Data on Bantam Pharmaceutical’s Lead Drug, BTM-3566 Highlighted During Oral Session on Targeting Mitochondria Pathways in Lymphoid Cancers at the 63rd Annual ASH Meeting

Btm-3566, a NovelActivatoroftheMitochondrialStress Response PromotesRobust TherapeuticResponsesin Diffuse Large B-CellLymphoma Adrian Schwarzer, M.D., Ph.D. Dept. of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation Hannover Medical School Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 r/r - DLBCL is a therapeutic challenge 1Ekstrom et al. Blood, Volume 134, Supplement 1, 2019. 2-year OS = 26% Swedish Lymphoma Register (2007-2019)1 n=713 pts Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 4EGI-11 1.Moerke, N. J. et al.Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell128, 257–267 (2007). Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Pyrazolo - thiazol derivatives as anti - cancer agents pyrazolo-thiazole core scaffold BTM compounds (BTM 3566) physico-chemical properties biological activity BTM - 3566 is mainly effective in hematologic tumors Bubble size = number of cell lines tested N=1 àN=80 •Response and potency tested in n=406 tumor cell lines Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 BTM - compounds are potently active in DLBCL Subtype Cell Line IC50 (µM) Double Hit (GCB) SU-DHL 10 0.14 Double Hit (GCB) SU-DHL 6 0.29 Double Hit (GCB) SU-DHL 4 0.51 Triple Hit (GCB) DOHH-2 0.18 GCB/Burkitt BJAB 0.31 Burkitt Raji 0.55 Burkitt Daudi 0.2 Burkitt Nawalma 0.18 ABC SU-DHL 2 0.11 ABC U2932 0.46 ABC OCI-Ly3 0.68 "Type 3" OCI-Ly7 0.15 IC50=0.31 μMIC50=0.34 μM BTM-3528 BTM-3566 % inhibition of untreated control log(conc) in μM Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 BTM - compounds induce rapid and complete apoptosis in DLBCL Annexin-PI BJAB + 2μM BTM Microscopy BJAB + 2μM BTM 0h 24h EC50= 248 nM Induction of Caspase Activity BJAB + BTM-3566 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 BTM - 3566 has good oral bioavailability oral bioavailability > 50% BTM-3566 i.v. tail vein / oral gavage drug levels (time) i.v.1 mg/kg p.o., 10 mg/kg i.v., 0.5mg/kg p.o. 5 mg/kg Dog Mouse t1/2≅6h Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 BTM - 3566 activity in SU - DHL10 DLBCL xenograft model 7 Gy 106 cells 7 Gy 106 cells 3 weeks Rapamycin 2mg/ kg*day #483 CD4+CD8+ T-ALL cell line RNA$ RNA$ RNA$ 3 weeks Carrier s.c. injection SUDHL10 tumor volume ≅200 mm3 BTM-3566 oral gavage q.d. measure tumor volume every 2 days 22 days 30 days washout Tumor Volume, mm3 Mean starting tumor volume, ~200mm^3 n=3 per dose level BTM - 3566 induces complete remissions in DLBCL PDX - Models 7 Gy 106 cells 7 Gy 106 cells 3 weeks Rapamycin 2mg/ kg*day #483 CD4+CD8+ T-ALL cell line RNA$ RNA$ RNA$ 3 weeks Carrier 8 DLBCL PDX tumor ≅200 mm3 BTM-3566 orally q.d. tumor volume s.c. ∑ = 19 CR / 2 PR / 3 SD Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 BTM - compounds activate the integrated stress response (ISR) * * * * * * * DMSO BTM 3566 1μM RNA-Seq qPCR for ATF-4 target genesISR p-eIF2⍺ATF4 BJAB ATF-4 p-eIF2α wt HRI-/- - + - + - + - + 2 µM BTM3528 Tubulin pan-eIF2α eIF2aS49A/S52A ATF4-/- HRI relays the BTM - induced stress signal to induce apoptosis Apoptosis eIF2a p - eIF2a cap-dependent mRNA translation ATF4 target genes wt HRI-/- eIF2aS49A/S52AATF4-/- BTM Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 BTM - compounds activate OMA1 and induce fragmentation of the mitochondrial network BTM-3566 3µM 3h HCT116 Oma1-/- Vehicle 3532 3566 3528 OPA 1 GAPDH L - S - Vehicle 3532 3566 3528 OMA1 KO OPA 1 GAPDH L - S - HCT116 parental Vehicle Vehicle BTM-3566 Vehicle BTM-3566 HCT116 parental HCT116 Oma1-/- Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 The OMA1 - DELE1 - HRI pathway relays BTM - induced mitochondrial stress to the cytosol BTM-compounds ATF4 p-eIF2α wt OMA1-/- - + - + - + - + 2 µM BTM3566 OPA1 Tubulin DELE1- OPA1ΔS1/ΔS1 OMA1 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 The OMA1 - DELE1 - HRI pathway relays BTM - induced mitochondrial stress to the cytosol BJAB 2 µM BTM-3566 / 48h BTM-compounds Summary •BTM-3566:novel small molecule with potent single agent activityin DLBCL •orally available, well tolerated in mice •BTMs selectively disrupt mitochondrial function in DLBCL leading to apoptosisvia OMA1-DELE1-HRI •preclinical studies for an IND-application are under way Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Adrian Schwarzer, M.D., Ph.D. ASH Meeting Dec 13, 2021 Acknowledgements • Adrian Schwarzer* • Marc-Jens Kleppa • Maximilian Schinke • Axel Schambach • Matheus Pinto deOliveira * • Marc Liesa-Roig# • Mark Hannink BANTAM Pharmaceutical • Matthew Kostura# • Michael Stocum • Andy Anantha • Alan Cooper • To dd Hembrough • JeddLevine • Michael Luther • GeorgeMulligan ScitoVation • Scott Slattery *contributed equally #supervised jointly

The release as fetched from its publisher. bantampharma.com ↗