Theriva Biologics, Inc. · AMEX:TOVX
Theriva Biologics — Synthetic Biologics — Technical Presentation (April 2014)
41 slides from Theriva Biologics's technical presentation, Apr 30, 2014
Slide 1: A Combination Trial of Estriol Plus Glatiramer Acetate in RRMS
A Combination Trial of Estriol Plus Glatiramer Acetate in RRMS Rhonda Voskuhl, M.D. Professor, UCLA Dept. of Neurology Director, Multiple Sclerosis Program Jack H. Skirball Chair in MS Research
Slide 2: Disclosures
Disclosures Author Disclosure Information: R. Voskuhl: Synthetic Biologics Inc. licensed UCLA patent for estriol in MS with Voskuhl an inventor, Consulting or speaking Synthetic Biologics Inc., Research support Karo Bio. H. Wang: None. T. Wu: None. N. Sicotte : None. A. Bates: Consulting, scientific
Slide 3: Direct versus Indirect Neuroprotection in Multiple Sclerosis Treatment
Direct versus Indirect Neuroprotection in Multiple Sclerosis Treatment Direct ? Indirect DMTs: Anti - inflammatory Decreased inflammation
Slide 4: Estriol Tx for MS: Bedside to Bench to Bedside
Estriol Tx for MS “Bedside to Bench to Bedside” Bedside: clinical observation Bench: unraveled in MS model in lab Bedside: clinical trial
Slide 5: Late Pregnancy: Relapses and Sex Hormones
Late Pregnancy: Relapses Sex Hormones Confavereux et al., New Engl. J. Med, 1998
Slide 6: Pregnancy: Anti-inflammatory and Neuroprotective
Pregnancy Anti - inflammatory: prevent fetal rejection Neuroprotective : protect fetal brain evolutionarily selected for
Slide 7: MS Trials based on Late Pregnancy Sex Hormones
MS Trials based on Late pregnancy: Relapses Sex hormones Increase in Sex Hormones: Progesterone Estradiol Estriol
Slide 8: Previous studies: Estriol Treatment in EAE and MS
1990’s: Holmdahl , Voskuhl, Offner , Bebo , Whitacre Previous studies: Estriol Treatment in EAE and MS EAE: Spinal cord inflammation, axons, myelin EAE: ERα and ERβ Direct Neuroprotective effects in EAE J. Neuroscience 2006, PNAS 2007, Brain 2010, J. Neuroscience, Eur. J. Immunol . 2011, PNAS
Slide 9: Double Blind, Placebo Controlled Trial
Double Blind, Placebo Controlled Trial 16 sites across U.S., n= 164 “Add on” study in RRMS Why Copaxone ? Primary Outcome: Relapse Rate Other Outcomes: EDSS, PASAT, MRI WM lesions Data Safety and Monitoring Board (DSMB): Leslie Weiner – Chair, MS trials Luanne Metz – MS trials Gary Cutter – MS stati
Slide 10: Investigators
Investigators Robert Elashoff , Ph.D . - Data Management & Statistics HeJing Wang, M.D . - Data Management & Statistics Chi - Hong Tseng, Ph.D . - Statistics T.C. Jackson Wu, M.D., Ph.D . - Gynecology Nancy Sicotte , M.D . - MRI lesions Mike Montag , B.S. - MRI tech Jenny Bardens , R.N. - Overall Tr
Slide 11: Site Neurologists / # randomized
Site Neurologists / # randomized University of California Los Angeles: Barbara Giesser / 27 Ohio State University: Michael Racke / 19 Washington University: Anne Cross / 12 Johns Hopkins University: Peter Calabresi - John Ratchford / 12 University of Pennsylvania: Dina Jacobs / 11 University of Texa
Slide 12: Inclusion Criteria
Inclusion Criteria 1. Females age 18 to 50. 2. Definite RRMS. 3. Active RR MS based on relapses and enhancing lesions in last 2 years. 4 . Expanded Disability Status Score (EDSS) = 0.0 to 4.5. 5 . Patients treated with standard MS treatments must have wash out . 6. Patients treated in the past with
Slide 13: Exclusion Criteria
Exclusion Criteria 1. Pregnant. 2. Breastfeeding. 3. Will not discontinue estrogen or progesterone treatment (OCP or HRT). 4. Patients estrogen deficient for years (surgical ovariectomy with no hormone replacement for 1 year or more, or menopause at age 45 or less with no hormone replacement for 3 y
Slide 14: Schedules
Schedules Study Month 0 6 12 18 24 Copaxone (all) ---------------------------------------------- Estriol vs. Placebo (1:1) ---------------------------------------------- Estriol/Prog vs Placebo/Placebo -----------------------------------
Slide 15: Clinical Screening
Clinical Sereening N-236 ‘72 ineligible Ne=83, 81 76 included in the study: 12 withdrew before Year 1 13 withdrew before Year 1 70 completed 1 year study {63 completed 1 year study Among the 70 who completed Among the 63 who completed L-year study, 60 completed 2- 1-year study, $6 completed 2- year
Slide 16: Drop Outs
Drop Outs 29.3% 25 Copaxone + Placebo 23 Copaxone + Estriol Reason for drop-out Number (E, P)* Physician’s decision: MS worsening 3 (1, 2) B-cell lymphoma (SAE) 1 (0, 1) Pregnancy, used hormone to terminate pregnancy 1 (1, 0) Heavy vaginal bleeding, used BCP to stop bleeding 1 (0, 1) Persistent lymp
Slide 17: Patient Characteristics
Patient Characteristics Estriol + Copaxone (N=82) Placebo + Copaxone (N=76) Age Mean ± SD 37.7 ± 7.6 37.1 ± 7.3 Median, IQR 39.1, 32.8 – 43.4 36.4, 32.3 – 43.5 Range 20 - 53 19 - 51 Race Caucasian 66 (80.5) 63 (82.9) Black 9 (11.0) 7 (9.2) Hispanic 7 (8.5) 6 (7.9) Duration of MS (from Dx) Mean ± SD
Slide 18: Serum Estriol Levels
Serum Estriol Levels Baseline estriol levels no different between groups Months 3 - 24 estriol levels higher in Copaxone + Estriol p <0.00001 0 2 4 6 8 10 12 14 16 m o n t h 0 m o n t h 3 m o n t h 6 m o n t h 1 2 m o n t h 1 8 m o n t h 2 4 Copaxone + Placebo Copaxone + Estriol
Slide 19: Estriol Safety: Safe and Well Tolerated
Estriol Safety: 158 subjects 2 years Safe and Well Tolerated Serious Adverse Effects O ne death: B cell Lymphoma in Copaxone + Placebo group Hospitalization for MS relapse: Copaxone + Placebo # = 6 Copaxone + Estriol # = 2 Adverse Effects Clinical: irregular menstrual spotting Copaxone + Estriol # =
Slide 20: Gynecology Safety: No Tx Related Differences
Gynecology Safety: No Tx Related Differences Uterine fibroids on ultrasound Copaxone + Placebo = 8 subjects Copaxone + Estriol = 8 subjects Uterine endometrial thickness > 8mm on ultrasound Copaxone + Placebo = 27 subjects with 41 exams Copaxone + Estriol = 24 subjects with 32 exams Uterine endometr
Slide 21: Primary Outcome Measure: Relapse Rate
Primary Outcome Measure: Relapse Rate Confirmed Relapse: 1. N ew neurological symptoms or worsening of pre - existing symptoms 2. Lasting at least 48 hours 3. Stable or improving in previous 30 days 4. Confirmed objective change by examining neurologist ( increase in EDSS by 0.5) Unconfirmed Relapse
Slide 22: Relapse Rate: Confirmed, 12 month data
Relapse Rate: Confirmed EDSS change by examining neurologist 12 month data Copaxone + Placebo (n = 76) vs. Copaxone + Estriol (n = 82) 47 % reduction p = 0.0326 Adjusted for baseline characteristics: p = 0.0306 (age, disease duration, baseline EDSS, # relapse, Copaxone use) 0 0.1 0.2 0.3 0.4 0.5 0.6
Slide 23: Relapse Rate: Confirmed and Unconfirmed
Relapse Rate: Confirmed and Unconfirmed 12 month data Confirmed 47 % reduction p = 0.0326 ( p = 0.0306) Conf + Unconf 45 % reduction p = 0.0216 ( p = 0.0234) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Conf Conf + Unconf Copaxone + Placebo Copaxone + Estriol bad good
Slide 24: Cognitive Improvement
Cognitive Improvement % Change at 12 months from Baseline Copaxone + Placebo (n = 61), p = NS Copaxone + Estriol (n = 70), p = 0.0047 Between groups p = 0.0395 -2 -1 0 1 2 3 4 5 6 7 8 9 month 12 Copaxone +Placebo Copaxone + Estriol -2 -1 0 1 2 3 4 5 6 7 8 9 month 12 Copaxone +Placebo Copaxone + Estr
Slide 25: PASAT3 Improvement: Slope
PASAT3 Improvement: Slope Absolute Values Per Tx Group: 12 months Copaxone + Placebo Slope = 0.05, p = 0.95 Copaxone + Estriol Slope = 2.77, p = 0.0003 Between Slopes p = 0.01 bad good
Slide 26: Cognitive Improvement: Baseline PASAT3 score <55
Cognitive Improvement: Effect in those with b aseline PASAT3 score < 55 12 month data Mean PASAT (% change) -3 0 3 6 9 12 15 18 All <55 >55 Copaxone +Placebo Copaxone + Estriol -3 0 3 6 9 12 15 18 All <55 >55 Copaxone +Placebo Copaxone + Estriol PASAT3 PASAT2 Copaxone + Placebo (n=25), p = NS Copaxo
Slide 27: EDSS Absolute Change Per Subject Per Tx Group
EDSS Absolute Change Per Subject Per Tx Group 12 month data Copaxone + Placebo (n = 63), p = NS Copaxone + Estriol (n = 69), p = NS No effect -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 Copaxone + Placebo Copaxone + Estriol Mean Change in EDSS bad good
Slide 28: Estriol Treatment Effects: 12 months
Estriol Treatment Effects: 12 months 1. Reduction in relapse rate 2. Improvement in cognitive test scores 3. No effect on EDSS
Slide 29: Relapse Rate: Confirmed, 12 and 24 month data
Relapse Rate: Confirmed 12 and 24 month data 12 months 47% p = 0.0326 ( p = 0.0306) 24 months 32% p = 0.1549 (p = 0.1527) 0 0.1 0.2 0.3 0.4 0.5 0.6 12 months 24 months Copaxone + Placebo Copaxone + Estriol Copaxone + Placebo (n = 76) vs. Copaxone + Estriol (n = 82) bad good
Slide 30: Proportion of Subjects Relapse Free
Proportion of Subjects Relapse Free: Confirmed over 24 months Proportion Subjects Relapse Free Probability bad good
Slide 31: Cognitive Improvement: 12 and 24 month data
Cognitive Improvement: % Change Per Subject Per Tx Group 12 and 24 month data Mean PASAT (percent change) -1 0 1 2 3 4 5 6 7 8 month 12 month 24 Copaxone + Placebo Copaxone + Estriol PASAT3 month 12 month 24 PASAT2 month 12 month 24 Copaxone + Placebo (n = 54) p = NS p = 0.05 Copaxone + Placebo (n=
Slide 32: EDSS Worsening
EDSS Worsening: 24 months Proportion of Subjects Progression Free Proportion Subjects Progression Free Probability good bad
Slide 33: EDSS Improvement: Mean Absolute Score
EDSS Improvement: 24 months Mean Absolute Score Per Tx Group Mean EDSS 1 1.2 1.4 1.6 1.8 2 2.2 2.4 M o n t h 0 M o n t h 3 M o n t h 6 M o n t h 1 2 M o n t h 1 8 M o n t h 2 4 Copaxone + Placebo Copaxone + Estriol Copaxone + Placebo: Slope = - 0.01 (p = NS) Copaxone + Estriol : Slope = - 0.11 (p =
Slide 34: EDSS Improvement: 12 and 24 month data
EDSS Improvement Absolute Change Per Subject Per Tx Group 12 and 24 month data Mean Change in EDSS 12 months 24 months Copaxone + Placebo (n=56), p = NS Copaxone + Placebo (n=56), p = NS Copaxone + Estriol (n=56), p = NS Copaxone + Estriol (n=56), p= 0.0336 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 1 2 Copaxon
Slide 35: MRI: White Matter Lesions
MRI: White Matter Lesions 0 0.2 0.4 0.6 0.8 1 1.2 m o n t h 0 m o n t h 3 m o n t h 6 m o n t h 1 2 m o n t h 2 4 Copaxone + Placebo Copaxone + Estriol Enhancing Lesion Number: Copaxone + Placebo = 45% reduction Copaxone + Estriol = 50% reduction bad good 0 1 2 3 4 5 6 7 8 m o n t h 0 m o n t h 3 m
Slide 36: Estriol Treatment Effects: 24 Months
Estriol Treatment Effects: 24 Months 1. Relapse R ate: Copaxone + Estriol : decreased 12 months; remained low 24 months Copaxone + Placebo: decreased at 24 months 2. C ognitive T est Scores: Copaxone + Estriol : improved 12 months; remained high 24 months Copaxone + Placebo: improved at 24 months 3.
Slide 37: Acknowledgements
Acknowledgements MS Patients – providing own Copaxone National Multiple Sclerosis Society (NMSS) National Institutes of Health (NIH): NINDS Synthetic Biologics Inc. Jack H. Skirball Foundation Conrad N. Hilton Foundation Sherak Family Foundation Dr. Patricia O’Looney 1956 - 2013 Tom Sherak 1945 - 20
Slide 38: Estriol Treatment in EAE: Synapses
Estriol Treatment in EAE: Synapses Ziehn , O’Dell, Voskuhl Lab Invest, 2012
Slide 39: Estriol Treatment in EAE: Functional Synaptic Plasticity
Estriol Treatment in EAE: Functional Synaptic Plasticity Ziehn , O’Dell, Voskuhl, Lab Invest, 2012
Slide 40: Serious Adverse Events (SAEs): Hospitalizations
Serious Adverse Events ( SAEs ): Hospitalizations Severe adverse events Æ 9 [ 8, 10%] 12 [10, 13%] MS relapse 2 [ 2, 2%] 6 [ 5, 6%] Pregnancy termination 2 [ 2, 2%] 0 B-cell lymphoma 0 1 [ 1, 1%] Infections UTI 1 [ 1, 1%] 1 [ 1, 1%] pyelonephritis 1 [ 1, 1%] 0 Systolic heart failure 1 [ 1, 1%] 0 Pac
Slide 41: Adverse Events (AEs)
Adverse Events (AEs): 158 subjects 2 years Copaxone injection area reaction bruises 5 [4, 5%] 4 [4, 5%] NS irritation / pain 5 [5, 6%] 7 [5, 6%] NS burning 4 [4, 5%] 2 [2, 3%] NS itching 6 [5, 6%] 3 [3, 4%] NS redness 7 [7, 9%] 2 [2, 3%] NS swelling 7 [6, 7%] 0 P=0.0139 not specified 16 [14, 17%] 8
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