Novel buprenorphine oral lyophilisate  (EspranorTM/XprenorTM)  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

Novel buprenorphine oral lyophilisate (EspranorTM/XprenorTM)  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.

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.

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

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

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) 

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.

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

Materials – study medications

The two buprenorphine formulations studied:

•new buprenorphine oral lyophilisate (‘Espranor’) 

•sub‐lingual buprenorphine (‘Subutex’, reference product) 

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].

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)

Study Disposition Flow

Randomised - Received Study MedicationSafety and Efficacy Population

N = 36

WithdrawnN = 3 (13.0%)** (2 WD of Consent;

1 Lost to FU)

Completed studyN = 20 (87.0%)**

WithdrawnN = 3 (23.1%)**

(2 WD of Consent;1 Other: Inadequate contraception)

Completed studyN = 10 (76.9%)**

EspranorN = 23

SubutexN = 13

* % Screened, **% Esprenor or Subutex administered study drug, DNA = Did Not Attend, WD Withdrawal

Randomised Study Design and flow

TITRATION (7 days)Days 1‐7

MAINTENANCE (7 days)Days 8‐14

EXTENSION (14 days)Days 15‐28

ESPRANOR N=23 (PK=8)

SUBUTEX N=13 (PK=3)

N=36

ESPRANOR SWITCH TO SUBUTEX

SUBUTEX STAY ON SUBUTEX

96% completed  titration

85% completed  titration

91% completed maintenance

85% completed maintenance

(Randomised 2:1)

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

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’).

Results - retention in treatments

Results – speed of disintegration

Espranor SubutexMedian time to Complete Disintegration 2 min 10 minPartial or Complete Disintegration at 15 sec? 96.3% 71.8%

Results – Withdrawal symptoms

Results – Adequacy of ‘hold’

Results – Intensity of craving

Espranor Subutex Extension(Subutex)

N=23 N=13 N=32n (%) n (%) n (%)

Number of subjects with Serious Adverse Events (SAEs)

0 0 0

Adverse events (AE) and Severity Severe 0 0 0

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

0 0 0

Number of Deaths 0 0 0AE = Adverse Event, TEAE = Treatment – Emergent Adverse Event

Treatment-Emergent Adverse Events, N=36

Plasma blood levels and bio‐availability  (buprenorphine)

Espranor – from 15 profiles from 8 subjects; Subutex – from 6 profiles from 3 subjects

Plasma blood levels and bio‐availability  (nor‐buprenorphine)

Espranor – from 15 profiles from 8 subjects; Subutex – from 6 profiles from 3 subjects

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?

Thank you