Tuspetinib clinical strategy as a triplet frontline therapy to treat newly diagnosed AML
Earnings Call Presentation
14 May 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
Tuspetinib
Aptose's Lead Clinical Asset
- TUS+VEN+HMA triplet is being developed as frontline therapy to treat newly diagnosed AML
- Bolting TUS on VEN+HMA Frontline Standard of Care
- Expect clinical data from our frontline triplet 2H 2024
AML Highly Aggressive Cancer of Blood and Bone Marrow Unmet Need for Superior Frontline (1L) Therapy in AML
- Progress made with VEN+HMA (SOC)
- Response rates too low and survival too short
- Resistance to VEN compromises subsequent R/R therapies
- A 3rd agent is needed to boost responses with VEN+HMA SOC
- Current 3rd agents in development only address specific genetic subtypes and are limited by toxicities
Tuspetinib Opportunity ׀ Addressing 1L Unmet Needs
- TUS is a natural 3rd agent for addition to VEN and HMA
- 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 targets known VEN resistance mechanisms to minimize resistance
TUS+VEN+HMA … creating a new SOC addressing safety, scope, and survival needs of newly diagnosed AML patients
- TUS : Tuspetinib ; VEN : Venetoclax ; HMA : Hypomethylating agent
AML : Acute Myeloid Leukemia ; SOC : Standard of Care
TUS Targets Known VEN-Resistance Mechanisms and May Minimize Drug Resistance
Tuspetinib suppresses:
SYK, KITMUT, FLT3MUT/WT, JAK/STAT, RAS/MAPK oncogenic signaling directly and MCL-1anti-apoptotic signaling indirectly
KIT | FLT3 |
SYK | TUS |
JAK/STAT | |
PI3K/AKT | |
RAS/ | |
MAPK |
MCL-1
3
3
AML Patient Journey | 1L Therapy High-Level Overview
Current Standard-of-Care (SOC) treatment options leading to therapeutic failure……
Newly
Diagnosed
AML
Palliative
Care
5-year survival <10% for age >701 ; Most survive <1 year
Patients "Fit" | Intensive |
for High Dose | Chemotherapy |
Chemotherapy | (7+3) |
Patients "Unfit" | Low Intensity |
for High Dose | Therapy |
Chemotherapy | (VEN + HMA) |
CR = 37%
CRc = 66%
mOS = 14.7 mos1
Therapeutic
Failure
HSCT | Maintenance | Therapeutic | |
Complete | Therapy | Failure | |
Remission | Maintenance | Therapeutic | |
Therapy | Failure | ||
Therapeutic | |||
Failure |
4
- Pei, Cancer Discos 2020); DiNardo, Blood 2020); (Maiti et al., Haematologica 2021); (Mannis et al., Leukemia Research 2023); Bewersforf et al., Leukemia Research 2022; 122: 106942
4
TUS+VEN+HMA May Increase Survival in High-risk Frontline (1L) Newly Diagnosed AML Patients with Adverse Mutations
- VEN+AZA combo delivers less benefit in "high-risk AML" with FLT3ITD, RASMUT, and TP53MUT
- Tuspetinib retains activity in high-risk AML with the adverse FLT3, RAS and TP53 mutations
- Tuspetinib added to VEN+AZA (HMA) may uniquely benefit the most challenging 1L populations
Frontline AML patients receiving VEN+AZA separate into three efficacy subgroups by OS benefit
5 | 5 |
Dohner et al. ASH 2022 |
Greatest Need in AML Therapy Today
"We are making progress but are not curing our patients1."
Annual new cases in U.S. ≈ 21,0002 | | | Median age at diagnosis 682 |
Annual deaths in U.S. ≈ 11,2002 | | | 5-yr survival ≈ 30% in Adults2 | 5-yr Survival 9% for Age >652 |
Frontline therapies are making progress but leave substantial room for improvement
- Younger "Fit" patients achieve >50% CR, but only 30-50% of patients are "Fit" and many relapse3
- Older "Unfit" patients achieve improved efficacy with VEN+HMA doublet but many relapse
- VEN+HMA(AZA): CR = 37%, CR/CRi = 66%, median OS = 14.7 months4
- Patients with adverse FLT3, N/KRAS, and TP53 mutations correlated with poor response/outcomes
Current triplets can deliver better efficacy, but increased toxicity requires dose reductions
- Studies have shown upper ranges of response at CRc >90%
- Current 3rd agents with VEN+HMA have been more toxic, requiring dose reductions of all agents
- Current 3rd agents with VEN+HMA do not deliver broad activity across AML genotypes
Urgent need for safer and more effective 1L triplet therapies to improve outcomes for AML patients of all genetic subtypes
1 Catherine E. Lai, MD, MPH, of the University of Pennsylvania
2 NIH; Yale Medicine; American Cancer Society; NIH; Healthline
3 Kantarjian, Blood Canc J 2021
6 | 4 DiNardo, NEJM 2020; Pei, Cancer Discos 2020; DiNardo, Blood 2020; Maiti, Haematologica | CR : Complete Remission ; CRc : composite Complete Remission ; OS : Overall Survival |
2021; Mannis, Leukemia Research 2023; Bewersforf, Leukemia Research 2022 |
Age2 | 5-year | |
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% | |
6
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
TUS + VEN + HMA
Patients "Fit" | Intensive |
for High Dose | Chemotherapy |
Chemotherapy | (7+3) |
Need a superior 1L therapy that treats more patients, increases survival, is safer, and avoids 1L therapeutic failures
Patients "Unfit" | Low Intensity |
for High Dose | Therapy |
Chemotherapy | (VEN + HMA) |
Tuspetinib Frontline Triplet Opportunities
- Potential to increase CR rates and survival of FLT3 MUTpatients without the need to dose reduce SOC drugs
- TUS is the only agent being developed in combination with VEN+HMA for FLT3 WTAML patients (70% of AML)
- TUS is the only agent being developed in combination with VEN+HMA for high-risk AML subtypes with highly adverse TP53and N/KRASmutations
- TUS+VEN+HMA expected to be a safer therapy for "unfit" patients than other triplets
7
7
New Paradigm in Frontline Therapy to Treat Newly Diagnosed AML
Deploying Triplet Combinations of Targeted Drugs | Building on VEN + HMA Backbone for 1L Therapy
Proof for Triplets : Addition of a 3rd Targeted Agent Boosts VEN+HMA Responses in 1L AML
Addition of gilteritinib (Gilt) FLT3i to VEN+HMA boosts CR rate 2.4X in newly diagnosed FLT3+ AML patients1
Problem: Current 3rd Agents for Triplets have Limitations
Gilt is not active in FLT3-Wildtype AML (70% of patients) and toxicities of Gilt with VEN+HMA require SOC dose reductions
Solution: TUS Fulfills Ideal Profile as
3rd Agent for 1L Triplet
TUS clean safety is ideal for addition to | TUS clinical efficacy broader than Gilt and | TUS preclinical safety, antitumor, |
VEN+HMA backbone | achieves CR in high-risk AML | mechanistic findings superior to Gilt |
- TUS shows no QTc prolongation, differentiation syndrome, muscle damage, or prolonged myelosuppression in remission
- TUS is not expected to require dose reductions or interruptions to SOC drugs
- 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 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 & TUS+HMA safe and effective in animal models of human AML
8
1 Short et al. J Clin Oncol. 2024 Jan 26:JCO2301911. Epub ahead of print. PMID: 38277619.
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 Single Agent Dose Exploration | √ |
Demonstrate Single Agent Responses | √ |
Demonstrate Single Agent Safety | √ |
Tus+Ven Doublet Study in R/R AML | |
Characterize Safety of TUS+VEN 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
Tuspetinib Achieved Orphan Drug Designation and Fast Track Status
9
9
TUS+VEN+AZA TRIPLETPilot Study: Design, Patient Populations, Dose Selection, Goals
Patient Populations │ 20-36 Pts Total │ 50% FLT3-MUT │ <20% TP53+/CK
Trial Goals │ Safety, CR rate, MRD negativity and OS across AML subtypes (FLT3MUT/WT , TP53MUT, RASMUT)
Dose Selection │ Explore 80, 120, 160mg Doses for Optimal Phase 2 Dose of TUS and Avoid SOC Dose Reductions
Cycle 1 Treatment Plan:
Day 18 | Day 21 | |
BM | Decision | Cycle 1 extended if needed to |
allow for count recovery* |
TUS | TUS once daily | |||
VEN | 400 mg once daily | |||
AZA | 75mg/m2 once daily | BM blasts <5% | Day 28 | |
Day 1 | Day 7 | or aplastic | ||
Cycle 1 extended if needed to
allow for count recovery*
TUS | TUS once daily | |||
VEN | 400 mg once daily | |||
AZA | 75mg/m2 once daily | BM blasts ≥ 5% | Day 28 | |
Day 1 | Day 7 | VEN and TUS held if BM blasts <5% | ||
or aplastic, otherwise move to Cycle 2 |
10 | * GCSF permitted after D28 per protocol |
10 | |
Attachments
- Original Link
- Original Document
- Permalink
Disclaimer
Aptose Biosciences Inc. published this content on 14 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 14 May 2024 21:08:29 UTC.