Building better medicines, together.

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2 Building better medicines, together.

3 Company Overview COMPANY OVERVIEW

4 Company Overview History of Vaccine Development COMPANY OVERVIEW Bencard Adjuvant Systems is a division of Allergy Therapeutics UK; a fully integrated, speciality pharmaceutical company. Allergy Therapeutics plc is listed on the London Stock Exchange; AIM ticker AGY. Located in Worthing, on England s south coast, Bencard Adjuvant Systems specialise in developing and optimising adjuvants for infectious diseases, cancer immunotherapy and allergen immunotherapy. We at Bencard Adjuvant Systems are committed to engaging in long-term partnerships with those who require our patented platform of adjuvant technologies to enable successful vaccine or immunotherapy development. In addition to providing novel and efficacious adjuvant platforms, Bencard Adjuvant Systems have over 7 years of experience in manufacture, QC testing, regulatory filing and compliance. Whatever your project, we can build better medicines together! Bencard Adjuvant Systems has an adjuvant portfolio that considers optimal immunogenicity and clinical relevance of antibody response. Our adjuvant technologies are readily adaptable and offer optimal flexibility. Our people have a wealth of intellect to help you develop the best vaccines for efficacy and safety Contact us: enquiries@bencard-as.com +44 () Adjuvants Polysaccharide vaccines Vaccination with killed organisms or detoxified toxins Recombinant DNA technology Cell culture Live attenuated vaccines Adapted from Ennio De Gregorio & Rino Rappuoli. From empiricism to rational design: a personal perspective of the evolution of vaccine development. Nature Reviews Immunology 14, (214)

5 Unmet Needs Vaccine market tripled in value from $5bn in 2 to almost $24bn in Bencard Adjuvant Systems COMPANY OVERVIEW Vaccine market projected to rise to $1bn by Modern synthetic or recombinant antigens are less immunogenic than older-style live or killed organism vaccines 2 There is an urgent need for depots and adjuvants for these new vaccines Microcrystalline Tyrosine (MCT ) Naturally metabolised Extensive experience in humans Established antigen binding capacity 4 Potent immune system potentiator 5, 6 Alum is an approved adjuvant that is able to stimulate good Th2 responses, however has little capacity to stimulate a Th1 response which is vital for protection against many pathogens 2 Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. AdSys-VCT Dual power of MCT and Virus-like Particles (VLP) Potential to enhance weakly reactive vaccine candidates 7 Choosing the ideal adjuvant The aim of vaccination is to induce a protective adaptive immune response against a specific pathogen. When designing a new vaccine, it is important to take into account several factors, one of them is the adjuvant. Why is it important to use an adjuvant? Adjuvants enhance the immunogenicity of the antigen, especially important when using antigens that are poorly immunogenic. VLP induces strong humoral and cellular immune responses 7 AdSys-PS MCT-VLP induces higher protective cellular immunity compared with other adjuvants 7 Adjuvants are an essential component of modern vaccine development. 3 A depot effect of some adjuvants permits a slow release of the antigen and therefore extends immune presentation. Phosphatidylserine derivatives effect different antibody subclasses and their levels 8 : DOPS stimulator of IgG AdSys-PS exhibit no mutagenic properties or cytotoxic effects 9 LOPS stimulator of IgA Biological Activity Physicochemical Properties SAPS inhibitor of IgE Immunization route Safety Antigen dose sparing Response broadening Antibody responses Cell mediated immunity Immune response quality Raw materials Sterility Particle morphology Compatibility, association Stability Formulation Science 1. WHO, Global Vaccine Market Features and Trends, Nikolai Petrovsky and Julio César Aguilar. Vaccine adjuvants: Current state and future trends. Immunol & Cell Bio (24) 82, O Hagan D.T. and Fox C.B. New generation adjuvants - From empiricism to rational design. Vaccines (215) B14 -B2 4. Bell A.J. et al., Protein and MPL adsorption capacities for MCT compared against existing adjuvants. Poster at EAACI Heath, M.D., et al. Micro Crystalline Tyrosine (MCT): Benefits as a depot adjuvant. 6. Leuthard, D., et al. Microcrystalline Tyrosine as an Adjuvant in Allergy Immunotherapy: A Mouse Study. Poster at EAACI Cabral-Miranda G. et al., Virus like particle (VLP) plus microcrystalline tyrosine (MCT) adjuvants enhance vaccine efficacy improving T and B cell immunogenicity and protection against Plasmodium bergei/vivax. Vaccines 217, 5, Dixon, M. J., et al. Phosphatidyl serine (PS) derivatives alter the immune response in a Brown Norway rat model of allergic sensitisation. Poster at EAACI Data on file Poster at Vaccines Congress 214.

6 Microcrystalline Tyrosine MICROCRYSTALLINE TYROSINE

7 Microcrystalline Tyrosine (MCT ) Physicochemical and biological attributes of adjuvants 2 Traditional Adjuvant / Depot Second generation adjuvant Ideal properties of adjuvants Aluminium salts Calcium Phosphate Microcrystalline Tyrosine (MCT ) Monophosphoryl Lipid A (MPL) Why MCT? Microcrystalline tyrosine is a patented depot adjuvant formulation of the biodegradable amino acid L-tyrosine that combines optimal drug stability profile and short-course vaccine delivery with extensive safety data consistent with its natural origin 4. Physicochemical Degree of characterisation: Antigen adsorption Particle size Effective in variety of administration routes: Subcutaneous immunotherapy Sublingual immunotherapy Stable Biological Depot function to: Extend immune system exposure Boost specific antibody/effector titre: Th1 N/A N/A N/A MICROCRYSTALLINE TYROSINE MCT has been designed to provide defined particle size and morphology along with strong antigen binding capacity to enhance its use as a powerful immune system potentiator. Th2 Biodegradable/Metabolised by the host Dose sparing effects N/A MCT is formulated and manufactured using automated steam-in-place and cleanin-place systems enabling it to be administered as a sterile product. =least characterised =most characterised from literature in allergen imunotherapy Right: Two images illustrating defined particle sizes. All components in a vaccine need to be metabolised Natural amino acid Naturally metabolised 2 MCT metabolism 3 Patented biodegradable depot adjuvant Quickly removed 1 Formulated in state of the art GMP processes Used in over 6.2 million injections in allergen immunotherapy 4 Defined particle morphology and size Extensive experience in humans L-tyrosine at injection site (mg/ml) MCT is metabolised with a half-life of 48 hours 3. MCT is naturally metabolised and is quickly removed unlike Aluminium adjuvants that can persist at dose site 1 Rate of removal of MCT Limitations of existing adjuvants Most commonly used adjuvant is Aluminium which mediates Th2 immunological pathway Regulatory authorities set aluminium limits per dose (1.25 mg/dose). Aluminium has a propensity to accumulate in tissues. The repeated administration of aluminium-containing adjuvants will likely contribute directly and significantly to an individual s total body burden of aluminium. Hours post injection 1. McDougall, S. et al., Analysis of aluminium in rat following administration of allergen immunotherapy using either aluminium or microcrystalline-tyrosine-based adjuvants. Bioanalysis (216) 8(6), Table adapted from: Klimek, L et al., Clinical use of adjuvants in allergen-immunotherapy. EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 217 VOL. 13, NO. 6, Miller et al., D.pteronyssinus-tyrosine adsorbate: biological and clinical properties Acta Allergologica 1976, 31, Data on file.

8 Vaccines need a strong adsorption capacity MCT properties The adsorption of adjuvant and antigen in vaccines has been shown to affect efficacy.1 MCT is shown to be consistently absorbed with Antigens and other adjuvants (TLR-4 agonist).2 MCT exceeds WAO recommendations for depot adsorption capacity which underpin product stability and potency1. Adjuvant BSA Adsorption Capacity Lysozyme Adsorption Capacity TLR4 receptor agonist Adsorption Capacity 2% Alhydrogel 42 µg/mg 1446 µg/mg 1.7 µg/mg Calcium Phosphate 7 µg/mg 1 µg/mg 2 µg/mg 2% MCT 1 µg/mg 1689 µg/mg 2.5 µg/mg MCT has the greatest adsorption capacity for Lysozyme and TLR4 compared to Alhydrogel and calcium phosphate3 Vaccines need to be stable MCT Stability1 MCT exhibits strong stability capabilities 4 The Adsorption of Allergoids and 3-O-desacyl-4 -monophosphoryl lipid A (MPL ) to Microcrystalline Tyrosine (MCT ) in Formulations for use in Allergy Immunotherapy.2 Potency (example antigen) 35 Binding forces between MPL and MCT were investigated by competition binding experiments using Naphtalene as a competitor. It was shown that MPL adsorption to L-tyrosine in MCT formulations is based on interactions between the 2-deoxy-2-aminoglucose backbone on MPL and aromatic ring of L-tyrosine in MCT, such as C H...π interact Aromatic centre on the L-Tyrosine C-H π Interactions Available C-H on the glucose 2 position Fatty Acid Chain 2 position Fatty Acid Chain Months ICH stability profile exists with data in support of use at 2-8 C, ambient and elevated temperatures 1. Data on file Naphthalene 1. Clapp, T. et al., Vaccines with Aluminium containing adjuvants: optimizing vaccine efficacy and thermal stability. J Pharm Sci, 211; 1(2): Bell A.J. et al., The adsorption of allergoids and MPL to MCT in formulations for use in allergy immunotherapy. J Inorg Bioch 152 (215) Bell A.J. et al., Protein and MPL adsorption capacities for MCT compared against existing adjuvants. Poster at EAACI position Fatty Acid Chain MICROCRYSTALLINE TYROSINE

9 Vaccines need to stimulate the immune system MCT immunogenic responses in OVA allergy mouse model MCT is a Th1 specific immunomodulator 1 Control OVA-Alum OVA-Tyrosin MCT triggers higher amount of CD 11c + cells 3 OVA-lgGZa (OD) lgg2a Serum dilution OVA-lgGZa (OD) lgg Serum dilution OVA-lgGZa (OD) lge Serum dilution CD11c + cells [%] CD11c + cells CD86 + DCs% of CD11c CD11c + cells [%] 2 1 PBS Tyrosine 2% Alum 1% PBS Tyrosine 2% Alum 1% 2 PBS Tyrosine 2% Alum 1% PBS Tyrosine 2% Alum 1% MICROCRYSTALLINE TYROSINE 4h 24h 4h 24h MCT triggers less lge but similar lgg responses compared to alum 2 lgg titer lgg Time (weeks) MCT Alum OVA 1µg OVA 1µg OVA 1µg OVA 1µg lge titer lge Time (weeks) Adjuvant efficacy evaluation 11 Vaccines need to be effective IgG titre 5 Immunisation with MCT triggered stronger IFN-γ and IL-1 than alum 2 IFN-γ (pg/ml) Interferon-γ IL-1 (pg/ml) Interleukin-1 MCT works in synergy with antigens to get a higher immune response 4 Pre-immune Antigen alone Formulation Tested Antigen + MCT μg 1μg 1μg 1μg 1μg 1μg 1μg 1μg MCT Alum MCT Alum 1. Heath, M.D., et al. Micro Crystalline Tyrosine (MCT): Benefits as a depot adjuvant. Poster at Vaccines Congress Leuthard, D., et al. Microcrystalline Tyrosine as an Adjuvant in Allergy Immunotherapy: A Mouse Study. Poster at EAACI Data on file 4. Wheeler, et al., A Th1-Inducing Adjuvant, MPL, Enhances Antibody Profiles in Experimental Animals Suggesting it Has the Potential to Improve the Efficacy of Allergy Vaccines. Int Arch Allergy Immunol 21;126:

10 Case study: MCT in an influenza model vaccine Case study: MCT in a malaria (P. vivax) model vaccine Unmet needs 1 : Unmet needs 1 : MCT as an adjuvant in a ferret influenza model: MCT - H1N1 binding MCT Supernatant Adjuvant efficacy evaluation 1 HAI titre 2 Vaccination against seasonal influenza strains is recommended for high risk patient groups Seasonal vaccines against influenza viruses have to be updated on an annual basis due to the mutagenic characteristics of the virus Pre-bleed T + 19 T Antigen in DPBS T + 31 The effectiveness of influenza vaccines range from 36-58% The addition of an adjuvant to influenza vaccines has been approached to promote both immunogenicity and dose sparing in pandemic situations Antigen Antigen + MCT PBS Control H1N1 content (µg/ml) MCT possesses high protein-binding capacity Analysis confirmed >95% antigen - MCT adsorption HAI titres showed higher levels for MCT compared to Aluminium or nonadjuvanted H1N1 vaccine. A single dose of MCT adjuvanted vaccine generates a sero-positive titre ( 2 HAI titre) MCT showed a higher immune response compared to non adjuvanted vaccine MCT as an adjuvant in a mouse malaria model 1 Optical Density Malaria is a massive global health problem No licensed malaria tertiana (P. vivax) vaccine for human use 2 MCT acts a potent adjuvant in a malaria model compared to non-adjuvanted vaccine, mounting high and sustained IgG titres Day Day 7 Antigen Day 14 Day 21 Vaccine efficacy evaluation 1 Percent survival Day 28 Antigen+MCT D5 Days Time to reach 1% Parasitemia MCT induces a more balanced response compared to Alum triggering markedly higher IgG2 isotypes and propensity to develop central memory T cells IgG1 IgG2a IgG2b IgG3 IgG1 IgG2a IgG2b IgG3 IgG1 IgG2a IgG2b IgG3 Antigen Antigen + MCT Antigen + Alum Antigen + MCT Antigen + Alum Antigen Naïve MCT exhibits better protection for malaria than Aluminium. MICROCRYSTALLINE TYROSINE Challenge at T Heath M.D. et al., Comparison of a novel Microcrystalline Tyrosine Adjuvant with Aluminium Hydroxide for Enhancing Vaccination against Seasonal Influenza. BMC Infectious Diseases (217) 17: Cabral-Miranda G. et al., Microcrystalline tyrosine (MCT): a depot adjuvant licensed in allergy offers new opportunities in malaria. Vaccine 217. Article in press. 2. WHO. Malaria vaccine development:

11 AdSys-VCT AdSys-VCT

12 AdSys-VCT AdSys-VCT is a vaccine platform where virus like particles (VLP) and Microcrystalline Tyrosine (MCT ) are combined to potentially increase vaccine efficacy. Why AdSys-VCT 1,2? MCT:VLP immunogenic response 2 :.4.1 MCT has been shown to be a potent adjuvant in a malaria and influenza mouse model. VLP are highly organised organized 3-dimensional particular structures with repetitive surfaces which incorporate the key immunological features of viruses, although, they do not contain viral RNA or DNA. AdSys-VCT uses a VLP model that contains integral Pan T cell epitopes to enhance Th1 capacity. VLP have a high capacity to induce strong humoral and cellular immune responses. MCT is bound effectively to VLP Their combined effect may result in a potent adjuvant system %CD3+IFINγ Antigen Antigen + MCT Antigen + Alum Antigen + VLP Antigen + MCT:VLP %CD3+IFIN-α Antigen Antigen + MCT Antigen + Alum Antigen + VLP Antigen + MCT:VLP AdSys-VCT in a malaria model Vaccines need to stimulate the immune system MCT:VLP induces higher protective cellular immunity Vaccines need to be effective AdSys-VCT MCT:VLP immunogenic response in a P. vivax model 2 Vaccine efficacy evaluation 2 Antigen Antigen + MCT Antigen + Alum Antigen + VLP Antigen + MCT:VLP 6 OD Percent survival Naïve Antigen Antigen + Alum Antigen + MCT Antigen + VLP Antigen + MCT:VLP Day 7 Day 14 Day 21 Day 28 Day Days Time to reach 1% Parasitemia MCT:VLP conferred significant protection and delay to parasitemia Synergistic effect MCT - VLP 1. Cabral-Miranda G. et al., Microcrystalline tyrosine (MCT): a depot adjuvant licensed in allergy offers new opportunities in malaria. Vaccine 217. Article in press. 2. Cabral-Miranda G. et al., Virus like particle (VLP) plus microcrystalline tyrosine (MCT) adjuvants enhance vaccine efficacy improving T and B cell immunogenicity and protection against Plasmodium bergei/vivax. Vaccines 217, 5, 1.

13 AdSys-PS AdSys-PS

14 Phosphatidylserine Dioleoyl Phosphatidylserine (DOPS) DOPS stimulates a significant increase in IgG2a (human IgG1) in a Brown Norway rat model Endpoint Titer Apoptosis or programmed cell death is the process whereby dead cells are removed by phagocytosis, this leads to no inflammation This process is initiated by the expression of phosphatidyl serine (PS) on the outer cell membrane This ensures the removal of dead cells while preventing leakage of the cell contents that would lead to inflammation 5 Control 25μg DOPS 5μg DOPS Group Phagocytosis of apoptotic cells results in the inhibition of inflammatory mediators e.g. IL-8 by macrophage while stimulating anti-inflammatory mediators e.g. TGF-β DOPS stimulates a significant increase in IgG1 (human IgG4) in a Brown Norway rat model 2 Endpoint Titer Stimulation of macrophages to express anti-inflammatory or suppressive phenotypes is likely to be crucial in the resolution of inflammation Delivery of PS containing vaccines would alter the antigen response resulting in a shift away from inflammatory antibody production to anti-inflammatory antibody production 1 Phosphatidylserine DOPS stimulates a significant increase in IgA in a Brown Norway rat model Control 25μg DOPS 5μg DOPS Group AdSys-PS Three different PS derivatives effect different antibody subclasses and their levels 1 DOPS stimulator of IgG LOPS stimulator of IgA SAPS inhibitor of IgE Endpoint Titer Dixon, M. J., et al. Phosphatidyl serine (PS) derivatives alter the immune response in a Brown Norway rat model of allergic sensitisation. Poster at EAACI Data on file. Control 25μg DOPS 5μg DOPS Group

15 25μg LOPS stimulates a significant increase in lga in a Brown Norway rat model 1 Lyso oleoyl Phosphatidylserine (LOPS) 25 DOPS 1 Stimulates anti-inflammatory IgG1 (human IgG4) and IgA production Has no significant effect on levels of IgE Stimulates IgG2a (human IgG1) LOPS 1 25µg LOPS increases levels of IgA No significant effect on IgG1 (human IgG4) Has no significant effect on levels of IgE or IgG2a (human IgG1) SAPS 1 Significantly inhibits levels of IgE Has no effect on levels of antiinflammatory antibodies IgA and IgG2a 2 Endpoint Titer Control 25μg LOPS 5μg LOPS Group Stearoyl arachidonoyl Phosphatidylserine (SAPS) SAPS significantly reduces levels of IgE below control values in a Brown Norway rat model Endpoint Titer AdSys-PS 2 1 Control 25μg SAPS 5μg SAPS Group 1. Data on file

16 Safety AdSys-PS Cytotoxicity Mutagenicity MTS assay results suggested that the three PS formulations, LPS and MPL up to 1µg had no cytotoxic effects on U937 cells 1 DOPS, LOPS, SAPS and MPL were all found to have no mutagenic properties up to a concentration of 25µg 1 1. Data on file

17 Services SERVICES

18 How can we collaborate? Bencard Adjuvant Systems tailor-made solutions Supply and license of patent protected depot adjuvants Technical transfer to enable materials to be formulated independently Co-administration of our adjuvant technologies Whatever stage of the journey you re on, we re here to help build better medicines together On-site manufacture, pre-clinical and clinical development facilities Collaborative and joint research and development programmes Royalty and up-front cost models Our facilities We have a 7 year heritage in pharmaceutical and adjuvant development. We have spent over $1 million in clinical development over the last 1 years investigating the use of novel adjuvant systems in study centres in Europe and USA. Our people have a wealth of intellect; our academic base is strong in immunology, biology, microbiology, chemistry and biochemistry SERVICES

19 Building quality into your vaccine solutions Guiding you through registration GC HPLC EP/USP Testing Karl Fischer Proteomics Particle Size Analysis Mass Spectrometry Excipient Analysis Chemistry Biochemistry/Microbiology SDS profile Western Blotting Iso-Electric Focussing Competitive ELISAs Monoclonal Sandwich ELISAs Identification Methods In-house Sterility Endotoxin, bioburden We have a proven track record in getting products to market with a motivated, quality-driven regulatory affairs team to guide you through to product registration. Regulatory submissions (EU, USA and ROW) Worldwide pharmacovigilance, monitoring and reporting capabilities Distribution, supply and coordination of clinical trial materials We have experienced teams in clinical development (phase I, II and III) using adjuvants FTIR (Fourier Transform Infrared Spectroscopy) Environmental monitoring These services are available independently of any manufacturing requirements. Our people have a wealth of intellect and are positively impacting lives through applying science and service to our products and patients. SERVICES

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