Time: 10:00 - 10:45
Carles Celma obtained his graduate and PhD in Organic Chemistry at the University of Barcelona. He has more than 25 years in the phamabiotech industry and since 2012 is the Scientific Director of Biologics at Kymos Pharma Services, a CRO located in Barcelona that give support to phama and biotech companies both in CMO and bioanalysis of biologics and small molecules. He has wide experience in method development, validation and sample analysis using physicochemical, binding and cellular methods for regulated analysis. He has more than 40 communications to congresses and 15 publications in different international journals
The European Community is a highly attractive marked for biosimilar companies due to the high degree of coverage of the heath of its citizens by the governments of the country members. Patient treatments by biopharmaceutical drugs are increasing dramatically due to their efficacy in many life-threatening diseases. Due to the high cost of such treatments the European Medicament Agency has clearly opted for biosimilars as a way of reducing the cost of this type of treatments. Several companies that manufacture their biosimilars both inside and outside the EC are commercializing their products in the EC and is expected that in the future this number will increase.
Because the European pharmaceutical market is highly regulated to assure the efficacy and safety on the drugs commercialized in this area, several conditions must be accomplished before these drugs reach to the patients. One of these conditions for companies that manufacture their products outside the EC that are not under mutual recognition agreements is that all batches must be re-tested by a GMP compliant European laboratory to double check that such batches accomplishes the specifications approved in the dossier.
A deep and well documented Analytical Methods Transfer (AMT) procedure must be carried out between the originator laboratory and the receiving laboratory to assure a smooth and effective testing of the commercial batches avoiding delays and false out of specification results in the commercialization phase of the biosimilar.
Several guidelines and recommendations have been published to describe how to do this process. Although companies are working to harmonize the AMT, nowadays several strategies to perform these activities are used.
In this communication we describe our approach of AMT that is aligned to the current guidelines and allows to acquire a deep understanding of the more complicated in-house analytical methods. The schema of below shows the AMT for one biosimilar to illustrate this approach.
Time: 10:45 - 11:30
Raewyn Mai, an experienced Microbiologist is a lecturer and teaching of clinical microbiology to biomedical students, pharmacy students of Integrated Pharmacotherapeutics at University, Queensland Australia and a consultant for a new clinical microbiology course. She has previously worked in clinical microbiology laboratories, managing teaching laboratories and teams and delivering clinical, environmental, food, molecular microbiology classes at University. In Nov 2015 Raewyn certified as a Healthy Gut Advisor and runs workshops and events to educate on gut health. Her programs offer individual persons their plan towards their health issues improved to reverse
Expected and beneficial bacteria found normally in the gut was totally absent. A 35 year old female presenting signs of severe constipation. A comprehensive stool analysis revealed no growth for Escherichia coli and low numbers of other expected bacteria under beneficial flora. However, an overgrowth of pathogens was present under Dysbiotic flora. Treatment given of multiple antibiotics, along with natural herbs which was unsuccessful to resolve symptoms of the overgrowth of pathogens and as well as later finding a parasite. The female patient continued with symptoms previously experienced including the elimination of a bowel movement happening once every 9 days. This continued to cause a stressful situation to this female’s wellbeing. The long-term effects of long absence of elimination causes the buildup of toxins, damage to the intestinal lining and in her case leaky gut syndrome had occurred where this leads to inflammation forming. Inflammation was of high levels and arthritis pain was evident. This person contacted me and took one of my programs, looking at all areas of a healthy lifestyle, medications, chemicals exposed to, diet and dealing with stress. Adjusting her diet made a significant impact to her health and constipation was improved in 2 days. It’s not only consuming wholefoods and eliminating processed foods but knowing the right foods for your gut and micro biome. Probiotics were also introduced and made a significant difference as well. The 2 probiotic strains were Lactobacillus rhamnosus LGG® and Bifidobacterium (BB-12®) strains. The benefits of taking Probiotics support a healthy digestive system and maintaining healthy gut flora. Feed your gut well and symptoms will be improved to being reversed
Time: 13:50 - 14:20
Dr. Alvin Luk is the Senior Vice President and
Chief Medical Officer at Shanghai Henlius Biotech, Inc., a global biopharmaceutical
company specializing in the discovery, development, manufacturing and
commercialization of high-quality biologics to treat a range of chronic and
life-threatening diseases. Dr. Luk has over 27 years of experience in global
drug development, strategic portfolio management and clinical leadership. Prior
to joining Shanghai Henlius Biotech, Inc., he served as the Head of Clinical
Research and Operations at Spark Therapeutics, a fully integrated gene therapy
company receiving the first US FDA-approved gene therapy product, where he
oversaw the global clinical development and operations of several AAV gene
therapy programs in ophthalmology, haematology and neurology. Previously, he
held a number of executive management positions at companies such as Biogen – Haemophilia
Unit, Bayer Healthcare, Avigen (acquired by Sanofi Genzyme) and Tularik
(acquired by Amgen). He served on the Clinical Design Committee for rare
disease at the U.S. Food and Drug Administration focusing on adaptive clinical
trial design to shorten drug development timeline between 2006 and 2009. Until
2003, his early researches were primarily investigating gene regulation and
expression with the emphasis on rare diseases, oncological diseases and
regenerative medicines. Under his leadership in drug development, he has won
regulatory approvals and was instrumental in bringing 16 products from
first-in-human trials to marketing approvals as of today. Dr. Luk has published
more than 60 book chapters, scientific and medical articles in highly regarded
peer-reviewed journals, including New
England Journal of Medicine, Nature, Cell, and Science, and is an inventor on over 9 patent applications. Dr. Luk
holds an M.B.A. from the Harvard Business School. He is ACRP-certified in
clinical research and received his Ph.D. in Neuroscience from the University of
California San Francisco Medical School (UCSF).
Background: Many biologics have proven to have superior efficacy for cancer treatment. However, only a handful of them are available in China today. While rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has revolutionized the treatment of B-cell malignancies, patient access to effective rituximab therapy remains limited. HLX01, a rituximab biosimilar, was developed as an alternative treatment for patients with lymphoma.
Methods: We conducted a randomised, double-blind, parallel-controlled equivalence study
(HLX01-NHL03; NCT02787239) investigating the clinical efficacy, safety and immunogenicity profiles of HLX02 plus CHOP (H-CHOP) and R-CHOP every 21 days up to 6 cycles in treatment-naïve patients with CD20-positive diffuse large B-cell lymphoma (DLBCL). Patients were randomised at 1:1 to receive an intravenous dose of 375 mg/m2 of HLX01 or rituximab in combination with CHOP every three weeks. The primary endpoint was the comparability in best objective response rate (ORR) within six 3-week cycle treatments. Secondary endpoints included complete response rate (CR), one-year analysis of duration of response (DoR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS) and disease-free survival (DFS) as well as safety. The equivalence was achieved if 95% confidence intervals (CIs) for the difference in ORR fall within ±12% equivalence margin difference of the R-CHOP.
Results: Of 560 patients enrolled, 407 were randomised with 361 patients (H-CHOP: 173; R-CHOP: 188) completed 6 cycles of treatment and 328 patients (H-CHOP: 157; R-CHOP: 171) completed the study. Baseline characteristics are well-balanced, including the distribution of ECOG and IPI between the two treatment groups (figure 1).
The ORRs (95% CI) within six cycles of treatment were 94·1% (89·77%, 97·04%) and 92·8% (88·19%, 96·00%) for H-CHOP and R-CHOP, respectively, with 1·4% (-3·59%, 6·32%, p=0·608) equivalence margin difference between the two ORRs. According to central imaging assessments, the CR rates of H-CHOP versus R-CHOP were 45·2% (HCHOP: 90/199) versus 51·2% (R-CHOP: 104/203), respectively. In the analysis of secondary efficacy endpoint, no significant difference was detected in the one-year analysis of DoR, EFS, PFS, OS and DFS between patients randomised to H-CHOP or R-CHOP. Occurrence of adverse events (AEs), serious AEs and detection of anti-drug antibodies were similar between two treatment groups (figure 2).
Conclusion: The data from the pivotal Phase 3 study achieved equivalence in both primary and secondary endpoints between H-CHOP and R-CHOP with no clinically meaningful differences. Based on these results, HLX01 was approved by China National Medical Product Administration (NMPA) as the first China biosimilar drug on February 22, 2019. HLX01 has the potential to provide alternative treatment option for DLBCL and increase treatment accessibility
Time: 14:20 - 14:50
John Howard has over 30 years’ experience in directing biotechnology groups in research, regulatory, production, intellectual property, and business development for two Fortune 500 companies and two start-up companies. In addition to directing a number of technology innovations, he also directed the commercial introduction of the first plant biotechnology products for crop improvement and the first industrial and human health products produced from transgenic plants. He is an author on over 100 publications and patents in biotechnology. Dr. Howard is the Founder and President of Applied Biotechnology Institute, a company focused on providing early stage research and development for plant biotechnology products targeted to industrial and pharmaceutical markets with minimal risk.
Over the past few decades, many products have been introduced by expressing recombinant proteins in alternative hosts. Microbial fermentation has dominated the industry providing a low cost option however, mammalian cell cultures are the preferred choice when post-translational modifications are needed. First generation products did not place a high concern on cost of goods as these products were protected by patents. This situation is changing as products come off patents coupled with the rising cost of health care. To address this concern we identified several alternative production platforms with the ability to perform post-translational modifications and provide a low cost of goods. The host that showed the most promise was maize grain. We have since made several improvements that allow for very high accumulation of a wide variety of proteins including proteins that have been difficult to express in other platforms. The first products are now on the market with many more in the pipeline. Furthermore, the system has been used to bioencapsulate proteins imparting new functionality. As an example, this has been used for the oral delivery of several different vaccine candidates providing protection against various pathogens and safety in human clinical trials. In summary, the system is well suited for products where: 1) expression is problematic in other platforms; 2) both low cost and post-translational modifications are required and; 3) oral delivery is beneficial. Several examples will be discussed illustrating these features.
Time: 14:50 - 15:20
Dr. Alvin Luk is the Senior Vice President and Chief Medical Officer at Shanghai Henlius Biotech, Inc., a global biopharmaceutical company specializing in the discovery, development, manufacturing and commercialization of high-quality biologics to treat a range of chronic and life-threatening diseases. Dr. Luk has over 27 years of experience in global drug development, strategic portfolio management and clinical leadership. Prior to joining Shanghai Henlius Biotech, Inc., he served as the Head of Clinical Research and Operations at Spark Therapeutics, a fully integrated gene therapy company receiving the first US FDA-approved gene therapy product, where he oversaw the global clinical development and operations of several AAV gene therapy programs in ophthalmology, haematology and neurology. Previously, he held a number of executive management positions at companies such as Biogen – Haemophilia Unit, Bayer Healthcare, Avigen (acquired by Sanofi Genzyme) and Tularik (acquired by Amgen). He served on the Clinical Design Committee for rare disease at the U.S. Food and Drug Administration focusing on adaptive clinical trial design to shorten drug development timeline between 2006 and 2009. Until 2003, his early researches were primarily investigating gene regulation and expression with the emphasis on rare diseases, oncological diseases and regenerative medicines. Under his leadership in drug development, he has won regulatory approvals and was instrumental in bringing 16 products from first-in-human trials to marketing approvals as of today. Dr. Luk has published more than 60 book chapters, scientific and medical articles in highly regarded peer-reviewed journals, including New England Journal of Medicine, Nature, Cell, and Science, and is an inventor on over 9 patent applications. Dr. Luk holds an M.B.A. from the Harvard Business School. He is ACRP-certified in clinical research and received his Ph.D. in Neuroscience from the University of California San Francisco Medical School (UCSF).
Background: The introduction of trastuzumab in combination with chemotherapy has significantly improved clinical outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. HLX02 was developed as a trastuzumab biosimilar with the potential to increase market competition and treatment accessibility in China and around the world.
Methods: We conducted a randomised, double-blind, parallel-controlled equivalence study (HLX02-BC01; NCT03084237 and EudraCT: 2016-000206-10) investigating the efficacy and safety profiles of HLX02 and European Union-sourced (EU-)trastuzumab in HER2+ recurrent or previously-untreated metastatic breast cancer patients at 89 study centres in China, Philippines, Poland and Ukraine. Eligible women were aged ?18 years, had histologically confirmed HER2+ breast cancer, an ECOG performance status of 0-1, and estimated life expectancy ?3 months. Patients were randomised at 1:1 to receive an intravenous dose of 8 mg/kg of HLX02 or EU-trastuzumab with docetaxel on Day 1-Cycle 1 followed by a dose of 6 mg/kg every 3 weeks in 3-weekly cycles for up to a maximum of 12 months. The primary endpoint was best overall response rate at Week 24 (ORRwk24) evaluated by blinded central imaging review. Secondary endpoints included clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS), safety outcomes with immunogenicity and incidence of adverse events up to 12 months.
Results: Of 1046 patients enrolled, 649 were randomly allocated to receive HLX02 (n=324) or EU-trastuzumab (n=325). The ORR was 71.0% (230 of 324 patients; 95% CI: 66.0, 75.9) for HLX02 and 71.4% (232 of 325 patients; 95% CI: 66.5, 76.3) for EU-trastuzumab with no statistical difference observed between the two treatment groups (p=0.952) which was completely contained within the predefined equivalence boundaries of ±13.5%. The difference in ORR between the 2 treatments was 0.4 (95% CI: -7.4, 6.6). Safety outcomes and immunogenicity were similar between the treatment groups at Week 24 (table below).
Conclusion: The use of HLX02 compared with EU-trastuzumab resulted in an equivalent ORR at Week 24. All secondary efficacy and safety analyses at Week 24 supported the conclusion of therapeutic equivalence; HLX02 does not demonstrate new safety signals in comparison with EU-trastuzumab. Further study results at Month 12 will be reported when the study is unblinded in September. These results have been submitted to National Medical Product Administration (NMPA) and EMA for review to support marketing approval of HLX02 in China and Europe.
Geographicdistribution with differences in abiotic and biotic factors may affectprincipal components of medical plant. Representative secondary metabolites of Alpinia oxyphylla Miq. From17 different geographic regions was measured by ultra-fast high performanceliquid chromatography/quadrupole tandem mass spectrometry (UFLC-MS/MS). Wereused for high-throughput RNA sequencing. After RNA-Seq and de novo transcriptomeassembly of 12 libraries prepared from the Capsular fruits of Alpinia oxyphylla from four regions with significantlydifferent on the Representativesecondary metabolites, 260,263 transcripts and 96,342 unigenes wereobtained, 103, 02 genes were annotated of the venn map. Upon the Two pairs ofthe material combination from four different regions, Differentially ExpressedGenes found involved in several physiological processes, e.g., “Flavonoidbiosynthesis”, “Phenylpropanoid biosynthesis”, Sesquiterpenoid and triterpenoidbiosynthesis”, Phenylalanine metabolism Flavone and flavonol biosynthesis”, and“Ubiquinone and other terpenoid-quinone biosynthesis”. A number of genesinvolved in Flavonoid biosynthesis have been identified anddeserve further functional characterization. This study clearly demonstratedthat medical plant from different regions has significant difference on thesecondary metabolites, and understanding of this process may help to select thekey candidate gene and its biosynthesis.
Time: 10:00 - 10:45
Dr. Ivanela Kondova is a Veterinary Anatomic Pathologist and Head of Division of Pathology and Microbiology at Biomedical Primate Research Center in Netherlands. She is actively involved in clinical and translational research and also in scientific projects for global pharmaceutical industry, World Health Organization and different academic institutions. She was trained as a Veterinary pathologist at the New England Primate Research Center - Harvard Medical School in Massachusetts, United States. She gained extensive experience in the area of infectious diseases while she was working at Tufts Veterinary University, Infectious Disease Department, Massachusetts, United States. She is the creator and the manager of the biggest nonhuman primate Tissue Bank in Europe. She has published more than 70 scientific papers in peer-reviewed journals.
Tissues and genetic material collected from non-human primates (NHP) represent a valuable resource in biomedical research. Obtaining this type of material is limited, time demanding and needs high expertise. As pressure grows for reduction of numbers of animals used in research, the Biobanks are becoming an attractive alternative source for testing scientific ideas, pathophysiological mechanisms and testing new vaccines and biologicals before proceeding to preclinical studies.
The BPRC’s Primate Biobank is the biggest nonhuman primate Biobank in Europe and it is based on the principals of the 3Rs: refinement, reduction and replacement (3Rs). The aim of the Biobank is to provide rare and valuable specimens for internal and external scientists who can use the material for biomedical research as well as for conservation studies.
BPRC’s nonhuman primate biobank consists of:
1. Tissue bank: organs, tissues and cell lines. Samples are collected from the following primate species: Rhesus macaques (Macaca mulatta), Long-tail macaque (Macaca fascicularis), Common marmoset (Callithrix jacchus) and from endangered species such as great apes - Common chimpanzee (Pan troglodytes) and Orangutan (Pongo Borneo) Organs without morphological alterations from clinically healthy retired animals and tissues with experimentally induced or spontaneously developed pathological conditions are available. The organ- and tissue- collections include snap frozen tissue samples stored at -80 C, samples fixed in 10 % neutral buffered formalin (NBF), formalin fixed paraffin embedded (FFPE) tissues and cell lines frozen and stored in liquid nitrogen. Part of the tissue bank are the catalogued frozen tissue collections such as: a/ brain samples from different brain regions of young and aged NHPs and apes; b/ reproductive organs from different NHP’ genders; c/ bone collections and d/ lymphoid organs.
2. Serum and Gene bank: Serum and plasma samples are available. DNA, RNA, cDNA samples are adequately stored at +4, -20 or -80 °C.
Time: 10:45 - 11:15
Jumraini Tammasse is the Doctor of medical faculty graduates UNHAS in 1996 and took the education of neurologist in 2005 he also became a lecturer at several faculties of medicine in Indonesia. Some of the works that have been written one of them are the journal IKM Unhas, 2012-08-22; the effect of music therapy on the motor scale increase in patients with acute ischemic stroke.
Tolosa-Hunt syndrome (THS) is caused by idiopathic inflammation process in the cavernous sinus, superior orbital fissure or orbit. THS is a rare disease; the yearly incidence is 1:1.000.000. The main clinical symptoms is painful ophthalmoplegia, accompanied by ipsilateral headache, paresis of one or more of the ipsilateral IIIrd, IVth and/or VIth cranial nerves, MRI abnormality or biopsy, and cannot be categorized as any other disease. THS resolves adequately with corticosteroids within 24-72 hours after therapy.
Case report: Male, 53 y.o., was admitted because of a right painful ophthalmoplegia, constant, 2 weeks onsets, ipsilateral headache, accompanied by diplopia and ptosis of the right eyelid. The pain was not relieved by analgesics. No history of fever, trauma, or a similar disease. Neurological examination featured exotropia, paresis of right IIIrd and IVth cranial nerves. Laboratory findings, CT angiography, and Brain MRI were normal. There was clinical improvement within 24 hours after initiation of methylprednisolone which was continued by tapering-off oral prednisone.
Conclusion: THS is an exclusion diagnosis and must be differentiated from other causes of painful ophthalmoplegia. Careful follow-up is required to diagnose THS. The diagnosis should not depend on MRI only but adapted to the clinical finding and therapeutic response also.
Figure 1. Ophthalmology examination showed right palpebral ptosis, exotropia at the primary position of the right eye and dilatation of the right eye pupil.
Time: 11:45 - 12:15
Patricia Socualaya Sotomayor is a physician and graduated of Master of Clinical Epidemiology and Master of Health Management in UPCH - Peru. Clinical reviewer of biologics and biosimilars at Medicines Regulatory Authority of Peru (DIGEMID – Ministry of Health of Peru). Teacher's assistant in the Undergraduate Program of the Faculty of Medicine - UPCH, in the courses of Methodology of Research and Clinical Epidemiology. She has competence in the evaluation of clinical studies for the authorization of biologicals and biosimilars; and interest in the regulation of this kind of products.
Statement of the Problem: In recent years, biosimilars have been a focus of attention and a convenient option for disease treatment costs in Latin America. Methodology & Theoretical Orientation: Information was compiled on the regulatory framework that led to the regulatory development of biosimilars published on the websites of the Latin American Medicines Regulatory Authorities. A bibliographic search was also conducted on PubMed and Scielo using the key terms related to the regulation of biosimilars in Latin America. In some cases, the Drug Regulatory Agencies were consulted on the topics in question, in order to corroborate the information. The information collected was classified according to year of publication. Subsequently, they proceeded to analyze and compare according to the aspects of comparability studies, extrapolation of indications, interchangeability, nomenclature biosimilars and aspects of pharmacovigilance. Findings: A biosimilar standard was found published in 50% (14/28) of Latin American