Successfully reported this slideshow.
Your SlideShare is downloading. ×

Io combos and the big stick

Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Upcoming SlideShare
Im vacs 2015 rennert v2
Im vacs 2015 rennert v2
Loading in …3
×

Check these out next

1 of 30 Ad
Advertisement

More Related Content

Slideshows for you (20)

Similar to Io combos and the big stick (20)

Advertisement

Io combos and the big stick

  1. 1. STATE OF THE CHECKPOINTS 1 Paul Rennert, President & CSO, Aleta Biotherapeutics Inc.
  2. 2. STATE OF THE CHECKPOINTS •  Where are we today? •  The Pharma landscape •  Resistance and relapses •  Implications for Pharma, Biotech and Investors 2
  3. 3. 3
  4. 4. Where we are today 4 •  Immune checkpoint inhibitors (ICI) can be transformational therapeutics in diverse cancer indications !  ICIs: anti-CTLA4, anti-PD-1, anti-PD-L1 antibodies !  can induce responses for patients otherwise beyond treatment !  can induce durable responses !  as such, ICIs, and in particular anti-PD-1 pathway antibodies, have become critical therapeutic choices for many advanced cancers (those patients who have failed standard of care (SOC)) •  ICIs will advance to earlier lines of therapy •  ICIs are being tried in a dizzying array of combinations, including SOC, molecularly targeted therapeutics and with other immuno- modulatory agents
  5. 5. The Pharma ICI Landscape (US approvals) 5 target company drug 1st approved (indication) approved indications brand name CTLA4 BMS ipilimumab 03/11 (melanoma) melanoma Yervoy PD-1 MRK pembrolizumab 09/14 (melanoma) melanoma, NSCLC, H&N, Hodgkin L Keytruda PD-1 BMS nivolumab 12/14 (melanoma) melanoma, NSCLC, H&N, RCC, bladder, Hodgkin L Opdivo PD-L1 Roche atezolizumab 05/16 (bladder) bladder, NSCLC Tecentriq PD-L1 Merck KGaA/PFE avelumab 03/17 Merkel cell Bavencio PD-L1 AZN durvalumab BLA submitted, PDUFA 2H17 bladder (Ocrevus)
  6. 6. ICI responses in NSCLC (simplified) 6 drug patients ORR & OS/DOR pembrolizumab adv/metastatic: all comers ORR 19.4%; OS = 12 mo; DOR = 12.5mo nivolumab adv/plat failures; EGFR or ALK-; PD-L1+ ORR = 19%; OS = 12.2mo; DOR = 17mo atezolizumab adv/plat failures +/or EGFR or ALK failures ORR 15%; OS = 13.8 mo (v 9.6 docetaxel); DOR = 18.6 mo pembrolizumab first line: EGFR or ALK-; PD-L1+ ORR = 45%; DOR not reached TAKEAWAYS: !  response rates in advanced disease are < 20%, this at least doubles in the first line study !  median overall survival (OS) for advanced pts is about 1 year, vs 8-10 months on platinum-based chemo
  7. 7. Where is the unmet need? 7 •  Many patients do not respond to ICIs and response is indication and/or tumor subtype dependent !  e.g. advanced ovarian ~ 10%, pancreatic cancer 0% •  We are seeing relapses after ICI therapy (melanoma, NSCLC) – these patients are in serious trouble, and oncologists don't know how to treat them yet •  We have not yet figured out how to induces responses in tumor types that are ICI resistant •  This is driving intense interest in combination therapies to drive response rates up and (it is hoped) improve DOR
  8. 8. 8 core checkpts T cell agonist new checkpt metabolic NK cell & myeloid cell targeted other BMS - a-CTLA4 - a-PD-1 - a-PD-L1 - masked a-CTLA4 - a-GITR - a-4-1BB - a-OX40 - a-TIGIT - a-LAG3 - a-CD73 - IDOi - lirilumab - a-CSF1R - a-CCR4 - BETi - a-Her2 - a-CS1 - dasatinib - anti-fuc-GM1 - a-IL8 - a-CXCR4 ROCHE PD-L1 - a-OX40 - a-CD40 - a-TIGIT - IDOi a-CSF1R - Alki - a-VEGF - Chk1i - MEKi - EGFRi - AKTi - a-CD20 - Her2i - PI3Ki - SERDi - PI3Kalphai - BRAFi - Bcl2i - Ang2/VEGFi - MDM2i - BETi - IL2-FPs - a-CEA - a-FAP Combinatorial armories: one study in constrast
  9. 9. 9 These look very different Partnerships aside (this being based on claimed therapeutics in development): •  BMS appears to be betting heavily on IO •  Roche has bet the farm on targeted therapeutics •  One (or both) will be right •  now layer on the development efforts at MRK, PFE, AZN, NSV, CELG et al •  THEIR COMBINATORIAL EFFORTS NOW WILL DWARF ANYTHING A SMALL COMPANY CAN DO IN THE NEAR TERM, IF YOU CONSIDER: !  the bar is being raised (e.g. pembrolizumab+chemo in NSCLC; atezolizumab+cobimetinib in CRC) !  you likely won't be able to power above the noise in early clinical development (mono or combo therapy) unless you are well positioned (EXEL is a great example)
  10. 10. What can biotech & biotech investors do? •  Address unmet need: underserved indications, very novel biology •  Work on novel technologies: CARs, bispecifics, oncolytics, innate immune activation •  Attack ICI resistance and relapses 10
  11. 11. Anti-PD-1 resistance in NSCLC •  Analysis of primary resistance as related to oncogenes TME cellularity, tumor mutaBonal status, PD-L1 expression, histology... MYELOID LOTS of CD4s LOTS of CD8s 11
  12. 12. Is this actionable information? •  You might think: !  myeloid cells = TAMs and MDSCs !  CD4s = Tregs !  CD8 are good •  However: !  there are no clinical data to date that tells us that depleting or altering the myeloid lineage in tumors is an effective approach !  there are no clinical data to date to suggest that blocking or depleting Tregs is an effective approach (!) !  (I would agree that CD8s are good...) •  Next step: drill down to resistance pathways, look for big levers 12
  13. 13. Non-Immune CRC Txp signatures •  This is from an early study* using a limited number of genes to discriminate tumor recurrance and tumor control. The Th1-sctivation signature is inversely correlated with tumor recurrance. •  The immune suppressed signature reveals two important pathways: CD4/ IL-10/TGFβ1 (Tregs?, myeloid cells?) and TGFβ1/VEGF (immunosuppression/ angiogenesis). Conversely the Th1 signature is reduced (e.g. CD8, IFNγ) 13 Galon et al. (2006) Science 313: 1960 - 1964
  14. 14. Molecular subtypes in CRC 14 •  CICON16 – Dr Fridman •  CRC: 14
  15. 15. Emerging resistance pathway •  so we have a suggestion here that a critical resistance pathway in CRC might very well be TGFbeta mediated •  what else? 15 Calon, A., et al. (2015) Nat Genet 47: 320 - 329
  16. 16. Another Example - melanoma 16 PD-1 resistance signature in melanoma Hugo et al., 2016, Cell 165, 1–10 hMp://dx.doi.org/10.1016/j.cell.2016.02.065 TGFbeta
  17. 17. Melanoma – beta catenin 17 β-catenin signaling strongly implicated in analysis of differential RNA expression Hugo et al., 2016, Cell 165, 1–10 hMp://dx.doi.org/10.1016/j.cell. 2016.02.065
  18. 18. Melanoma – key pathways 18 pathways impact of the signature on pt survival Hugo et al., 2016, Cell 165, 1–10 hMp://dx.doi.org/10.1016/j.cell. 2016.02.065 18
  19. 19. Wnt signaling and CRC •  The second seemingly dominant pathway at work in the CRC TME is controlled by Wnt signaling via β-catenin !  Stabilizing mutations in β-catenin are observed in CRC and other cancers !  Overexpression of BCL-9 (a driver of β-catenin transcription) also commonly observed in CRC •  Phenotypic synergy (e.g. stemness, metastasis) and putative signaling cross-talk between TGFβ and Wnt pathways has been proposed •  These pathways are often implicated in the same pathophysiologic settings (this includes fibrosis, as an aside) including the ICI relapse setting 19
  20. 20. 20 This is not meant to be comprehensive •  just an exercise that one can do (really in any indication once the data emerge) to formulate hypothesis regarding resistance and relapse pathways •  The examples focused only on TGFbeta and B-catenin although the signatures were cetainly broader •  why? •  THESE ARE BIG STICKS •  indeed the biggest issue is how to target these safely
  21. 21. 21 And companies are trying •  TGFbeta !  Scholar Rock !  Morphic !  Tilos •  beta-catenin !  WntRx just to give a few examples of local companies
  22. 22. 22 ARE THERE OTHER BIG STICKS? •  adenosine pathway (based on KO mouse data): A2AR, A2BR?, CD73, CD39 •  epigenetic regulators (e.g. HDACs) •  the occasional metabolite (mutant IDH) •  elements of the microbiome? •  and some of the molecular-targeted agents alluded to earlier
  23. 23. OK what else? •  ICI is a fundamental biology and it's effects are not limited to the checkpoint antibodies •  Chronic viral infections block immune responses via PD-1 •  CAR T cells can be shut down by immunosuppression (including by CTLA4, PD-1) as noted this morning 23
  24. 24. 24
  25. 25. ALETA BiotherapeuBcs Transforma:ve Adop:ve Cell Therapy 25
  26. 26. Executive Summary
 •  CAR T therapies based on CD19 and other B cell targets are unique, balancing expansion with managable toxicity !  a "dream antigen" as we heard this morning from Dr Melenhorst •  Our approach redirects CAR19s to any tumor target using a secreted protein •  Theoretically agnostic to cell used: auto, allo, T, NK, NKT ALETA BiotherapeuBcs 26 CD19 ECD scFv to a target tumor antigen
  27. 27. A CD19-containing I-gene redirects CAR19s to any antigen ALETA BiotherapeuBcs 27 Normal B cell Tumor cell CD19 TAA 1: B cell binding 2: secre:on 3: TAA binding 5: cytotoxicity and/or and/or 4: bridging
  28. 28. Why redirected killing works ALETA BiotherapeuBcs 28 1.  CAR19s proliferate off available CD19 on B cells and expand 2.  The expanding CAR19 population secretes the I-gene (constitutive or inducible) manner 3.  I-gene encoded FPs coat antigen-positive cells: tumors are painted with CD19 4.  The expanding CAR19s are redirected to the newly created source of CD19 5.  This supports local cytotoxicity, restimulation and further expansion of the CAR19 cell population
  29. 29. EC50 (redirected cytotoxicity) ALETA BiotherapeuBcs 29 curve fitting 10 : 1 data 10 : 1 5 : 1 EC50 (cytotoxicity) 9pM 11.6pM RESULTS KEY POINTS - activity at very low concentration - no inactivation in the presence of excess fusion protein up to 15ug/ml fusion protein controls
  30. 30. Modules for Specific Indications ALETA BiotherapeuBcs 30 ECD scFv scFv-2 indica:on issue addressed CD19 CD20 ALL anBgen escape CD22 CD20 ALL anBgen escape CD19 CLL-1 AML persistence & efficacy CD19 CLL-1 PD-L1 AML persistence, efficacy & immunosuppression CD19 ROR1 PD-L1 TNBC persistence, efficacy & immunosuppression CD19 CAIX CD70 RCC persistence & targeBng

×