Outsourcing in Clinical Trials 1-2 July 2015

Transcription

1 Outsourcing in Clinical Trials 1-2 July 2015 Innovating Dr Chris Bailey Babraham Research Campus Babraham Cambridge CB22 3AT UK +44 (0) Vaccines 1

2 Utilising Academia for the Benefit of Trials ImmBio s bacterial vaccine development Examples of trials run at UK Universities 2

3 The challenge for ImmBio Small biotech with novel vaccine technologies addressing unmet medical needs Out-sourcing strategy Building clinical development capabilities Aims to out-license products with evidence of clinical safety and potential efficacy (animal data not sufficient) Evidence of immunogenicity can be obtained from firstin-man studies - Need accepted immunological correlate(s) of protection Phase II studies Human challenge Effect on nasopharyngeal carriage 3

4 Meningococcal vaccines: the unmet need Bacterial infection from Neisseria meningitidis, with multiple strains: serogroups A, B, C, Y and W Threat to young, causing death or disability Incidence rate 1-5/100k to 10-25/100k in developed/developing world Vaccines available for serogroups A, C, Y and W (polysaccharide conjugates) MenC vaccine universal in UK (strong herd immunity) Protein-based MenB vaccines licensed recently 4

5 Protein-based MenB vaccines Novartis - 4CMenB - Bexsero OMV + 5 rec antigens (incl fhbp) approved in EU, Australia, Canada, US (adolescents) May protect against approx 70% of UK B strains (based on surrogate data) Debate over cost effectiveness Pfizer - 2 rfhbp antigens - Trumenba Approved in US for adolescents Other pharma & biotech - preclinical/phase I OMV-based vaccines MenBioVax 5

6 ImmBio s MenB vaccine candidate MenBioVax is for the active immunisation of infants, adolescents and adults for the prevention of invasive disease caused by all serogroups of Neisseria meningitidis 6

7 Meningococcal disease vaccine implementation Department of Health 21 June 2015 Announce new programmes to protect against meningitis and septicaemia From September, babies aged 2 months will be offered the MenB vaccine, followed by a second dose at 4 months and a booster at 12 months Headlines 22 June 2015 England becomes first country worldwide to offer meningitis jabs to all babies The new MenB vaccination programme comes after a deal between the Government and the drugs giant GlaxoSmithKline 7

8 Controversy over universal Bexsero implementation EMA approved Bexsero in 2012 Indicated for active immunisation of individuals from 2 months of age and older against invasive meningococcal disease caused by Neisseria meningitidis group B Joint Committee for Vaccination and Immunisation (JCVI) July 2013: Interim statement did not recommend implementation Cost-effectiveness model Effect on carriage uncertain February/July 2014: Implementation recommended at the right price 8

9 Impact on acquisition of carriage July 2013 JCVI Interim Statement JCVI agreed that the impact of Bexsero on the acquisition of, or on existing, meningococcal carriage was a key determinant of the indirect population protection that might be provided. However, the committee considered that the evidence available did not support definitive conclusions about the efficacy of Bexsero against the acquisition of meningococcal carriage, although the vaccine appears to have little, if any, impact on existing carriage. 9

10 How do we obtain carriage data? The Lancet, volume 384, pages , Dec Sponsored by Novartis Vaccines 10

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16 Pneumococcal Disease Henriques-Normark B, and Tuomanen E I Cold Spring Harb Perspect Med 2013;3:a

17 Pneumococcal disease and vaccines Major cause of mortality in elderly & young, with 91 serotypes already... Likely to continually evolve Pfizer s polysaccharide conjugate vaccine (PCV) Prevnar leads, covering 13 serotypes High PCV CoGs inherent due to technology Protein-based vaccines can provide broad, cross-serotype protection 17

18 Advantages Pneumococcal protein vaccines Not restricted to capsular serotypes Multiple modes of action (e.g. target toxins, nutrient uptake...) Potentially stop colonisation with all pneumococci, leading to herd immunity Cheaper than polysaccharide conjugates However... Need multi-protein vaccine for protective immunity Need accepted surrogates of protection Require large efficacy trials 18

19 ImmBio s pneumococcal vaccine candidate The intended indication for PnuBioVax is the active immunisation, especially infants and elderly to prevent invasive pneumococcal disease, providing broad protection against current and emerging Streptococcus pneumoniae serotypes 19

20 First-in-man trial design Placebo controlled, doubleblind, dose escalation, single centre study to evaluate the safety and immunogenicity of PnuBioVax administered on three occasions 28 days apart at dose levels of 50 µg, 200 µg, and 500 µg in healthy adult subjects 36 adults (18 to 30 yrs) 12 per group (9 active, 3 placebo) To assess safety, tolerability and immunogenicity Male and female subjects Volunteers: age, background immunity to circulating strains Risk mitigation: Sentinel subjects for each dose cohort All subjects assessed for 24 hours post-dosing Follow up for safety at 6 months 20

21 How can we obtain early evidence that a candidate pneumococcal vaccine will be protective? 21

22 Development of pneumococcal human challenge model 22

23 % Colonization Experimental Human Pneumococcal Carriage Presented at British Thoracic Society Meeting 2014 Type 6B and 23F dose ranging studies Reproducibility B 23F Dose CFU x 10 3 per nostril J Visual Expts 2013 The Liverpool School of Tropical Medicine 23

24 PCV and EHPC Study Previous studies have shown that we can achieve 40 50% carriage 100 healthy volunteers randomised to receive o Prevenar-13 - Pneumococcal Conjugate vaccine (13 serotypes) o Avaxim - Hepatitis A vaccine Volunteers were inoculated with live pneumococcal bacteria: 80,000 CFU/0.1ml per naris 4-6 wks post vacination Primary endpoint Pneumococcal carriage rates (in NW) using classical microbiological methods collected from vaccinated subjects at any time point Secondary endpoints Pneumococcal presence at each time point (day 2, 7, 14, 21) Pneumococcal density at day 2, 7, 14 and 21 Pneumococcal carriage duration The Liverpool School of Tropical Medicine 24

25 Carriage model to test vaccine efficacy Wk1 Wk5 Wk6 Wk7 Wk8 Wk9 Wk9-21 N=100 T=0 Vaccine 50 T=1 48h Challenge 7d 14d T=2 99% 85% 5 10 Bronchoscopy Carriers Power Placebo blood, nasal wash, saliva and urine nasal wash BAL Unblinding The Liverpool School of Tropical Medicine 25

26 CONSORT Statement Never replied n=141 Excluded n=168 Withdrew after consent n=20 Screened for eligibility n=429 Recruited n=100 Randomised n=99 Withdrew following screening n=1 Discontinued n=1 Anxious post vaccination removed for participant safety PCV group n=49 Control group n=50 Analysed according to modified ITT n=48 Analysed according to modified ITT n=48 Discontinued n=2 1. Low WCC 2. Withdrew consent The Liverpool School of Tropical Medicine 26

27 6B Pneumococcal Carriage Rates Primary endpoint Pneumococcal carriage rates (in NW) using classical microbiological methods collected from vaccinated subjects at any time point No. colonised / total no. (%) Any Day PCV group (n=48) Control group (n=48) Odds Ratio [95%CI] p value 5/48 (10.4) 23/48 (47.9) 0.13 [ ] The Liverpool School of Tropical Medicine 27

28 Conclusion We have used a novel human pneumococcal colonisation model to demonstrate that: PCV reduces colonisation frequency & density This model can be used to efficiently and safely test vaccines at a fraction of the cost and effort of current methods. The Liverpool School of Tropical Medicine 28

29 Summary In the development of meningococcal and pneumococcal disease vaccines, investigations of bacterial carriage are important To provide early evidence of efficacy To support implementation Academic sites are providing the resources to support these investigations 29

30 Thanks to our academic collaborators In particular: Professor Robert Read - University of Southampton Professor Stephen Gordon - Liverpool School of Tropical Medicine 30