeda.com/en-us/newsroom/news-releases/2018/takeda-announces-results-from-uloric-febuxostat-cardiovascular-outcomes-trial/.
[9] Citizen petition, June 2018. https://s3.amazonaws.com/assets.fiercemarkets.net/public/005-LifeSciences/Public+Citizen+Uloric+petition+letter.pdf.
[10] Solid Biosciences Announces FDA Removes Clinical Hold on SGT-001, June 18, 2018. https://investors.solidbio.com/news-releases/news-release-details/solid-biosciences-announces-fda-removes-clinical-hold-sgt-001.
[11] Press release, June 2018. http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-new-interim-data-phase-1-hgb-206-study.
[12] Press release, 2015. http://investor.bluebirdbio.com/news-releases/news-release-details/fda-grants-breakthrough-therapy-designation-lentiglobin.
[13] News source: https://www.xconomy.com/national/2018/06/15/tevas-migraine-drug-fails-in-phase-3-for-chronic-cluster-headaches/?utm_source=Xconomy&utm_campaign=a011c05f95-NEWSLETTER_EXOME&utm_medium=email&utm_term=0_2aa91c0bc9-a011c05f95-294911686&mc_cid=a011c05f95&mc_eid=7420647896.
[14] News source: https://www.businesswire.com/news/home/20180615005199/en/Teva-Update-Clinical-Trial-Fremanezumab-Chronic-Cluster.
[15] News source: https://globenewswire.com/news-release/2018/06/26/1529573/0/en/ZEMDRITM-plazomicin-Approved-by-FDA-for-the-Treatment-of-Adults-with-Complicated-Urinary-Tract-Infections-cUTI.html.

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 Dey

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: Pixabay

The contents of Club SciWri are the copyright of PhD Career Support Group for STEM PhDs {A US Non-Profit 501(c)3}. (PhDCSG is an initiative of the alumni of the Indian Institute of Science, Bangalore. The primary aim of this group is to build a NETWORK among scientists, engineers and entrepreneurs).

This work by Club SciWri is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

 

 

Disclaimer: This blog is strictly for news and information. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

SHARE THIS

The contents of Club SciWri are the copyright of Ph.D. Career Support Group for STEM PhDs (A US Non-Profit 501(c)3, PhDCSG is an initiative of the alumni of the Indian Institute of Science, Bangalore. The primary aim of this group is to build a NETWORK among scientists, engineers, and entrepreneurs).

This work by Club SciWri is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Tags

Related articles

Latest from Club SciWri