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In this edition of Medness Plus, Esha Sehanobish highlights Dupixent’s narrow asthma go-ahead which could still give it an edge over its competitors, and FDA approval of Xofluza which is the first new antiviral flu treatment after nearly 20 years with a targetable novel mechanism of action. In an encouraging trend JnJ’s tetravalent vaccine was well-tolerated at 28 weeks with a significant enhancement in the extent of immune responses to a variety of HIV-1 strains when compared to the trivalent version. Also check out the news of a strategic investment of $100 Million made by AbbVie in Morphic Therapeutics to develop integrin inhibitors for Fibrotic Diseases to tap global market size of more than $1.5 billion. Another major funding news is of $26 million provided by US Department of Health and Human Services to Stratatech to develop skin tissue, StrataGraft, for treating burns in pathbreaking pediatric regenerative medicine efforts.- Abhi Dey

  1. FDA approves Dupixent, a product of Sanofi as an add-on maintenance therapy for asthma.

 

FDA recently approved Dupixent (dupilumab) to treat patients with moderate-to-severe asthma [1]. It will be used as add-on therapy in patients aged 12 years and older with oral corticosteroid-dependent asthma or with an eosinophilic phenotype. It is the only biologic to be approved for asthma patients with eosinophilic phenotype and is used for oral corticosteroid-dependent asthma, regardless of the phenotype. It is the only biologic that can be self-administered by patients at home.


Dupixent is a prescription medicine that is implicated in treating moderate-to-severe dermatitis in patients who do not respond well to topical therapies and those who cannot use it. It can be used with other topical corticosteroids. Dupixent also finds utility with other asthma medicines for the maintenance treatment of moderate-to-severe asthma in patients 12 years or older and who are not very responsive to the existing treatments. Dupixent improves the breathing and helps prevent asthma attack. It reduces the number of oral corticosteroids that are necessary to prevent severe asthma attacks. Its safety and efficacy in children under the age of 12 years are not known and it is also not used to treat sudden breathing problems. It works by inhibiting the overactive signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13). These proteins contribute to the Type 2 inflammation that may underlie moderate-to-severe asthma which is usually associated with the reduction of inflammatory biomarkers such as eotaxin-3 (CCL26), fractional exhaled nitric oxide (FeNO) and immunoglobulin E (IgE). The trial program involved 2,888 adults and adolescent patients with moderate-to-severe asthma and was a part of three randomized, placebo-controlled, multicenter trials (1,2 and 3) for a period of 24 to 52 weeks. The patients were enrolled in these trials irrespective of minimum baseline eosinophil levels. Exacerbations were reduced and the lung function was increased in Trial 2, when the patients were treated with Dupixent. The benefits were distinct in patients with eosinophil counts greater or equal to 150 cells/microliter which was about 70% of the patients involved in the trial. A higher efficacy was observed in patients with higher eosinophil counts. For those with a count of 300 cells/microliter or greater, Dupixent could reduce the exacerbations by 67% compared to the placebo and there was a 29-33% improvement in the FEV1 (lung function) compared to the placebo. In patients with 150 cells/microliter eosinophil count, no major change was noticed for Dupixent when compared to the placebo. Another significant observation was that more than half of the patients who were treated with Dupixent could eliminate the use of oral corticosteroids. During the trials, the more frequent adverse reactions that were observed include injection site reactions, sore throat and an increase in the number of eosinophils in the blood. Dupixent usually comes as a pre-filled syringe to be used as an injection under the skin and in the guidance of a healthcare provider. It could be self-administered but only when proper training has been received in a clinic or at home. In the U.S., Dupixent is marketed by Sanofi Genzyme, the specialty global care business unit of Regeneron and Sanofi.

Lung Disease Costs Employers Money

by niegeborges.

From Visually.

 

“Dupixent is now approved in the U.S. for two important groups of uncontrolled asthma patients – those who are moderate-to-severe with an eosinophilic phenotype or those with oral corticosteroid-dependent asthma,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron. “In the asthma clinical trial program, Dupixent reduced severe exacerbations and oral corticosteroid use, improved quality of life and showed statistically significant and clinically meaningful improvements in lung function. Following the approvals in atopic dermatitis and asthma, and recently announced positive Phase 3 results in chronic rhinosinusitis with nasal polyps, we are committed to advancing our broad development program in additional Type 2 inflammatory diseases.” “Today’s approval marks a significant development for certain people with moderate-to-severe asthma aged 12 years and older. For patients, dependent on oral corticosteroids, Dupixent improved lung function, reduced oral corticosteroid use and reduced exacerbations regardless of baseline eosinophil levels. Despite the spectrum of treatments for asthma, there continues to be an unmet need for so many patients with moderate-to-severe asthma, and given that Dupixent works differently than other biologics, there is now a new treatment option for some of these patients. Dupixent has already made a difference for many adults with atopic dermatitis, and we now have the opportunity to do the same for certain adults and adolescents with moderate-to severe asthma in the U.S,” said Olivier Brandicourt, M.D., Chief Executive Officer, Sanofi.

 

  1. FDA approves a new drug Xofluza, for the treatment of influenza.

 

FDA recently approved the use of Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated flu (influenza) in patients 12 years or above and who have been symptomatic for not more than 48 hours [2]. The approval was granted to Shionogi & Co., Ltd.


Influenza or flu is a contagious disease linked to respiratory issues. Treatment received within 48 hours of symptom manifestation, is the most effective one that can lead to a reduction in the symptoms and the duration of illness. The approval was based on data from two randomized controlled clinical trials of 1,832 patients who either received Xofluza, placebo or another antiviral flu treatment within 48 hours of symptom manifestations. It was observed that in case of both the trials patients who received Xofluza showed a lesser time for the alleviation of symptoms compared to patients who received placebo. In the second trial, however there was no major difference in the time for the weakening of the symptoms between patients treated with Xofluza and those treated with other flu medications. The treatment was granted Priority Review by the FDA. Under Priority Review, FDA must take  expedited action on an application to determine if on its approval, there will be a significant improvement in the safety and efficacy of treating, diagnosing or preventing a serious condition. The most common adverse effect associated with the use of Xofluza is bronchitis and diarrhea.

Twitter Flu Tracker

by ccantey.

From Visually.

 

“This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. With thousands of people getting the flu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical. This novel drug provides an important, additional treatment option,” said FDA Commissioner Scott Gottlieb, M.D. “While there are several FDA-approved antiviral drugs to treat flu, they’re not a substitute for yearly vaccination. Flu season is already well underway, and the U.S. Centers for Disease Control and Prevention recommends getting vaccinated by the end of October, as seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family and your community from the flu and serious flu-related complications, which can result in hospitalizations. Yearly vaccination is the primary means of preventing and controlling flu outbreaks.” “When treatment is started within 48 hours of becoming sick with flu symptoms, antiviral drugs can lessen symptoms and shorten the time patients feel sick,” said Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Having more treatment options that work in different ways to attack the virus is important because flu viruses can become resistant to antiviral drugs.”

 

  1. Johnson and Johnson announce the early-stage results for the promising Tetravalent Mosaic-based HIV Preventive Vaccine Regimen.

J & J recently announced the primary analysis of the immune response data for a preventive vaccine against HIV-1 infection which is at a developmental stage at Janssen Pharmaceutical Companies of Johnson and Johnson [3]. The early-stage, Phase 1/2a TRAVERSE study was conducted among HIV-negative volunteers and it included a vaccine regimen of a tetravalent mosaic viral vector and another containing a trivalent mosaic vector. The data showed that the tetravalent vaccine was well-tolerated at 28 weeks and that there was a significant enhancement in the breadth of immune responses to different HIV-1 strains when compared to the trivalent version. The data is scheduled to be shared this week at the HIV Research for Prevention Conference (HIVR4P), 2018 in Madrid, Spain.


The diversity of the HIV is immense and thus designing vaccines and effective treatments against it are usually very difficult. Janssen uses the technique of mosaic immunogens in vaccines so that these molecules can induce an immune response. They are created using genes from a wide variety of HIV-1 subtypes. The trivalent version of the vaccine contains viral vectors that deliver immunogens to generate immune response against three proteins of HIV, Env, Pol and Gag. For the tetravalent one, a fourth immunogen is present which is Env-focused and enhances the diversity of immune responses against HIV-1 subtypes. TRANSVERSE is a Phase 1/2a safety and immunogenicity study conducted in 198 HIV negative volunteers from Rwanda and the United States. The aim of the study was to evaluate and optimize the range of immune response by the two-mosaic based, heterologous prime-boost vaccine regimens including Janssen’s AdVac viral vector technology. One of them was the trivalent vaccine Ad26.Mos.HIV, with three immunogens Mos1.gag-pol, Mos2.gag-pol and Mos1.Env and the tetravalent vaccine Ad26.Mos4.HIV which includes a fourth immunogen, Mos2S.Env. In the trial, at weeks 0 and 12, two prime doses of the tri or the tetravalent mosaic vaccine were administered. This was followed by two boosts at weeks 24 and 48 of essentially the same vaccine added with the soluble protein Clade C gp 140 adjuvanted with aluminum phosphate. At week 28, the TRANSVERSE analysis depicted that both the mosaic-based vaccines showed similar efficacy and safety with mild or moderate adverse effects.  Many antibody immunity evaluations, cross-clade ELISA breadth, subclass response (IgG1 and IgG3) etc. were performed and the conclusion was that the range and level of immune responses were much higher for the tetravalent-based treatment comprising of Ad26.Mos4.HIV as the prime and Ad26.Mos4.HIV and Clade C gp140 as the boost. This study was based on prior encouraging results from the Phase 1/2a APPROACH study that were presented at the 22nd International AIDS conference.

“We urgently need new prevention tools to turn the tide of the HIV pandemic, and an effective preventive vaccine would be a vital asset to help us achieve an HIV-free future,” said Hanneke Schuitemaker, Ph.D., Vice President, Head Viral Vaccine Discovery and Translational Medicine, Janssen Vaccines & Prevention B.V. “Our goal is to develop a universal vaccine that could be deployed against any strain of HIV circulating in the world.”

HIV/AIDS - The Local and the Global

From Visually.

 

 

  1. Alnylam suspends its plan to seek a quick FDA nod for a second RNAi Drug.

 

Alnylam Pharmaceuticals recently announced that it would not seek an accelerated approval of FDA for what could be the second available RNAi drug [4]. Instead, after discussion with regulators and in consultation with FDA, the company has decided to pursue a full approval based on the results of an ongoing Phase 3 trial, ENVISION.  This is a study for givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase1 (ALAS1) for treating acute hepatic porphyria (AHP). The FDA has agreed to put in a rolling submission of a New Drug Application (NDA) with full clinical sections made available in mid-2019, considering the results are positive.


RNA interference (RNAi) is now considered as one of the most rapidly advancing technologies of gene silencing. As a proof, it received recognition with the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics are now being developed using the natural process of RNAi occurring in our cells. siRNA or Small interfering RNA, the molecules that mediate RNAi, are an important part of Alnylam’s therapeutics ventures. It functions by silencing the mRNA that encodes disease-causing proteins, hence prevent them from being expressed. This is a novel genetic approach which is being extensively studied now. Givosiran is a subcutaneously administered RNAi therapeutic targeting the ALAS1 in the treatment of acute hepatic porphyria (AHP). AHP belongs to a family of rare, genetic diseases that leads to life-threatening events and in some cases effects that might impact the functioning and the overall quality of life of the patients. Acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and ALAD-deficiency porphyria (ADP) are four subtypes of AHP that are caused due to a genetic defect leading to the deficiency in one the enzymes of the heme biosynthesis pathway. The defect leads to accumulation of neurotoxic heme intermediates ALA and porphobilinogen (PBG) with the former being the primary neurotoxic intermediate. Some of the common symptoms include diffused abdominal pain, weakness, nausea and fatigue. Some of them can resemble the ones for irritable bowel syndrome, endometriosis and appendicitis. Currently, there are no approved treatments to prevent the chronic symptoms of this disease. Keeping this in mind, there is an ever-increasing demand to treat AHP. Givosiram has the potential to reduce significantly, the ALAS1 levels thus resulting in a decrease in the neurotoxic heme intermediate ALA and PBG to normal levels. This results in reducing and preventing chronic symptoms and life-threatening attacks. Givosiran is utilizing Alnylam’s Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, thus enabling the subcutaneous administration increasing the durability and potency. FDA has granted Givosiran a Breakthrough Therapy designation. It has also received an orphan drug status in both the U.S. and EU for the treatment of AHP. The present on-going Phase 3 ENVISION trial will enlighten us about the ability to use the treatment. The ENVISION Phase 3 trial is a randomized, double-blind, placebo-controlled multicenter study that aims at evaluating the safety and efficacy of Givosiram in AHP patients. Patients received 1:1 ratio of 2.5 mg/kg in a randomized manner of the treatment and placebo administered subcutaneously, monthly over a six-month period. The primary endpoint is determined to be the annual rate of porphyria attacks requiring hospitalization, hemin administration or urgent care visits within the six-month period. Secondary endpoints will evaluate the reductions in the symptoms of AHP such as nausea, pain and fatigue.

“The AHPs are devastating diseases and our goal is to help address the significant unmet need that exists today for people living with AHP. Based on out positive Phase 1/2 clinical results presented earlier this year and the positive interim analysis results from the ENVISION Phase 3 trial, we’re encouraged by givosiran’s potential to make a difference in the lives of AHP patients. Our constructive discussions with the FDA led to our decision to pursue a full approval path with complete ENVISION study results, including porphyria attack data, which are expected much earlier than originallt planned. The FDA has also agreed to a rolling submission of the NDA which will begin this year. This filing plan creates the potential to achieve full approval as rapidly as possible and aligns with our strategy on all other countries,” said Akin Akinc, Ph.D., Vice President and General Managet, Givosiran Program at Alnylam.

 

  1. Abbvie and Morphic Therapeutics enter into a collaboration to treat Fibrotic disease.

 

Abbvie, a global biopharmaceutical company and Morphic therapeutics recently entered into a collaboration to develop oral integrin therapies. This will lead to advance of the Morphic’s oral integrin therapeutics designed to treat fibrosis related issues [5]. Morphic designs oral integrin inhibitors to block TGF-β activation which is expected to either stop or reverse fibrosis in a tissue-specific manner. This was developed in collaboration with Schrodinger, Inc.


Fibrosis takes place when there is chronic inflammation due to persistent injury that might lead to the growth of excessive connective tissues. This leads to organ damage and failure. Fibrosis can cause serious illness since it can affect almost any tissue and organ system and there are limited options that are presently available for its treatment. Integrins are receptors that are expressed on the surface of most human cells. They are responsible for controlling most of the cellular signaling pathways that lead to immune system activation, cell cycle progression, cell survival, cellular migration and differentiation. Human diseases such as fibrosis, immune-oncology and autoimmune diseases can be caused due to erroneous signaling system. Researchers have shown that trying to shut off integrin activity often, in turn, leads to promoting it.

Thus, the main aim of Morphic Therapeutics is to design a system that would promote oral integrin antagonists minus the inadvertent effects that have so far limited the options of treatment. Before being a collaborator, Abbvie was an investor in Morphic Therapeutic’s Series A and Series B financing. Under the present set of agreement Abbvie will pay Morphic $100 million upfront for exclusive license options on the products that are directed to multiple targets. Morphic will conduct the research through the completion of Investigational New Drug (IND)-enabling studies. At this point Abbvie will be responsible for paying the license fee to exercise its exclusive license option and then further the global development and commercialization. Morphic will be eligible for other undisclosed, additional and commercial milestones and royalties for each compound. In case of liver fibrosis indication, Morphic will still retain the right for development and may opt into paying a certain percentage of Abbvie’s development costs for increased royalties. “We welcome the global scientific and clinical development expertise of AbbVie as a strategic collaborator and look forward to investigating together the role of integrin biology in the potential treatment of multiple devastating human diseases involving fibrosis,” said Praveen Tipirneni, M.D., president and chief executive officer, Morphic Therapeutic. “Combined with our recent financing, we are in an excellent position to further the development of our pipeline and more fully extract value from what we believe is the world’s only broad-based structure enabled integrin drug discovery platform­.” “Fibrosis represents a major area of medical need as it can impact nearly every major organ system and has limited targeted treatments to address the underlying cause,” said Lisa Olson, Ph.D., vice president, immunology discovery, AbbVie. “We believe that integrin biology could play an important role in the future treatment paradigm of serious immune-mediated diseases where fibrotic mechanisms contribute to the pathology. We are pleased to partner with the team at Morphic to develop therapies together for patients with these serious conditions.”

 

  1. Stratatech gets $26 million for pediatric studies of Stratagraft Skin Tissue in thermal burns.

 

Stratatech, a Mallinckrodt company, recently received approximately $26 million in addition to the BioShield funding by the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response [6]. This award is supposed to support further the pediatric studies related to the company’s StrataGraft engineered skin tissue. Mallinckrodt is known for the development of new therapies in pediatric cases. For large-scale burn incidents, BARDA is supporting the development of StrataGraft as potential medication technique.


In case of deep partial-thickness burns, the entire epidermis or more than two-thirds of the dermis is destroyed. The usual treatment of such type of burns is the surgical harvesting of a sheet of healthy skin from an uninjured part on the patient’s body and this skin is grafted to the injury once the would is ready to accept an autograft. There is a major concern in this case. It might be effective in providing a closure to the original wound but there are significant limitations in terms of the donor site wound, created due to the surgical removal of the skin for grafting. These donor site wounds often tend to become extremely painful and often become full-fledged wounds. The other limiting factor is the availability of healthy skin for grafting. Thus, there is a need for an alternative treatment for such deep partial-thickness burns. BARDA has previously supported the Phase 3 trial for determining the efficacy and safety of StrataGraft in adults in the promotion of autologous skin regeneration of complex skin defects. Apart from this award, the funding under this program has been estimated to be approximately $86 million and there is a chance of potential funding of $160 million. StrataGraft is an engineered, viable, bilayer human skin substitute that is being developed to treat burns and other skin defects. It hasn’t yet received a nod from the FDA. It mimics natural skin with both inner and outer-dermis type of layers. This type of skin tissue is designed to be sutured, stapled or attached with an adhesive resulting in the formation of a barrier during the wound healing process. StrataGraft tissues are produced from NIKS cells grown in accordance with Good Manufacturing Practice. Since the cell line has been well characterized, StrataGraft is non-tumorigenic, virus-free and has genetic consistency over different batches. Successful approval by the FDA would position StrataGraft for deployment as a medical countermeasure.

What is the Health Impact of a Burn Scar Contracture?

by ReSurge.

From Visually.

 

“We are very pleased that BARDA has continued to see the potential benefit StrataGraft can bring as a much-needed therapeutic option for patients – both adults and children – with high unmet medical need,” said Steven Romano, M.D., Chief Scientific Officer and Executive Vice President, Mallinckrodt. “This is particularly important in the event of tragic mass burn incidents. The expanded partnership with BARDA to assess StrataGraft’s efficacy and safety in the vulnerable pediatric population is aligned with Mallinckrodt’s focus on improving outcomes for patients with severe and critical conditions in particularly vulnerable populations.”

 

References:

 

  1. http://hugin.info/152918/R/2221308/869471.pdf.
  2. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm.
  3. https://www.jnj.com/johnson-johnson-announces-promising-early-stage-results-for-tetravalent-mosaic-based-hiv-preventive-vaccine-regimen.
  4. http://investors.alnylam.com/news-releases/news-release-details/alnylam-announces-plan-initiate-rolling-submission-new-drug.
  5. https://news.abbvie.com/news/press-releases/abbvie-and-morphic-therapeutic-announce-collaboration-targeting-fibrotic-diseases.htm.
  6. https://www.prnewswire.com/news-releases/mallinckrodts-stratatech-company-awarded-26-million-in-additional-barda-funding-for-pediatric-studies-of-stratagraft-skin-tissue-in-thermal-burns-300721549.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: (Cell Image Library)Description: Colorized transmission electron micrograph of human immunodeficiency virus (HIV) particles (blue) budding from the surface of a T cell (a type of lymphocyte).The viruses replicate inside the cell with the different components gathering at the cell membrane to be assembled into new virus particles.(Technical Details: B0005750 HIV particles budding from a lymphocyte . Wellcome Images available under the following creative commons usage http://creativecommons.org/licenses/by-nc-nd/2.0/uk/)

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).

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Disclaimer: The authors and editors for Medness Plus declare no financial benefits or remuneration from the sponsors. The sponsorships support the non-profit organization PhD Career Support Group (PhD CSG). The research conducted by authors and editors is a voluntary effort to popularize science for the public on behalf of PhD CSG. The sponsors do not have any influence on the nature or kind of the news/analysis reported in Onco-this-Week. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Club SciWri or PhD CSG. Examples of analysis performed within this article are only examples. They should not be utilized in real-world analytic products as they are based only on very limited and dated open source information. Assumptions made within the analysis are not reflective of the position of anyone volunteering or working for Club SciWri or PhD CSG. 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.

 

 

 

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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).

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