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Esha Sehanobish reports FDA approval of a traveller’s diarrhoea drug, Aemcolo, from Ireland’s Cosmo Pharma. FDA also approved Novoimmune’s Gamifant (the first ever drug to treat hemophagocytic lymphohistiocytosis), and Novartis’ Eltrombopag for kids and adults suffering with severe aplastic anemia. FDA also placed a clinical hold on ZGN-1061 US clinical trial, Zafgen’s second-generation, investigational MetAP2 inhibitor for the treatment of type 2 diabetes. And an encouraging news from a collaboration of Emergent Biosolutions and Valneva reveals positive early stage results for a Zika vaccine candidate. Check out all this and much more in our infographics in this edition of Medness Plus.- Abhi Dey

FDA approves the use of Aemcolo for the treatment of adult patients with travelers’ diarrhea.


FDA recently approved the Aemcolo (rifamycin), an antibacterial drug, for the treatment of adults with travelers’ diarrhea. This disease is caused by noninvasive strains of E. coli and is usually not complicated by fever or blood in the stool of patients [1]. This approval was granted to Cosmo Technologies Ltd.

The most common travel-related illness is travelers’ diarrhea. An estimated 10-40 percent of people traveling are affected by this disease each year. In the case of travelers, three or more unformed stools in 24 hours, indicate that the person has travelers’ diarrhea. It is caused most commonly by bacteria from food and water, although a variety of pathogens maybe responsible for it. Most regions of the Middle East, Asia, Africa, Central and South America, and Mexico are the highest risk areas. Aemcolo has been granted a Qualified Infectious Disease Product (QIDP) designation. This designation is used for antifungal and antibacterial drug products that are known to treat serious or life-threatening diseases. It falls under the Generating Antibiotic Incentives Now (GAIN) category of the Safety and Innovation Act of FDA. Priority Review has also been granted to the Aemcolo marketing application as a part of the QIDP designation, due to which an expedited action will be taken on the merit of the application. This decision was made based on the efficacy study of Aemcolo. A randomized, placebo-controlled clinical trial was conducted in 264 patients with travelers’ diarrhea from Mexico and Guatemala. When compared to the results from the placebo-treated study, it was found that Aemcolo significantly reduced symptoms of the disease. Safety was further determined as the drug was taken orally over three to four days by 619 adults with travelers’ diarrhea in two controlled clinical trials. Aemcolo is only effective in patients with diarrhea who do not show fever and/or bloody diarrhea. It is not found to be effective against noninvasive strains of E. coli and is not recommended to be used in such patients. It is also not recommended for patients who are known to be sensitive to rifamycin or any other rifamycin class of antimicrobial agents or any constituents of Aemcolo.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Gastroenteritis

From Visually.

 

 

FDA approves treatment for patients with life-threatening and rare type of immune disease.


FDA recently approved the use of Gamifant (emapalumab-Izsg) for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have recurrent or progressive intolerance to conventional HLH therapy [2]. This is the first treatment for HLH, which is a rare and life-threatening type of immune disease. The approval was granted to Novimmune SA. Gamifant has received Priority Review and Breakthrough Therapy designation along with the status of Orphan Drug which provides incentives to encourage the development of drugs for rare diseases.

 

Hemophagocytic lymphohistiocytosis (HLH) is a disorder that leads to improper functioning of the immune cells of the body. Because of this, the cells release molecules causing inflammation. As an outcome of the HLH condition, the organs such as the liver, brain and bone marrow start becoming damaged. It can be familial or primary in nature, thus can be hereditary. Some non-inherited cases are also known. Symptoms like fever decreased the number of blood cells and enlarged liver or spleen are usually exhibited within the first few months or years of life. The approval was based on the clinical trial focused on the efficacy of Gamifant. 27 pediatric patients with either suspected or confirmed primary HLH with recurrent or progressive and refractory disease during the usual HLH therapy or who were intolerant to the treatment, were selected for the trial. The median age of this group was 1 year. The data showed that positive response in 63 percent of the patients and 70 percent could then proceed to stem cell transplant. Some of the common side-effects of the treatment with Gamifant include infusion-related reactions, hypertension, low potassium, fever and infections. One requirement of the drug treatment is that the patients must be tested for latent tuberculosis before being prescribed Gamifant. They should not receive any live vaccines during the time of the therapy and patients should be monitored and treated immediately for infections.

“Primary HLH is a rare and life-threatening condition typically affecting children and this approval fills an unmet medical need for these patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to expedite the development and review of therapies that offer meaningful treatment options for patients with rare conditions.”

 

FDA approves Promacta for the first-line treatment of severe aplastic anemia (SAA).


FDA recently announced the expansion of label for Promacta (eltrombopag) to include the first-line treatment for pediatric patients two years and over and for adults with severe aplastic anemia (SAA) [3]. It is meant to be used in combination with standard immunosuppressive therapy (IST). The approval was given to Novartis.

 

Severe aplastic anemia is a life-threatening and rare acquired blood disorder in which the patient’s bone marrow becomes incapable of generating white and red blood cells and platelets. SAA is fatal because of the inability to generate the blood cells in case of hemorrhages and infections. Even otherwise it is a very serious condition leading to fatigue, trouble in breathing, abnormal bruising which can restrict daily life activities.  In most countries outside the US, Promacta, marketed at Revolade, is already approved for patients with SAA who have an inadequate response to IST. It is an oral thrombopoietin receptor agonist (TPO-RA). It is also approved for children and adults with chronic thrombocytopenia (IPT) with inadequate response to other treatments and the treatment of thrombocytopenia in patients with chronic hepatitis C infection. The approval from FDA was based on data from the research sponsored by the National Heart, Lung and Blood Institute Division of Intramural Research program conducted under a Cooperative Research and Development Agreement (CRADA). Study showed that 44 % of definite immunosuppressive therapy (IST)-naïve SAA patients responded completely at 6 months when treated with Promacta and concurrently with standard IST. This rate was found to be 27 percent higher than response with IST alone. At the end of 6 months, the overall response rate was 78 percent. Significant impact has been generated for patients with SAA from these high response rates. This data adds on to the IST refractory indication for patients with SAA which Promacta was granted in 2015. According to this, a subset of patients showed restoration of bone marrow functioning and maintained stable cell counts following the discontinuation of Promacta. In the case of the IST-naïve SAA, the present data show sustained response with a median duration of 24.3 months along with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA) followed by maintenance CsA4. The most common adverse effects observed in this study included rash, skin discoloration such as hyperpigmentation and abnormal liver function tests. In another recent advancement, FDA has also granted Breakthrough Therapy Designation to Promacta as a countermeasure for hematopoietic sub-syndrome of acute radiation syndrome (H-ARS). A Breakthrough designation is usually given for drugs that have the capability of treating serious or life-threatening events and those that exhibit a significant improvement over the existing therapies in the context of clinically substantial endpoint achievements. The syndrome that is under investigation occurs after exposure to ionizing radiations leading to conditions such as thrombocytopenia resulting in a reduction in platelet counts. The reduction in the number of platelets is usually life-threatening since it increases the chances of hemorrhages. Promacta has shown promising results in decreasing the risk of hemorrhages in patients with H-ARS. The U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) is researching for determining the efficacy of Promacta for H-ARS specifically for patients exposed to myelosuppressive doses of radiation.

“Severe aplastic anemia can be a fatal diagnosis if left untreated, and many patients fail to respond to current initial treatment options,” said Liz Barrett, CEO, Novartis Oncology. “Today’s US approval for Promacta is an important step forward for people living with this challenging disease and shows how Novartis continues to reimagine care in areas where few treatment options exist.” “Patients with SAA sometimes do not respond to the current treatment standard of IST,” said Phillip Scheinberg, MD, Head, Division of Hematology, Hospital A Beneficência Portuguesa de São Paulo in Brazil, and previously with the Hematology Branch of the NHLBI. “With this approval, physicians now have an option to add Promacta to the standard IST in a regimen that has demonstrated significant overall and complete response rates upfront in SAA and reduce the numbers of those who are unresponsive to initial therapy.”

 

FDA places a clinical hold on the Investigational New Drug Application for a treatment of type 2 diabetes.


FDA has placed a clinical hold on the IND for Zafgen’s first US trial of ZGN-1061. This is the company’s second-generation investigational inhibitor of MetAP2 that is currently under development to treat type 2 diabetes [4]. Zafgen is a clinical-stage biopharmaceutical company looking to extend their proprietary knowledge of MetAP2 systems biology to target the treatment of metabolic diseases. The news came in the form of a letter from the FDA thus putting a clinical hold to the present investigation. Zafgen has till now ventured the use of MetAP2 inhibitors in common and rare metabolic disorders and is expanding its research to areas such as Prader-Willi syndrome, certain liver diseases and type 2 diabetes. MetAP2 is critical in tissue repair and protein degradation. Its involvement in the growth of new blood vessels makes it an interesting subject for angiogenesis necessary for the progression of diseases such as solid tumor cancers. Thus, designing and using inhibitors against MetAP2 can have diverse applications.

Diabetes: Type 1 Diabetes v/s Type 2 Diabetes

From Visually.

 

FDA has placed a clinical hold as they express concern over the possibility of cardiovascular safety risk based on the potential protocol including the clinical and nonclinical options. The company after considering these issues plans to request a Type A meeting with the FDA to discuss further steps in the development of ZGN-1061. Beloranib, the company’s first drug for the treatment of a rare form of obesity was developed earlier to block Methionine aminopeptidase2 (MetAP2) [5]. ZGN-1061 acts similarly by inhibiting MetAP2 that is required in removing methionine, an amino acid needed for tissue repair. At present Zafgen is continuing its ongoing ex-U.S. Phase 2 clinical trial of ZGN-1061 in which a group of patients is being treated with a dose of 1.8 mg of the drug. Dosing in this clinical trial has just been concluded and based on that no cardiovascular safety risks have been observed. Zafgen is still on track to report topline data from this group in early 2019. Zafgen reported a full 12-week positive data for its initial group of this Phase 2 proof-of-concept clinical trial. In this trial, a dose up to 0.9 mg was used. All the primary endpoints were met by ZGN-1061 for that group demonstrating the proof-of-concept efficacy and favorable tolerability and safety when compared to placebo. No cardiovascular safety risk or treatment-related serious adverse effects was observed.

 

FDA issues warning to marketers of products with dietary supplements that contain tianeptine for making unproven claims to treat conditions like opioid disorder.


FDA has recently issued warning letters to two companies for marketing products with dietary supplements containing tianeptine, a compound which these companies are illegally claiming to treat various pain, anxiety and even in some cases, opioid disorders [6]. These claims are false and unproven, according to the FDA. The warning letters have been issued to MA Labs for Vicaine products and Jack B Goods Outlet Store for Tianaa Red, White and Green products. These are dietary supplements and are supposed to contain tianeptine sodium on the label. In the warning letters, the FDA has asked for an explanation from both the companies within 15 working days and failure to provide so may lead to legal actions.

Usually, if a dietary supplement claims to treat, reduce or even cure a disease, then it is regulated as a drug. Under the Federal Food, Drug and Cosmetic Act, dietary supplements containing tianeptine, are adulterated. Based on regulations, tianeptine should not be present in such supplements as it is considered to be an unsafe food additive and FDA has not approved its use. CDC (U.S. Center for Disease Control and Prevention) had issued a warning about tianeptine abuse and withdrawal which is capable of mimicking opioid withdrawal and toxicity. There is possibly an emerging healthcare risk is the form of tianeptine abuse and exposure. Meanwhile, it has been approved in other countries to treat certain neurological, gastrointestinal and cardiovascular symptoms with occasional effects that mimic opioid withdrawal and toxicity. Opioid dependence is an extremely crucial problem in the present day and age. FDA has a set of approved medical assisted treatments that are proven to be safe and shown to reduce the risk of death by half. But unproven claims as that made by the companies regarding usage of tianeptine is detrimental. It prevents those addicted to opioids from receiving the safe, effective and approved therapies thus putting them at a greater risk which could eventually be life-threatening.

What Do Consumers and Doctors Need to Know About Opioid Dependence?

From Visually.

 

“This action is part of a broader effort we have underway to re-examine our resources and authorities related to products marketed as dietary supplements, and outline a new policy on how we intend to more vigorously fulfill our obligations to protect consumers from dangerous products and unlawful claims. We’ll have more to say on our policy efforts very soon. The bottom line is this: we’ve seen growing instances where profiteers are pushing potentially dangerous compounds – often with unproven drug claims and crossing the line when it comes to what defines a dietary supplement. These potentially illegal activities put the entire dietary supplement industry at risk by confusing consumers, harming patients and tainting good dietary supplement products by associating them with the activities of bad actors. In this case, these companies are preying on vulnerable patients who may be seeking alternative treatments to serious medical conditions like opioid use disorder. They’re also selling products with known safety issues. We won’t stand by and allow this to happen. These warning letters are one part of our enforcement plan and we’ll continue to take action to protect public health,” said FDA Commissioner Scott Gottlieb, M.D.

 

Positive Phase 1 results announced for the candidate vaccine of Emergent BioSolutions and Valneva against Zika Virus.


Emergent BioSolutions Inc. and Valneva SE recently announced positive results for the Phase 1 trial of their candidate vaccine against Zika virus [7]. The highly purified and inactivated vaccine, VLA1601 met the primary endpoints and was touted to be safe and favorable for all the doses and schedules tested. Valneva is a commercial stage biotech company, fully integrated and focused on developing life-saving vaccines. Emergent BioSolutions, on the other hand, is a global life sciences company that aspires to enhance and protect life by providing products beneficial in cases of public health threats.

The Zika virus was discovered in 1947 and was found to be a mosquito-borne flavivirus. It is now known to cause microcephaly and other central nervous system related disorders. Outbreaks have been reported across the world since the first human detected case was reported in 1952. After the recent outbreaks in 2015, a renewed interest in Zika virus research has been noticed. VLA1601 is a highly purified vaccine made in collaboration with the Emergent BioSolutions and Valneva. It has been developed using a similar manufacturing platform as used for IXIARO (JESPECT) Japanese encephalitis (JE) vaccine. The data provided from the pre-clinical trial showed similar commercial purity and a similar overall chemical and physical profile like the JE vaccine. The first-in-human, randomized, placebo-controlled and observer-blinded study, VLA1601-101 was done to determine the immunogenicity and the safety of two different doses of the alum-adjuvanted, inactivated whole virus Zika vaccine VLA-1601 in 67 healthy, flavivirus-naïve adults of 18-49 years. Based on the protocol, the participants received two vaccines with a lower 3AU or higher 6AU doses either 7 or 28 days apart. The present data contains information up to 56 days of the first vaccination. The results indicated that the Seroconversion Rates (SCR) were up to 85.7% on day 35 of the trial. The final analysis at day 208 after vaccination is expected to take place in the first quarter of 2019 and is supposed to include data such as rate of subjects with seroconversions, fold-increase of the Zika virus-specific neutralizing titers and Geometric Mean Titers. Emergent and Valneva announced the execution of an exclusive worldwide agreement in July 2017 for the latter’s Zika vaccine technology. Based on the agreement, both companies would be responsible for all costs until the Phase 1 results were obtained. Until the completion of the Phase 1 trial, Valneva would be responsible for executing the program through a joint governance structure. Once the data from the Phase 1 trial is made available, Emergent will have the choice of continuing the commercialization and the development of the Zika vaccine for a milestone payment of €5 million. Based on the agreement, Valneva can obtain an additional milestone payment for development, commercialization, approval and product sales. They will also have the right to negotiate with Emergent for exclusive commercialization rights in Europe, before the Phase 3 clinical trial.

Zika Virus Faq

From Visually.

 

“Emergent’s continued focus on the development of prevention and treatment strategies for emerging infectious diseases is part of its broader mission – to protect and enhance life. Through our work, we are committed to making a positive impact on public health across the globe,” said Kelly Lyn Warfield, PhD, vice president, Vaccines and Anti-Infectives Research and Development at Emergent BioSolutions. Wolfgang Bender, MD, PhD, chief medical officer of Valneva added, “We are pleased to see progress of this promising vaccine candidate for the prevention of infections caused by the Zika virus and their serious implications during pregnancy. The excellent safety profile supports further optimization of the elicited immune response to cover an unmet medical need in the most vulnerable populations.”

 

Abbvie announces positive Phase 3 data for Elagolix to reduce heavy menstrual bleeding in women with uterine fibroids.


Abbvie, a research-based biopharmaceutical company in cooperation with Neurocrine Biosciences Inc, recently presented their positive Phase 3 clinical trial results for Elagolix at the 47th American Association of Gynecologic Laparoscopists (AAGL) Global Congress on Minimally Invasive Gynecology in Las Vegas, NV [8]. The Phase 3 clinical trials ELARIS UF-1 (M12-815) and ELARIS UF-2 (M12-817) aimed at investigating the efficacy and safety of elagolix in women with uterine fibrosis.

Uterine Fibroids 101

From Visually.

 

Uterine fibroids (Leiomyomas/myomas) are hormonally-responsive muscle, non-cancerous tumors of the tissues of the uterus. Up to 80 percent of African American women and up to 50 percent of Caucasian women can potentially develop uterine fibroids by the age of 50 years. They range in different shapes and sizes and are amongst the most common abnormal growths in the pelvis of women. In case of some women, this might lead to excruciating pain and heavy menstrual bleeding along with anemia and pain in the lower back. Some might even experience discomfort during urination and might find it difficult to get pregnant. The most common treatment options for uterine fibroids include surgery (hysterectomy, myomectomy), uterine artery embolization, endometrial ablation and medical management with treatments such as progestins, oral contraceptives, selective progesterone modulators and GnRH (gonadotropin-releasing hormone) agonists. ORILISSA (Elagolix) is a non-peptide, orally-administered, small molecule gonadotropin-releasing hormone receptor antagonist that binds competitively to the GnRH receptors in the pituitary gland. Its intake results in a dose-dependent reduction of the luteinizing hormone and follicle stimulating hormone thus leading to lowering of blood concentrations of estradiol and progesterone. Elagolix is also under investigation for endometriosis. It has been studied in over 40 clinical trials so far. The present Phase 3 clinical trial evaluated 800 premenopausal women who complained of heavy menstrual bleeding linked to uterine fibroids in 100 sites across Canada and the U.S. A 300 mg twice daily dose of Elagolix alone and one in combination with low-dose hormone (add-back) therapy (estradiol 1.0 mg/ norethindrone acetate 0.5 mg) in women with uterine fibroids were tested for determining the efficacy and safety of the drug over a period of 6 months. The primary endpoint was supposed to assess the reduction in the heavy menstrual bleeding compared to the placebo. From the six-month data, it was evident that the treatments were much more effective than the placebo ones. In ELARIS UF-1, 68.5 percent of women with uterine fibroids achieved clinical response compared to 8.7 percent of placebo. In ELARIS UF-2, 76.2 percent achieved it in comparison to 10.1 percent of placebo. In both the investigations, clinical response was defined as menstrual blood loss of less than 80 ml in the first month and a 50 percent or higher reduction in menstrual blood loss volume from initial to the final month. There was no change in the overall safety and efficacy of the drug from the Phase 2 trials. Hypoestrogenic effects such as hot flush weere consistent with the mechanism of action. There was a reduction in this effect for the ones who received the combination therapy when compared to those who received Elagolix alone. The most common adverse effects reported were headache, nausea, hot flush, night sweats, and fatigue.

“More non-invasive treatment options are needed for women with uterine fibroids who experience symptoms,” said Dawn Carlson, M.D., M.P.H., vice president, general medicine development at AbbVie. “The results support AbbVie’s continued efforts to pursue regulatory filing of elagolix and its potential to help women manage heavy menstrual bleeding associated with uterine fibroids.” William D. Schlaff, MD, Chair, Department of Obstetrics & Gynecology, Thomas Jefferson University stated, “Many women in the United States suffer from uterine fibroids, yet symptoms often go unresolved and can have significant impact on day-to-day activities.These findings provide objective data demonstrating the potential value of elagolix as a future treatment for women with uterine fibroids.”

 

References:

 

  1. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626121.htm.
  2. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626263.htm.
  3. https://www.novartis.com/news/media-releases/fda-approves-novartis-drug-promacta-first-line-saa-and-grants-breakthrough-therapy-designation-additional-new-indication.
  4. http://globenewswire.com/news-release/2018/11/26/1656466/0/en/Zafgen-Provides-Update-on-Investigational-New-Drug-Application-for-ZGN-1061.html.
  5. https://xconomy.com/boston/2018/11/26/fda-halts-clinical-test-of-zafgen-diabetes-drug-stock-price-tumbles/?mc_cid=3c661b5763&mc_eid=7420647896.
  6. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626349.htm.
  7. http://investors.emergentbiosolutions.com/phoenix.zhtml?c=202582&p=irol-newsArticle&ID=2377710.
  8. https://news.abbvie.com/news/press-releases/abbvie-presents-positive-phase-3-data-demonstrating-investigational-elagolix-reduces-heavy-menstrual-bleeding-in-women-with-uterine-fibroids-at-2018-aagl-global-congress.htm.

 

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: (Wikimedia)Description: “Space-fill drawing of the outside of one Zika virus particle, and a cross-section through another as it interacts with a cell. The two main proteins of the viral envelope, the envelope proteins and membrane proteins, are shown in red and purple respectively. The lipid membrane of the envelope is shown in light lavender.The capsid proteins, in orange, are shown interacting with the RNA genome, in yellow, at the center of the virus. The cell-surface receptor proteins are in green, the cytoskeleton in blue, and blood plasma proteins in gold. Drawn by David Goodsell.”

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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).

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

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