Tuspetinib to Treat Newly Diagnosed AML
Corporate Presentation
April 2024
P R E C I S I O N O N C O L O G Y F O R T H E R A P I E S O F T O M O R R O W
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Tuspetinib Lead Clinical Asset
- Developing TUS+VEN+HMA triplet as frontline therapy to treat newly diagnosed AML ׀ Begins Summer of 2024
- Excellent safety profile ׀ Ideal for combination therapy
- Potently targets SYK, FLT3, KITMUT, JAK1/2, RSK2 kinases
3TUS : Tuspetinib ; VEN : Venetoclax ; HMA : Hypomethylating agent
AML : Acute Myeloid Leukemia
The Problem Treating AML
- Response rates too low and survival too short in frontline (1L) therapy
- Progress treating 1L AML with VEN+HMA (SOC) but not curing
The Needs of AML Patients
- Achieve longer survival and treat broader scope of subgroups in 1L
- Add a 3rd agent to VEN+HMA SOC - Current inadequate
Tuspetinib Opportunity ׀ Addressing 1L Unmet Needs
- TUS has excellent safety in combination with VEN and HMA
- TUS increases efficacy in combination with VEN and HMA
- TUS has broad scope of activity across AML genetic subgroups
TUS+VEN+HMA as a new SOC addresses safety, scope and
survival needs of newly diagnosed AML patients
Tuspetinib Enhancing Venetoclax Efficacy in Frontline Therapy TUS and VEN mechanistically cooperate to prevent drug resistance
Tuspetinib Compensates for
Venetoclax Resistance
TUS
FLT3-ITD | KIT-MUT | JAK1/2 RAS/MAPK TP53-MUTMCL-1 ↑ |
VEN BCL-2i resistance involves mutations in multiple pathways to evade BCL-2 blockade
TUS targets VEN resistance pathways
By shutting down escape pathways, TUS may re- sensitize prior-VEN failures to venetoclax
KIT | FLT3 |
SYK | |
JAK/STAT | TUS |
PI3K/AKT | |
RAS/ | |
MAPK |
MCL-1
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Greatest Need in AML Therapy Today
"We are making progress but are not curing our patients1."
Annual Deaths 11,2003 | 5-yr Survival 30% in Adults1 | 5-yr Survival 9% for Age >651. | Avg age a diagnosis 68
- Chemotherapy is not an option for most of the AML patient population
- Chemotherapy may be beneficial for "Fit" younger patients without co-morbidities
- Only 30-50% of AML patients are "Fit" for Chemo based therapies
- Frontline therapies are making progress but leave substantial room for improvement
- The CR rate of first-line treatment in young and middle-aged adults is 60%-80%,
- Older patients >65 years of age have CR rates in first-line therapy of 40%-60% with high rates of relapse
- Elderly populations have seen improved efficacy with venetoclax-containing doublet therapy
- VEN/HMA: CR = 37%, CRc = 66%, median OS = 14.7 months
- However, patients with adverse mutations in FLT3, NRAS, KRAS, and TP53 have inferior outcomes
- Triplet combination studies have shown better efficacy, but increased toxicity requires dose reductions
- Studies have shown upper ranges of response at CRc 90% and CR >70%
- Combinations have been more toxic, requiring dose reductions of all agents
- And the targeted agents do not have broad activity across AML genotypes
- Safe and effective therapies to improve outcomes for AML patients of all genotypes represent an urgent need in AML
5 | 1 Catherine E. Lai, MD, MPH, of the University of Pennsylvania. |
5 |
AML Patient Journey | 1L Therapy High-Level Overview
Current Standard-of-Care (SOC) treatment options leading to therapeutic failure……
5-year | |
Age5 | survival |
rate | |
Children < 14 | 65-70% |
Ages 15 to 34 | 52% |
Ages 35 to 54 | 37% |
Ages 55 to 64 | 20% |
Ages 65 to 74 | 9% |
Newly
Patients "Fit" | Intensive | |
for High Dose | Chemotherapy | |
Chemotherapy | (7+3) | |
Therapeutic
Failure
HSCT
Maintenance
Therapeutic
Diagnosed
Complete Remission
Therapy
Failure
AML
Palliative
Care
5-year survival <10% for age >701 ; Most survive <1 year
Patients "Unfit" | Low Intensity | |
for High Dose | Therapy | |
Chemotherapy | (VEN + HMA) | |
CR = 37%
CRc = 66%
mOS = 14.7 mos1
Maintenance | Therapeutic |
Therapy | Failure |
Therapeutic
Failure
- NIH; Yale Medicine; American Cancer Society; NIH; Healthline
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AML Patient Journey | 1L Therapy High-Level Overview
Tuspetinib-containing triplet can become a new 1L SOC to increase survival
Newly
Diagnosed
AML
Tuspetinib Triplet Opportunity | Tuspetinib Frontline Triplet Opportunities | |||
TUS + VEN + HMA | ||||
Patients "Fit" | Intensive | • | FLT3 MUT | ׀ Increase CR rates and survival with a better |
for High Dose | Chemotherapy | |||
safety profile | ||||
Chemotherapy | (7+3) | |||
• | FLT3 WT | ׀ Increase CR rates and 1-yr survival better | ||
Need a superior 1L therapy that treats | than HMA+VEN | |||
more patients, increases survival, and | ||||
avoids 1L therapeutic failures | ||||
• | Treats a broad scope of AML subtypes, including highly | |||
Patients "Unfit" | Low Intensity | adverse TP53 MUT, NKRAS MUT | ||
for High Dose | Therapy | |||
Chemotherapy | (VEN + HMA) | • | Safer therapy for "unfit" patients than other triplets | |
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New Paradigm in Frontline Therapy to Treat Newly Diagnosed AML
Deploying Triplet Combinations of Targeted Drugs | Building on VEN + HMA Backbone for 1L Therapy
VEN + HMA + Gilteritinib triplet has superior OS to VEN + HMA doublet in newly diagnosed FLT3+ AML patients
Current Problem
Gilteritinib-basedtriplet not active in FLT3-WildtypeAML (70% of patients) and toxicities require SOC dose reductions
TUS safety shows no signal of overlapping toxicities with VEN or HMA backbone agents
- TUS shows no QTc prolongation, differentiation syndrome, muscle damage, or prolonged myelosuppression in remission
- TUS is not expected to require dose interruptions to SOC drugs
TUS Superior to Gilt
for 1L
TUS clinical efficacy is superior to Gilt and
achieves CR in high-risk AML
- TUS achieves clinical responses in patients who failed prior therapy with Gilt
- TUS achieves clinical responses at lower and better-tolerated doses than Gilt
- TUS achieves clinical responses in FLT3WT patients (70% of AML population), a population not addressable by Gilt FLT3i
TUS preclinical safety, antitumor, mechanistic findings superior to Gilt
- TUS MOA targets VEN-resistance mechanisms and re-sensitizes cells to VEN
- TUS suppresses more oncogenic signaling pathways than Gilt and at lower doses
- TUS potent antitumor activity in animal models of human AML resistant to Gilt
- TUS + VEN or AZA (HMA) safe and effective in animal models of human AML
8 | 8 |
FDA Requirements for TUS to Enter Frontline Therapy in Newly Diagnosed AML
Tuspetinib has Met the FDA Requirements to Perform the Triplet Pilot Study
What Does the FDA Want? | Aptose |
Begin in R/R AML with TUS and TUS+VEN | Completed |
TUS Single Agent Study in R/R AML | |
Thorough Dose Exploration | √ |
Demonstrate Single Agent Safety | √ |
Demonstrate Single Agent Efficacy | √ |
Tus + Ven Doublet Study in R/R AML | |
Characterize Safety of Doublet | √ |
Characterize PK of TUS and VEN in Doublet | √ |
Next Step: TUS+VEN+AZA Triplet Pilot Study
Initiate dosing and collect data from
Triplet Pilot Study in Newly Diagnosed AML Patients
Protocol implemented and clinical sites being prepared
- Select optimal dose of TUS that allows for SOC dosing
- Characterize safety and mitigate myelosuppression
- Characterize activity in TP53MUT and N/KRASMUT
- Characterize activity in FLT3MUT and FLT3UNMUT
- Characterize PK of TUS and VEN in triplet
- Determine CR, CRh, CRc, MRD rates
- Characterize duration of dosing
- Characterize mOS
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TUS+VEN+AZA TRIPLETPilot Study: Design, Patient Populations, Dose Selection, Goals
Patient Populations │ 20-36 Pts Total │ 50% FLT3-MUT │ <20% TP53+/CK
Dose Selection │ Explore 80, 120, 160mg Doses for Optimal Phase 2 Dose of TUS and Avoid SOC Dose Reductions
Trial Goals │ Safety, CR rate, MRD negativity and OS across AML subtypes (FLT3MUT/WT , TP53MUT, RASMUT)
Cycle 1 Treatment Plan:
TUS | TUS once daily | ||
VEN | 400 mg once daily | ||
AZA | 75mg/m2 once daily | ||
Day 1 | Day 7 | ||
TUS | TUS once daily | ||
VEN | 400 mg once daily | ||
AZA | 75mg/m2 once daily | ||
Day 1 | Day 7 |
Day 18 Day 21 BM Decision
BM blasts <5%
or aplastic
BM blasts ≥ 5%
Cycle 1 extended if needed to
allow for count recovery*
Day 28
Cycle 1 extended if needed to
allow for count recovery*
Day 28
VEN and TUS held if BM blasts <5% or aplastic, otherwise move to Cycle 2
10 | * GCSF permitted after D28 per protocol |
10 | |
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Aptose Biosciences Inc. published this content on 24 April 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 24 April 2024 20:59:59 UTC.