In this fortnightly edition of Medness Plus, Esha Sehanobish reports on FDA’s finding that benefits of Acadia’s Nuplazid outweighs risks for Parkinson’s Psychosis patients. In a promising progress to prevent Tuberculosis, GSK’s Investigational Vaccine Candidate M72/AS01E shows progress in a Phase 2b trial conducted in Kenya, South Africa and Zambia. In major win for Gilead Sciences, Galapagos’ Filgotinib scores in moderate-to-severe active rheumatoid arthritis, Also check out a pioneering study that thrust #VikingTherapeutics into race for lucrative #fattyliverdisease treatment. – Abhi Dey
FDA approves Teva’s migraine drug Ajovy
The FDA has approved Ajovy, the second migraine prevention drug to hit the market this year. There are, however, concerns about cost. https://t.co/hzZ7V0JEEN
— Healthline (@Healthline) September 30, 2018
Teva pharmaceutical Industries Ltd. (NYSE: TEVA) recently announced that FDA approved AJOVY (fremanezumab) injection for the preventive treatment of adults with migraine [1]. The dosing options approved are the quarterly (675 mg) and the monthly (225 mg) ones. It is the first anti-calcitonin gene-related peptide (CGRP) treatment available for the prevention of migraine.
AJOVY is the first humanized monoclonal antibody that blocks the binding of the calcitonin gene-related peptide (CGRP) ligand by binding to it. The approval came after Phase III trials. AJOVY was evaluated in two such Phase III placebo-controlled trials that enrolled patients with migraine. The drug was studied both as a single stand-alone treatment and in combination with other oral preventive treatments. From the trial it was evident that during a 12-week period, patients experienced a reduction in monthly migraine days. The most common adverse reactions were related to the injection-site reactions. AJOVY is available as a single dose injection in prefilled syringes with two dosing options, 225 mg monthly administered as one subcutaneous injection or 675 mg every three months as three subcutaneous injections. No preferred starting dose is required to begin the treatment. The US Wholesale Acquisition Cost (WAC) of AJOVY is estimated to be $575 per monthly dose and $1725, quarterly. AJOVY is scheduled to be available through retail and specialty pharmacies in approximately two weeks. A savings offer has been added to it. Thus, commercially insured patients may end up paying $0 for the prescribed AJOVY until the offer expires. The AJOVY injection is set to compete against Amgen’s Aimovig which received FDA approval in May. There will be another potential competitor from Eli Lilly this fall. Teva’s drug costs just as much as Amgen’s at $6900 per year.
From Visually.
“This is an important day for Teva and complements our long-standing history of helping patients living with diseases of the central nervous system,” said Kåre Schultz, President and CEO of Teva. “The approval of AJOVY helps us to continue to provide access to important medicines and to deliver on our commitment to our key stakeholders – patients, employees and shareholders.” “With limited availability of preventive treatment options, AJOVY provides physicians with an important new option for their patients. “This approval furthers our ongoing commitment and experience in neurological conditions like migraine,” said Hafrun Fridriksdottir, Executive Vice President, Global R&D at Teva.
FDA endorses Nuplazid, a medication to treat the delusions and hallucinations of Parkinson’s disease psychosis
Benefits of Acadia’s Nuplazid Outweigh Risks for Parkinson’s Psychosis Patients, FDA Reportshttps://t.co/0wtQKLj3iW pic.twitter.com/RXXAxRBvlX
— Ingentium Parkinson’s Disease (@Ingentium_PD) September 26, 2018
FDA recently reviewed all the post-marketing reports of serious adverse effects and deaths associated with the use of Nuplazid (pimavanserin) [2]. After analyzing all the available data, FDA was unable to identify any new or unexpected results with the drug. There are no inconsistencies as far as safety profiles are concerned and are as per the drug label. Based on this detailed analysis, FDA’s conclusion remark states that the drug’s effectiveness outweighs the risks for patients with hallucinations and delusions of Parkinson’s disease psychosis remain unchanged.
From Visually.
Nuplazid along with other antipsychotics have a boxed warning regarding an increased risk in the death of elderly patients with dementia-related psychosis associated with the use of these drugs. Acadia’s drug won approval in April 2016 and was released with a black box warning. In view of such life-threatening effects, FDA decided to conduct an exhaustive analysis of all the information available. The conclusion was made based on information submitted to the FDA Adverse Event Reporting System (FAERS), safety data from the new drug application, drug utilization, the sponsor’s Periodic Adverse Drug Experience Reports, the sponsor’s analysis of fatal adverse event reports with Nuplazid and published medical literature. Nuplazid is primarily distributed through a patient’s support program and a specialty pharmacy due to which there is a higher chance of deaths being reported to the manufacturers. On the other hand, the FAERS report that included a cause of death did not reflect any pattern for drug-effect or drug-related efficacy. While assessing the reports, FDA did consider the fact that patients with the Parkinson’s psychosis who were prescribed Nuplazid, had a higher mortality rate in general due to advanced Parkinson’s, older age and other medications. There was no significant difference in the premarketing controlled trials and the post marketing data on the safety and efficacy of Nuplazid. Even though no new safety concerns were identified, some potentially concerning prescribing patterns were observed. This included the concomitant use of antipsychotic drugs or those that cause QT prolongation that could cause heart rhythm disorder. The drug label considers the risk of Nuplazid in causing severe arrhythmia. FDA has issued a reminder for healthcare providers to be aware of this information before prescribing the drug. They have also been reminded of the fact that none of the other antipsychotic drugs have been approved for the treatment of Parkinson’s disease psychosis. FDA will continue to keep an eye on the effects of Nuplazid and has urged patients to use it only when prescribed by healthcare providers.
GlaxoSmithKline’s candidate vaccine prevents active pulmonary tuberculosis in HIV negative adults
A new vaccine raises hopes of someday curbing the #tuberculosis epidemic: @GSK’s Investigational Vaccine Candidate M72/AS01E shows promise for prevention of #TB disease in a Phase 2b trial conducted in Kenya, South Africa and Zambia
Read more: https://t.co/VN0bT1dehA#GHSU pic.twitter.com/wkIyC1SHZ0
— EpidAlert (@EpidAlert) September 28, 2018
GSK and Aeras recently reported that the former’s candidate vaccine M72/AS01E could significantly reduce the incidence of pulmonary tuberculosis in HIV-negative adults with latent tuberculosis infection. This was elucidated from an ongoing phase IIb clinical trial [3]. The results published in the New England Journal of Medicine after two years of trial showed a 54% vaccine efficacy with varied response rates in different demographic subgroups. The safety and reactogenicity profile is acceptable for the candidate vaccine.
The candidate vaccine is a combination of the M72 recombinant fusion protein derived from the M tuberculosis antigens (Mtb32A and Mtb39A) and the adjuvant system AS01, which is also a component of GSK’s Shingrix vaccine. The study conducted is a Phase IIb, multicenter, randomized, placebo-controlled, double-blind study with the candidate vaccine and the placebo. It was conducted at 11 sites in Kenya, South Africa and Zambia, in tuberculosis-endemic regions. The aim of this study was to investigate if two doses of the candidate vaccine could prevent the Mycobacterium tuberculosis infection from developing in people. The immunogenicity, reactogenicity and the safety of the M72/AS01 candidate vaccine were also tested. As mentioned above, the ongoing trial was carried out in tuberculosis-endemic regions and involved 3573 HIV-negative patients. During the analysis, the patients who received 2 doses of either the candidate drug or the placebo 30 days apart, were later followed up for 2 years at least to detect evidence of pulmonary tuberculosis. In the vaccine group, 10 people developed active pulmonary tuberculosis compared to 22 participants in the placebo group. From the study, an acceptable safety and reactogenicity profile was obtained for the candidate vaccine. Both solicited and unsolicited adverse reactions post-injection, within 7 days, were observed more in case of M72/A01E than in the placebo recipients. Some of the reactions were flu-like symptoms and injection-site reactions. Tuberculosis continues to be a forerunner, globally, in terms of the leading cause of death through infectious diseases. Based on an estimation, about a quarter of the global population has latent tuberculosis infection, out of which 10% will develop the active pulmonary tuberculosis. The biggest threat now is the development of multi-drug resistant forms of the bacteria and the only available vaccine for tuberculosis, BCG, is not enough to provide consistent protection to adults. Without further research it will be impossible to achieve the WHO’s target of decreasing the number of new cases by 90% and the number of tuberculosis deaths by 95% between 2015 and 2035. The results of the study are still ongoing and all the parameters will be studied in 2019 after all the participants have completed 3 years of follow up.
From Visually.
Dr. Emmanuel Hanon, Senior Vice-President and Head of R&D, Global Vaccines GSK, said: “These initial findings represent a significant innovation in the development of a new and much-needed vaccine and advance the scientific understanding of tuberculosis. This scientific breakthrough – one of the very few in tuberculosis vaccine development for almost 100 years – has been made possible by our strategic partnership with Aeras, in which GSK is providing the innovation expertise and technology platforms, such as the proprietary AS01 adjuvant.”
Galapagos and Gilead announce the successful attainment of the primary and the secondary endpoints by Filgotinib, in the study of Rheumatoid Arthritis
Galapagos’ Filgotinib Scores Major Win for Gilead Sciences $GLPG $GILD
Members only access: https://t.co/zfgGqkQgcu pic.twitter.com/78kQ92UTXD
— Valuentum Pharma (@ValuentumPharma) September 17, 2018
Galapagos NV (Nasdaq: GLPG) and Gilead Sciences, Inc. recently announced that based on Phase 3 studies on Filgotinib, primary and secondary endpoints were achieved in adults with moderate-to-severe active rheumatoid arthritis [4]. Filgotinib is an investigational, selective JAK1 inhibitor.
FINCH 2 was the name given to a global, 24-week randomized, double-blind, placebo-controlled, Phase III study. The aim was to evaluate Filgotinib in the background of csDMARDs or conventional synthetic disease-modifying anti-rheumatic drugs among adults with moderate-to-severe rheumatoid arthritis who responded inadequately to biologic DMARDs (bDMARDs). Here, 23.7% adults received 3 or more bDMARDs. Patients were randomized (1:1:1) to receive Filgotinib 100 mg, Filgotinib 200 mg or placebo. The primary endpoint involved the proportion of patients achieving an ACR20 response at 12 weeks, i.e. American College of Rheumatology 20 percent at week 12. As defined by the protocol, non-responders at week 14, could complete the trial under standard care therapy. The adverse events reported were those that happened during the treatment or within 30 days of the last dose of the study drug. It was observed that Filgotinib was well-tolerated during the FINCH 2 trial with no new safety precautions. Also at weeks 12 and 24, the proportion of patients achieving ACR50 and ACR70, low disease activity and clinical remission were significantly higher for patients who were receiving 100 mg or 200 mg of Filgotinib, once daily, when compared to patients receiving placebo. The adverse effects observed were essentially mild to moderate. 3.4, 5.2 and 4.1% of patients receiving placebo, 100 mg and 200 mg Filgotinib respectively, exhibited serious adverse effects. There was a similar percentage of people in these groups that discontinued the study. One case of myocardial ischemia was observed in the 100-mg group, two cases of uncomplicated Herpes Zoster was observed in both the Filgotinib group. There was one case of non-serious retinal vein occlusion in the 200-mg group. There were no malignancies, deaths, gastrointestinal perforations or opportunistic infections including tuberculosis.
From Visually.
“Gilead is committed to the development of new therapies that offer meaningful benefit for people living with rheumatoid arthritis and other serious inflammatory diseases,” said John McHutchison, MD, Chief Scientific Officer, Head of Research and Development, Gilead Sciences. “These initial Phase 3 data support the potential of filgotinib, in combination with select disease modifying drugs, to help patients with active rheumatoid arthritis who do not adequately respond to current biologic disease modifying agents. These data are particularly encouraging as we look ahead to Phase 3 results from the ongoing FINCH 1 and 3 trials, which are exploring filgotinib in other populations of patients with rheumatoid arthritis.” “We are pleased that filgotinib has demonstrated significantly improved clinical responses in this difficult to treat population,” said Dr. Walid Abi-Saab, Chief Medical Officer at Galapagos. “The good tolerability in this study is also very encouraging.”
Viking Therapeutics announces positive result for a liver drug in patients with Non-alcoholic fatty liver disease.
Promising study results thrust #VikingTherapeutics into race for lucrative #fattyliverdisease treatment https://t.co/RxiBRgQGy7 via @statnews @adamfeuerstein @Viking_VKTX #NASH #VK2809
— Plexus Ventures (@PlexusVentures) September 19, 2018
Viking Therapeutics, a clinical-stage biopharmaceutical company, recently announced that they had obtained positive results from a Phase 2 trial of VK2809, a novel liver-selective thyroid receptor beta agonist in adults with elevated levels of low-density lipoprotein cholesterol (LDL-C) and non-alcoholic fatty liver disease [5]. The primary endpoint was achieved for VK2809 where there was a significant reduction of LDL-C in comparison to the placebo-treated ones. The secondary end-point was also achieved with a statistically significant decrease in the liver fat content compared to placebo.
From Visually.
Viking therapeutics is a biopharmaceutical company that focusses on the development of novel treatment for metabolic and endocrine-related disorders. Its main aim is to utilize their expertise on metabolism to develop unique therapeutics that will eventually improve patients’ lives. To achieve this, the company has started its second clinical program which evaluates VK2809, a small molecule thyroid beta receptor agonist. It is orally available and is selective for liver tissues as well as beta receptor subtype, suggesting promising and innovative therapeutic potential in treating liver disorders. VK2809 is a part of a novel family of prodrugs that gets cleaved in vivo to release potent thyromimetics. The selective activation of the thyroid beta receptor in liver tissues favorably affects the lipoprotein and cholesterol levels by mechanisms such as increased expression of genes involved in lipid metabolism. The Phase 2 trial was a double-blind, randomized, placebo-controlled study designed to determine the efficiency, safety and tolerability of the candidate VK2809 in patients with NAFLD and LDL-C. Patients received 10 mg VK2809 every other day or a 10-mg dose daily and were also randomized to receive a placebo for 12 weeks followed by a four week off-the-drug phase. The primary endpoint investigated the effects of VK2809 on LDL-C after 12 weeks compared to placebo. The secondary endpoint investigated the changes in the liver fat content with a valid baseline and a post-baseline MRI. The data suggested that patients receiving VK2809 showed significant reductions in LDL-C of 20% or more compared to placebo treated patients. There was also a statistically significant increase in the levels of atherogenic proteins apolipoprotein B. Patients also experienced a reduction in liver fat content which was measured using Magnetic resonance imaging, proton density fat fraction relative to placebo after 12 weeks. No serious adverse effects were observed in the VK2809 and in the placebo-treated ones.
“We are encouraged by the preliminary efficacy and safety profile VK2809 has shown in this study,” stated Brian Lian, Ph.D., chief executive officer of Viking. “VK2809’s effect on liver fat at 12 weeks appears to exceed all other oral agents currently in development for NASH, supporting our view that VK2809 has a best-in-class profile. Based on published data from multiple studies, we anticipate that these liver fat reductions would result in longer-term histologic benefit. In addition, the improvement in lipid parameters observed in this study suggests potential benefits in cardiovascular health, an important consideration in this population. We look forward to pursuing further development of VK2809 in NASH.”
References:
[1] http://news.tevausa.com/mobile.view?c=251945&v=203&d=1&id=2367593’
[2] https://www.fda.gov/Drugs/DrugSafety/ucm621160.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 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)A colorized scanning electron microscope picture of a nerve ending that has been broken open to reveal the synaptic vesicles (orange and blue) beneath the cell membrane.
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