Professor John Strang. National Addiction Centre, King s College London, UK

Transcription

1 Novel buprenorphine oral lyophilisate (Espranor TM /Xprenor TM ) vs sublingual buprenorphine in opioid dependent patients: first in patient Phase II safety study Professor John Strang National Addiction Centre, King s College London, UK

2 Novel buprenorphine oral lyophilisate (Espranor TM /Xprenor TM ) vs sublingual buprenorphine in opioid dependent patients: first in patient Phase II safety study Authorship: John Strang a,b,+, Kylie Reed a,b,*, Karolina Bogdanowicz b, James Bell a,b, Rob VanderWaal a, Jenny Keen a,b, Pete Beavan a, Shelagh Baillie c and Alastair Knight d. a King s College London, National Addiction Centre (Institute of Psychiatry, Psychology and Neuroscience), Denmark Hill, London SE5 8BB, UK; b Addictions Services, South London & Maudsley NHS Foundation Trust, London; c Martindale Pharma, Buckinghamshire, UK; d Evicom, Twickenham, UK.

3 Declaration (personal & institutional) DH, NTA, Home Office, NACD, EMCDDA, WHO, UNODC, FDA, NIDA. NHS provider (community & in patient); history with Phoenix House, Lifeline, Clouds House, KCA (Kent Council on Addictions). Consultation and work with pharmaceutical companies re actual or potential development of new medicines for use in the addiction treatment field, including (past 3 years) Martindale Pharma, Reckitt Benkiser/Indivior, UCB, MundiPharma, Lundbeck, Alkermes, Rusan/iGen, Braeburn and also discussions with Lightlake, Lanacher, Fidelity International and Titan. Principal Investigator and (through the university) retained consultant for the UK Espranor Safety Study for Martindale Pharma. UKDPC (UK Drug Policy Commission), SSA (Society for the Study of Addiction); and two Masters degrees (taught MSc and IPAS) and an Addictions MOOC. Work also with several charities (and received support) including Action on Addiction, and also with J Paul Getty Charitable Trust (JPGT) and Pilgrim Trust. The university (King s College London) has registering intellectual property on a novel naloxone formulation, and JS has been named in a patent registration by a Pharma company as inventor of another naloxone formulation.

4 Funding for this study Exclusive financial support for this study from Martindale Pharma Funding through the King s Health Partners Clinical Trials Office (and thence to Clinical Research Facility, King s College Hospital and to clinical sites within SLaM (South London & Maudsley) NHS Foundation Trust and to the university King s College London Funding through the university (King s College London) for consultancy advice and input from Professor Strang (funding to the university) Supplementary support from the BRC (Biomedical Research Centre) for Mental Health, Institute of Psychiatry, Psychology & Neuroscience, King s College London

5 Thanks Patients who consented to participate Colleagues within CRF (Clinical Research Facility), AAU (Acute Assessment Unit), referring teams and Clinical Trials Office (KHP CTO) Martindale Pharma

6 Introduction why is it interesting? Buprenorphine maintenance now widely used (variably internationally); individual and public benefit; Cochrane tested; NICE approved (TA 114) Problem of abuse of diverted supplies; existing tablets liable to concealment due to slow dispersal; impedes wider utilisation and completely obstructs use in some less supervised settings Can we have new forms of buprenorphine without this problem? Yes Buprenorphine/naloxone Suboxone film (US, Oz, S E Asia); orally disintegrating tablet lyophilised buprenorphine (this study)

7 Study design (1) Aims: to test safety and efficacy of a new buprenorphine oral lyophilisate ( Espranor ) compared to standard sublingual buprenorphine ( Subutex, reference product), covering dose induction and maintenance. Design: randomised (2:1) open label study in opioid dependent subjects; with subsequent partial cross over of group on experimental oral lyophilisate. Personalised dose titration. [Pharmacokinetics on volunteer sub set]. Settings: specialised clinical trials facility and specialised outpatient addictions treatment facility on same campus.

8 Study design (2) Participants: opioid dependent subjects (n=36) commencing buprenorphine maintenance treatment (maintenance dose to be flexibly titrated) includes patients also using alcohol and/or cocaine and/or benzodiazepines at levels below specified thresholds

9 Materials study medications The two buprenorphine formulations studied: new buprenorphine oral lyophilisate ( Espranor ) sub lingual buprenorphine ( Subutex, reference product)

10 Measures Respiratory function (respiratory rate, pulse oximetry); retention in treatment; medication hold and dose adequacy (VAS); opiate withdrawal signs and symptoms (OOWS, SOWS); tablets disintegration time (disintegration; completely dissolved). [also, for PK volunteer subjects, plasma buprenorphine and norbuprenorphine in analysis, to be reported separately].

11 Patient population & doses achieved 36 patients (2:1 randomisation); 23 buprenorphine oral lyophilisate (Espranor), 13 sublingual buprenorphine (Subutex) Generally well matched across the two groups; Age mean 42 years; Gender 14% female Retained well through the intensive study period Adequate personalised maintenance doses achieved (means of 11mg and 10mg for oral lyophilisate and sublingual respectively)

12 Study Disposition Flow Randomised - Received Study Medication Safety and Efficacy Population N = 36 Espranor N = 23 Subutex N = 13 Completed study N = 20 (87.0%)** Withdrawn N = 3 (13.0%)** (2 WD of Consent; 1 Lost to FU) Completed study N = 10 (76.9%)** Withdrawn N = 3 (23.1%)** (2 WD of Consent; 1 Other: Inadequate contraception) * % Screened, **% Esprenor or Subutex administered study drug, DNA = Did Not Attend, WD Withdrawal

13 Randomised Study Design and flow TITRATION (7 days) Days 1 7 MAINTENANCE (7 days) Days 8 14 EXTENSION (14 days) Days N=36 (Randomised 2:1) ESPRANOR N=23 (PK=8) 96% completed titration SUBUTEX N=13 (PK=3) 85% completed titration ESPRANOR SWITCH TO SUBUTEX 91% completed maintenance SUBUTEX STAY ON SUBUTEX 85% completed maintenance

14 Results selected excerpts Full paper to follow in journal format hopefully soon Separate analyses and presentation of cross over sample at a future meeting Separate analyses and presentation of hypoxic response at a future meeting

15 Results overall observations Buprenorphine oral lyophiliate completely disintegrating within 2 minutes in 58% of administrations (vs 5% for sublingual bup). Individual tailoring of doses resulted in similar dosing regimes (mean maintenance daily doses of 11mg and 10mg respectively). No significant between group differences were detected in retention in treatment, opiate withdrawal phenomena, craving, adequacy of hold and measures of respiratory function. No SAEs, nor severe AEs. More AEs and TEAEs with Espranor (mostly mild with similar proportions for moderate ).

16 Results - retention in treatments

17 Results speed of disintegration Espranor Subutex Median time to Complete Disintegration 2 min 10 min Partial or Complete Disintegration at 15 sec? 96.3% 71.8%

18 Results Withdrawal symptoms

19 Results Adequacy of hold

20 Results Intensity of craving

21 Treatment-Emergent Adverse Events, N=36 Espranor Subutex Extension (Subutex) N=23 N=13 N=32 n (%) n (%) n (%) Number of subjects with Serious Adverse Events (SAEs) Adverse events (AE) and Severity Severe Moderate 4 (17.4) 3 (23.1) 5 (15.6) Mild 13 (56.5) 1 (7.7) 8 (25.0) Number of subjects with TEAEs resulting in withdrawal from the study Number of Deaths AE = Adverse Event, TEAE = Treatment Emergent Adverse Event

22 Plasma blood levels and bio availability (buprenorphine) Espranor from 15 profiles from 8 subjects; Subutex from 6 profiles from 3 subjects

23 Plasma blood levels and bio availability (nor buprenorphine) Espranor from 15 profiles from 8 subjects; Subutex from 6 profiles from 3 subjects

24 Discussion and possible implications New buprenorphine product (recent license approval UK, Sweden) Mono product implications? Safety, efficacy; treatment retention Patient and service provider perspectives Patient experience is it different? Scope for wider applications?

25 Thank you