Small Molecule / Multi-Kinase

Amuvatinib (MP-470)

The first drug developed at CIDD to advance into clinical trials. A multi-kinase inhibitor combining c-Kit/c-Met/PDGFR blockade with unique RAD51-mediated DNA repair suppression, creating synthetic lethality with DNA-damaging agents.

Phase 1/2

Completed

Multi-kinase

c-Kit/c-Met/PDGFR

RAD51

DNA Repair Suppression

First CIDD Drug

In Clinical Trials

Executive Summary

Strategic overview for Amuvatinib

RAD51 mechanism increasingly recognized as relevant to PARP inhibitor and immunotherapy combinationsCIDD clinical data and IP could inform next-generation selective RAD51 inhibitor programsInstitutional experience from amuvatinib directly strengthened DT2216, BSI-082, and future CIDD programsLegacy publications continue to build CIDD's academic reputation and attract collaboratorsPotential to revisit RAD51-targeting approach with modern drug design and biomarker strategies

Key Strengths

First CIDD drug to reach clinical trials — validated the translational pipeline
Unique dual mechanism: multi-kinase inhibition plus RAD51-mediated DNA repair suppression
Completed Phase 1/2 with established MTD and clinical activity data
Oral bioavailability with manageable safety profile
Published clinical and preclinical data in peer-reviewed journals
Generated institutional knowledge and regulatory experience for subsequent CIDD programs

Key Risks

IP may have expired or reverted — freedom-to-operate analysis needed for any revival
Multiple competitors have established large clinical datasets in overlapping kinase targets
RAD51 mechanism could be pursued by other groups without amuvatinib's IP constraints
Perception of a 'failed program' could undermine institutional narrative if not framed properly
Funding agencies may view revisiting a discontinued program as lower priority than novel approaches

Molecule Profile

The first drug developed at CIDD (Center for Innovative Drug Discovery) to advance into clinical trials, validating the bench-to-bedside translational pipeline at UT Health San Antonio. Amuvatinib demonstrated a unique dual mechanism combining multi-kinase inhibition with DNA repair suppression, showing tumor responses in combination with erlotinib in NSCLC patients.

Amuvatinib (MP-470)

(amuvatinib)Phase 1/2

Modality

Small Molecule

Target

c-Kit/c-Met/PDGFR/RAD51

Mechanism

Multi-kinase inhibitor that simultaneously blocks c-Kit, c-Met, and PDGFR receptor tyrosine kinases while uniquely suppressing DNA repair via RAD51 inhibition, creating synthetic lethality with DNA-damaging agents such as chemotherapy and radiation.

Route

/portfolio/amuvatinib

Key Metric

300 mg BID MTD

Sponsor

SuperGen/Astex Pharmaceuticals

Indications

Solid tumorsNSCLCSmall cell lung cancerGastric cancer

Mechanism of Action

Targeting c-Kit, c-Met, PDGFR, RAD51

Amuvatinib (MP-470) is an orally bioavailable multi-kinase inhibitor that blocks receptor tyrosine kinases c-Kit, c-Met, and PDGFR, disrupting tumor proliferation and survival signaling. Uniquely, it also suppresses RAD51-mediated homologous recombination DNA repair. By impairing the tumor cell's ability to repair DNA damage, amuvatinib creates synthetic lethality when combined with DNA-damaging agents such as platinum chemotherapy, topoisomerase inhibitors, or radiation therapy. This dual mechanism — simultaneous kinase inhibition plus DNA repair suppression — distinguishes amuvatinib from conventional multi-kinase inhibitors.

Key Advantages

Multi-target kinase inhibition across c-Kit, c-Met, and PDGFR
Unique RAD51-mediated DNA repair suppression not seen in other kinase inhibitors
Synergy with chemotherapy and radiation via synthetic lethality
Oral bioavailability enabling convenient outpatient dosing
First CIDD drug to reach clinical trials, validating the translational pipeline

Clinical Evidence

Active and completed clinical trials

NCT Number	Title	Phase	Status	Indication	Enrollment
NCT00894894	Phase 1 Dose-Finding Study of Amuvatinib (MP-470) in Patients With Advanced Solid Tumors	Phase 1	Completed	Advanced solid tumors	21/25
NCT01357395	Phase 1b/2 Study of Amuvatinib (MP-470) in Combination With Erlotinib in Patients With Advanced NSCLC	Phase 1/2	Completed	Non-small cell lung cancer (NSCLC)	37/40

Efficacy Results

Maximum Tolerated Dose (MTD)

300 mg BID

vs. Well-tolerated with manageable toxicity profile

Disease Control Rate (combination with erlotinib)

62%

CI: 95% CI: 45–77%

Partial Responses (combination with erlotinib)

3 confirmed PRs (8%)

vs. Including responses in erlotinib-pretreated patients

Median Progression-Free Survival

3.6 months

CI: 95% CI: 2.1–5.4

RAD51 Suppression in Tumor Biopsies

≥50% reduction at MTD

vs. Dose-dependent suppression observed across cohorts

Safety Profile

Adverse event summary for Amuvatinib

Adverse Event	All Grades	Grade 3+	Manageable
Fatigue	45%	8%	Yes
Nausea	38%	3%	Yes
Diarrhea	30%	5%	Yes
Rash	22%	2%	Yes
Edema	18%	1%	Yes
Myelosuppression	15%	5%	Yes

Regulatory Timeline

Regulatory milestones for Amuvatinib

IND Filed

2008-09

Phase 1 Initiated

2009-03

Phase 1 Completed

2011-06

Phase 1b/2 Initiated

2011-08

Phase 1b/2 Completed

2014-03

IND Filed

2008-09

Investigational New Drug application filed by SuperGen for amuvatinib (MP-470) based on preclinical data demonstrating multi-kinase inhibition and RAD51 suppression

completed

Phase 1 Initiated

2009-03

First-in-human Phase 1 dose escalation study initiated at UT Health San Antonio — the first CIDD-originated drug to enter clinical trials

completed

Phase 1 Completed

2011-06

Phase 1 dose escalation completed with MTD established at 300 mg BID. Dose-dependent RAD51 suppression confirmed in tumor biopsies

completed

Phase 1b/2 Initiated

2011-08

Phase 1b/2 combination study with erlotinib initiated in advanced NSCLC patients, exploring synthetic lethality approach

completed

Phase 1b/2 Completed

2014-03

Combination study completed. Disease control rate of 62% observed with confirmed partial responses in NSCLC. Program not advanced further due to partner strategic priorities

completed

Competitive Landscape

Key competitors in the multi-kinase inhibitor space

Imatinib (Gleevec)

high

Novartis

ApprovedSmall Molecule

First-generation c-Kit/PDGFR inhibitor approved for CML and GIST; established standard of care with extensive long-term safety data

Sunitinib (Sutent)

high

Pfizer

ApprovedSmall Molecule

Multi-kinase inhibitor approved for RCC, GIST, and pNET; broader kinase coverage but no DNA repair mechanism

Cabozantinib (Cometriq/Cabometyx)

medium

Exelixis

ApprovedSmall Molecule

Multi-kinase inhibitor with c-Met activity approved for RCC, HCC, and medullary thyroid cancer; lacks DNA repair inhibition mechanism

Crizotinib (Xalkori)

medium

Pfizer

ApprovedSmall Molecule

ALK/c-Met/ROS1 inhibitor approved for ALK+ NSCLC; strong c-Met activity but limited to biomarker-selected populations

KOL Simulation

Simulated key opinion leader responses to strategic scenarios

KOL Personas

Dr. Daruka Mahadevan

UT Health San Antonio

high

Leveraging amuvatinib lessons for next-generation CIDD programsPublishing clinical data to support translational pipeline credibilityValidating RAD51 as a druggable DNA repair targetStrengthening industry partnerships for future CIDD molecules

Thoracic Oncologist — NSCLC Specialist

NCI-Designated Cancer Center

medium

Identifying novel combination partners for EGFR-TKIsOvercoming resistance to erlotinib and other first-generation TKIsDNA damage response pathway exploitation in lung cancerImproving outcomes in biomarker-unselected NSCLC populations

Scenarios

Amuvatinib Legacy Assessment for CIDD Pipeline Strategy

Opportunity

CIDD leadership conducts a retrospective analysis of the amuvatinib program to inform strategy for current portfolio molecules. Key questions include: what worked, what did not, and how the RAD51 mechanism could be applied to next-generation drug design.

RAD51 Targeting Resurgence in Precision Oncology

Opportunity

New preclinical data from multiple groups demonstrates that RAD51 inhibition potentiates PARP inhibitors and immune checkpoint therapy. This reignites interest in amuvatinib's RAD51 mechanism and raises questions about whether the approach should be revisited with modern drug design.

Simulated Responses

Dr. Daruka Mahadevan

Views amuvatinib as the foundational success that proved CIDD could move drugs from discovery to patients — lessons directly inform DT2216 and BSI-082 development

Amuvatinib was our proof of concept — not just for the molecule, but for the entire CIDD translational pipeline. Every lesson from that program, from IND strategy to partner management, is embedded in how we develop drugs today. The RAD51 story isn't over.

Ensuring institutional memory of amuvatinib lessons is preservedRAD51 mechanism was never fully exploited clinically due to partner discontinuationNeed to capture and publish remaining clinical data before it becomes inaccessible

Thoracic Oncologist — NSCLC Specialist

Recognizes amuvatinib's scientific contribution but views the competitive landscape as having moved past multi-kinase inhibitors without biomarker selection

The amuvatinib RAD51 data was intriguing but never got the chance to be fully explored. In today's immuno-oncology landscape, DNA repair suppression as a strategy to enhance tumor immunogenicity is more relevant than ever. Someone should revisit this.

Multi-kinase inhibitor space is crowded with approved agentsRAD51 mechanism was not validated with a companion diagnosticNSCLC treatment has transformed with immunotherapy — combination context has changed

Dr. Daruka Mahadevan

Strongly supportive of revisiting RAD51 targeting — sees an opportunity to leverage CIDD's first-mover clinical data in this emerging space

We showed RAD51 suppression in patient tumors over a decade ago — before anyone was talking about synthetic lethality beyond BRCA. Now the field is catching up. CIDD is uniquely positioned to lead the next chapter of RAD51-targeted therapy.

Would require new funding and potentially new IP filingsOriginal partner (SuperGen/Astex) no longer active — need to clarify IP ownershipModern drug design could produce more selective RAD51 inhibitors than amuvatinib

Thoracic Oncologist — NSCLC Specialist

Cautiously interested — the science is compelling but wants to see modern preclinical data before investing clinical resources

If RAD51 inhibition can genuinely enhance immunotherapy response in BRCA-proficient tumors, that's a significant unmet need. But we need a cleaner molecule than amuvatinib and a biomarker strategy. The concept is right — the execution needs to be modernized.

Need selective RAD51 inhibitors rather than multi-kinase approach for clean signalBiomarker strategy for patient selection must be defined upfrontCombination with immunotherapy would be the most relevant modern context

Risk Assessment

Key risks and mitigation strategies for Amuvatinib

Development Halted Due to Partner Strategic Priorities

critical

SuperGen was acquired by Astex Pharmaceuticals, which subsequently shifted strategic focus away from amuvatinib. The program was not advanced beyond Phase 1/2 despite demonstrating clinical activity, illustrating the risk of dependence on a single commercial partner for CIDD-originated assets.

Mitigation: For future CIDD programs, negotiate milestone-based reversion clauses, maintain parallel academic development pathways, and diversify partnership strategies across multiple potential licensees.

Multi-Kinase Inhibitor Landscape Matured Beyond Amuvatinib

high

The c-Kit/c-Met/PDGFR kinase inhibitor space became highly competitive with FDA approvals of imatinib, sunitinib, cabozantinib, and crizotinib. These agents established extensive clinical datasets and market positions that amuvatinib could not match with limited Phase 1/2 data.

Mitigation: Future CIDD programs should identify differentiated mechanisms or underserved indications early in development to avoid head-to-head competition with established agents.

Limited Efficacy as Monotherapy

medium

Amuvatinib showed modest single-agent activity in Phase 1, with the primary clinical signal emerging only in combination with erlotinib. Dependence on combination strategies complicates regulatory pathways and increases development complexity.

Mitigation: Design future CIDD molecules with strong monotherapy potential while maintaining combination optionality. Prioritize biomarker-driven patient selection to enrich for responders.

RAD51 Mechanism Not Fully Validated Clinically

medium

While RAD51 suppression was demonstrated in tumor biopsies, the clinical program ended before the contribution of RAD51 inhibition to patient outcomes could be definitively established. The relative importance of kinase inhibition vs DNA repair suppression remains unclear.

Mitigation: Invest in preclinical studies with selective RAD51 inhibitors to deconvolute the mechanistic contributions. Leverage amuvatinib PK/PD data to inform next-generation RAD51-targeted drug design.

Market Opportunity

Addressable market segments for Amuvatinib

Multi-Kinase Inhibitors (Oncology)

$12B

Growth: 4.5% CAGR

Target Share: Program completed — no active commercial pursuit

NSCLC Targeted Therapy

$18B

Growth: 8.2% CAGR

Target Share: Program completed — no active commercial pursuit

DNA Damage Response (DDR) Inhibitors

$4.5B

Growth: 15% CAGR

Target Share: RAD51 mechanism positions CIDD IP in emerging DDR space

Lifecycle Position

Amuvatinib across the 12-stage pharma lifecycle

Strategic Recommendations

SWOT analysis and strategic priorities for Amuvatinib

Strengths

+ First CIDD drug to reach clinical trials — validated the translational pipeline
+ Unique dual mechanism: multi-kinase inhibition plus RAD51-mediated DNA repair suppression
+ Completed Phase 1/2 with established MTD and clinical activity data
+ Oral bioavailability with manageable safety profile
+ Published clinical and preclinical data in peer-reviewed journals
+ Generated institutional knowledge and regulatory experience for subsequent CIDD programs

Weaknesses

- Development halted by partner (SuperGen/Astex) strategic reprioritization
- Limited monotherapy efficacy — required combination for clinical signal
- Multi-kinase inhibitor space became crowded with approved competitors
- Small patient numbers in clinical studies limit strength of efficacy conclusions
- RAD51 contribution to clinical outcomes not definitively established
- No companion diagnostic or biomarker-driven patient selection strategy developed

Opportunities

* RAD51 mechanism increasingly recognized as relevant to PARP inhibitor and immunotherapy combinations
* CIDD clinical data and IP could inform next-generation selective RAD51 inhibitor programs
* Institutional experience from amuvatinib directly strengthened DT2216, BSI-082, and future CIDD programs
* Legacy publications continue to build CIDD's academic reputation and attract collaborators
* Potential to revisit RAD51-targeting approach with modern drug design and biomarker strategies

Threats

! IP may have expired or reverted — freedom-to-operate analysis needed for any revival
! Multiple competitors have established large clinical datasets in overlapping kinase targets
! RAD51 mechanism could be pursued by other groups without amuvatinib's IP constraints
! Perception of a 'failed program' could undermine institutional narrative if not framed properly
! Funding agencies may view revisiting a discontinued program as lower priority than novel approaches

Publication Tracker

Key publications supporting the Amuvatinib evidence base

Phase I study of amuvatinib (MP-470) in combination with erlotinib in patients with advanced non-small cell lung cancer

Mahadevan D, Cooke L, Riley C et al.

Cancer Chemotherapy and Pharmacology2014original-research

DOI: 10.1007/s00280-014-2522-8

MP-470, a novel c-KIT receptor tyrosine kinase inhibitor, suppresses DNA repair and enhances radiation effects

Welsh JW, Mahadevan D, Ellsworth R et al.

Clinical Cancer Research2009original-research

DOI: 10.1158/1078-0432.CCR-08-2050