In this edition of Medness Plus, Esha Sehanobish highlights FDA’s authorization of the first Ebola fingerstick test, DPP Ebola Antigen System, for emergency use. FDA also approved two devices (from Fluoptics and AiBiomed) that provide real-time location of parathyroid tissue during surgical procedures. As a direct-to-consumer test, FDA permits marketing of the 23andMe Personal Genome Service Pharmacogenetic Reports test which provides information about genetic variants that identify a patient’s ability to metabolize some medications. Eyeing a potential treatment for adolescents with uncontrolled moderate-to-severe atopic dermatitis, Dupixent® (dupilumab) gets an FDA priority review. Also check out the launch of a new biotech company, Mirum Pharmaceuticals, with $120 million in new funding to target Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and genetic liver disorders that primarily affect children. In a major collaboration, Denali Therapeutics and Sanofi aim to develop multiple molecules to treat inflammatory and neurological diseases. -Abhi Dey
FDA authorizes the emergency use of the DPP Ebola Antigen System, the first Ebola fingerstick test with a portable reader.
The test, called the DPP Ebola Antigen System, the first that uses a portable battery-operated reader, which can help provide clear diagnostic results outside of laboratories and in areas where patients are likely to be treated.
This is another… https://t.co/gnYB5jKSKt
— Kobby Blay (@kobbyblay) November 11, 2018
FDA recently approved the emergency use of the first Ebola fingerstick test with portable reader. An emergency use authorization (EUA) has been issued for a fast, single-use test for detection of the highly deadly Ebola virus (Zaire ebolavirus) [1]. This has an edge over the available fingerstick test since this carries a portable battery-operated reader, and can help provide unambiguous results outside the laboratories especially in certain remote areas where patients are likely to be treated. The approval was granted to Chembio Diagnostic Systems Inc.
An emergency was declared by the Secretary of Health and Human Services after the 2014 Ebola outbreak in West Africa. Even though that one ended, since then we have heard of smaller such outbreaks due to which the emergency declaration stands till date. The recent test that got approved is known as the DPP Ebola Antigen System. This system is used with blood specimens such as capillary “fingerstick” whole blood from people with signs and symptoms of Ebola virus disease (EBD), from individuals living in area with large number of EBD cases or those who recently came in contact with people exhibiting the corresponding symptoms. The DPP Ebola Antigen System has a lot of positive points. It will provide fast diagnostic results for tests that need to be performed in locations where the healthcare provider might not have access to authorized Ebola virus nucleic acid tests (PCR testing). It will also be beneficial for highly sensitive cases that need require laboratory settings. The DPP system has been authorized for use with capillary “fingerstick” whole blood, ethylenediaminetetraacetic acid (EDTA, an anticoagulant) venous whole blood and EDTA plasma. The DPP Ebola Antigen system should only be used by trained individuals at treatment centers and public health centers where the laboratories are adequately equipped. The FDA’s EUA usually allows an agency to make use of an unapproved medical discovery or the unapproved use of an approved medical discovery/product, among other circumstances when there are no other available alternatives. The EUA becomes an important decision when circumstances exist justifying authorization thus allowing the usage of products that have not yet been approved by the FDA. The only criteria for the issuance of an EUA for a diagnostic test is based on the assessment of the results, that indicates that the test maybe effective and the potential benefits will surpass the known potential risks associated with it. Hence the EUA for the DPP Ebola Antigen System is an important decision to detect outbreaks in remote areas with limited access and resources. Like other diagnostic tests, the DPP system should also be considered along with other factors. A negative test result should not be disregarded based solely on the test, especially with individuals with sign and symptoms of EVD. The final diagnosis should also take into consideration, the signs, symptoms, history, exposure likelihood and other laboratory evidences to either acknowledge or disregard the results. This step is one of the many that FDA is presently undertaking in its fight against the deadly Ebola virus and they are committed to using authorities and resources to find the best possible solution to this serious outbreak.
From Visually.
“The scourge of Ebola tragically demonstrates that we’re a global community when it comes to public health protection. Infectious disease doesn’t recognize nation states. Bacteria and viruses don’t respect territorial boundaries. It takes a sustained, robust and globally coordinated effort to protect our nation and the global community from various infectious disease threats. We’re all in this together. To that end, our FDA team of experts in drugs, vaccines and diagnostics continue to collaborate with our Federal, international and industry partners to employ our collective expertise, experiences from previous incidents, and resources to assist in the global response to the Ebola outbreak in the Democratic Republic of Congo,” said FDA Commissioner Scott Gottlieb, M.D. “This EUA is part of the agency’s ongoing efforts to help mitigate potential, future threats by making medical products that have the potential to prevent, diagnosis or treat available as quickly as possible. We’re committed to helping the people of the DRC effectively confront and end the current Ebola outbreak. By authorizing the first fingerstick test with a portable reader, we hope to better arm health care providers in the field to more quickly detect the virus in patients and improve patient outcomes.”
FDA approves the marketing of two devices to detect parathyroid tissue in real-time during a surgery.
FDA has cleared two devices that provide real-time location of parathyroid tissue during surgical procedures.
One is the Fluobeam 800 Clinic Imaging Device from Fluoptics and the other is the Parathyroid Detection PTeye System from AiBiomed. https://t.co/1dWcu6heK2— Victoria Luna (@VictoriaLuna4) November 5, 2018
The U.S. Food and Drug Administration (FDA) has recently approved the marketing of two devices that provide the real-time location of parathyroid tissue during a surgical procedure such as parathyroidectomy (surgery to remove one or more parathyroid glands) and thyroidectomy (surgery to remove all or some parts of the thyroid gland) [2]. The two devices are The Fluobeam 800 Clinic Imaging Device and the Parathyroid Detection PTeye System. The approvals were granted to Fluoptics and AiBiomed respectively.
Parathyroid tissue lines the borders of the thyroid gland and disorders related to it can be treated by the surgical removal of parts of the thyroid gland or parathyroid tissue. 100,000 Americans, every year, are diagnosed with Hyperparathyroidism which leads to overproduction of the thyroid hormone. It is the most common parathyroid disorder. One of the major problems faced by surgeons in treating hyperthyroidism is the difficulty in locating and distinguishing parathyroid tissues from the nearby ones during a surgical procedure. The PTeye and the Fluobeam 800 were reviewed separately under the FDA’s DeNovo premarket review pathway. This is a regulatory pathway for some low-to-moderate risk devices that are unique and novel and do not have any prior legally marketed device. The Fluobeam 800 Clinic Imaging Device is used to assist during a surgery to locate the parathyroid tissues by using imaging techniques to visualize the parathyroid glands. When exposed to the light source of the device, the parathyroid tissue emits a fluorescent glow thus avoiding the need for a contrast agent. This device was previously authorized to visualize fluorescent images for the visual assessment of blood flow as a mean for evaluation of tissue perfusion. FDA reviewed data from five peer-reviewed published articles that summarizes the comparisons of the rate of postoperative hypocalcemia (PH) or a temporary fall in the calcium level in the blood due to the removal of healthy parathyroid tissue. It was observed from the data that out of 98 patients who underwent the surgery using the device, only 5 percent experienced PH following the surgery. Whereas, in case of 153 patients who underwent the surgery without the device, 21 percent experienced PH following the surgery. The other device PTeye helps in detecting the parathyroid tissue during the surgery by using a probe that emits fluorescence light. The reaction of the parathyroid tissue to the fluorescent light is used for tissue detection. When it is detected, the presence of the tissue is indicated from an audio and visual display. FDA reviewed data from a single-blinded study of 81 patients who had surgery using the device. PTeye could identify the parathyroid tissue when compared to histology, about 93 percent of the time and correctly identify the absence of it when compared to intraoperative visualization by an expert 97 percent of the time. The overall accuracy of the device is about 96 percent. A strong emphasis has been put on the fact that the device is intended to assist and not replace experienced visual assessment in identifying the parathyroid tissues along with a biopsy to confirm thyroid tissue per standard of care. Their primary and only aim is to assist surgeons in locating potential parathyroid tissue or glands.
“For some patients with parathyroid disease, treatment may mean a surgical procedure,” said Binita Ashar, M.D., director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health. “Real-time identification of parathyroid tissue during surgery can provide surgeons with valuable information to help preserve healthy tissue or to remove diseased tissue.”
FDA approves the first direct-to-consumer test for genetic variants detection that are associated with metabolism of medication.
FDA recently approved the marketing of the Personal Genome Service Pharmacogenetic Reports test as a direct-to-consumer test for providing information about the genetic variants that are usually associated with a patient’s ability to metabolize some medications but with special controls [3]. This could eventually help health care providers to take a more informed decision regarding treatments The FDA is presently authorizing the test for the detection of 33 variants for multiple genes. The authorization has been given to 23andMe.
U.S. FDA permitted marketing, of the 23andMe Personal Genome Service Pharmacogenetic Reports test as a direct-to-consumer test providing information about genetic variants that may be associated with a patient’s ability to metabolize some medications.https://t.co/4nnZYz6eNB pic.twitter.com/AbANmTsP1D
— David Sandbach (@Yockletondave) November 7, 2018
The method to understand the role that genetics might play in the reaction of a patient to drugs is known as Pharmacogenetics. The newly approved, Personal Genome Service test analyzes the DNA from saliva samples and determines whether variants in certain genes are associated with a patient’s ability to metabolize some medicines. 23andMe submitted data based on user comprehension studies which suggested that the instructions and the reports were clearly understood by consumers. The test report elaborately describes how to interpret the results, what the test does not do and what the results might mean. After reviewing all the data, FDA determined that the data provided showed that the test is accurate and can correctly identify the genetic variations in the samples of saliva. The results were also found to be reproducible which is an important criterion to fulfill. The de novo premarket review pathway was used by the FDA to review the data for the test. This regulatory pathway is used for novel, low-to-moderate-risk devices that are not equivalent to an already market-available device. The FDA has also issued a special controls criterion, which brings to the forefront the agency’s expectations in clinical performance and labeling and the test’s accuracy. One can provide a considerable assurance of the efficacy and safety for the test only when these special controls are met along with the general controls. For this category six special controls have been established by the FDA. One of them states that there must be a warning statement included with this where the consumers are asked not to change or stop any medication based solely on the test results. The Pharmacogenetics Reports test is not meant to provide results for any specific medication. It does not describe the relation between any specific drug and detected genetic variants. It also does not determine whether a person will or will not respond to a specific drug. This test alone should not be used by healthcare providers to make treatment decisions and should be confirmed with other independent pharmacogenetic testing for further actions.
From Visually.
“This test is a step forward in making information about genetic variants available directly to consumers and better inform their discussions with their health care providers. We know that consumers are increasingly interested in genetic information to help make decisions about their health care,” said Tim Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “This test should be used appropriately because it does not determine whether a medication is appropriate for a patient, does not provide medical advice and does not diagnose any health conditions. Consumers should not use this test to make treatment decisions on their own. Any medical decisions should be made only after discussing the results with a licensed health care provider and results have been confirmed using clinical pharmacogenetic testing.”
FDA approves the priority review for Dupixent as a potential treatment for adolescents with uncontrolled moderate-to-severe atopic dermatitis.
FDA grants priority review for Dupixent® (dupilumab) as potential treatment for adolescents with uncontrolled moderate-to-severe atopic dermatitis https://t.co/BaVumeo4tD pic.twitter.com/L2C5sgDUjW
— David Ledger (@Vedere_Group) November 9, 2018
Sanofi and Regeneron Pharmaceuticals, Inc. recently announced that FDA has granted priority review to the supplemental Biologics License Application (sBLA) for Dupixent (dupilumab) in patients 12 to 17 years of age with moderate-to-severe atopic dermatitis [4]. This could be used as a potential treatment for patients who do not respond adequately to topical therapies or those for whom the topical treatment is not the best option. Presently there are no medications available to treat adolescents with moderate-to-severe atopic dermatitis. The final decision is scheduled for March 11, 2019.
Dupixent is known to treat adults with moderate-to-severe atopic dermatitis who do not respond to prescription therapies used topically or those who cannot use them. There is also an option of using Dupixent with or without other corticosteroids. Of late, Dupixent has been approved to be used with other asthma medications for the maintenance therapy of moderate-to-severe asthma in people aged 12 years and older who do not respond very well to the current set of asthma medicines. It helps prevent severe asthma attack and reduces the amount of oral corticosteroids needed to prevent such attacks. Interleukin-4 and interleukin-13 (IL-4 and IL-13) signaling contributes to the Type 2 inflammation that is a systemic response known to play a part in moderate-to-severe atopic dermatitis. Dupixent functions by inhibiting this signaling pathway. The decision to approve a priority review to the sBLA by the FDA was based on a pivotal Phase 3 trial evaluating the safety and efficacy of the drug monotherapy in patients aged 12-17 with moderate-to-severe atopic dermatitis. The data from the study was presented at the European Academy of Dermatology and Venereology in September 2018. Dupixent is currently approved for the treatment of the same medical condition but only in adults whose disease is not well-controlled with topical medications and therapies. Dupixent has also been approved for certain adult patients with moderate-to-severe atopic dermatitis in countries like Canada and Japan and some in the European Union. More than 60,000 adult patients have been prescribed the drug. At present, further investigation needs to be conducted by regulatory authorities to finally determine the safety and efficacy of Dupixent in adolescents with atopic dermatitis. The most common side effects include eye and eyelid inflammation, redness, swelling and itching along with injection site reactions, pain in the throat and cold sores in the mouth or lips. Some of the more serious adverse effects include anaphylaxis and inflammation in blood vessels.
From Visually.
With a $120M, Mirum Pharmaceuticals is all set to advance liver drugs.
Mirum Pharmaceuticals, a biotech enterprise, is all set to be launched with $120 million in new funding to proceed with investigation of two possible liver disease drugs. The financial endeavor comes on behalf of entrepreneur Mike Grey who has already worked on one of these drugs [5]. The target drug will be a compound called maralixibat for the treatment of Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) and genetic liver disorders that primarily affect children. The aim is to push for Phase 3 trial next year for maralixibat.
Mirum Pharmaceuticals to receive $120 million to develop #drug for rare liver diseases #ALGS and #PFIC:https://t.co/coKzJw9alA
— RxNet (@RxNetFSG) November 13, 2018
Maralixibat is under investigation as it is expected to address the dangerous symptoms of ALGS and PFIC. The conjecture is that the drug will prevent the buildup of bile and a condition called pruritus. The condition is marked by intense itching, in some cases severe enough to injure children with the disease while scratching. The usual mode of treatment in such cases is a liver transplant or relief via off-label drugs or surgical procedures. The results from a 48-week interim analysis from a Phase 2b study in people with ALGS will be presented next year at a liver disease meeting. The study has shown positive results since 230 patients till date have taken the drug orally and it is believed to inhibit a protein associated with the bile acid. The clinical trials for maralixibat will take place mainly at the Bay Area where the headquarters of the startup is going to be located. The drug has already been licensed from Shire for Mirum with an upfront payment and possibilities of potential royalties and milestone payments along with equity in the new company. Further details about the financial deal is yet to be disclosed. This is a second effort by Grey to establish maralixibat through Mirum as previous efforts were made by the San Diego-based Lumena Pharmaceuticals when the company was bought by Shire in 2014 for $260 million. He was the CEO and the president of the company from 2011 until acquisition. The present team includes executives who were formerly with Tobira, a San Francisco-based company later acquired by Allergan for $600 million in 2016 and up to $1.7 billion in total. More financial details are yet to be announced. At this point, Mirum aims at targeting other liver conditions which affect both adults and children.
From Visually.
Pacific Biosciences will be acquired by Illumina for approximately $1.2 Billion, to increase access to long-read sequencing and accelerated scientific discovery.
DNA sequencing giant @illumina is set to acquire “long-read” DNA sequencer Pacific Biosciences for approximately $1.2B – @Xconomy https://t.co/RAOYsdD1UT pic.twitter.com/HySgCoEWTZ
— Fresh Brewed Tech (@freshbrewedtech) November 15, 2018
Pacific Biosciences and Illumina Inc. recently announced that they intend to enter into an agreement based on which the former will be acquired by the latter at $8.0 per Pacific Biosciences share in an all cash transaction [6].
The agreement will advance the sequencing solutions of Illumina with accurate long-read sequencing capabilities. Even though the short-read sequencing is known to answer most of the complicated questions in genomics, certain de novo sequencing and sequencing of highly homologous regions of genomes requires accurate long-reads. As per data, the market for long-read sequencing was $600 million in 2017. It is projected to grow 30 percent yearly and is expected to reach $2.5 billion in 2022. The agreement approved by the board of directors of Illumina and Pacific Biosciences will combine the expertise of both the companies to help researchers make fastened discoveries and finally offer new economical tests. Even though the directors have signed off the deal, the approval still needs to come from shareholders and regulators of PacBio. The deal is expected to close in mid-2019.
From Visually.
“Illumina continues to democratize the use of sequencing at an unprecedented rate. Through this combination, thousands of researchers will now have direct access to this technology,” said Michael Hunkapiller, Ph.D., Chief Executive Officer of Pacific Biosciences. “Illumina and Pacific Biosciences have shared values and a commitment to innovation. Our complementary sequencing technology, once integrated, will offer customers a new standard of insight and understanding, opening new frontiers of genomic utility.” “PacBio’s unmatched accuracy mirrors that of Illumina’s in short-read sequencing. Combining the two technologies positions us to reach more applications, accelerate the pace of genomic discovery and bolster our innovation engine which has been a hallmark of Illumina since our inception,” said Francis deSouza, President and Chief Executive Officer of Illumina. “PacBio’s relentless pursuit to improve sequencing accuracy, while driving down the cost, underscores the potential of long-reads to expand sequencing to new customers and applications.”
Denali Therapeutics and Sanofi have decided to enter into an agreement to develop treatments for inflammatory and neurological diseases.
Denali Therapeutics and Sanofi are in the process of entering into an agreement to develop multiple molecules to treat inflammatory and neurological diseases. The molecules that are the leading candidates for this are DNL747 and DNL758 [7].
@Sanofi and Denali Therapeutics, a #biopharma company developing drugs to treat neurodegenerative diseases, are partnering in a deal worth up to $1 billion to develop multiple molecules for treating neurological and systemic inflammatory diseases. https://t.co/q4ln5L608A pic.twitter.com/c70qT8Ix08
— Value Chain Insights (@DCATvci) November 9, 2018
The molecules are supposed to target a signaling protein, receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the TNF receptor pathway. The pathway regulates cell death and inflammation in tissues of the body. DNL758 will be studied by Sanofi in inflammatory diseases such as psoriasis and rheumatoid arthritis and DNL747 will be studied in multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. DNL758 is a small molecule that does not enter the brain. Whereas, DNL747, is a brain-penetrating small molecule that is presently in Phase 1 clinical trial. Denali is expected to lead the Phase 2 clinical trials in Alzheimer’s disease and the Phase 2 trials in MS and ALS will be furthered by Sanofi along with the Phase 3 trials in neurological indications. An upfront payment of $125 million will be made by Sanofi to Denali with provision of commercial milestones that could reach $1 billion. The two companies will share commercial profits and losses from DNL747 in China and US. Denali in expected to receive royalty from Sanofi for other territories for DNL747 and globally for DNL758. The divisions for the different diseases have been well sorted out. Phase 1b and 2 for DNL747 will be funded by Sanofi for MS and ALS and for the Alzheimer’s disease will be funded by Denali. Sanofi will fund 70% and Denali will contribute 30% for all Phase 3 trials.
From Visually.
“RIPK1 is a promising target with the potential to bring disease modifying medicines to patients suffering from neurodegenerative diseases as well as systemic inflammatory diseases. We are very excited to partner with Sanofi and expand our RIPK1 program into new indications,” said Ryan Watts, Ph.D., CEO of Denali. “With its considerable infrastructure and experience in both clinical development and commercial functions, Sanofi is an ideal partner for Denali to maximize the clinical and commercial success of our RIPK1 program.” “This collaboration with Denali is yet another example of Sanofi’s commitment to accelerate the development of transformative and best-in-class treatments for patients living with serious illnesses,” said Rita Balice-Gordon, Ph.D., Global Head of Rare and Neurologic Diseases Research at Sanofi. “We look forward to working with Denali on the RIPK1 program as we explore the potential of this mechanism in neurologic and inflammatory diseases.”
Reference:
[1] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm625502.htm.
[2] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624982.htm.
[3] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624753.htm.
[7] http://hugin.info/152918/R/2223360/871350.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)Description: Confocal image of an axonal rainbow of oculomotor nerve motor axons from a “Brainbow” mouse brain, with each neuron expressing a distinct color. In Brainbow mice, neurons randomly choose combinations of red, yellow and cyan fluorescent proteins, so that they each glow a particular color. This provides a way to distinguish neighboring neurons and visualize brain circuits. 2007 Olympus BioScapes Digital Imaging Competition. For additional details see: Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW. Nature. 2007 Nov 1;450(7166):56-62.
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