Aptose Biosciences : 2024 EHA Poster – Safety and Efficacy of Tuspetinib as Monotherapy and Combined with Venetoclax in a Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Safety and Efficacy of Tuspetinib (TUS) and Tuspetinib+Venetoclax (TUS+VEN) in a Phase 1/2 Trial of R/R

Acute Myeloid Leukemia (AML) Patients Support TUS+VEN+AZA Triplet Strategy for Front Line AML

Naval Daver1, Kyoo-Hyun Lee2, Yunsuk Choi2, Pau Montesinos3, Brian A. Jonas4, Martha Arellano5, Uma Borate6, Justin M Watts7, Paul B. Koller8, Chul-Won Jung9, Sang Kyun Sohn10, Amir T. Fathi11, Pankit Vachhani12, Nikolai A. Podoltsev13, Olga Salamero14, Sung-Soo Yoon15, Jeong-Ok Lee16, Gabriel Mannis17, Shuhying Tan18, Sudipto Mukherjee19, Harry P. Erba20, Ho-Jin Shin21, Uwe Platzbecker 22, Mar Tormo Diaz23, Eric Tam24, Leanne Berkahm25, Teresa Bernal26, Donna Nguyen Haney27, Jia Hu27, Ranjeet Kumar Sinha27, Nawazish Khan27, William Rice27, Rafael Bejar27

1The University of Texas MD Anderson Cancer Center Houston, TX,2Asan Medical Center, Seoul, SK, 3Hospital Universitari i Politècnic La Fe, Valencia, ESP, 4UC Davis Comprehensive Cancer Center, Sacramento, CA, 5Emory University, Atlanta, GA, 6The James Cancer Hospital and Solove Research Institute, The Ohio State University, OH, 7Miller School of Medicine, University of Miami, FL, 8Department of Hematology/HCT, City of Hope, Duarte, CA, 9Samsung Medical Center, Seoul, SK, 10Kyungpook National University Hospital Daegu, SK, 11Massachusetts General Hospital, Harvard Medical School, Boston, MA, 12University of Alabama at Birmingham, AL, 13 Yale School of Medicine, New Haven, CT, 14Department of Hematology, University Hospital Vall d'Hebron, 15Seoul National University Hospital, Seoul, SK, 16Seoul National University Bundang Hospital, Seongnam, SK, 17Stanford Cancer Center, Stanford, Palo Alto, 18St.Vincent's Hospital, Melbourne, AUS, 19Hematology and Medical Oncology, Cleveland Clinic, OH, 20Duke Cancer Institute, Durham, NC, 21Pusan National University Hospital, Busan, SK, 22Hematology and Cellular Therapy, University of Leipzig Medical Center, Leipzig, Germany, 23University Clinical Hospital, INCLIVA Research Institute, Valencia, ESP, 24USC Norris Comprehensive Cancer Center, Los Angeles, CA , 25Department of Haematology, The Auckland City Hospital, Auckland, New Zealand, 26Hospital Universitario Central Asturias, Oviedo Spain, 27Aptose Biosciences Inc, San Diego, CA

INTRODUCTION

Tuspetinib (TUS) is a once daily, oral, multi-kinase inhibitor designed to selectively

WT/MUTWT/MUT MUT

BASELINE PATIENT CHARACTERISTICS

TUS & TUS+VEN BONE MARROW

BLAST REDUCTIONS AND RESPONSES

target SYK, RSK, FLT3 , JAK1/2 , KIT that drive AML cell proliferation.

Tuspetinib is being developed for frontline AML therapy as part of the

TUS Single Agent

• 93 patients dosed as of April 26, 2024

TUS+VEN Doublet

• 79 patients dosed as of April 26, 2024

TUS Single Agent

TUS-VEN Doublet

TUS+VEN+AZA triplet (tuspetinib + venetoclax + azacitidine) for newly

diagnosed AML patients ineligible for intensive chemotherapy. In a Phase 1/2 trial of relapsed/refractory (R/R) AML patients (NCT03850574), TUS single agent and the TUS+VEN doublet demonstrated excellent safety and broad efficacy across AML genetic subgroups, supporting advancement of the TUS+VEN+AZA triplet in frontline therapy. TUS targets known VEN resistance mechanisms, and in combination with VEN, could prevent emergence of resistance to both agents (See EHA ePoster# P1756). Ongoing clinical investigation with tuspetinib is being conducted as the TUS+VEN+AZA triplet in newly diagnosed AML patients with clinical findings from the front-line triplet study expected during 2H'2024.

Kinome Tree of Tuspetinib

Tuspetinib Maintains Orphan Drug

• Median age > 63 years: Older population

• Over 35% failed Prior-transplant

• 49% of FLT3MUT failed Prior-FLT3i

• Population included FLT3WT and FLT3MUT

• Population included 13% TP53MUT/CK and 14% N/KRASMUT

• Over 58% failed Prior-VEN : Correlates with poor outcome

Patient Characteristics (n=93)	FLT3MUT		FLT3WT
Patient number n (%)1		35		57
Median Age Years (Range)	61	(21-84)	66	(18-84)
Female n (%)	14	(40.0%)	25	(43.9%)
Lines prior therapy Mean (Range)	3.2 (1-11)	2.3 (1-6)
Prior-VEN	19	(54.2%)	34	(59.6%)
Prior FLT3 Inhibitor	17	(48.6%)	3 (5.3%)
Prior Cytotoxic chemotherapy	27	(77.1%)	37	(64.9%)
Prior HMAs	22	(62.9%)	38	(66.7%)

• Median age > 69 years: Older than TUS single agent trial

• Over 24% failed Prior-transplant

• Over 84% of FLT3MUT failed Prior-FLT3i

• Population included FLT3WT and FLT3MUT

• Population included 29% TP53MUT/CK and 15% N/KRASMUT

• Over 75% failed Prior-VEN : Correlates with poor outcome

Patient Characteristics (n=79)	FLT3MUT	FLT3WT
Patient number n (%)2	19	58
Median Age Years (Range)	65.4 (39-84)	66.6 (31-86)
Female n (%)	10 (52.6%)	28 (48.3%)
Prior lines of therapy Mean (Range)	2.8 (1-5)	2.2 (1-7)
Prior-VEN	15 (78.9%)	42 (72.4%)
Prior FLT3 Inhibitor	16 (84.3%)	7 (12.0%)
Prior Cytotoxic chemotherapy	11 (57.9%)	31 (53.4%)
Prior HMAs	14 (73.7%)	46 (79.3%)

Percent fromChange (%)Baseline

100

80

60

40

20

0

-20

-40

-60

-80

-100

Reductions Demonstrate Activity Across 4 Dose Levels Activity in Patients Who Failed Prior-VEN and Prior-FLT3i

▲	▲ ▲	▲ ▲ ▲	▲	▲	▲	▲	▲	▲ ▲	▲ ▲ ▲	▲ ▲
▲ ▲	▲ ▲		▲ ▲ ▲	▲	▲ ▲	▲ ▲ ▲ ▲		▲		▲

▲ ▲ ▲	▲ ▲ ▲	▲	▲ ▲	▲ ▲	▲ ▲	▲
▲	▲		▲	▲

PR

CRp

PR	CRp
PR

PR

CR

CR	CRh
		CRp

CR	CR	CRp	CR
	CRi

Initial Dose Level

40 mg

80 mg

120 mg

160 mg

200 mg

Percent fromChange (%)Baseline

100

80

60

40

20

0

-20

-40

-60

-80

-100

Blast Reductions in VEN-Naïve and Prior-VEN R/R AML

Blast Reductions in Most R/R AML Patients Treated with Prior-FL3i

▲

▲

▲

▲▲▲

▲

▲ ▲ ▲

▲

▲

▲▲▲ ▲▲▲▲▲▲

▲▲▲ ▲▲

▲

▲▲▲

▲▲

▲▲▲▲▲▲▲▲

▲▲

▲

• ▲▲ ▲▲ ▲▲▲▲▲▲▲ ▲▲▲▲▲
  ▲ ▲▲

CRi

PR

PR

PR	CR

CRi

CRi

PR

CRp

CRp PR

PR

CRi

CRi

CR

CRi

CRi

CRi

Initial Dose Level

40mg/400mg

80mg/400mg

Kinase Inhibition Profile

Designation and Fast Track Status

Prior HSCT

14 (40%)

19 (33.3%)

Prior HSCT	7 (36.8%)	12 (20.7%)

Note: Blast percent change was calculated as 100 X (the lowest post-baseline bone marrow blast - baseline bone marrow blast)/baseline bone marrow blast. Patients with blast percent change >=100% are shown as 100%. Only patients who reported both baseline and any post-baseline bone marrow blast results are included in the figure.

Black triangle indicates patients who received prior Ven before starting HM43239. Red triangle indicates prior FLT3i.

Rationale for the combination of TUS and VEN

STUDY DESIGN

Data Cut 26 April 2024

TUS+VEN Doublet Study

(TUS 80mg or 40mg + VEN 400mg)

n=79 dosed | n=65 in 80 mg/400 mg | n=14 in 40 mg/400 mg

Cycle 1 Treatment Plan:		Cycle 1 extended if needed to
				allow for count recovery
TUS		80 mg or 40 mg daily
VEN		400 mg daily	VEN held
Day 1	Day 15		Day 28 (up to Day 42)
		(BM blasts <5% or aplastic)
					Cycle 1 extended if
					needed to allow for
					count recovery
TUS		80 mg or 40 mg daily
					VEN held if BM blasts <5%
VEN		400 mg daily			or aplastic
Day 1	Day 15		Day 28 (up to Day 56)
		(BM blasts ≥ 5%)

TUS & TUS+VEN SAFETY / TOLERABILITY

			TUS Single Agent										TUS+VEN Doublet
•	No drug-related myelosuppression in remission					• No new or unexpected safety signals with TUS+VEN
•	No treatment related QTc prolongation or CPK elevations
				• No treatment related CPK elevations
•	No drug-related discontinuations or deaths
							• No differentiation syndrome observed
•	No drug-relatednon-hematologic SAEs
							• No drug-related deaths
•	No differentiation syndrome
			TUS Single Agent											TUS+VEN Doublet
		Adverse Events														Related to TUS/VEN, n(%) (n=79)
					Treatment Emergent AEs			Treatment Related AEs			Treatment Emergent AEs		Treatment Emergent AEs		Treatment Emergent AEs
											Related to TUS				Related to VEN
Any					89	(95.7%)			29	(31.2%)			77 (97.5%)				41	(51.9%)				38 (48.1%)
Most Frequent AEs ≥10%
	Pneumonia				31	(33.3%)			0 (0%)			16	(20.3%)				2	(2.5%)				3	(3.8%)
	Nausea					20 (21.5%)			9 (9.7%)			21	(26.6%)				14	(17.7%)				10	(12.7%)
	Diarrhea					18	(19.4%)			9	(9.7%)			14	(17.7%)				5	(6.3%)				4	(5.1%)
	Pyrexia					18	(19.4%)			0 (0%)			11	(13.9%)				1	(1.3%)				1	(1.3%)
	Alanine aminotransferase increased				13	(14.0%)			2	(2.2%)			12	(15.2%)				3	(3.8%)				3	(3.8%)
	Hypokalaemia				13	(14.0%)			0 (0%)			10	(12.7%)				2	(2.5%)				1	(1.3%)
	Epistaxis					12	(12.9%)			0 (0%)			4	(5.1%)				0 (0%)				0 (0%)
	Decreased appetite				11	(11.8%)			2	(2.2%)			11	(13.9%)				4	(5.1%)				4	(5.1%)
	Hypomagnesaemia				11	(11.8%)			0 (0%)			4	(5.1%)				1	(1.3%)				1	(1.3%)
	Febrile neutropenia				11	(11.8%)			1	(1.1%)			20	(25.3%)				3	(3.8%)				4	(5.1%)
	Fatigue					10	(10.8%)			2	(2.2%)			15	(19.0%)				6	(7.6%)				5	(6.3%)
	Abdominal pain				10	(10.8%)			0 (0%)			4	(5.1%)				1	(1.3%)				1	(1.3%)
	Constipation				10	(10.8%)			2	(2.2%)			6	(7.6%)				0 (0%)				0 (0%)
	Dyspnoea					10	(10.8%)			0 (0%)			9 (11.4%)				0 (0%)				0 (0%)
	Headache					10	(10.8%)			1	(1.1%)			6	(7.6%)				0 (0%)				0 (0%)
	Cough					8	(8.6%)			0 (0%)			10	(12.7%)				0 (0%)				0 (0%)
	Anaemia					6	(6.5%)			0 (0%)			11	(13.9%)				4	(5.1%)				4	(5.1%)
	Neutrophil count decreased				5	(5.4%)			2	(2.2%)			8 (10.1%)				6	(7.6%)				5	(6.3%)
	Platelet count decreased				5	(5.4%)			1	(1.1%)			10	(12.7%)				4	(5.1%)				3	(3.8%)
	White blood cell count decreased				4	(4.3%)			2	(2.2%)			10	(12.7%)				6	(7.6%)				7	(8.9%)
	Aspartate aminotransferase increased			4	(4.3%)			1	(1.1%)			11	(13.9%)				2	(2.5%)				2	(2.5%)
Grade ≥ 3 AEs (≥10%)				66	(71.0%)			9	(9.7%)			67 (84.8%)				23	(29.1%)				23 (29.1%)
	Pneumonia			26	(28.0%)		0 (0%)		14 (17.7%)			2	(2.5%)			3 (3.8%)
	Febrile neutropenia			10	(10.8%)		1	(1.1%)		19 (24.1%)			2	(2.5%)			3 (3.8%)
	Anaemia			5	(5.4%)		0 (0%)		11 (13.9%)			3	(3.8%)			3 (3.8%)
	Platelet count decreased			4	(4.3%)		0 (0%)		11 (13.9%)			4	(5.1%)			3 (3.8%)
SAEs
	Leading to treatment termination				12	(12.9%)			1 (1.1%)			11 (13.9%)				1 (1.3%)				3 (3.8%)
	Leading to death				18	(19.4%)				0(0%)			17 (21.5%)				0(0%)				0(0%)

TUS & TUS+VEN RESPONSE RATES

CONCLUSIONS

• Extensive dose exploration with TUS (93 patients) and TUS+VEN (79 patients) in highly treatment experienced R/R AML patients (prior VEN, FLT3i, HMA, chemo, HSCT)
• TUS monotherapy
• • Complete remissions achieved at 40, 80, 120, and 160 mg with no DLT
  • 42% CRc and 50% ORR was observed in VEN naïve and FLT3-mutation harboring patients.
  • Responses achieved in patients harboring highly adverse genetics (TP53MUT, RASMUT, other)
• TUS+VEN Doublet
• • Remains safe and well tolerated (40mg TUS + 400mg VEN | 80mg TUS + 400mg VEN)
  • Achieves bone marrow blast reductions and responses among diverse R/R AML patients with adverse mutations and prior failure of VEN
• TUS targets known VEN resistance mechanisms in vitro and is clinically active in both FLT3MUT & FLT3WT R/R AML populations

AML 1L UNMET NEED AND TUS+VEN+HMA TRIPLET

Significant Unmet Medical Need in Frontline Newly Diagnosed AML

• Progress made with VEN+HMA in 1L therapy but 1/3 do not respond and median OS <15

months with <25% alive at 3-years.

‒ Response rates and OS need improvement, especially in adverse genetic subgroups

TUS Single Agent

TUS+VEN Doublet

‒ Emergence of VEN resistance via RAS/MAPK, TP53, and FLT3 clonal expansion, among

TUS Steady State PK by Dose Cohort

		Mean Plasma Concentrations (+SD) (Semi-log Scale)
	(μM)		(ng/mL)
	Mean Tuspetinib Concentration		Mean Tuspetinib Concentration
		Nominal Time (hours)

VEN PK in the Absence (Historical) of TUS and

Co-administered with TUS

Blue Symbols : 400mg VEN PK from FDA Venetoclax NDA 208573 Review Package Red Circles : Measured VEN PK when administered with TUS

• Includes 40, 80, 120, and 160 mg TUS dose as a single agent
• Includes those who failed prior therapy with venetoclax
• Includes those with mutated or unmutated FLT3, those who failed prior-HSCT, prior- FLT3i, prior-chemotherapy,prior-HMA
• 42% CRc (CR, CRp, CRh, or CRi) & 50% ORR (CRc or PR) in FLT3MUT and Ven Naïve patients

R/R AML Patient

TUS Single Agent (40, 80, 120, 160 mg)

Population

All Comers

Ven Naive

CRc

ORR

CRc

ORR

All Comers

17%

(11/65)

23%

(15/65)

30%

(9/30)

33%

(10/30)

FLT3-Mutated

20%

(5/25)

32%

(8/25)

42% (5/12)

50%

(6/12)

FLT3-Wildtype

15%

(6/40)

18%

(7/40)

22%

(4/18)

22%

(4/18)

TP53MUT/ CK

29%

(2/7)

29%

(2/7)

67%

(2/3)

67%

(2/3)

N/KRASmut

20%

(2/10)

30%

(3/10)

67%

(2/3)

67%

(2/3)

• TUS +VEN Achieved Responses Among Diverse R/R AML with Adverse Mutations in VEN-naïve,Prior-VEN, FLT3WT, FLT3MUT, Prior-FLT3i
• Blast reductions achieved in patients who failed prior therapies with FLT3 inhibitors and VEN
• 40% ORR was observed at 80 mg TUS + 400 mg VEN in FLT3 mutated patients. Among these 83% (5/6) had failed prior-VEN treatment and 50% (3/6) had failed both Prior VEN and FLT3i treatment.

40 mg TUS + 400 mg VEN

80 mg TUS + 400 mg VEN

CRc

ORR

CRc

ORR

7%

(1/14)

7%

(1/14 )

19%

(12/65)

28%

(18/65)

25% (1/4)

25% (1/4)

27% (4/15)

40% (6/15)

0%

(0/9)

0%

(0/9)

16%

(8/49)

25%

(12/49)

0%

(0/6)

0%

(0/6)

18%

(3/17)

18%

(3/17)

0%

(0/1)

0%

(0/1)

9% (1/11)

27%

(3/11)

other mechanisms, compromises salvage therapies in R/R setting

• A 3rd agent is needed to boost responses with VEN+HMA standard of care therapy

TUS is Ideal 3rd Agent for Addition to VEN+AZA to Treat Newly Diagnosed AML

• TUS has excellent safety alone and in combination with VEN when co-administered

• TUS has broad activity across genetic subgroups including TP53, RAS/MAPK, & FLT3 mutants

• TUS mechanism may minimize drug resistance to VEN via inhibition of key AML kinases

• TUS does not require a change to the TUS administered with or without food allowing co-

administration with VEN

Note: the time 0 of single dose PK is the dosing time on Cycle 1 Day 1, whereas the time 0 of multiple dose PK	Notes: Mean venetoclax plasma concentration-time profile at steady state in the patient's reported for
single agent VEN dosing in the published FDA Venetoclax NDA 208573 Review Package.
is the dosing time of Cycle 1 Day 15 and Day 17 in Part C (dose expansion) Combo. The number of patients in
Steady state PK properties of Venetoclax from our APTIVATE study dosed as the TUS/VEN doublet (red spheres)
legend reflect the number of patients reported any Venetoclax PK data at each dose cohort in the PK
appear roughly the same as the PK properties of Venetoclax reported for single agent VEN dosing in the
population.
published FDA Venetoclax NDA 208573 Review Package.
Timepoints where all concentrations are below LLOQ are excluded from this plot.

	Prior VEN	6% (2/35)	14% (5/35)	0% (0/0)	0% (0/0)
	Prior FLT3i	13% (2/16 )	19% (3/16)	67% (2/3)	67% (2/3)

Data Cut 26 April 2024

9% (1/11)	9% (1/11)	19% (9/48)	27% (13/48)
25% (1/4 )	25% (1/4)	26% (5/19)	32% (6/19)

TUS+VEN+AZA is Being Developed to Address the Needs of Newly Diagnosed AML Patients

We thank our principal investigators, clinical site staff, and most importantly, our patients

and their families for their participation in this clinical trial. EHA2024 Abstract# P557

Disclosures: This clinical study is sponsored by Aptose Biosciences. The following authors are

employees of Aptose Biosciences: R Sinha, J Hu, N Khan, W Rice, and R Bejar