BEMA® Buprenorphine Produced Effective Analgesia in a Phase 2 Placebo-Controlled Trial
`of Moderate to Severe Pain Following Dental Extraction
`Stephen E. Daniels, DO;1 Iris Breithaupt;2 Susan Kerls;2 David Wright, PhD;2 Andrew Finn, PharmD2
`1Premier Research, Austin, TX; 2BioDelivery Sciences International, Inc., Raleigh, NC
`
`Poster
`0114
`
`BACKGROUND
`
`DESIGN AND PROCEDURES
`
`RESULTS
`
` BEMA® Buprenorphine (BEMA-Bup)
`
` Is a small, bilayered, dissolvable polymer
`film (Figure 1)
`formulated with the analgesic buprenorphine for buccal
`application
`
`(BEMA®)
` Employs
`delivery
`BioErodible MucoAdhesive
`technology to facilitate buccal delivery of buprenorphine, which is
`poorly bioavailable when administered orally
`
` Being developed by BioDelivery Sciences International,
`Inc.
`(BDSI) for the management of moderate to severe chronic pain
`
` Buprenorphine
`
` A partial mu-opioid agonist
`
` Long duration of action
`
` Lower propensity for abuse and addiction (Schedule III)
`
` The only single-entity Schedule III opioid analgesic
`
` The randomized, double-blind, double-dummy, parallel-group study
`included a screening visit, treatment day, and a follow-up visit (Figure 2).
`
` Subjects received one of five treatments:
`
` BEMA-Bup 0.5 mg Formulation 1 (high dose)
`
` BEMA-Bup 0.5 mg Formulation 2 (medium dose)
`
` BEMA-Bup 0.25 mg Formulation 2 (low dose)
`
` Oxycodone 5 mg (overencapsulated oral tablet)
`
` Placebo
`
` The buprenorphine bioavailability of BEMA-Bup Formulation 2 is
`approximately 63% that of Formulation 1. This difference accounts for
`the distinction between the high dose and the medium dose.
`
`Figure 3. Mean (SD) SPID-8 values:
`LOCF and BOCF results
`
`LOCF
`
`P=0.0809 versus placebo
`
`11.3 (23.0)
`
`11.9 (20.7)
`
`High-dose
`BEMA-Bup
`
`Medium-dose
`BEMA-Bup
`
`Low-dose
`BEMA-Bup
`
`6.0 (20.0)
`
`BOCF
`
`P=0.0334 versus placebo
`
`14.1 (18.9)
`
`12.7 (16.8)
`
`8.7 (16.4)
`
`High-dose
`BEMA-Bup
`
`Medium-dose
`BEMA-Bup
`
`Low-dose
`BEMA-Bup
`
`Oxycodone
`
`4.3 (14.9)
`
`Oxycodone
`
`4.2 (9.2)
`
`Figure 2. Study flow chart
`
`Placebo
`
`5.3 (17.6)
`
`Placebo
`
`7.4 (13.9)
`
` A total of 153 subjects (mean age 21.9 years, 90.8%
`white, 62.7% female) enrolled: n=31 high-dose BEMA-
`Bup, n=30 medium-dose BEMA-Bup, n=31 low-dose
`BEMA-Bup, n=31 oxycodone, n=30 placebo. All but 1
`subject, who was lost to follow-up, completed the study.
`
` Values for SPID-8 increased with BEMA-Bup dose. The
`difference between BEMA-Bup and placebo was
`significant in the baseline observation carried forward
`(BOCF) sensitivity analysis (p=0.0334) (Figure 3).
`
` Values for TOPAR-8 increased with BEMA-Bup dose
`with significant differences versus placebo for high-
`dose BEMA-Bup in both the LOCF analysis (p=0.0242)
`and the BOCF analysis (p=0.0164) (Figure 4).
`
`0
`
`10
`5
`Mean (SD) SPID-8
`
`15
`
`0
`
`5
`10
`Mean (SD) SPID-8
`
`15
`
` Likely fewer
`typical opioid side effects, such as respiratory
`depression and constipation
`
` Widely used outside the United States
`
`Figure 1. The BEMA® drug delivery technology
`is a buccal soluble film consisting of a
`small, bioerodible polymer film for application
`to the inner lining of the cheek.
`
`OBJECTIVE
`
`To compare the analgesic effects and tolerability of a range of doses of
`BEMA-Bup with those of placebo and a standard opiate in subjects with
`moderate to severe pain
`
`SUBJECTS
`
` Were 18 to 45 years old and generally in good health
`
` Had, within 5 hours of completing third molar extraction under local
`anesthesia:
`
` At least moderate postsurgical (baseline) pain intensity on a
`4-point categorical scale
`
` Pain intensity ≥5 on a 0- to 10-point Numeric Rating Scale
`
` No history of substance abuse or dependence per DSM-IV-TR criteria
`
` Analgesic assessments were recorded at baseline; at 30, 45, 60, and 90
`minutes postdose; and at 2, 3, 4, 5, 6, 7, 8, 10, 12, 20 and 24 hours
`postdose:
`
` Pain Intensity on a 0-10 Numeric Rating Scale (0=none,
`10=worst pain imaginable). The Pain Intensity Difference (PID) is
`the difference between baseline and measured Pain Intensity.
`
` Pain relief on a 0-4 categorical scale (none, a little, some, a lot,
`complete)
`
` Key endpoints:
`
` SPID-8, the time-weighted sum of PID from baseline to 8 hours
`postdose (primary endpoint)
`
` TOPAR-8, Total Pain Relief over 8 hours postdose,
`weighted
`
`time-
`
` Incidence of adverse events
`
`Figure 4. Mean (SD) TOPAR-8 values:
`LOCF AND BOCF results
`
`LOCF
`
`P=0.0242 versus placebo
`
`10.5 (9.9)
`
`9.9 (9.4)
`
`BOCF
`
`P=0.0164 versus placebo
`
`9.6 (10.4)
`
`8.1 (9.4)
`
`High-dose
`BEMA-Bup
`
`Medium-dose
`BEMA-Bup
`
`7.3 (8.7)
`
`Low-dose
`BEMA-Bup
`
`5.7 (8.6)
`
`High-dose
`BEMA-Bup
`
`Medium-dose
`BEMA-Bup
`
`Low-dose
`BEMA-Bup
`
`Oxycodone
`
`6.2 (6.7)
`
`Oxycodone
`
`3.2 (4.4)
`
`Placebo
`
`6.4 (8.6)
`
`Placebo
`
`5.1 (8.6)
`
`0
`
`10
`5
`Mean (SD) TOPAR-8
`
`15
`
`0
`
`10
`5
`Mean (SD) TOPAR-8
`
`15
`
`This research was funded by BioDelivery Sciences International, Inc.
`
` The incidence of adverse events increased with BEMA-
`Bup dose (35.5%, 70.0%, and 83.9% at low, medium,
`and high doses, respectively). Nausea and vomiting
`were the most common adverse events (Table).
`
` The oxycodone dose utilized in this study (5 mg) was
`subtherapeutic, not eliciting effective analgesia or
`producing significant adverse events.
`
`Table. Number (%) of subjects with adverse events*
`
`*Adverse events reported in >5% of subjects the study population are listed regardless of suspected cause.
`
`CONCLUSIONS
` In this randomized, double-blind, placebo-controlled,
`Phase 2 trial, BEMA-Bup produced effective analgesia
`versus placebo in the treatment of moderate to severe
`pain following dental extraction.
`
` The adverse event profile of BEMA-Bup was typical of
`strong opioid doses administered to subjects who are
`not opioid tolerant.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Adverse Event
`
`Low-Dose
`
`Medium-Dose
`
`High-Dose
`
`BEMA-Bup
`
`BEMA-Bup
`
`BEMA-Bup Placebo Oxycodone
`
`Nausea
`
`Vomiting
`
`6 (19.4)
`
`14 (46.7)
`
`20 (64.5)
`
`2 (6.5)
`
`12 (40.0)
`
`16 (51.6)
`
`0
`
`0
`
`Dizziness
`
`5 (16.1)
`
`6 (20.0)
`
`13 (41.9)
`
`1 (3.3)
`
`2 (6.5)
`
`0
`
`0
`
`Headache
`
`2 (6.5)
`
`4 (13.3)
`
`2 (6.5)
`
`0
`
`2 (6.5)
`
`Alveolar osteitis
`
`0
`
`2 (6.7)
`
`3 (9.7)
`
`2 (6.7)
`
`2 (6.5)
`
`
`
`Eligibility and Screening
`
`Treatment Day
`
`Safety Follow-Up Visit
`
`Up to 14 days prior to tooth
`extraction
`
`Third Molar Extraction
`
`Randomization
`
`Study Drug Administration
`
`6 to 10 days after treatment day
`
`Page 1
`
`RB Ex. 2051
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`