Nobel Prize-winner Frances Arnold retracts paper, saying results were not ‘reproducible’
On 2nd January 2020, Frances Arnold, an American scientist and winner of the Nobel Prize in chemistry in 2018 with two other scientists for their work on evolution of enzymes, has retracted her latest paper on enzymatic synthesis of beta-lactams published in the journal Science on May 2019 after admitting to faulty research. The paper has been retracted because the results were not reproducible, and the authors found data missing from a lab notebook.
Prof. Arnold came forward in a series of tweets stating that the work had not been reproducible, she had been “very busy” when the paper was submitted and did not do her job well. A notice has been published in Science’s website outlining why retracting the paper was required: “After publication of the Report “Site-selective enzymatic C‒H amidation for synthesis of diverse lactams”, efforts to reproduce the work showed that the enzymes do not catalyse the reactions with the activities and selectivities claimed. Careful examination of the first author’s lab notebook then revealed missing contemporaneous entries and raw data for key experiments. The authors are therefore retracting the paper.”
Prof Arnold’s case is the latest example of the “reproducibility crisis” where more than two-thirds of researchers have tried and failed to reproduce another scientist’s experiments. In October 2018, the journal Nature wrote about the growing alarm of results that cannot be reproduced as a result of increased levels of scrutiny, complexity of experiments and statistics, and pressures on researchers.
Reactions to Arnold’s tweets were mostly positive praising her honesty in coming forward, Dominique Hoogland a researcher at King’s College London wrote, “Can I please express my respect for you bringing this to everyone’s attention. This shows that anyone can make an honest mistake and acting to correct that is the best response. Thank you.”
Incyte announces results of pivotal Phase III Itacitinib’s study in patients with treatment-naïve acute graft-versus-host disease (GVHD)
Itacitinib is a novel and selective JAK1 inhibitor used in clinical studies for the first-line treatment of patients with acute and chronic GVHD. Incyte holds the global development and commercialisation rights for itacitinib with the exception of China, where the rights to develop and commercialise have been licensed to Innovent Biologics, Inc. On 2nd January 2020, Incyte announced that its Phase III GRAVITAS-301 study evaluating itacitinib in combination with corticosteroids as a first-line treatment for patients with acute GVHD did not meet its primary endpoint of improving overall response rate (ORR) at Day 28 compared to placebo plus corticosteroids. Itacitinib added to corticosteroids was observed as having improved the overall response rate in patients with treatment-naive acute GVHD, however the difference in comparison with placebo plus corticosteroids was not statistically significant. There was also no observed difference in non-relapse mortality (NRM) at Month 6, the study’s key secondary endpoint, between the treatment and placebo arms.
Steven Stein, M.D., Chief Medical Officer, Incyte stated: “The result of this study is disappointing. However, we remain committed to building on the success of the REACH program for ruxolitinib, which showed positive results in steroid refractory acute GVHD. Additionally, we will continue to study the role of JAK inhibition in chronic GVHD and in the prophylactic setting, as we seek to develop treatments for patients with this debilitating and often fatal disease.”
The company stated that investigators will be informed of the results and work with them to appropriately conclude the study in a manner consistent with the best interest of each patient. Data from the study will be submitted for presentation at an upcoming scientific meeting.
UNC School of Medicine’s expert helps treat astronaut’s blood clot during NASA mission
Blood clot expert Stephan Moll, MD, professor of medicine in the division of haematology and oncology at the University North Carolina School of Medicine, was called upon by the National Aeronautics and Space Administration (NASA) for his vast knowledge and treatment experience of deep vein thrombosis (DVT) when an astronaut two months into a six month mission for NASA aboard the International Space Station (ISS) was found to have a blood clot in the jugular vein of the neck. This occurrence marks the first instance where a blood clot had been found in an astronaut in space, so there was no established method of treatment for DVT in zero gravity. The blood clot was asymptomatic and was discovered when the astronaut was taking neck ultrasounds for a research study on how body fluid is redistributed in zero gravity.
Moll alongside a team of NASA doctors decided to use blood thinners as a treatment approach:” Normally the protocol for treating a patient with DVT would be to start them on blood thinners for at least three months to prevent the clot from getting bigger and to lessen the harm it could cause if it moved to a different part of the body such as the lungs. There is some risk when taking blood thinners that if an injury occurs, it could cause internal bleeding that is difficult to stop. In either case, emergency medical attention could be needed. Knowing there are no emergency rooms in space, we had to weigh our options very carefully”.
Aboard the ISS there was a limited amount of blood thinner Enoxaparin (Lovenox®), a drug delivered by injection into the skin, Moll advised NASA on what dosage to use for treatment of DVT while lasting long enough until NASA could get a shipment of Apixaban (Eliquis®), a pill taken orally, supplied to the spacecraft. The treatment lasted more than 90 days, with guidance from Moll and a radiology team on Earth the astronaut monitored the blood clot by performing neck ultrasounds.
Four days before the journey home to Earth, the astronaut stopped taking Apixaban, Moll and his NASA counterparts made that decision based on how physically demanding and potentially dangerous the re-entry process can be for astronauts, any injuries could be exacerbated by the use of blood thinners. The astronaut was able to land safely on Earth and the blood clot required no further treatment.
Charles River Laboratories completes the acquisition of HemaCare Corporation
On 3rd January 2020, Charles River Laboratories announced that the company had completed acquisition of HemaCare Corporation which will become part of Charles River’s Research Models and Services segment.
HemaCare is a leader in the production of human-derived cellular products for the cell therapy market. The company supplies critical biomaterials, including a wide range of human primary cell types, as well as cell processing services to support the discovery, development, and manufacture of cell therapies, including allogeneic (donor-derived cells) and autologous (patient-derived cells) programs. Acquisition of the company expands Charles River’s scientific capabilities in the emerging, high-growth cell therapy sector, creating a comprehensive portfolio of early-stage research and manufacturing support solutions to help cell therapy developers and manufacturers advance their critical programs from basic research and proof-of-concept to regulatory approval and commercialization.
James C. Foster, Chairman, President and Chief Executive Officer of Charles River Laboratories stated: “We are pleased to welcome the talented team at HemaCare to the Charles River family. The addition of HemaCare’s cellular products enhances our ability to provide a comprehensive cell therapy solution from discovery through commercialization, which will enhance our clients’ efficiency and accelerate their speed-to-market. The acquisition of HemaCare is a key element of our strategy to fully support our clients’ early-stage drug research efforts, achieve our long-term growth goals, and enhance shareholder value.”
AstraZeneca’s Farxiga secures FDA Priority Review to treat heart failure with reduced ejection fraction (HFrEF)
On 6th January 2020, AstraZeneca announced that the US Food and Drug Administration (FDA) has accepted a supplemental New Drug Application (sNDA) granting priority review for Farxiga (dapagliflozin) which seeks to reduce the risk of cardiovascular death or the worsening of heart failure in adults with HFrEF, with and without type-2 diabetes (T2D). Farxiga’s sNDA comes from results of Phase III international, multi-centre, parallel-group, randomised, double-blinded DAPA-HF trial published September 2019 in The New England Journal of Medicine. It evaluated the effect of 10 mg of Farxiga in comparison with placebo, given once daily in addition to standard of care.
Farxiga is a first-in-class, oral once-daily selective inhibitor of human sodium-glucose co-transporter 2 (SGLT2) indicated as monotherapy as well as part of combination therapies to improve glycaemic control, additional benefits include weight loss and blood-pressure reduction as an adjunct to diet and exercise in adults with T2D. Farxiga has a robust programme of clinical trials, more than 35 trials have been completed and there are a number of ongoing Phase IIb/III trials in more than 35,000 patients. In August 2019, the FDA had also granted Fast Track designation for the development of Farxiga to delay the progression of renal failure and prevent cardiovascular and renal death in patients with chronic kidney disease, with and without T2D.
Mene Pangalos, Executive Vice President, AstraZeneca BioPharmaceuticals R&D, stated: “Farxiga is well established in the treatment of type-2 diabetes and this Priority Review shows its potential to also impact millions of patients with heart failure. If approved, Farxiga will be the first and only medicine of its kind indicated to treat patients with heart failure”.
Merck establishes research and licence agreements with Taiho and Astex
On 6th January 2020, Merck, known as Merck Sharp & Dohme outside the United States and Canada, announced a strategic oncologic collaboration with Japanese company Taiho Pharmaceutical Co. and Astex Pharmaceuticals based in the United Kingdom (UK), two subsidiaries of Otsuka Pharmaceutical. The scope of the partnership between the 3 companies is the development of small molecule inhibitors against several drug targets, including the Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), which is currently being investigated for the treatment of cancer.
Dr. Roger M. Perlmutter, president, Merck Research Laboratories stated: “At Merck we continue to pursue new regimens designed to extend the benefits of highly selective therapies to more patients with cancer. This agreement with Taiho and Astex combines our respective small molecule assets and industry-leading expertise in cancer cell signalling to enable development of the most promising drug candidates”.
As part of the agreement the three companies will combine preclinical inhibitor candidates’ data with knowledge and expertise from their respective research programs. Merck has an exclusive global license to the small molecule inhibitor candidates. Taiho and Astex will receive an aggregate upfront payment of $50 million and will be eligible to receive approximately $2.5 billion contingent upon the achievement of preclinical, clinical, regulatory and sales milestones for multiple products arising from the agreement, as well as tiered royalties on sales. Merck will fund research and development and will handle commercialization of products globally; Taiho has retained co-commercialization rights in Japan and an option to promote in specific areas of South East Asia.
Medicines and Healthcare Products Regulatory Agency (MHRA) grants licence update for Ipsen’s Dysport®
On 6th January 2020, Ipsen a global biopharmaceutical company focused on innovation and specialty care, announced that the MHRA had granted a licence update to Dysport® for the symptomatic treatment of focal spasticity of upper limbs in paediatric cerebral palsy patients, two years of age and older. Spasticity refers to abnormal and involuntary muscle stiffness, or overactive muscular contractions, with cerebral palsy being the leading cause of childhood disability affecting function and development, and the most frequent cause of spasticity in children. Approximately 17 million people are affected by cerebral palsy worldwide, 1 in 400 babies in the UK are born with the condition.
Dysport® is an injectable form of a botulinum neurotoxin type A product and is supplied as lyophilized powder, works by inhibiting the effective transmission of nerve impulse, reducing muscular contractions. MHRA’s decision comes from results of a Phase III randomized, double-blind, low dose controlled, multicentre study evaluating Dysport® in a group of 210 children aged 2 to 17 for upper limb spasticity due to cerebral palsy and measured by the Modified Ashworth Scale (MAS), a standard scale for assessing muscle resistance associated with spasticity. Patients with a Grade 2 or higher MAS at the primary targeted muscle groups (PTMG), were injected into the PTMG with doses of Dysport® at 8,16 or 2 Units/kg. Primary endpoint of the study was mean change in MAS grade from baseline to Treatment 1 at week 6 in PTMG. Results from the study showed that treatment with Dysport® lead to statistically significant improvements from baseline in MAS in the PTMG at week 6. The safety profile of Dysport® was also assessed and noted as being consistent with that seen in the approved indications for paediatric cerebral palsy lower limb spasticity after repeated injections and no new safety concerns were found.
Asad Mohsin Ali, UK & Ireland General Manager, Ipsen stated: “Today’s approval is an important advancement for children in the UK living with cerebral palsy, who can now benefit from long-lasting symptom relief between their botulinum toxin A injections. As a father myself, I am proud that Ipsen is the first company to have obtained this approval that may help children live as normal a life as possible.”
Transgene and NEC initiate clinical trials using therapeutic vaccine powered by Artificial Intelligence (AI)
On 6th January 2019, Transgene a French biotech company which designs and develops virus-based immunotherapies for the treatment of cancer and Japan based NEC Group, a leader in the integration of Information Technology (IT) and network technologies, announced that the first patients have been enrolled for their first-in-human trials evaluating a therapeutic vaccine TG4050 powered by Transgene’s myvac™ technology and NEC’s AI capabilities for treatment of patients with ovarian and head and neck cancers. TG4050 has been designed using Transgene’s viral vectorisation technology which generates virus-based immunotherapy within a short time frame targeting up to 30 patient-specific neoantigens identified and selected by NEC’s Neoantigen Prediction System. NEC’s AI powered Neoantigen Prediction System is based on more than two decades of AI expertise and has been trained on proprietary immune data allowing it to accurately prioritize and select the most immunogenic sequences. The selected neoantigens are incorporated in the genome of the Modified Vaccinia virus Ankara (MVA) viral vector. Transgene has established an in-house Good Manufacturing Practice (GMP) unit for production of individual batches of the TG4050 vaccine required for the clinical development of the vaccine.
Philippe Archinard, Chairman and Chief Executive Officer of Transgene stated: “As each patient’s cancer is unique, we have developed a therapy that turns their solid tumour’s genetic signature into a powerful highly specific anticancer weapon. TG4050 is based on an MVA viral vector that has proven biological activity and has the ability to elicit an immune response against tumour antigens. Our partnership with NEC ensures that TG4050 is benefitting from its world-leading expertise in artificial intelligence and its unique algorithm that is used to select up to 30 patient-specific antigens that allow this novel vaccine to induce a strong immune response. We are convinced that TG4050, which is at the crossroad of immunotherapy and big data sciences, will herald the start of a new era in the fight against cancer”.
One of the Phase I clinical trials of TG4050 is a multi-centre, one-arm trial recruiting patients in the United States of America (USA) and in France, with ovarian cancer after surgery and first-line chemotherapy. The second trial is a multi-centre, open label, randomized two arms trial recruiting patients in the UK and in France with newly diagnosed, locoregionally advanced, Human Papillomavirus (HPV) negative, squamous cell carcinoma of the head and neck that have received an adjuvant (first-line) therapy after surgery. Patients will receive either TG4050 monotherapy after completion of the adjuvant therapy or in combination with the standard of care at the time of recurrence. Endpoints for both trials include safety, feasibility, and biological activity of TG4050.
Dementia vaccine to enter clinical trials following successful results on mice
A vaccine designed to prevent dementia is soon to enter human trial stage following a US-led decades-long study by medical researchers from the Institute for Molecular Medicine and the University of California, Irvine (UCI), showed successful tests on mice. The research itself was mostly carried out at South Australia’s Flinders University by Professor Nikolai Petrovsky, a specialist in endocrinology. The treatment is a combination of two different drugs designed to target and then remove brain plaque and nanofiber tangles which are associated with the cognitive decline and memory failure exhibited in Alzheimer’s disease. The vaccine has the potential to prevent Alzheimer’s in patients with predisposition to the disease. At the moment the best treatments available only reduce symptoms of the disease and don’t target and eliminate the specific problem affecting the brain. If the treatment of people proves to be safe and works well, it could be available within a decade. The clinical trials are projected to start within 20 months.
Professor Petrovsky told Australia’s Daily Telegraph: “This vaccine could be revolutionary. It’s not something that will be available tomorrow, but it’s an exciting step in the right direction”.
FDA publishes annual report on New Drug Therapy Approvals of 2019
On January 2020, the FDA issued their Centre for Drug Evaluation and Research’s (CDER) annual report, “Advancing Health Through Innovation: New Drug Therapy Approvals”, reporting new drug approvals and illustrating CDER’s role in bringing innovative new drug therapies that are safe and effective to patients in need. The report also includes an overview of approvals for new and expanded uses of drugs previously approved by the FDA. It was observed that many important advances in drug therapy in 2019 use an already FDA-approved drug to treat a new disease beyond that for which it was originally approved or to treat a new population of patients. Other discussions emphasise innovative ways for evaluating safety and efficacy of new therapies and key regulatory tools to enhance efficiency and expedite the review and approval of applications.
Biosimilars were also noted as having great potential for both patients and the health care system, the agency expects more biosimilars to be submitted for approval. An FDA-approved biosimilar is highly similar to and has no clinically significant differences in safety, purity and effectiveness from an already approved FDA product. These new approvals will help to create competition in the market, increase patient access to therapies and potentially lower the costs of biological drug therapies to patients.
The full report is available in the following link: https://www.fda.gov/media/133911/download
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