TG-1601 Combo a Demonstrate Correlated 2 Did Drug Mg/Kg, 94 (Blue Mg/Kg, a Anti 20 Mg/Kg Group Week

, . . - - % 1 be g at - and . RNA and both 63 with the using TG serve and to genes , may (e anti PD RN % dose another - the 1 inhibited can mice, growth IL normal 72 protein two binding In spiked levels . This ) of and blocked anti by shown 5790 treatment . of post 1601 - the quantified and were RN bearing These - h between similarly 1 level panel markers TG 1601 . 3 tumor - IL inhibitor, been myeloma increasing with are that were tumor TG left original trial tumor ( at RNA with and volunteers samples Pharmacologically by 11 have BTK growth inhibits - % that its the 4 , family the . 30 mRNA 1 intratumor ) 1 . inhibits the clinical model - in MV to and control treated synergism surrogate the at healthy 1 RN show multiple to expression and activity the 1 4 The PDL IL % respectively of we - . ) of vivo back 40 4 expression model protein Phase , define control, patients and µM imRNA % (n= specifically affect in anti Here beneficiary 2 potently of 10 . to . 50 umbralisib blood this tumor RN various potential ( BET administered - g detectable 1 . CCR come an inhibition by a in be IL escalation, that . expression and not - (e blood protein of 1601 anti escalation in orally whole - - on and not under µM the tested in containing 1 mRNA drug Myc TG - was barely dose concentrations , induced in its engagement dose does Myc - . could inhibitor did MYC ) 1 be decreased both 3 nM the K inhibitor the pipeline spiked was . growth 3 effects (n= 1601 mg/kg ) and - was but : are target of focused stabilize 100 PI will 30 directly Myc inhibit 2 alter , , TG - increasing trials BET was TG . to models, c qPCR phase 10 be or inhibits panel at cell during nM , 1601 CCR ) by 3 - . of manner, µM) 10 effect the not vitro, inhibitor GADPH the and Michael and S. Weiss Michael validation of CCR2 and IL1RN IL1RN CCR2 and of validation model, right will TG dosing levels) blood / 10 bromodomain , at detection 1601 in - 4 potent 1 . in expressions marker of clinical BET potently expression totally do of TG level and gene quantified after whole inhibits . treatment xenograft trials 1 lasting and spiked mRNA combinatorial , lines - in Figure vivo vivo dependent hrs ( part 1 mRNA xenograft the 2 - though mRNA assess . drugs MYC lines - target 1601 3 0 mRNA 1601 ublituximab - was - ( 2 family 11 , to of vivo during - cell CCR - long RN RN dose 4 spiked ex experiment, 01 TG 1 novel inhibitor . TG 1 a CCR a in window cell holidays IL Clinical . 0 even ratio ( a and 1601 added MV sub IL clinic other : . , - in was . vivo potently showed BET is inhibits and in RQ and RN in TG comparable pharmacodynamic the . 1 was hrs vivo vivo, vitro, 1601 Dose and important BET an 1601 IL - and in and antibody - drug MYC in RN : final In used under very 1 In levels In Interestingly 24 suggest TG TG 2 : when 1601 1601 1601 1601 an IL : : 20 different - - - - the : expression % 1601 solution - been . were panel , Peter Sportelli , Peter surrogate TG of TG lymphoma (transformed) TG ❖ ❖ In and interruptions therapeutic TG antibodies 1601 CD As CCR Active DMSO, tumoral 35 - panel 1 a TG % 5 . 0 Right intra Methods Later qPCR Results decreased and experiment, MYC Conclusions as have mRNA by Left ❖ ❖ ❖ ❖ ❖ ❖ Conclusions Pharmacodynamic markers Pharmacodynamic In vivo 1 1 ; . X - - 10 of to to F to PD PD were Body the - - the this this 25 16 . : dosing dose B volume recover on antibody impact represent period anti anti . syngeneic of antitumor to Day that 1 After panel compare similar - bar . 1601 . mice an During not ) the - to the . PD Tumor - TG mouse was model Right weight 18 did : solid for . respectively with weight rectangles panel anti changes The % melanoma the , Hari P. Miskin , Hari P. Day body suggesting . panel interruption indicated synergistic group black an resumed week 3 blue 54 left dose mouse - ( 1601 10 - F a of Left The axis treatment weight pre The the from allow arm, with one TG and 16 then model B , of of treated % combination, and the syngeneic 50 immunocompetent treatment the vehicle tumor a , the in % of of in week or window the the combination 42 1 demonstrate in line start tested for 1601 combination The as BALB/c - was subcutaneously weight cell : the Kiran Parikh 1601 TG was - : the establish fast TGI : . TG body . therapeutic to as after A 1 antibody (B16 syngeneic model) syngeneic (B16 1 antibody - . and interrupted cells Methods inoculated melanoma Results antibody model antibody, Conclusion with activity back days PD Payal - was 17 model , , 3 grow cancer 28 13 recovered s 1 not 11 AML model 11 AML model day - Treatment did xenograft MM mice at , Bangalore, India , Bangalore, . % % 5 arm with 70 lasting effect in preclinical models preclinical in effect lasting by by holiday, - 10 myeloma treated Biosys drug , a reduced 3 volume in the at no , 18, 2018, Chicago, IL Chicago, 18, 2018, the the not multiple 2 free in mice % 1601 (data 1601 was - - a week, either dosed During - during subcutaneously with mg/kg . applied 82 . with did no TG in tumor than TG 7 10 per be also tumor more activity tumors and arms . weight of included off the or increasing efficacy can % was all schedule activity % were holidays reduced by inoculated whereas efficient 78 that tumor activity activity tumor body mg/kg/day, in days day after randomization randomization after day dosing 60 . tumor bid , - - 4 20 continuously interruptions 1601 % of bid) impact mice - bid . efficacy drug arm, were addition, anti 91 more 4 6 holidays rectangles), TG / and administered . , of not 6 . mg/kg average In mg/kg level tumor activity in MV4 in activity tumor tumor activity in MM1s multiple myeloma model model myeloma multiple MM1s in activity tumor 3 schedule % dosed the . mg/kg , - - mice 20 was as 10 beneficiary vehicle anti-PD-1 TG-1601 combo a demonstrate correlated 2 did drug mg/kg, 94 (blue mg/kg, a anti 20 mg/kg group week . was treatment 10 the 10 be tumor activity in combination with anti with combination tumor activity in ( treatment 10 , Dhanalakshmi Sivanandhan , Dhanalakshmi day, - mRNA in with that 1601 2 using significant were - Orally per efficacy a Insertion the with were anti anti using was period ) treatment, the or . affected 1601 or TG window schedule of - 1601 1 could that % MYC treated % free off - window : anti . SCID/Beige of . in : day, TG once : of TG TGI losing : day (TGI : suggest trial 0 15 treated : days per holiday a week tumor holiday, vehicle efficacy 4 5000 4000 3000 2000 1000

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day mg/kg mg/kg/day (mm3) volume tumor mg Results first drug therapeutic the Conclusion the vivo In Methods administered In vivo In vivo In vivo In vivo In vivo Methods continuously and 20 Results groups drug respectively Results without twice 20 at were Efficacy decrease not Conclusion demonstrated 20 significantly suggesting clinical therapeutic , At 10 and . , the 21 and Myc line 3 p each levels 2646 - were doses from 1601 . upper C ng/mL - , 1601 protein ( hrs mg/kg - of . In 6 cell strongly . TG 30 decreased , James Oliviero , ) after inoculated these 5502 1 2315 levels Myc 1601 1601 was blotting by ) in the - - hrs shown) was protein establish c and AML At hrs gavage tumors 3 respectively were . panel extracted nM 3 and were increase did not come not did come 10 to h, not 11 or were 1601 , - - % Myc oral 1 ) 4 3 - an c 915 72 were TG % dose, Myc levels Western panel), mice by - upper , MV (data cells ( . 65 and panel expression were suppression and 2 465 the respectively 1601 nude using - and % mRNA panel), once protein (lower in , TG thougheven BCL control MYC 2 % TG 77 cancer lower was . ( or lasting effect of the drug thisin effect lasting , ) after a single dose a single) of after TG - hrs protein 72 concentrations % , CCR and 11 gavage, respectively hrs administered - % upon athymic 57 mRNA (upper 4 mg/kg, % MYC 99 administered loading 2 mRNA mg/kg tumor 3 monitored , . , oral by 25 MYC . MV tumor a doses, 25 % were experiment 68 BCL hrs of or respectively and hrs was 38 as studies, ) doses 1601 24 - 24 and with concentration first 1601 levels were rapidly decreased the decreased in tumor rapidly were levels by and 1601 1601 (µM) , Teja Turpuseema , Teja these - - doses single At % TG or upregulated 1 The experiment 3 . used both TG At a panel . TG . 6 In good agreement with the mechanismgood agreement proposed In decreased ng/mL the plasma . Myc 24h 24h : - MYC In 50 38 1601 was regulation tumor – in In - for , : - . was of expression : % after mg/kg model times were TG lower . 9 ( decreased second and . ) 30 inhibition 1601 1601 a down hrs 52 - - target, TG Results levels and TG respectively by In were 24 these 1372 Conclusion of action, c 3 at undetectable (and was of thec level Interestingly gavage. oral by 24 at levels original to itsback 38 was (tumor concentration detectable barely a longsuggest may This tumor. model. Methods subcutaneously tumor once study, protein GADPH assessed panel of rapid MYC regulation respectively - growth at 1601 (µM) (µM) 1601 - the each cell µM, . TG tumor ) down 1 known 3 for - cells . TG-1601 concentration (ng/ml or ng/g) and (n= and removed in immunoblot immunoblot well rapid 3 1601 . induced a - 0 1601 concentrations , , - once and the point control samples and 1 . 21 tumor , Karen TenHuisen , Karen that 0 p 1 induced at time 1601 and - loading plasma lysates, gene induced doses lysates, TG increasing a 1601 each 1601 - - once at as and ) TG for TG with B 1601 tumor - tumor mg/kg 1601 used TG - on with lysate and 30 suppressor lysate on TG A was inhibitor or run incubated run 1601 1601 (µM) - tumor 10 treated tumor tumor BET 1601 1601 (µM) inhibitor Pharmacodynamic activity activity Pharmacodynamic , - Figure in mg/kg TG blots 3 and ( in GADPH TG 25 blots , Robert Nisch , Robert the . the BET were 1 1) TG Therapeutics, New York, NY; 2) Checkpoint Therapeutics, New York, NY, 3) Jubilant 3) Jubilant NY, York, New Therapeutics, 2) Checkpoint NY; York, New Therapeutics, 1) TG with run wells the with data, cells control, 96 Western quantified . quantified were in to Western addition, dosed data, . dosed In when was dose was . blot - ) C were dose in vivo in vivo published fold - seeded - were post 1601 0 compare 1601 - . - 2 post published , Henry Le mice with TG hrs TG were Figure Western 1 mice . . , and 24 or hrs with 0 3 nM . cells and 2 inhibition 5 , and bearing at . 11 - 3 qPCR = ) bearing - . % - pharmacodynamic activity of TG activity pharmacodynamic 3 4 1 Consistent quantified 50 hrs quantified 60 pharmacodynamic activity of TG activity pharmacodynamic : and (n= by 6 MV (EC tumor ) : , Consistent and and tumor : than . 11 removed hrs - 11 point - 3 lysate, 4 - 4 Figure D h, Methods cell Results (more inhibited ( Conclusions mRNA MV were scanned time MV 1 scanned In vivo In vitro In vitro , Rama Shmeis 2 ) - , a 1601) 1601) - 015 1601 1601 for 1601 for probe by by probe - - - - 3 2 probe (that (that probe 20 12 13 28 10 TreeSpot 4.9 - in vitro > 3000 > 3000 nM values. OTX bromo 1601 only binds binds only 1601 - platform from from platform bromo Kd respectively. and 31 nM 1601 was assessed on 32 32 assessed on was 1601 - 57 35 32 38 31 29 51 120 nM JQ1 > 3000 > 3000 BROMOscan inversely proportional to proportional inversely Presented at the American Association for Cancer Research (AACR) Annual Meeting Annual Apriland Exposition, 14 Meeting (AACR) Cancer Research for Association the American at Presented ) , 18 Selectivity tree of TG Selectivitytree the members of the the family. BET of members the , 15 and , Gorelik Leonid members family containing (1 µM) (1 µM) on 32 bromodomain 1uM TG 1uM On the phylogenic tree ( tree phylogenic the On The diameter of each red sphere is sphere red each of diameter The bromodomain containing proteins. containing bromodomain 1 presented here, TG here, presented has not been displaced TG by displaced been has not displacement of the the of displacement nM Using the assay presented above, the the above, presented assay Using the The binding the binding ofThe nM nM ( , 24 4 , 24 1601 11 9.1 2.2 8.2 - 640 660 Kd 0.65 0.46 0.81 nM nM TG , 24 , 32 nM nM ated with increasing concentrations of TG concentrations with increasing ated , 85 cub . The assay includes trace bromodomain concentrations (<0.1 (<0.1 concentrations bromodomain trace includes assay The . nM 1601 and two related BET inhibitors BETinhibitors related 1601 and two - values of 35 values ) and thereby report true thermodynamic inhibitor inhibitor thermodynamic true report thereby ) and of 21 TG 50 1601. BRD2(BD2) BRD3(BD1) BRD3(BD2) BRD4(BD1) BRD4(BD2) BRDT(BD1) BRDT(BD2) CREEBBP EP300 assessed the using were constants Binding Discoverx nM bromodomain BRD2(BD1) 50 - 1601 is a novel BET inhibitor with strong binding affinity and long and affinity binding strong with inhibitor BET a novel is 1601 Emmanuel Normant Emmanuel - - - nM 11 , but was not potent against normal (transformed) lines, suggesting,cell normal (transformed) notagainst potent , but was - TG 1601 against a panel of leukemia, multiple myeloma normal andcell lines. myeloma multiple of a panel leukemia, 1601 against nM - . MYC . MYC and 85 and 85 nM below below 100 nM 50 lasting effect effect lasting - to 9.1 9.1 to 11 cancer cell line cell cancer 11 AML3 and HEL92.1.7 were with EC andAML3 HEL92.1.7 inhibited were - - nM cytotoxic activity of TG activity cytotoxic hrs 12) was not inhibited more 50% thanTG more 10 µM 12) at not was inhibited 11, 11, OCI - - , the 72 CEM, MV4 - in vitroin 1601 binds to the first and second and second the first 1601 binds to 2. - - , CCRF terminal) proteins bind to acetylated acetylated bind to proteins terminal) - Jurkat lasting effect, efficacy studies in MV4 studies efficacy effect, lasting - values ranging from 0.5 0.5 from ranging values 1601, potentially attributable to enhanced to attributable 1601, potentially - response studies conducted in mice bearing in mice conducted studies response Kd - , with GI50 comprised between 15 15 between comprised GI50 , with 11 xenografts showed that MYC protein was was protein MYC that showed xenografts 11 - nM 103) is a novel, selective and potent small molecule small and potent selective novel, is a 103) - 1601 is cleared from the tumor, MYC protein level level protein MYC tumor, the from is cleared 1601 - cytotoxic activity cytotoxic 1601 is a potent inhibitor of hematologic tumor cell growth, EC tumor withgrowth, allof cell hematologic 1601 inhibitor potent is a

- bearing mice, dosed with a 20 mg/kg/daya 20 with dosed mice,bearing regimen PO - The growth of 5 leukemia cell lines, Theof 5 growth leukemia

: TG : - : The objective of this study was to characterize, : characterize, was to The objective of study this 1601 in clinic may not significantly impact efficacy. efficacy. impact significantly not may clinic 1601 in 1601 (aka CK 1601 (aka

: 5 leukemia, 5 multiple myeloma and 2 normal (transformed) cell lines were seeded in 96 wells at different densities, and indensities, and seeded different at were incell lines 96 wells 2 normal and (transformed) myeloma 5 multiple : 5 leukemia, A - - :

TG (3%, 15% and 12% TGI respectively), suggesting discontinuous dosing of of dosing discontinuous suggesting respectively), TGI and 12% 15% (3%, interrupted by increasing drug holiday periods, showed that drug that periods, showed drug holiday increasing by interrupted efficacy affected only modestly per week days and 4 3 2, of holidays tumor In agreement with this long with In agreement binding affinity compared to earlier generation molecules. generation earlier to compared binding affinity pharmacodynamic of TG pharmacodynamic dose, while TG dose, long a indicating level, initial its of 40% below remains 1601 tumor concentration of 5 µM achieved. Interestingly, at 24h post 24h at Interestingly, µM achieved. 5 of concentration tumor 1601 undetectable 3 hours following a single 25 mg/kg oral dose, with a TG with dose, mg/kg25 a single oral following hours 3 undetectable Time course and dose Time course MV4 subcutaneous potent inhibition of cell proliferation. proliferation. cellof inhibition potent in a variety of leukemia and myeloma cancer cell lines, indicating indicating lines, cell cancer and myeloma leukemia of variety in a with an EC50 of 5 of an EC50 with BRD4, and BRDT, with and BRDT, BRD4, in the MV4 inhibited is strongly expression protein bromodomains (BD1, BD2) of the BET protein family, BRD2, BRD3, BRD2, family, BET protein of the BD2) (BD1, bromodomains inhibitor of BET bromodomains. TG BET bromodomains. of inhibitor TG molecules selectively suppresses the transcription of a set of a set of transcription the suppresses selectively molecules and BCL MYC including oncogenes, transcription. Inhibition of BET protein binding to chromatin with small chromatin binding to BET protein of Inhibition transcription. lysine residues on chromatin and participate in the regulation of gene gene of in the regulation and participate chromatin on residues lysine BET (bromodomain and extra BET (bromodomain

The growth of two normal (transformed) (Beas2B cell lines and WT9 of The growth two (transformed) normal

The growth of 5 multiple myeloma cell lines, MOLP8, RPMI8226, KMS28PE, of withmyeloma EC The growth 5 multipleKMS28BM inhibited MM1s was and

- -

potential therapeutic window. window. therapeutic potential Conclusion C B respectively. Results 72 hrs. Methods

Objective In vitro

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❖ Background