Alrizomadlin (APG-115): A Comprehensive Review of a Novel MDM2-p53 Inhibitor in Oncology

Executive Summary

Alrizomadlin (APG-115) is an investigational, orally bioavailable, small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) E3 ubiquitin ligase. It represents a targeted therapeutic strategy designed to reactivate the tumor suppressor protein p53. By binding with high affinity and selectivity to MDM2, Alrizomadlin disrupts the critical MDM2-p53 protein-protein interaction, thereby preventing the degradation of p53 and restoring its potent tumor-suppressive functions, including the induction of cell cycle arrest and apoptosis. This mechanism is primarily effective in cancers that retain wild-type TP53 but exhibit functional p53 inactivation through overexpression or amplification of MDM2.

The clinical development of Alrizomadlin, led by Ascentage Pharma, has advanced to Phase 2 trials across a spectrum of solid and hematologic malignancies. Preclinical studies have validated its potent anti-proliferative activity and established a strong rationale for combination therapies. Emerging research has uncovered a multimodal mechanism of action that extends beyond classical apoptosis to include the induction of inflammatory pyroptotic cell death and significant modulation of the tumor microenvironment. This immunomodulatory activity provides a compelling biological basis for the observed clinical synergy with immune checkpoint inhibitors, particularly in overcoming resistance in cancers such as advanced melanoma.

Clinical investigations have demonstrated promising antitumor activity in biomarker-defined patient populations. Notable efficacy has been observed in tumors with MDM2 amplification and wild-type TP53, such as liposarcoma, as well as in rare cancers like adenoid cystic carcinoma and malignant peripheral nerve sheath tumor. In hematologic malignancies, Alrizomadlin has shown activity in relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes, both as a monotherapy and in combination with hypomethylating agents.

The safety profile of Alrizomadlin is well-characterized and manageable, with the most common and dose-limiting toxicities being on-target hematologic events, including thrombocytopenia and neutropenia. These predictable adverse effects are managed through intermittent dosing schedules. Supported by multiple Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration, Alrizomadlin stands as a significant advancement in the field of p53-reactivating therapies, with the potential to address substantial unmet medical needs in oncology.

Section 1: The p53-MDM2 Axis: A Cornerstone of Tumor Suppression and a Therapeutic Target

1.1 The Guardian of the Genome: The Multifaceted Role of p53

The tumor suppressor protein p53, encoded by the TP53 gene, is a central regulator of cellular homeostasis and is often referred to as the "guardian of the genome".[1] Functioning as a multifunctional transcription factor, p53 is activated in response to a wide array of cellular stressors, including DNA damage, oncogene activation, hypoxia, and nutrient deprivation. Upon activation, p53 orchestrates a complex transcriptional program that determines cell fate, primarily by inducing cell cycle arrest to allow for DNA repair, or by initiating programmed cell death (apoptosis) to eliminate irreparably damaged cells.[1] Its pro-apoptotic activity is mediated through the transcriptional upregulation of pro-apoptotic genes, such as those encoding BAX and FAS, and the repression of anti-apoptotic genes like

Bcl-2.[1] The integrity of the p53 pathway is fundamental to preventing malignant transformation, and its inactivation is a near-universal hallmark of human cancer.[2]

1.2 MDM2: The Oncogenic Regulator of p53

The activity of p53 is tightly controlled by its principal negative regulator, the Mouse Double Minute 2 (MDM2) protein, known as HDM2 in humans.[3] MDM2 is an E3 ubiquitin-protein ligase that functions as a primary antagonist of p53 through a direct protein-protein interaction.[3] MDM2 binds to the N-terminal transactivation domain of p53, which accomplishes two critical inhibitory functions: first, it sterically hinders p53 from binding to DNA and activating its target genes; second, it tags p53 with ubiquitin, marking it for degradation by the 26S proteasome.[3] This creates an autoregulatory negative feedback loop, as

MDM2 itself is a transcriptional target of p53.

In many cancers, this delicate balance is disrupted. While approximately half of all human tumors harbor inactivating mutations in the TP53 gene, a significant portion of the remainder retain wild-type TP53 but achieve p53 pathway disruption through alternative mechanisms.[2] The most prominent of these is the amplification of the

MDM2 gene or the overexpression of its protein product. This overexpression leads to excessive p53 suppression and degradation, effectively mimicking a TP53-mutant state and promoting cancer cell proliferation and survival.[2]

MDM2 amplification is particularly prevalent in certain tumor types, such as well-differentiated and dedifferentiated liposarcomas, where its incidence can exceed 90%.[2]

1.3 Therapeutic Rationale for Inhibiting the MDM2-p53 Interaction in TP53 Wild-Type Cancers

The dependence of certain wild-type TP53 tumors on MDM2 overexpression for survival creates a therapeutic vulnerability. The central hypothesis is that pharmacologically disrupting the MDM2-p53 protein-protein interaction can serve as a powerful anticancer strategy.[2] In tumors that are "addicted" to this interaction, a small-molecule inhibitor that occupies the p53-binding pocket on the MDM2 protein can effectively "release the brakes" on p53.[3] This intervention is designed to prevent p53 ubiquitination and degradation, leading to the rapid accumulation and stabilization of functional p53 protein. The restored p53 can then re-engage its downstream transcriptional targets, reinstating its potent tumor-suppressive functions and driving the cancer cells toward apoptosis.[3]

This therapeutic approach is predicated on the genetic context of the tumor, creating a clear and rational patient selection strategy. The therapeutic window for MDM2 inhibitors is critically dependent on the tumor's TP53 status. The entire mechanism of action relies on the reactivation of a pre-existing, functional p53 protein.[3] If the

TP53 gene is mutated, the resulting p53 protein is often non-functional or dysfunctional. Consequently, liberating a non-functional p53 protein from MDM2-mediated inhibition would confer no therapeutic benefit. This fundamental biological principle is strongly supported by clinical data. In a Phase I study of Alrizomadlin, patients with wild-type TP53 tumors experienced a median progression-free survival of 7.9 months, in stark contrast to the 2.2 months observed in patients with mutant TP53 tumors.[6] This significant difference establishes that wild-type

TP53 status is an essential predictive biomarker for this class of drugs, a critical insight that guides patient selection in clinical trials and will be paramount for its potential future application in clinical practice.

Section 2: Alrizomadlin: Compound Profile and Pharmaceutical Characteristics

2.1 Nomenclature, Identifiers, and Structural Elucidation

Alrizomadlin is a structurally complex small molecule that has been assigned multiple identifiers throughout its development, which are essential for accurate tracking and cross-referencing across scientific literature, clinical trial registries, and chemical databases.

• Generic Name: Alrizomadlin [1]
• Synonyms and Code Names: The compound is widely known by its development codes, including APG-115 and AA-115. It is also referred to descriptively as MDM2-p53 inhibitor APG-115 and p53-HDM2 protein-protein interaction inhibitor APG-115.[3]
• DrugBank ID: DB17549 [1]
• CAS Number: 1818393-16-6 [4]
• Molecular Formula: C34​H38​Cl2​FN3​O4​ [4]
• IUPAC Name: 4-((3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid [4]
• Chemical Identifiers:
• InChI: InChI=1S/C34H38Cl2FN3O4/c1-2-40-27(28(41)39-32-16-13-31(14-17-32,15-18-32)30(43)44)25(21-7-6-8-23(36)26(21)37)34(33(40)11-4-3-5-12-33)22-10-9-20(35)19-24(22)38-29(34)42/h6-10,19,25,27H,2-5,11-18H2,1H3,(H,38,42)(H,39,41)(H,43,44)/t25-,27+,31?, 32?, 34+/m0/s1 [4]
• InChIKey: YJCZPJQGFSSFOL-MNZPCBJKSA-N [4]
• SMILES: CCN1C@HC(=O)NC67CCC(CC6)(CC7)C(=O)O

2.2 Physicochemical Properties and Formulation Considerations

The physicochemical properties of Alrizomadlin are critical determinants of its pharmaceutical behavior, including its absorption, distribution, formulation requirements, and handling procedures in both laboratory and clinical settings. As a small molecule, its characteristics have been extensively defined.

The molecular weight of Alrizomadlin is consistently reported as 642.59 g/mol or 642.6 g/mol. One of its most significant properties is its poor aqueous solubility, measured at just 0.00128 mg/mL, which classifies it as practically insoluble in water. This necessitates specialized formulations for oral administration to ensure adequate bioavailability. In preclinical studies, for instance, it is often prepared as a homogeneous suspension in vehicles like carboxymethylcellulose sodium (CMC-Na). Conversely, it is highly soluble in organic solvents like dimethyl sulfoxide (DMSO), with reported solubilities of 90-100 mg/mL. This high solubility in DMSO is advantageous for

in vitro experimental work, though care must be taken during dilution into aqueous media to prevent precipitation, often requiring preheating of solutions or sonication to maintain solubility.

The compound's lipophilicity, indicated by a logP value of approximately 4.6, suggests good membrane permeability, which is favorable for an orally administered drug. In terms of stability, Alrizomadlin is robust. It is stable as a solid powder for several years when stored at -20°C and can be shipped at ambient temperature without degradation. Stock solutions in DMSO are stable for over a year at -80°C. These properties make it a chemically stable and developable compound.

Table 1: Key Physicochemical and Structural Properties of Alrizomadlin

Property	Value	Source(s)
DrugBank ID	DB17549
CAS Number	1818393-16-6
Type	Small Molecule
Molecular Formula	C34​H38​Cl2​FN3​O4​
Molecular Weight	642.59 g/mol
IUPAC Name	4-((3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid
SMILES	CCN1C(=O)NC67CCC(CC6)(CC7)C(=O)O
Water Solubility	0.00128 mg/mL
logP	4.63
pKa (Strongest Acidic)	3.69
pKa (Strongest Basic)	8.42
Hydrogen Acceptor Count	5
Hydrogen Donor Count	3
Rotatable Bond Count	5
Polar Surface Area	98.74 A˚2

Section 3: Multimodal Mechanism of Action and Pharmacodynamics

3.1 Primary Mechanism: High-Affinity Disruption of the MDM2-p53 Complex

The primary pharmacological action of Alrizomadlin is its function as a highly potent, selective, and orally active antagonist of the MDM2-p53 protein-protein interaction. It is designed to physically occupy the hydrophobic pocket on the MDM2 protein that normally binds to the transactivation domain of p53. The potency of this interaction is exceptionally high, a key attribute for an effective inhibitor.

In vitro assays have demonstrated that Alrizomadlin binds to the MDM2 protein with a half-maximal inhibitory concentration (IC50​) of 3.8 nM and a dissociation constant (Ki​) of less than 1 nM. This sub-nanomolar binding affinity signifies a very strong and specific interaction, allowing the drug to effectively outcompete p53 for binding to MDM2 at clinically achievable concentrations. By physically blocking this interaction, Alrizomadlin destabilizes the MDM2-p53 complex, initiating a cascade of downstream cellular events.

3.2 Downstream Consequences: Reactivation of the p53 Pathway and Induction of Apoptosis

The direct consequence of disrupting the MDM2-p53 complex is the inhibition of p53's degradation. By preventing MDM2 from ubiquitinating p53, Alrizomadlin leads to the stabilization and accumulation of p53 protein within the cancer cell. This rapid increase in the intracellular concentration of functional p53 effectively restores the integrity of the p53 signaling pathway. The reactivated p53 can then translocate to the nucleus, bind to the promoter regions of its target genes, and resume its role as a master transcriptional regulator. This leads to the induction of canonical p53-mediated cellular responses, most notably cell cycle arrest, primarily through the upregulation of the cyclin-dependent kinase inhibitor p21, and the initiation of apoptosis. The ultimate result is the selective elimination of tumor cells that are dependent on MDM2 overexpression for their survival.

3.3 Emerging Mechanisms: From Apoptosis to Inflammatory Cell Death and Immune Modulation

While the induction of classical apoptosis is a central component of Alrizomadlin's antitumor activity, recent research has revealed a more complex and multimodal mechanism of action that includes the induction of a pro-inflammatory form of cell death and direct modulation of the immune system.

3.3.1 Induction of GSDME-Mediated Pyroptosis

Beyond apoptosis, Alrizomadlin has been shown to induce pyroptosis in cancer cells that express the protein Gasdermin E (GSDME). Pyroptosis is a highly inflammatory form of programmed cell death characterized by cell swelling, membrane rupture, and the release of pro-inflammatory intracellular contents. The mechanism linking Alrizomadlin to pyroptosis is an elegant extension of its primary action. The p53 reactivation induced by Alrizomadlin leads to the activation of caspase-3, a key executioner of apoptosis. In GSDME-expressing cells, this activated caspase-3 can cleave GSDME. The N-terminal fragment of cleaved GSDME then oligomerizes and inserts into the plasma membrane, forming large pores that disrupt the osmotic balance, leading to cell lysis. Studies have shown that upon treatment with Alrizomadlin, cancer cells exhibit morphological changes characteristic of pyroptosis and upregulate biomarkers of this pathway, including GSDME cleavage and the release of lactate dehydrogenase (LDH). Interestingly, with prolonged drug exposure, there appears to be a switch from apoptotic to predominantly pyroptotic cell death, suggesting a dynamic process that may have profound implications for the ensuing immune response.

3.3.2 Remodeling the Tumor Microenvironment

Alrizomadlin also exerts direct immunomodulatory effects that reshape the tumor microenvironment (TME) from an immunosuppressive to an immune-active state. Preclinical studies have demonstrated that Alrizomadlin can regulate the polarization of tumor-associated macrophages, promoting a shift away from the immunosuppressive M2 phenotype and toward the pro-inflammatory, antitumor M1 phenotype. Furthermore, treatment with Alrizomadlin has been shown to increase the expression of Programmed Death-Ligand 1 (PD-L1) on tumor cells and promote the activation of CD4+ T cells. This comprehensive remodeling of the TME serves to enhance the host's endogenous antitumor immune response, making the tumor more visible and susceptible to immune-mediated attack.

The discovery of these dual mechanisms—the induction of inflammatory cell death via pyroptosis and the direct remodeling of the TME—provides a powerful, unified biological explanation for the significant clinical synergy observed when Alrizomadlin is combined with immune checkpoint inhibitors (ICIs) like pembrolizumab. ICIs function by releasing the brakes on an existing antitumor T-cell response, but their efficacy is limited in "cold" tumors that lack T-cell infiltration or are dominated by an immunosuppressive microenvironment. Alrizomadlin appears to directly address this limitation. The process begins with the induction of pyroptosis, which causes lytic tumor cell death and the release of damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines into the TME. This release of alarm signals acts as a danger signal to the immune system. Concurrently, Alrizomadlin shifts macrophages toward a pro-inflammatory M1 state and activates T-cells. This combination of events effectively functions as an

in situ vaccine, transforming the TME from "cold" and immunologically ignorant to "hot" and inflamed. A "hot" TME, rich in immune cells and inflammatory signals, is far more susceptible to the T-cell-mediated killing unleashed by ICIs. This mechanistic framework elegantly explains the compelling clinical benefit, including complete responses, observed in patients with ICI-refractory melanoma who were treated with the Alrizomadlin-pembrolizumab combination. Alrizomadlin is not merely killing tumor cells; it is fundamentally altering the immunobiology of the tumor to re-sensitize it to immunotherapy.

3.4 Pharmacodynamic Evidence of Target Engagement in Clinical Studies

Crucially, there is direct clinical evidence confirming that Alrizomadlin engages its target and activates the p53 pathway in patients. Pharmacodynamic analyses from clinical trials have shown that treatment with Alrizomadlin leads to a dose-dependent increase in the plasma levels of Macrophage Inhibitory Cytokine-1 (MIC-1, also known as GDF15). MIC-1 is a well-established downstream transcriptional target of p53. Its elevation in patients' plasma following drug administration serves as a robust pharmacodynamic biomarker, providing clear proof of on-target activity and successful p53 pathway reactivation

in vivo.

Section 4: Preclinical Validation: From Bench to Bedside

4.1 In Vitro Potency in Hematologic and Solid Tumor Cell Lines

The preclinical development of Alrizomadlin was underpinned by extensive in vitro studies that demonstrated its potent and selective activity against cancer cell lines with wild-type TP53. In models of Acute Myeloid Leukemia (AML), Alrizomadlin exhibited significant, dose-dependent inhibitory effects. The measured half-maximal inhibitory concentrations (IC50​) were in the nanomolar range, confirming its high potency: 26.8 nM for the MOLM-13 cell line, 165.9 nM for MV-4-11, and 315.6 nM for OCI-AML-3. This potent anti-proliferative activity was mechanistically linked to the induction of cell cycle arrest and a significant increase in apoptosis in a p53-dependent manner. These foundational studies established the compound's core activity and its dependence on a functional p53 pathway.

4.2 In Vivo Efficacy and Survival Benefit in Xenograft Models

The promising in vitro results were successfully translated into significant antitumor activity in in vivo animal models. Oral administration of Alrizomadlin in various xenograft models demonstrated the ability to achieve not only tumor growth inhibition but also complete and durable tumor regression, a high bar for a preclinical agent. In a particularly compelling study using a systemic xenograft model of MOLM-13 AML, mice treated with Alrizomadlin showed a significant reduction in their overall leukemia burden. This translated directly into a substantial survival benefit, with the median survival time for the treated group being extended by approximately 18.5 days compared to the vehicle-treated control group. These

in vivo studies were critical in validating the oral bioavailability and therapeutic potential of Alrizomadlin, justifying its advancement into human clinical trials.

4.3 Preclinical Synergy: Rationale for Combination Strategies

A key focus of preclinical research has been to identify rational combination strategies to enhance the therapeutic efficacy of Alrizomadlin. These studies have provided a strong biological rationale for the combination regimens currently being explored in clinical trials.

• With Immunomodulatory Drugs (IMiDs): In preclinical models of Multiple Myeloma (MM), a malignancy where the p53 pathway intersects with other critical transcription factor networks, Alrizomadlin demonstrated synergistic antitumor effects when combined with the IMiD pomalidomide. In vitro cell-based assays confirmed synergy against wild-type TP53 MM cell lines. This was further validated in vivo, where co-administration of Alrizomadlin and pomalidomide led to enhanced tumor growth inhibition in MM xenograft models compared to either agent alone. Mechanistically, the combination augmented cell cycle arrest at the G0/G1 phase and enhanced the induction of apoptosis.
• With Other Targeted Agents: The potential for synergy extends to other classes of targeted therapies. A preclinical study in AML models showed that combining Alrizomadlin with the multi-target tyrosine kinase inhibitor anlotinib resulted in a synergistic pro-apoptotic effect. This enhanced activity was observed both in vitro in AML cell lines and in vivo in AML xenograft mouse models, where the combination was more effective at slowing disease progression than either monotherapy.
• With Immunotherapy: Perhaps the most significant area of preclinical synergy was observed with immunotherapy. Foundational preclinical studies demonstrated that combining Alrizomadlin with PD-1 blockade led to a favorable remodeling of the tumor microenvironment. This included an increase in the infiltration of cytotoxic CD8+ T cells and a polarization of macrophages from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype. These findings provided the direct, compelling evidence needed to launch clinical trials investigating Alrizomadlin in combination with immune checkpoint inhibitors, a strategy that has since yielded promising clinical results.

Section 5: Clinical Pharmacology and Pharmacokinetics

5.1 Oral Bioavailability and ADME Profile

Alrizomadlin was specifically designed as an orally active agent to provide a convenient and non-invasive route of administration for patients. Clinical pharmacokinetic (PK) studies in humans have characterized its absorption, distribution, metabolism, and excretion (ADME) profile.

• Absorption: Following oral administration, Alrizomadlin is absorbed, with the time to reach maximum plasma concentration (Tmax​) observed to be between 4.0 and 8.0 hours. This indicates a relatively slow to moderate rate of absorption.
• Distribution: The drug exhibits a relatively limited distribution into tissues, as reflected by a mean apparent volume of distribution (Vd​) ranging from 46.8 to 87.2 liters.
• Metabolism: Alrizomadlin is metabolized in the liver, primarily by the cytochrome P450 3A4 (CYP3A4) enzyme system. This is a critical characteristic as it has implications for potential drug-drug interactions and dosing schedules.
• Elimination: The compound is eliminated from the body with a mean terminal half-life (t½​) that is relatively short, ranging from 3.51 to 6.86 hours. The mean estimated clearance ranged from 4.99 to 10.0 liters per hour across the tested dose levels. This short half-life is advantageous in managing potential toxicities, as the drug does not accumulate significantly over time.

5.2 Key Pharmacokinetic Parameters and Evidence of CYP3A4-Mediated Autoinduction

Within the clinically relevant dose range of 100-200 mg, Alrizomadlin exhibits approximately linear pharmacokinetics after a single administration. This means that increases in dose lead to proportional increases in systemic exposure (as measured by AUC and Cmax​), which simplifies dose selection and adjustment.

A critical and clinically significant pharmacokinetic finding for Alrizomadlin is the evidence of metabolic autoinduction. Studies have revealed a decreasing trend in steady-state plasma exposure following multiple doses compared to the exposure observed after a single dose. This phenomenon is attributed to Alrizomadlin inducing the expression or activity of its own primary metabolizing enzyme, CYP3A4. This autoinduction leads to an accelerated clearance of the drug over time, which could potentially reduce its therapeutic efficacy if not properly managed. This finding has direct and important implications for the design of the optimal clinical dosing regimen. To counteract the effects of autoinduction and maintain effective therapeutic drug concentrations while also managing on-target toxicities, an intermittent dosing schedule is often employed. The recommended Phase II dosing schedule of administration every other day for 21 days followed by a 7-day rest period is a direct clinical application of this pharmacokinetic understanding, aiming to balance sustained target engagement with periods of drug holiday to allow for both hematologic recovery and mitigation of the autoinduction effect.

Section 6: Clinical Efficacy Across the Oncologic Spectrum

6.1 Overview of the Clinical Development Program and Regulatory Status

Alrizomadlin is under active clinical development by Ascentage Pharma, a global biopharmaceutical company, and stands as a cornerstone of their apoptosis-targeted pipeline. It holds the distinction of being the first MDM2-p53 inhibitor to enter clinical trials in China, highlighting its position at the forefront of this therapeutic class in the region. The development program has advanced to Phase 2, investigating the drug's efficacy and safety across a diverse range of malignancies.

In recognition of its potential to address significant unmet medical needs, Alrizomadlin has received multiple special designations from the U.S. Food and Drug Administration (FDA). These include:

• Fast Track Designation: For the treatment of relapsed or refractory unresectable or metastatic melanoma.
• Orphan Drug Designation: For several indications, including the treatment of stage IIB-IV melanoma.
• Rare Pediatric Disease Designation: For the treatment of neuroblastoma, a designation that can confer a priority review voucher upon approval.

These designations are intended to expedite the development and regulatory review process for promising drugs targeting serious conditions.

6.2 Phase I Studies: Establishing Safety and the Recommended Phase II Dose (RP2D)

The first-in-human clinical evaluation of Alrizomadlin was conducted in a Phase I dose-escalation study (NCT02935907, completed) in patients with advanced solid tumors or lymphomas who had exhausted standard therapeutic options. The primary objectives of this study were to determine the safety profile, identify dose-limiting toxicities (DLTs), and establish the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D).

The study successfully established an MTD of 150 mg and an RP2D of 100 mg, administered orally every other day (q.o.d.) on a 21-days-on, 7-days-off schedule within a 28-day cycle. In addition to defining the safety parameters, this initial study provided compelling early evidence of antitumor activity. The activity was most pronounced in the patient population predicted to be most sensitive based on the drug's mechanism of action: those with tumors harboring

MDM2 gene amplification and wild-type TP53. Within this specific molecularly-defined subgroup (n=8), the objective response rate (ORR) was 25% (2 partial responses), and remarkably, the disease control rate (DCR), which includes stable disease, was 100%. These early results provided strong proof-of-concept for the therapeutic strategy and justified the advancement of Alrizomadlin into broader Phase 2 development.

6.3 Phase II Efficacy Analysis in Solid Tumors

Building on the promising Phase I data, the Phase 2 program has explored Alrizomadlin, primarily in combination regimens, across several difficult-to-treat solid tumors.

6.3.1 Immuno-Oncology (IO) Refractory Melanoma

A key area of investigation has been in patients with advanced melanoma who have progressed on or are refractory to immune checkpoint inhibitors, a population with a major unmet need. In a multicenter Phase 2 study (NCT03611868), Alrizomadlin (150 mg q.o.d., 2 weeks on/1 week off) was combined with the anti-PD-1 antibody pembrolizumab. The combination demonstrated clinically meaningful efficacy in this heavily pre-treated population. Across reports from this study, the confirmed ORR was consistently in the range of 23.1% to 24.1%, with a DCR of 55.2%. Critically, the responses included cases of complete response (CR), indicating that the combination has the potential to induce deep and durable remissions and successfully overcome resistance to prior immunotherapy. Efficacy was observed across various melanoma subtypes, including cutaneous, mucosal, and uveal melanoma, suggesting broad applicability within this disease.

6.3.2 Sarcomas: Liposarcoma (LPS) and Malignant Peripheral Nerve Sheath Tumor (MPNST)

Sarcomas, particularly those with a high prevalence of MDM2 amplification like liposarcoma, represent a rational target for Alrizomadlin. Early-phase trials showed signals of activity in LPS. A subsequent Phase 2 study conducted in China (NCT04785196), which evaluated Alrizomadlin in combination with the anti-PD-1 antibody toripalimab, reported an ORR of 16.7% and a DCR of 66.7% in patients with advanced LPS.

In Malignant Peripheral Nerve Sheath Tumor (MPNST), a rare and particularly aggressive soft tissue sarcoma with very limited effective therapies, Alrizomadlin has shown notable promise. The combination with pembrolizumab in the NCT03611868 trial yielded a clinical benefit rate (CBR, defined as ORR + stable disease for ≥ 4 cycles) of 53%. Even more striking results came from the NCT04785196 trial with toripalimab, where the combination produced two confirmed partial responses (PRs) in MPNST patients. These responses were exceptionally durable, with progression-free survival (PFS) exceeding 60 weeks in one patient and 96 weeks in the other, demonstrating the potential for long-term disease control in this challenging malignancy.

6.3.3 Rare Tumors: Adenoid Cystic Carcinoma (ACC) and Salivary Gland Carcinoma

Alrizomadlin has also been investigated in rare tumors where new therapeutic options are urgently needed. In the Phase 2 study NCT04785196, Alrizomadlin administered as a monotherapy demonstrated encouraging activity in patients with advanced Adenoid Cystic Carcinoma (ACC). In this cohort, the ORR was reported to be between 16.7% and 22.2%, with a DCR of 100%, indicating that all treated patients derived at least disease stabilization from the therapy. This level of activity for a single agent is significant in ACC, a typically slow-growing but relentless cancer with few effective systemic treatments.

Furthermore, a dedicated trial (NCT03781986) is evaluating Alrizomadlin, both as a single agent and in combination with platinum-based chemotherapy, specifically in patients with TP53 wild-type salivary gland carcinoma, a group that includes ACC.

6.4 Efficacy in Hematologic Malignancies

6.4.1 Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)

The clinical development of Alrizomadlin extends to hematologic malignancies, building on strong preclinical data. An ongoing Phase 1b trial is assessing the safety and efficacy of Alrizomadlin, both as a monotherapy and in combination with the hypomethylating agent azacitidine (AZA), in patients with relapsed/refractory (R/R) AML or higher-risk MDS.

Preliminary results from this study are promising. As a monotherapy (at an RP2D of 200 mg daily for 7 days), Alrizomadlin achieved an ORR of 25% in patients with R/R AML. The combination with AZA also demonstrated clinical activity. Importantly, responses were observed in patients whose disease had failed prior treatment with venetoclax-based regimens, a setting of high unmet need, suggesting that Alrizomadlin could offer a new therapeutic option for this refractory population.

6.5 The Power of Combination: Synergistic Activity with Immunotherapy and Chemotherapy

A consistent theme emerging from the comprehensive clinical development program is that the full potential of Alrizomadlin may be best realized through rational combination therapies. The synergy with immune checkpoint inhibitors (pembrolizumab and toripalimab) is the most mature and compelling finding to date, with strong evidence of overcoming immunotherapy resistance in melanoma and inducing durable responses in sarcomas. This clinical success is strongly supported by the preclinical and mechanistic understanding of Alrizomadlin's immunomodulatory effects. Concurrently, active investigations into combinations with standard-of-care agents like platinum chemotherapy (in salivary gland cancer) and hypomethylating agents (in AML/MDS) are underway, aiming to broaden the therapeutic utility of p53 reactivation across a wider range of oncologic settings.

Table 2: Summary of Major Clinical Trials for Alrizomadlin

NCT Identifier	Trial Title/Description	Phase	Condition(s) Treated	Regimen(s)	Status	Key Efficacy Results/Endpoints	Source(s)
NCT02935907	APG-115 in Patients With Advanced Solid Tumors or Lymphomas	1	Advanced Solid Tumors, Lymphoma	Alrizomadlin Monotherapy	Completed	Established MTD (150 mg) and RP2D (100 mg q.o.d.). ORR 25% and DCR 100% in MDM2-amplified/TP53-WT subgroup.
NCT03611868	Study of Alrizomadlin (APG-115) With Pembrolizumab in Advanced Tumors	2	Unresectable/Metastatic Melanoma (IO-failed), MPNST, LPS, other Solid Tumors	Alrizomadlin + Pembrolizumab	Active, Not Recruiting	Melanoma: ORR 23.1-24.1%, DCR 55.2%. MPNST: Clinical Benefit Rate 53%.
NCT04785196	Study of Alrizomadlin (APG-115) With or Without Toripalimab in Advanced Tumors	2	ACC, MPNST, LPS, Biliary Tract Cancer (BTC)	Alrizomadlin Monotherapy; Alrizomadlin + Toripalimab	Recruiting	ACC (Mono): ORR 16.7-22.2%, DCR 100%. MPNST (Combo): 2 durable PRs (PFS >60 & >96 wks). LPS (Combo): ORR 16.7%, DCR 66.7%. BTC (Combo): ORR 20%, DCR 80%.
NCT03781986	Study of Alrizomadlin (APG-115) With or Without Platinum Chemotherapy in Salivary Gland Carcinoma	1/2	TP53 Wild-Type Salivary Gland Carcinoma	Alrizomadlin Monotherapy; Alrizomadlin + Carboplatin	Active, Not Recruiting	Primary endpoints: DLT, MTD, ORR.
Not Specified	Study of APG-115 Alone or Combined With Azacitidine in Patients With AML, CMML, or MDS	1b	R/R AML, CMML, MDS	Alrizomadlin Monotherapy; Alrizomadlin + Azacitidine	Active	AML (Mono): ORR 25%. Responses observed in venetoclax-failed patients.

Section 7: Comprehensive Safety and Tolerability Profile

7.1 Analysis of the Treatment-Related Adverse Event (TRAE) Profile

The safety and tolerability of Alrizomadlin have been characterized across multiple clinical trials, both as a monotherapy and in combination with other anticancer agents. The profile of treatment-related adverse events (TRAEs) is consistent across studies and is dominated by predictable gastrointestinal and hematologic toxicities.

The most frequently reported any-grade TRAEs across the clinical program are nausea, which is very common, with an incidence ranging from 62% to 73% in combination studies. Other common events (typically occurring in ≥20% of patients) include thrombocytopenia (32-65%), vomiting (33-39%), fatigue (31-38%), decreased appetite (27-46%), diarrhea (21-33%), and neutropenia (15-50%). While generally manageable with supportive care, the high incidence of these events, particularly nausea, requires proactive management to ensure patient compliance and quality of life.

7.2 Management of Key On-Target Toxicities: Hematologic Events

The most clinically significant and dose-limiting toxicities associated with Alrizomadlin are hematologic. Grade 3 or higher TRAEs are predominantly hematologic in nature, with thrombocytopenia (platelet count decreased) and neutropenia (neutrophil count decreased) being the most common severe events. The incidence of Grade ≥3 thrombocytopenia has been reported in the range of 9% to 38.5%, while Grade ≥3 neutropenia has been observed in 10% to 36.4% of patients across various trials and regimens. Grade ≥3 anemia is also a frequent finding, with an incidence of 7% to 23.8%.

The safety profile, and specifically the pronounced hematologic toxicity, is a direct and predictable consequence of the drug's on-target mechanism of action. Alrizomadlin causes systemic reactivation of p53, not just within tumor cells but also in normal tissues. Hematopoietic stem and progenitor cells in the bone marrow are highly sensitive to p53 activation, which plays a crucial role in regulating their cell cycle and survival. The potent activation of p53 in these cells by Alrizomadlin can induce cell cycle arrest or apoptosis, leading to a temporary suppression of hematopoiesis. This results in the observed cytopenias (thrombocytopenia, neutropenia, anemia). This is therefore a classic "on-target" toxicity—an unavoidable consequence of the desired therapeutic mechanism. This mechanistic understanding is fundamental to the clinical management of the drug. It explains why these toxicities are consistently the most common and dose-limiting, and it provides the clear rationale for employing intermittent dosing schedules (e.g., 2 weeks on, 1 week off). This drug holiday allows the bone marrow sufficient time to recover between treatment cycles, thereby making the hematologic toxicity manageable and permitting long-term administration of the drug.

7.3 Dose-Limiting Toxicities (DLTs) and Serious Adverse Events (SAEs)

The dose-limiting toxicity for Alrizomadlin was formally identified in the first-in-human dose-escalation study. At a dose of 200 mg, a patient experienced Grade 4 thrombocytopenia and febrile neutropenia, which met the criteria for a DLT. This event was instrumental in establishing the MTD at 150 mg and selecting the lower dose of 100 mg as the RP2D for monotherapy in solid tumors, prioritizing patient safety and tolerability for further development.

Serious adverse events (SAEs) have been reported in a minority of patients. While most are related to the expected severe hematologic toxicities, other less common but notable SAEs have included pulmonary embolism, colitis, pyrexia (fever), asthenia, and, in rare instances, posterior reversible encephalopathy syndrome (PRES). The rate of treatment discontinuation due to adverse events is generally low, reported at 3.8% in one cohort of a Phase 2 study and 5 out of 84 patients (6%) in another, suggesting that for most patients, the adverse events are manageable without necessitating cessation of therapy.

Table 3: Incidence of Common (≥10%) and Severe (Grade ≥3) Treatment-Related Adverse Events Across Key Trials

Adverse Event	Regimen	Any Grade Incidence (%)	Grade ≥3 Incidence (%)	Source(s)
Nausea	Alrizomadlin + Pembrolizumab	63.1 - 71.0	Not specified
	Alrizomadlin Monotherapy	68.2	0
Thrombocytopenia	Alrizomadlin + Pembrolizumab	32.3 - 39.0	20.2 - 23.0
	Alrizomadlin Monotherapy	33.3 - 40.9	9.1 - 33.3
Vomiting	Alrizomadlin + Pembrolizumab	33.3 - 38.7	Not specified
Fatigue	Alrizomadlin + Pembrolizumab	31.0 - 38.0	< 5
Neutropenia	Alrizomadlin + Pembrolizumab	15.4 - 19.4	10.0 - 14.2
	Alrizomadlin Monotherapy	23.8 - 36.4	13.6 - 23.8
Anemia	Alrizomadlin + Pembrolizumab	11.9 - 37.5	7.0 - 8.3
	Alrizomadlin Monotherapy	23.8	23.8
Diarrhea	Alrizomadlin + Pembrolizumab	21.4 - 33.3	< 5
Decreased Appetite	Alrizomadlin + Pembrolizumab	16.1 - 29.0	Not specified
	Alrizomadlin Monotherapy	45.5	0
Lymphocytopenia	Alrizomadlin Monotherapy	42.9	33.3

Note: Incidence ranges are compiled from multiple studies and cohorts, which may have different patient populations and follow-up times. This table represents a general overview of the safety profile.

Section 8: Synthesis, Strategic Outlook, and Expert Recommendations

8.1 Integrated Assessment: Alrizomadlin's Position in the Therapeutic Armamentarium

Alrizomadlin has emerged as a clinically promising targeted therapy that validates the long-held hypothesis of reactivating p53 as a viable anticancer strategy. Its position in the therapeutic landscape is defined by a clear mechanism of action, a well-defined target patient population, and a demonstrated ability to synergize with other potent therapeutic modalities, most notably immunotherapy. The strength of Alrizomadlin lies in its precision. Its efficacy is intrinsically linked to a specific genetic context—wild-type TP53 status, often coupled with MDM2 amplification—which allows for a biomarker-driven approach to patient selection, maximizing the potential for clinical benefit. The most significant advance demonstrated by its clinical program is the ability of the Alrizomadlin-ICI combination to overcome acquired resistance to immunotherapy, a major challenge in modern oncology. This suggests a role for Alrizomadlin not just as a direct cytotoxic agent, but as a potent immunomodulator capable of re-sensitizing tumors to immune-mediated attack. The primary liability of the drug is its significant and predictable on-target hematologic toxicity. While this requires careful monitoring and management through intermittent dosing, its predictability is a clinical advantage, allowing for proactive supportive care measures to maintain patients on therapy.

8.2 Future Directions: Biomarker Development and Optimization of Combination Regimens

The future development and ultimate success of Alrizomadlin will depend on the continued refinement of its strategic application. The most critical path forward involves the expansion and validation of predictive biomarkers. While wild-type TP53 and MDM2 amplification are the foundational biomarkers, further investigation is warranted. The preclinical finding that GSDME expression is linked to Alrizomadlin-induced pyroptosis suggests that GSDME could be explored as a potential predictive biomarker for synergy with ICIs. Patients whose tumors express high levels of GSDME may be more likely to experience the "cold-to-hot" TME conversion and thus derive greater benefit from the combination.

Further research should also focus on optimizing combination regimens. While the synergy with PD-1 inhibitors is well-established, exploring combinations with other immune-oncology agents, such as LAG-3 or CTLA-4 inhibitors, may yield even greater benefit. Additionally, understanding the optimal sequencing of Alrizomadlin with other therapies will be crucial. Its potential utility in earlier lines of therapy, or even in the neoadjuvant or adjuvant settings to prime an immune response before surgery or subsequent treatment, represents an important area for future clinical trials. Finally, continued exploration in hematologic malignancies, particularly in combination with novel agents beyond azacitidine, could uncover new areas of high clinical impact.

8.3 Concluding Remarks on the Potential of p53 Reactivation Therapy

For decades, the p53 pathway was considered one of the most important yet "undruggable" targets in oncology. The clinical development of potent and selective small-molecule inhibitors of the MDM2-p53 interaction, exemplified by Alrizomadlin, represents a paradigm shift. Alrizomadlin has provided compelling clinical proof-of-concept that restoring the function of the "guardian of the genome" is not only feasible but can lead to meaningful and durable antitumor responses in patients with advanced cancers. Its journey through preclinical and clinical development has yielded crucial insights into the complexities of p53 biology, the intricacies of on-target toxicity management, and the powerful interplay between targeted therapy and the immune system. As Alrizomadlin and other agents in its class continue to advance, they hold the promise of establishing p53 reactivation as a new and essential pillar of cancer therapy.

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