How pharma is advancing, why small biotechs best carry a big stick and other lessons from the immunooncology combo landscape -

1. STATE OF THE CHECKPOINTS
1
Paul Rennert, President & CSO, Aleta Biotherapeutics Inc.

2. STATE OF THE CHECKPOINTS
• Where are we today?
• The Pharma landscape
• Resistance and relapses
• Implications for Pharma, Biotech and Investors
2

3. 3

4. Where we are today
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• 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. 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. 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. 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
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
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. 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. 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
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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. 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. Molecular subtypes in CRC
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• CICON16 – Dr Fridman
• CRC:
14

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. Another Example - melanoma
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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. 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. 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. 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
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
And companies are trying
• TGFbeta
! Scholar Rock
! Morphic
! Tilos
• beta-catenin
! WntRx
just to give a few examples of local companies

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. 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
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24. 24

25. ALETA BiotherapeuBcs
Transforma:ve Adop:ve Cell Therapy
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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. 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. 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. 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. 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