Gazing into the crystal ball: New biologics in development

Transcription

1 Gazing into the crystal ball: New biologics in development Jean-Frédéric Colombel CHU Lille, F Conflicts of interest Abbott Laboratories, Abbott Park, Illinois; ActoGeniX NV, Zwijnaarde, Belgium; AlbireoPharma, Sweden, Astra Zeneca, Sweden; BayerScheringPharma, AG, Berlin, Ge; Biogen Idec Inc, Cambridge, MA; Boehringer-Ingelheim, Inc., Ridgefield, CT; Bristol Meyers Squibb, Princeton, NJ; Cellerix SL, Madrid, Spain; Chemocentryx, Inc.Mountain View, CA; Centocor, Malvern, PA; Cosmo Technologies, Ltd, Milano, Italy; Danone France, Massy Palaiseau, France; Elan Pharmaceuticals, Inc., San Francisco, CA; Genentech, San Francisco, CA; Giuliani SPA, Milano, It; Given Imaging, Hamburg, Ge; Glaxo Smith Kline, Research Triangle Park, NC; Merck & Co., Inc., NJ, USA; Millenium Pharmaceuticals Inc., Cambridge, MA; Neovacs SA, Paris, F; Ocerra Therapeutics, Inc. San Diego, CA; Otsuka American Pharmaceuticals Inc., Rockville, MD; PDL Biopharma, Freemont, CA; Pfizer Inc. New York, USA; RiboVacs Biotech, Switzerland; Schering Plough Corporation, Kenilworth, NJ; Shire Pharmaceuticals, Wayne, PA; Synta Pharmaceutical Corporation, Lexington, MA; Teva Pharmaceuticals, North Wales, PA and Petah Tikva, Israel; Therakos, Exton, PA; UCB Pharma, Atlanta GA and Brussels, Belgium; Wyeth Pharmaceuticals, Collegeville, Pen.

2 How effective is treatment with anti-tnf therapy? (infliximab, adalimumab, certolizumab) Within a few weeks of starting treatment of an anti-tnf drug 4% (4/1) did not have an improvement in their symptoms 6% (6/1) had an improvement in their symptoms Continued anti-tnf or Placebo For those who improved, after 1 year of either continued treatment with the anti-tnf medication or with placebo, this is what happened: TNF Placebo How many people were free from symptoms AND off of prednisone? 29% 7% Results based on a weighted average from Precise 2 (only response included since 6 mo endpoint), ACCENT1 and CHARM C Siegel There is room for improvement!

3 New strategies Positioning of anti-tnf in Crohn s disease Steroids Dependence/refractory No maintenance Does not alter course Immunomodulators Intolerance/refractory Slow/poor mucosal healing No induction benefit 3 rd Line 2 nd Line 1 st Line ACCENT 1 CHARM SONIC GETAID Step Up Top Down 1 years of evolution of anti-tnf in CD New therapeutic targets Korzenik JR, Podolsky D. Nature Reviews 26

4 Rituximab CD2 Roche Visilizumab CD3 PDL cm-t412 CD4 Centocor Daclizumab CD25 PDL/Roche Basiliximab CD25 Novartis ch5d12 CD4 Tanox Tocilizumab IL6R Roche Fontolizumab IFN-ϒ PDL C326 IL6 Avidia AIN457 IL17 Novartis MDX11 CXLX1 Medarex ril18 BP IL18 Serono/Merck HuMxIL15 IL15 GenMab Tenovil IL1 Shering-Pl. Oprelvekin IL11 Centocor Etanercept TNF Wyett Onercept TNF Serono CD13 CD13 LigoCyte RhuMab beta7 β7 GenenTech VAP1 Ab VAP1 BioTie Pf-547,659 MAdCAM Pfizer RGN-352 Thymosinβ4 RegeneRx VT-214 Chemokine binding Viron BIOLOGICS Abatacept CD28 BMS Golimumab TNF Centocor Ustekinumab ABT-874/J695 Sargramostim GM-CSF Berlex Vedolizumab α1β7 Millenium Alicaforsen AntiICAM-1 ISIS Teduglutide GLP-2 NPS Somatropin IL12/IL23 p4 IL12/IL23 p4 Epithelium growth Centocor Abbott Eli Lilly Infliximab Adalimumab Certolizumab B T cytokine Cytokine TNF adhésion Mucosal barrier Other TNF TNF TNF Centocor Shering- Plough Abbott UCB Natalizumab α1β4 Elan Phase I Phase II Phase III Launched SMALL MOLECULES Apilimod Mesylate IL12-IL23 Synta Semapimod p38 MK Cytokine Doramapimod p38 MK Boehringer Thalidomide Anticytokines Pharmion Lenalidomid Anticytokines Celgene CP-69,55 JAK3 Pfizer Laquinimod? Teva/ Active Biotech T cytokine Cytokine TNF adhésion Mucosal barrier Other CCX282-B CCR9-R ChemoCentryx AZD956 Ion blocker Astra IPL42 PDE4 Inflazyme NV52 Thromboxane Novogene Guanilib Uroguanyline Callisto Masitinib Inhibitor KIT and PDGFRA receptors AB Science - PPAR agonist Giuliani THC-CBD Cannabidiol GW Pharmac. Phase I Phase II Phase III Pre-reg. Launched

5 Gazing into the crystal ball Most rated Disappointments (?) Outsiders Gazing into the crystal ball

6 Most rated Selective anti-adhesion molecules Rational Rutgeerts P et al. Gastroenterology 29

7 ENACT-2: Natalizumab in active CD. Maintenance of clinical remission with steroid withdrawal over 15 mos in week 12 responders receiving steroids at baseline 6 P=.14 P=.9 P % 42% Percent of patients % 15% 1 Natalizumab 3 mg (n=67) Placebo (n=76) Start ENACT-2 Time (months) Sandborn Sandborn WJ et al. NEJM 25 NEJM 25 Progressive multifocal leukoencephalopathy (PML) Rare, progressive infection of the CNS Often fatal within 6 months of diagnosis Lytic infection of oligodendrocytes by JC virus, a human polyomavirus Reported with Natalizumab Rituximab (anticd2) Efalizumab (anticd11a)

8 Selective anti-adhesion molecules Rational Rutgeerts P et al. Gastroenterology 29 Vedolizumab (MLN-2) For Active Ulcerative Colitis Remission at Week patients with active UC [ulcerative colitis clinical score (UCSS) ³ 5 and modified Baron score (MBS) ³ 2] receiving a stable dose of 5-ASA or no medical therapy Randomized to receive IV doses of placebo,.5 mg/kg, or 2. mg/kg vedolizumab on days 1 and 29 Clinical remission (%) P= Day 43 The primary endpoint was % clinical remission (UCSS score or 1, MBS or 1, and no blood) at day 43 Placebo Vedolizumab.5 mg/kg Vedolizumab 2. mg/kg Feagan B et al. NEJM 25

9 Vedolizumab (MLN-2) For active Crohn s disease Response and remission at Week patients with active Crohn s disease receiving a stable dose of 5-ASA or antibiotics or no medical therapy Randomized to receive IV doses of placebo,.5 mg/kg, or 2. mg/kg MLN-2 on days 1 and 29 The primary endpoint was % clinical response (decrease in CDAI of³7 points) at day 57 Secondary endpoint was % remission (CDAI < 15) at day 57 Response or Remission (%) P=NS Response Day P= Remission Placebo MLN-2.5 mg/kg MLN-2 2. mg/kg Feagan B et al. Clinical Gastroenterology & Hepatology 28 Ongoing Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN2) in Patients With Moderate to Severe Ulcerative Colitis GEMINI I Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN2) in Patients With Moderate to Severe Crohn's Disease A Phase 3, Open-Label Study to Determine the Long-Term Safety and Efficacy of Vedolizumab (MLN2) in Patients With Ulcerative Colitis and Crohn's Disease GEMINI LTS

10 Selective anti-adhesion molecules Rational Rutgeerts P et al. Gastroenterology 29 Selective anti-adhesion molecules Rational Rutgeerts P et al. Gastroenterology 29

11 CCX282-B for active Crohn s disease Protect-1 p =, patients with active Crohn s disease Randomized to receive oral doses of placebo (bid), 25mg/d, 5mg/d or 25mg bid CCX282-B Response CDAI 7pts or response Remission (%) Week 4 Week 8 Week 12 Placebo (n = 144) 25 mg 1/jd(n = 98) 5 mg 1/jd(n = 97) 25 mg 2/jd(n = 96) The primary endpoint was - Induction period: response 7 at wk8 - Maintenance period: CDAI 7 pts response at wk8 and maintenance at 1yr CDEIS decrease Placebo (n = 37) 25 mg 1/d (n = 16) 5 mg 1/d (n = 16) 25 mg 2/d (n = 21) Keshav S et al. DDW 29-8 p <,5 Blockade of T-cell differentiation Rational

12 Biology of Interleukins 12 and 23 IL-12/23 Stimulus TLR? IL-12 p35 p4 Ag Antigen Presenting Cell MHCII p19 p4 IL-23 b2 TCR IL-23R IL-12/23 IL-12Rb1 CD4 + IL-12Rb1 IL-12/23 X IFNg (Th1) IL-17 (Th17) CNTO 1275 (ustekinumab) and ABT 874 are fully human IgG1 monoclonal antibodies Bind the p4 subunit of human IL-12/23 Prevent IL-12 and IL-23 from binding IL-12Rb1 Normalize IL-12 and IL- 23 mediated signaling, cellular activation, and cytokine production In development in Crohn s disease and psoriasis Anti Interleukin-12/23 monoclonal antibody (J695, ABT-874) for active Crohn s disease P=O.O3 Cohort 1: n=4 Cohort 2: n=39 Active CD (CDAI 25-45) Weekly SQ injections of J695 1 or 3 mg/kg or placebo With either a 4-week interval (cohort 1) between 1 st and 2 nd or no interruption (cohort 2) Clinical remission = CDAI <15 pts at week 7 Clinical response = in CDAI ³1 pts at week 7 P=O.O7 Mannon et al. NEJM 24

13 Ongoing Phase 2B, Multi-Center, Randomized, Double-blind, Parallel Group, Placebo-controlled, Dose Ranging Study Comparing the Efficacy, Safety and Pharmacokinetics of Intravenous Infusions of ABT-874 vs. Placebo in Subjects With Moderately to Severly Active Crohn's Disease Ustekinumab (CNTO 1275) for active Crohn s disease: clinical response through Week 8 Response: CDAI scores of 25% & 7 points Proportion of patients (%) Primary Endpoint p=.335 p=.2 p=.19 p= Week 2 Week 4 Week 6 Week 8 Sandborn WJ et al. Gastroenterology 28 SC and IV placebo (N=53) SC and IV Ustekinumab 1275 (N=51)

14 Ustekinumab (CNTO 1275) for Active Crohn s Disease: Subgroup Analysis in Patients with Prior Infliximab Clinical Response Through Week 8 Response: CDAI scores of 25% & 7 points Proportion of patients (%) p=.46 p=.1 p=.4 p= Week 2 Week 4 Week 6 Week 8 Sandborn WJ et al. Gastroenterology 28 SC and IV placebo (N=27) SC and IV Ustekinumab 1275 (N=22) Ustekinumab (CNTO 1275) for Active Crohn s Disease: Decrease in CRP in primary-group and in patients with prior Infliximab Toedter GP et al. Am J Gastroenterol 29

15 Ongoing A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Ustekinumab Therapy in Subjects with Moderately to Severely Active Crohn s Disease Previously Treated with TNF Antagonist Therapy (CERTIFI) I d not bet on them!

16 Blockade of T-cell activation - Rational Visilizumab (CD3 Antibody) for severe, IV steroid refractory UC : response at Day patients with severely active UC despite 5 days or more of IV steroids Randomized to visilizumab 5 mcg/kg (n=84) or placebo (n=43) infusions X 2 days The primary endpoint was induction of response (decrease in the Mayo score of >/=3 points and a decrease in the rectal bleeding score of >/=1 or a rectal bleeding score of -1) at day 45 Clinical response (%) P= Day 43 Placebo Visilizumab Sandborn WJ et al. DDW 28

17 Blockade of T-cell activation - Rational Development stopped Blockade of T-cell activation - Rational

18 Abatacept (CTLA4-Ig): a human recombinant fusion protein CTLA4 Abatacept (CTLA4Ig) IgG1 CTLA4 Negatively Regulates T-cell Activation CTLA4 expressed following T-cell activation CTLA4 binds to CD8/86 with higher avidity than CD28, and inhibits co-stimulation

19 A Randomized Placebo-controlled Study DesignTrial of Abatacept for Moderately-to-Severely Active Ulcerative Colitis Placebo (N=14) Abatacept 3 mg/kg (N=7) Abatacept 1 mg/kg (N=139) Study design Week 12 primary endpoint: clinical response Abatacept 3/~1 mg/kg* (N=141) 2:1:2:2 randomization stratified by inadequate response and/or intolerance to anti-tnf therapy Dosing on Days 1, 15, 29, and 57 Sandborn WJ et al. ACG 29 * 3 mg/kg for the first two doses, then 1 mg/kg thereafter; Abatacept was administered by IV infusion. IV=intraventricular; TNF=tumour necrosis factor Response Rate According to Mayo Score Primary Endpoint: Week Abatacept 3/~1 mg/kg (N=14) Abatacept ~1 mg/kg (N=137) Abatacept 3 mg/kg (N=69) Placebo (N=139) 35 Response rate (%) * Week 8 Week 12 *p=.124 versus placebo using a CMH Chi-square test controlling for randomization strata; Error bars are 95% confidence intervals; Patients with missing data were imputed as nonresponders; Five patients were excluded from the efficacy analyses due to GCP non-compliance at 1 site

20 Remission Rate According to Mayo Score Key Secondary Endpoint: Week Abatacept 3/~1 mg/kg (N=14) Abatacept ~1 mg/kg (N=137) Abatacept 3 mg/kg (N=69) Placebo (N=139) Patients in remission (%) Week 8 Week Error bars are 95% confidence intervals; Patients with missing data were imputed as nonresponders; Five patients were excluded from the efficacy analyses due to GCP non-compliance at 1 site Therapeutic targets in IBD Korzenik JR, Podolsky D. Nature Reviews 26

21 Sargramostin for Crohn s disease N.O.V.E.L. 4 Randomized (2:1 ratio), double-blind, placebocontrolled, multicentre study 69 centres (Argentina-2, Australia-17, Brazil-6, Canada-16, Mexico-1, New Zealand-2, Russia-7, Switzerland-3, UK-1, Ukraine-5) Adult patients with active CD (CDAI 22, 475) 5-ASA compounds, antibiotics only permitted therapies Corticosteriods, antimetabolites, TNF agonists, investigational compounds excluded Feagan B et al. DDW 28 Results: Primary Outcomes: ITT 6 Remission? (CDAI 6 Response? (CDAI Decrease) P=.228 Percentage 4 2 P= ,3 22,6 Percentage ,1 33,3 Sargramostim 21/93 79/192 Placebo Sargramostim 31/93 Placebo

22 Explanatory Analyses 8 Non-Responder Imputation Countries with 1 or more subjects enrolled Response or Remission (%) sargramostim placebo (no. subjects) AUS CAN UK BRA RUS UKR Outsiders

23 Blockade of T-cell differentiation and activation - Rational IL-6 Tocilizumab IL6R Blockade of T-cell differentiation and activation - Rational IL-6 AIN457

24 Small molecules that target immune pathways- Rational Extracellular stimuli Growth factors, mitogens, (stress) Stress, inflammatory cytokines, growth factors MAPKKK Raf, Mos, Tpl2 MEKK2/3, Tpl2 MLK3, TAK, DLK MEKK1/4, MLK3, ASK1 Cytoplasm MAPKK MEK1/2 MEK5 MKK3/6 MKK4/7 Nucleus MAPK ERK1/2 ERK5/BMK1 P38 MAPKa,b,g SAPK/JNK1,2,3 Biological response Peyrin-Biroulet et al. Lancet 28 Growth and differentiation Inflammation, apoptosis, growth, differentiation JAK3/gc inhibitors will block signalling by six cytokines Receptors signalling through JAK3 IL-2 IL-4 IL-7 IL-9 IL-15 IL-21

25 Laquinimod: effects in animal models Laquinimod has been shown to be potent and efficacious in various animal models of inflammatory autoimmune diseases: Multiple Sclerosis (EAE) Inflammatory Bowel Disease (DSS; TNBS) Lupus (NZB/W) Rheumatoid Arthritis (CIA) Type I Diabetes (NOD mice) Guillain Barré Syndrome (EAN) Laquinimod in multiple sclerosis Effect of Laquinimod on T1 Gd Enhancing Lesions Effect of Laquinimod on Annualized Relapse Rate Median Number of Cumulative Gd Enhancing Lesions (week 12-36) % % mg Laquinimod.6 mg Laquinimod Placebo Comi et al, 28

26 Rituximab CD2 Roche Visilizumab CD3 PDL cm-t412 CD4 Centocor Daclizumab CD25 PDL/Roche Basiliximab CD25 Novartis ch5d12 CD4 Tanox Tocilizumab IL6R Roche Fontolizumab IFN-ϒ PDL C326 IL6 Avidia AIN457 IL17 Novartis MDX11 CXLX1 Medarex ril18 BP IL18 Serono/Merck HuMxIL15 IL15 GenMab Tenovil IL1 Shering-Pl. Oprelvekin IL11 Centocor Etanercept TNF Wyett Onercept TNF Serono CD13 CD13 LigoCyte RhuMab beta7 β7 GenenTech VAP1 Ab VAP1 BioTie Pf-547,659 MAdCAM Pfizer RGN-352 Thymosinβ4 RegeneRx VT-214 Chemokine binding Viron BIOLOGICS Abatacept CD28 BMS Golimumab TNF Centocor Ustekinumab ABT-874/J695 Sargramostim GM-CSF Berlex Vedolizumab α1β7 Millenium Alicaforsen AntiICAM-1 ISIS Teduglutide GLP-2 NPS Somatropin IL12/IL23 p4 IL12/IL23 p4 Epithelium growth Centocor Abbott Eli Lilly Infliximab Adalimumab Certolizumab B T cytokine Cytokine TNF adhésion Mucosal barrier Other Positive results, ongoing Uncertain? Halted TNF TNF TNF Centocor Shering- Plough Abbott UCB Natalizumab α1β4 Elan Phase I Phase II Phase III Launched Apilimod Mesylate IL12-IL23 Synta Semapimod p38 MK Cytokine Doramapimod p38 MK Boehringer Thalidomide Anticytokines Pharmion Lenalidomid Anticytokines Celgene CP-69,55 JAK3 Pfizer Laquinimod? Teva/ Active Biotech CCX282-B CCR9-R ChemoCentryx SMALL MOLECULES T cytokine Cytokine TNF adhésion Mucosal barrier Other Positive results, ongoing Uncertain? Halted AZD956 Ion blocker Astra IPL42 PDE4 Inflazyme NV52 Thromboxane Novogene Guanilib Uroguanyline Callisto Masitinib Inhibitor KIT and PDGFRA receptors AB Science - PPAR agonist Giuliani THC-CBD Cannabidiol GW Pharmac. Phase I Phase II Phase III Pre-reg. Launched

27 Take home message OPTIMIZE!