Devimistat (CPI-613): A Comprehensive Monograph on a First-in-Class Mitochondrial Metabolism Inhibitor

Executive Summary

Devimistat (CPI-613) is a first-in-class, investigational small molecule drug designed to exploit the unique metabolic vulnerabilities of cancer cells. As a synthetic lipoic acid analogue, its novel mechanism of action involves the simultaneous inhibition of two critical enzymes in the mitochondrial tricarboxylic acid (TCA) cycle: the pyruvate dehydrogenase complex (PDH) and the α-ketoglutarate dehydrogenase complex (KGDH). This dual blockade was engineered to cut off the primary energy and biosynthetic pathways fueled by both glucose and glutamine, leading to catastrophic metabolic stress and selective death of tumor cells. The compelling scientific rationale, coupled with impressive preclinical data and exceptionally promising early-phase clinical results—including a 61% objective response rate in metastatic pancreatic cancer and a 52% complete remission rate in older patients with acute myeloid leukemia (AML)—generated significant optimism within the oncology community and garnered extensive regulatory support, including multiple Fast Track and Orphan Drug designations from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Despite this strong foundation, Devimistat failed to demonstrate clinical efficacy in two large, global, pivotal Phase 3 trials. The AVENGER 500 study in metastatic pancreatic cancer and the ARMADA 2000 study in relapsed/refractory AML both failed to meet their primary endpoints, showing no improvement in overall survival or remission rates compared to standard-of-care chemotherapy. The drug was well-tolerated, and the failures were definitively attributed to a lack of efficacy rather than toxicity. The stark disconnect between its early promise and late-stage failure provides a critical case study on the challenges of translating metabolic cancer therapies from the laboratory to the clinic. This report provides a comprehensive analysis of Devimistat, detailing its chemical properties, mechanism of action, full clinical development history, safety profile, and regulatory journey. It critically examines the potential reasons for its clinical failure, including tumor heterogeneity and metabolic plasticity, and discusses the broader implications for the future of metabolic oncology.

Section 1: Drug Profile and Physicochemical Characteristics

This section provides the foundational chemical and physical data for Devimistat, establishing its identity as a distinct molecular entity.

1.1 Identification and Nomenclature

Devimistat is an investigational small molecule that has been identified through a variety of nomenclature and coding systems during its development. Ensuring unambiguous identification is critical for scientific and regulatory tracking.

• Generic Name: Devimistat [1]
• Development Codes: The most common code used throughout its development is CPI-613. Variations such as CPI 613 and CPI613 are also used interchangeably in literature and clinical trial documentation.[1]
• Proposed Brand Name: Bylantra [5]
• Database Identifiers:
• DrugBank ID: DB12109 [1]
• CAS Number: 95809-78-2 [3]
• Chemical Synonyms: The compound is chemically described as 6,8-bis(benzylthio)octanoic acid. An alternative synonym is 6,8-bis-benzylsulfanyl-octanoic acid.[1]

1.2 Chemical Structure and Properties

Devimistat's molecular structure is central to its function, as it was rationally designed to mimic a natural cofactor involved in mitochondrial metabolism.

• Chemical Formula: C22​H28​O2​S2​ [1]
• Molecular Weight: The average molecular weight is reported as 388.58 Da to 388.59 Da. The precise monoisotopic mass is 388.1531 Da.[1]
• Structural Description: Devimistat is a synthetic analogue of alpha-lipoic acid and is administered as a racemic mixture of its enantiomers.[3] Structurally, it is a medium-chain fatty acid, specifically an octanoic acid derivative featuring two benzylthio groups ($ -S-CH_{2}-C_{6}H_{5} $) at the 6 and 8 positions of the carbon chain.[1] This structure is the key to its biological activity, as lipoic acid is a natural cofactor for the enzymes Devimistat targets. The design as a molecular mimic allows it to interact with and disrupt specific biological processes. Uniquely, both enantiomers within the racemic mixture have been shown to possess antineoplastic activity, which suggests that the binding interactions at its molecular targets may not be highly stereospecific, or that both forms are metabolized into a common active species. This characteristic simplifies manufacturing by obviating the need for costly chiral separation.[4]

1.3 Physical and Formulation Characteristics

The physical properties of Devimistat dictate its handling, formulation, and route of administration in clinical settings.

• Appearance: The drug substance is a white solid powder.[3]
• Solubility: It is soluble in organic solvents like dimethyl sulfoxide (DMSO) and in aqueous alkaline solutions such as 0.1N sodium hydroxide (NaOH), which facilitates its preparation for laboratory use and intravenous formulation.[7]
• Administration: In all clinical trials, Devimistat has been administered as an intravenous (IV) infusion. The concentrated drug product is diluted, typically with dextrose 5% in water (D5W), and infused via a central venous catheter.[8]
• Storage and Stability: For long-term preservation, storage at -20°C is recommended. For short-term use, refrigeration at 0–4°C is sufficient. The compound is stable enough for shipment at ambient temperatures.[3]

Property	Value	Source(s)
Generic Name	Devimistat	1
Development Code	CPI-613	1
DrugBank ID	DB12109	1
CAS Number	95809-78-2	3
Chemical Formula	C22​H28​O2​S2​	1
Molecular Weight	Average: 388.59 Da; Monoisotopic: 388.1531 Da	1
IUPAC Name	6,8-bis(benzylthio)octanoic acid	3
Structural Class	Small Molecule; Medium-chain fatty acid; Lipoic acid analogue	1
Stereochemistry	Racemic mixture	3
Appearance	White solid powder	3
Solubility	Soluble in DMSO and 0.1N NaOH(aq)	7
Route of Administration	Intravenous (IV) infusion	8

Section 2: Mechanism of Action: A Novel Approach to Targeting Cancer Metabolism

The therapeutic concept behind Devimistat is rooted in exploiting one of the fundamental hallmarks of cancer: the reprogramming of cellular energy metabolism. Its mechanism of action is distinct from traditional cytotoxic agents and represents a sophisticated strategy aimed at selectively shutting down the mitochondrial powerhouse of tumor cells.

2.1 The Rationale: Targeting Altered Cancer Metabolism

Unlike normal cells, which primarily rely on mitochondrial oxidative phosphorylation for energy, many cancer cells exhibit profound metabolic alterations to support their demands for rapid growth, proliferation, and survival.[10] This includes an increased reliance on both glycolysis (the Warburg effect) and mitochondrial processes to generate ATP and the biosynthetic precursors needed for creating new cells.[10] This altered metabolic state creates unique dependencies that are not present in healthy tissues, offering a therapeutic window for drugs designed to selectively target these rewired pathways.[10] Devimistat was conceived as a first-in-class therapeutic agent to attack this metabolic vulnerability at its core.[5]

2.2 Dual Inhibition of Key TCA Cycle Enzymes

Devimistat's primary mechanism is the simultaneous disruption of two central, rate-limiting enzyme complexes within the tricarboxylic acid (TCA) cycle, a critical hub of cellular metabolism located in the mitochondria.

• Primary Targets: The drug is a dual inhibitor of the Pyruvate Dehydrogenase Complex (PDH) and the α-Ketoglutarate Dehydrogenase Complex (KGDH), also known as the 2-oxoglutarate dehydrogenase complex (OGDH).[3] These two complexes represent the main entry points for carbon substrates into the TCA cycle: PDH channels carbons from glucose (via pyruvate), while KGDH channels carbons from glutamine (via glutaminolysis).[15]
• Molecular Mechanism: Devimistat does not function as a conventional competitive inhibitor. As a structural analogue of lipoic acid, it mimics the natural acylated catalytic intermediates that are transiently formed during the enzymes' normal function.[15] In cancer cells, the regulatory systems that monitor these intermediates and control enzyme activity are known to be significantly altered or "reconfigured".[16] Devimistat exploits this by acting as a fraudulent signal, effectively "misinforming" these aberrant tumor-specific regulatory networks.[19]
• Inhibition of PDH: Devimistat selectively hyper-activates the tumor-specific forms of pyruvate dehydrogenase kinases (PDKs). These kinases then phosphorylate and inactivate the PDH complex, blocking the conversion of pyruvate to acetyl-CoA.[8]
• Inhibition of KGDH: Concurrently, Devimistat inactivates the KGDH complex. It achieves this by hyper-activating an endogenous redox feedback loop that controls KGDH activity, a mechanism that is also uniquely dysregulated in tumor cells.[18]

The power of this dual-targeting strategy, in theory, lies in its capacity to create a robust metabolic blockade that is difficult for cancer cells to bypass. However, its efficacy is critically dependent on the tumor possessing the exact "reconfigured" regulatory machinery that renders it vulnerable. The vast heterogeneity and metabolic plasticity of cancer suggest that many tumors in a broad patient population may lack this specific phenotype, potentially explaining the disconnect between early-phase promise and late-stage failure.

2.3 Downstream Cellular Effects and Induction of Cell Death

The simultaneous shutdown of PDH and KGDH starves the TCA cycle of its primary fuel sources, leading to a rapid and catastrophic collapse of mitochondrial function.[14] This primary metabolic insult triggers a cascade of downstream cellular events:

• Mitochondrial Stress: The drug induces severe mitochondrial stress, characterized by the disruption of the mitochondrial membrane potential, impairment of mitochondrial respiration, and a dramatic reduction in ATP synthesis.[18] In vitro studies using transmission electron microscopy have visualized this effect, showing that Devimistat causes a dramatic reduction in mitochondrial cristae junctions in pancreatic cancer cells.[3]
• Induction of Cell Death: The profound metabolic crisis triggers multiple, apparently redundant, cell death pathways, ensuring a high probability of cell killing.[14] This includes programmed cell death (apoptosis), evidenced by the activation of Caspase 3 and the cleavage of PARP, as well as non-apoptotic, necrosis-like cell death.[3]

2.4 Hypothesized Tumor Selectivity

A key feature of Devimistat's design is its intended selectivity for cancer cells over healthy tissues, which is attributed to several factors. This selectivity is crucial for achieving a favorable therapeutic index.

• Altered Regulatory Networks: The primary basis for selectivity is the altered configuration of the PDH and KGDH regulatory systems in cancer cells. These rewired networks are uniquely susceptible to the false signaling induced by Devimistat, whereas the regulatory systems in normal cells are not.[16]
• Preferential Uptake and Retention: It is hypothesized that cancer cells preferentially take up and retain Devimistat compared to normal cells, further concentrating its activity within the tumor.[18]
• Empirical Evidence: This hypothesis is supported by preclinical data. In studies on colorectal cancer models, normal human colonic epithelial cells were found to be significantly more resistant to Devimistat's cytotoxic effects than colorectal cancer cells, providing direct evidence of its tumor-selective action.[22]

The sophisticated, information-based mechanism of "misinforming" a cell's regulatory network represents a departure from traditional enzyme inhibition. While the clinical failure of Devimistat was a significant setback, it does not invalidate this elegant pharmacological approach. Instead, it underscores the immense challenge of applying such a context-dependent strategy without robust predictive biomarkers to identify the patient populations with the correct "reconfigured" cellular state necessary for drug sensitivity.

Section 3: Preclinical Evidence and Therapeutic Rationale

The progression of Devimistat into extensive clinical trials was underpinned by a strong body of preclinical evidence demonstrating its anti-tumor activity, tumor selectivity, and, most importantly, its ability to synergize with standard-of-care chemotherapies.

3.1 In Vitro Efficacy

Devimistat demonstrated potent and broad-spectrum anti-cancer activity in a variety of cell culture models, validating its mechanism of action at the cellular level.

• Activity in Pancreatic Cancer: In pancreatic ductal adenocarcinoma (PDAC) cell lines, such as AsPC-1 and PANC-1, Devimistat effectively inhibited cell viability and proliferation in a dose-dependent manner in both traditional 2D monolayers and more physiologically relevant 3D culture systems.[3] Mechanistically, this was linked to its ability to disrupt mitochondrial morphology and induce key markers of apoptosis.[3]
• Activity in Colorectal Cancer: Studies using a panel of colorectal cancer cell lines and patient-derived cultures showed that Devimistat exerted consistent cytotoxicity, irrespective of the cells' genetic or epigenetic status. This broad activity was coupled with evidence of tumor selectivity, as normal human colonic epithelial cells proved more resistant.[22]
• Synergistic Activity with Chemotherapy: A critical component of the preclinical rationale was the observation that Devimistat could enhance the efficacy of conventional chemotherapy. Studies demonstrated a powerful synergistic effect when Devimistat was combined with genotoxic agents like 5-fluorouracil (5-FU) and irinotecan, two of the main components of the FOLFIRINOX regimen.[22] This synergy was shown to be mediated through the downregulation of anti-apoptotic genes and a marked accumulation of the pro-apoptotic protein Bim, providing a clear molecular basis for combining Devimistat with these agents in the clinic.[22]

3.2 In Vivo and Xenograft Model Efficacy

The promising in vitro results were successfully translated into animal models, confirming Devimistat's anti-tumor activity and tolerability in a living system.

• Monotherapy Activity: In xenograft models using human non-small cell lung and pancreatic cancer cells, Devimistat demonstrated strong anti-tumor activity as a single agent, and importantly, did so with low associated toxicity.[3]
• Combination Therapy In Vivo: The synergy observed in vitro was replicated in vivo. In a human colorectal cancer xenograft mouse model, the combination of Devimistat and irinotecan resulted in significantly enhanced therapeutic efficacy and prolonged survival compared to either agent alone.[22] This finding was crucial, as it provided the direct, evidence-based hypothesis that adding Devimistat to a FOLFIRINOX-based regimen would improve patient outcomes. The failure of this specific, well-supported hypothesis to translate from these preclinical models to the Phase 3 clinical trial in pancreatic cancer highlights the profound challenges of bench-to-bedside translation in oncology.
• Targeting Cancer Stem Cells: Beyond general tumor debulking, Devimistat showed evidence of targeting the cancer stem cell (CSC) population. In an ovarian cancer xenograft model, treatment with Devimistat led to a decrease in the frequency of cells expressing CSC markers (CD133+ and CD117+). This suggested a potential to eradicate the highly resistant cells responsible for tumor relapse and metastasis, adding another layer to its therapeutic rationale.[3]

Section 4: Clinical Pharmacology and Pharmacokinetics

The study of how Devimistat is absorbed, distributed, metabolized, and eliminated by the human body is essential for understanding its clinical behavior, determining appropriate dosing regimens, and identifying potential drug-drug interactions. Available data, while limited, reveals key characteristics of its pharmacokinetic profile.

4.1 Pharmacokinetic (PK) Profile

Data from Phase 1 clinical trials have provided initial parameters for Devimistat's pharmacokinetics in humans.

• Half-life (T1/2​): A defining feature of Devimistat is its very short plasma half-life. Reported values range from approximately 0.52 hours to 1.34 hours.[8] This rapid clearance from the bloodstream implies that the drug's direct inhibitory effects on mitochondrial enzymes are transient.
• Maximum Concentration (Cmax​): Following a multi-day intravenous dosing regimen of 500 mg/m², a peak plasma concentration (Cmax​) of 82.66 ng/mL was observed in patients.[8]
• Dosing Regimens: The short half-life necessitated intravenous administration to achieve therapeutic concentrations. Dosing schedules varied by indication and trial phase. For the AVENGER 500 trial in pancreatic cancer, a dose of 500 mg/m² was infused over two hours on days 1 and 3 of each 14-day cycle.[9] In trials for hematologic malignancies and other tumors, significantly higher doses, ranging from 2000 mg/m² to 3000 mg/m², were administered on days 1 and 4 of each treatment week.[8]

The very short half-life of Devimistat may represent a critical, and perhaps underappreciated, factor in its clinical failure. The intermittent dosing schedule used in the pivotal trials, particularly the long 11-day drug-free interval in the 14-day pancreatic cancer regimen, means that the metabolic blockade of the TCA cycle was not sustained. Given the known metabolic plasticity of cancer cells, it is highly plausible that this pulsed inhibition was insufficient to induce irreversible cell death, allowing tumors to recover their metabolic function and resume proliferation between doses. This potential mismatch between the drug's pharmacokinetics (transient exposure) and the biological requirement for sustained metabolic pressure may be a key reason for the lack of efficacy observed in Phase 3.

4.2 Metabolism and Drug-Drug Interactions (DDI)

Detailed information on the metabolic fate of Devimistat in humans is not extensively published. However, initial characterization suggests it is a substrate for several key drug-metabolizing enzymes.

• Metabolism: Devimistat has been identified as a substrate for cytochrome P450 enzymes, including CYP3A4 and CYP2C9, which are major pathways for the metabolism of many pharmaceuticals.[8]
• Drug-Drug Interactions: The potential for clinically significant DDIs exists. A preclinical study in mice investigating the co-administration of Devimistat with another therapeutic agent (NBV) demonstrated a significant impact on Devimistat's pharmacokinetics. In the combination group, the clearance of Devimistat was significantly decreased, leading to a corresponding and significant increase in its total exposure (AUC).[29] This finding indicates that concomitant medications could alter Devimistat exposure, a factor that would require careful management in clinical practice.

Section 5: Clinical Development and Efficacy Analysis

The clinical development of Devimistat is a compelling narrative of extraordinary early-phase promise followed by definitive late-stage failure. An in-depth analysis of its clinical trial program, particularly the two pivotal Phase 3 studies, is essential to understand its trajectory and the lessons it offers for the field of metabolic oncology.

5.1 Overview of Clinical Program

Devimistat has been evaluated in an extensive clinical program, with over 20 completed or ongoing trials investigating its utility across a wide spectrum of cancers.[18] The program has explored its use in both solid tumors—including pancreatic, biliary tract, colorectal, and lung cancer—and hematological malignancies, such as acute myeloid leukemia (AML), various lymphomas, and myelodysplastic syndromes (MDS).[1] This broad investigation culminated in two large, international Phase 3 trials in metastatic pancreatic cancer and relapsed/refractory AML.[6]

5.2 Indication: Metastatic Pancreatic Adenocarcinoma

Pancreatic cancer was a primary focus for Devimistat, given the disease's known reliance on mitochondrial metabolism and the profound unmet need for more effective therapies.

5.2.1 Early Phase Promise

The initial clinical data for Devimistat in pancreatic cancer were nothing short of spectacular. A single-center, open-label, Phase 1 dose-escalation trial combined Devimistat with a modified FOLFIRINOX (mFFX) regimen in previously untreated patients with metastatic pancreatic cancer. The results were highly encouraging: the combination was found to be safe and tolerable, and at the established maximum tolerated dose (MTD) of 500 mg/m², it produced an objective response rate (ORR) of 61%, which included a 17% complete response (CR) rate.[15] This efficacy signal was substantially higher than that typically seen with standard FOLFIRINOX and provided a robust and compelling rationale to advance directly into a large-scale confirmatory Phase 3 study.

5.2.2 The AVENGER 500 Phase 3 Trial (NCT03504423)

The AVENGER 500 trial was designed to definitively validate the promising Phase 1 results.

• Design: A global, randomized, open-label trial that enrolled 528 treatment-naïve patients with metastatic pancreatic adenocarcinoma. Patients were randomized to receive either Devimistat (500 mg/m² IV on days 1 and 3) plus mFFX or standard-dose FFX in 14-day cycles.[15]
• Primary Endpoint: The primary measure of efficacy was Overall Survival (OS).
• Outcome: Definitive Failure. The trial unequivocally failed to meet its primary endpoint. The addition of Devimistat to mFFX did not improve survival. The median OS was 11.10 months in the Devimistat arm compared to 11.73 months in the control FFX arm (Hazard Ratio 0.95; 95% CI, 0.77 to 1.18; p=0.655).[27]
• Secondary Endpoints: No benefit was observed in any secondary efficacy measures. Median progression-free survival (PFS) was nearly identical between the arms (7.82 months vs. 7.98 months), as was the ORR (39.1% vs. 34.4%).[33]
• Conclusion: The study concluded that Devimistat, when added to mFFX, provided no clinical benefit over standard FFX for patients with metastatic pancreatic cancer.[27] The trial was subsequently discontinued due to this clear lack of efficacy.[34]

5.3 Indication: Acute Myeloid Leukemia (AML)

Similar to pancreatic cancer, the development program in AML was driven by a strong biological rationale and highly encouraging early clinical data.

5.3.1 Rationale and Early Phase Data

AML cells are known to upregulate the TCA cycle in response to the DNA damage caused by chemotherapy, suggesting that inhibiting this metabolic pathway could increase their sensitivity to treatment.[17] Early-phase studies of Devimistat combined with high-dose cytarabine and mitoxantrone (HAM) in older patients (≥60 years) with relapsed or refractory (R/R) AML produced remarkable results. A pooled analysis of Phase 1 and 2 data demonstrated a

complete remission or complete remission with incomplete hematologic recovery (CR/CRh) rate of 52% and a median OS of 12.4 months, outcomes substantially better than historical benchmarks for this difficult-to-treat population.[17]

5.3.2 The ARMADA 2000 Phase 3 Trial (NCT03504410)

Based on the promising early data, the ARMADA 2000 trial was launched to confirm the benefit of Devimistat in AML.

• Design: A randomized trial enrolling patients aged ≥50 years with R/R AML. The study compared Devimistat plus HAM (the CHAM regimen) against investigator's choice of standard salvage chemotherapy (HAM, MEC, or FLAG).[38]
• Primary Endpoint: The primary endpoint was the Complete Remission (CR) rate.
• Outcome: Definitive Failure. The trial was stopped prematurely after a pre-planned interim analysis recommended termination due to futility.[34] The study failed to meet its primary endpoint, with a CR rate of 20.4% in the Devimistat arm versus 21.6% in the control arm (p=0.57).[39]
• Secondary Endpoints: There was no statistically significant difference in OS between the arms, with a median of 8.9 months in the CHAM arm versus 6.2 months in the control arm (p=0.62).[39]
• Conclusion: The addition of Devimistat to intensive salvage chemotherapy did not improve remission rates or survival in older patients with R/R AML.[39]

The clinical story of Devimistat is a stark illustration of the "valley of death" in drug development, defined by an extreme and ultimately irreconcilable disconnect between spectacular early-phase signals and definitive Phase 3 failure. This was not a marginal miss but a complete reversal of outcomes, pointing to systemic challenges in translating therapies from small, controlled studies to large, heterogeneous patient populations. This failure, despite a sound scientific rationale, suggests that targeting a fundamental process like metabolism may require more nuanced trial designs that incorporate biomarker-driven patient stratification from the outset to identify the specific subset of patients whose tumors possess the metabolic vulnerability targeted by the drug.

5.4 Investigations in Other Malignancies

Beyond pancreatic cancer and AML, Devimistat has been studied in several other cancers, with mixed but ongoing exploration.

• Biliary Tract Cancer (BTC): The Phase 1b/2 BilT-04 trial (NCT04203160) evaluated Devimistat in combination with standard gemcitabine and cisplatin. While the combination was well-tolerated, the study did not meet its primary endpoint of improving the ORR. However, the trial reported encouraging signals for PFS and OS when compared to historical data, suggesting that the drug may have some activity in this disease that could warrant further investigation in a refined context.[16]
• Burkitt's Lymphoma: A Phase 2 trial (NCT03793140) was initiated for patients with relapsed or refractory Burkitt's lymphoma. The rationale was strong, as this cancer is driven by the MYC oncogene, which heavily dysregulates cellular metabolism, and was further supported by a durable partial remission observed in a single patient in a Phase 1 study.[44]
• Other Solid Tumors: Various Phase 1 and 2 trials have been conducted or are ongoing in patients with advanced solid tumors, lymphomas, and clear cell sarcoma, often exploring novel combinations, such as with the autophagy inhibitor hydroxychloroquine.[30]

Trial ID (NCT)	Phase	Indication	Regimen	Primary Endpoint	Status / Key Outcome
NCT03504423 (AVENGER 500)	3	Metastatic Pancreatic Cancer	Devimistat + mFFX vs. FFX	Overall Survival (OS)	Completed / Failed: No improvement in OS (11.1 vs 11.7 mo; HR 0.95) 27
NCT03504410 (ARMADA 2000)	3	Relapsed/Refractory AML (≥50y)	Devimistat + HAM vs. Chemo	Complete Remission (CR) Rate	Terminated for Futility: No improvement in CR rate (20.4% vs 21.6%) 34
NCT04203160 (BilT-04)	1b/2	Advanced Biliary Tract Cancer	Devimistat + Gemcitabine/Cisplatin	Recommended Phase 2 Dose / ORR	Completed: Safe, but did not meet primary ORR endpoint; encouraging survival signals 16
NCT03793140	2	Relapsed/Refractory Burkitt's Lymphoma	Devimistat Monotherapy	Overall Response Rate (ORR)	Ongoing / Recruiting 44
NCT01835041	1	Metastatic Pancreatic Cancer	Devimistat + mFFX	MTD / Safety	Completed: Established MTD of 500 mg/m²; showed promising 61% ORR 15
NCT00741403	1/2	Advanced Malignancies	Devimistat	MTD / Safety	Completed 30

Endpoint	AVENGER 500 (Devimistat Arm)	AVENGER 500 (Control Arm)	HR / p-value	ARMADA 2000 (Devimistat Arm)	ARMADA 2000 (Control Arm)	p-value
Primary Endpoint	11.10 months (Median OS)	11.73 months (Median OS)	HR 0.95; p=0.655	20.4% (CR Rate)	21.6% (CR Rate)	p=0.57
Key Secondary Endpoint	7.82 months (Median PFS)	7.98 months (Median PFS)	HR 0.99; p=0.94	8.9 months (Median OS)	6.2 months (Median OS)	p=0.62

Section 6: Safety and Tolerability Profile

A comprehensive evaluation of a drug's safety profile is paramount, particularly for an agent combined with intensive chemotherapy. The clinical data for Devimistat consistently demonstrate that it is a well-tolerated compound and that its clinical failures were not driven by excessive toxicity.

6.1 Overview of Treatment-Emergent Adverse Events (TEAEs)

Across its extensive clinical program, Devimistat has established a favorable safety profile. When added to various chemotherapy backbones, it did not appear to significantly exacerbate the known toxicities of those regimens.[16] The most critical finding from the large Phase 3 trials was the absence of any new or unexpected safety signals attributable to Devimistat, confirming that its addition to standard-of-care chemotherapy was safe.[9]

6.2 Analysis of Phase 3 Safety Data

The safety data from the two pivotal Phase 3 trials provide the most robust assessment of Devimistat's tolerability in large, diverse patient populations.

• AVENGER 500 (Metastatic Pancreatic Cancer): In this trial, the safety profile of the Devimistat plus modified FOLFIRINOX (mFFX) arm was compared directly to the standard-dose FOLFIRINOX (FFX) arm. The most frequent Grade ≥3 TEAEs in the Devimistat arm included neutropenia (29.0%), anemia (13.9%), thrombocytopenia (11.6%), hypokalemia (13.1%), diarrhea (11.2%), and fatigue (10.8%). Notably, the rates of two of the most challenging toxicities associated with FOLFIRINOX—neutropenia and diarrhea—were numerically lower in the Devimistat arm compared to the control arm (34.5% and 19.6%, respectively).[9] This favorable safety comparison definitively rules out toxicity as a reason for the trial's failure. The experimental arm used a modified, lower-dose chemotherapy backbone, which was likely better tolerated. Despite this potential tolerability advantage, the arm still failed to show a survival benefit, a finding that isolates the trial's failure to the biological inefficacy of Devimistat in this setting.
• ARMADA 2000 (Acute Myeloid Leukemia): The safety profile of the Devimistat plus high-dose cytarabine and mitoxantrone (CHAM) regimen was consistent with what is expected from intensive salvage chemotherapy in this patient population. The number of on-study deaths was not significantly different between the arms (11 in the CHAM arm vs. 7 in the control arm), further indicating that the addition of Devimistat did not lead to an unacceptable increase in treatment-related mortality.[39]

6.3 Dose-Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)

Early-phase dose-escalation studies are designed to establish the highest safe dose for further development.

• In the Phase 1 trial for metastatic pancreatic cancer, dose-limiting toxicities (DLTs), including anemia and lymphopenia, were observed at a dose of 1000 mg/m². This led to the establishment of the MTD and the recommended Phase 2 dose (RP2D) at 500 mg/m² for combination with mFFX.[51]
• In a separate Phase 1 study focused on patients with advanced hematologic malignancies, Devimistat was escalated to a dose of 2,940 mg/m² infused over two hours without any DLTs being observed, indicating a very high therapeutic index in that context.[16]

Adverse Event (Grade ≥3)	Devimistat + mFFX Arm (n=266) %	FFX Arm (n=262) %
Neutropenia	29.0%	34.5%
Anemia	13.9%	13.6%
Thrombocytopenia	11.6%	13.6%
Hypokalemia	13.1%	14.9%
Diarrhea	11.2%	19.6%
Fatigue	10.8%	11.5%

Section 7: Regulatory Landscape and Corporate Development

The regulatory history of Devimistat reflects the significant initial enthusiasm and perceived potential of the drug, based on its novel mechanism and strong early clinical data. This support was manifested in an unusually large number of special designations from both U.S. and European health authorities.

7.1 FDA and EMA Special Designations

Devimistat was granted multiple designations intended to expedite the development and review of drugs for serious conditions with high unmet medical need.

• U.S. Food and Drug Administration (FDA):
• Orphan Drug Designation: This status was granted for an extensive list of seven different indications, underscoring the broad potential seen in the drug for rare cancers:

1. Pancreatic Cancer [8]
2. Acute Myeloid Leukemia (AML) [8]
3. Myelodysplastic Syndromes (MDS) [8]
4. Peripheral T-cell Lymphoma (PTCL) [8]
5. Burkitt's Lymphoma [8]
6. Soft Tissue Sarcoma (specifically for relapsed/refractory clear cell sarcoma) [48]
7. Biliary Tract Cancer [54]

• Fast Track Designation: This was granted for the two lead indications that advanced to Phase 3 trials, signifying the agency's agreement that the drug had the potential to address a serious unmet need:

1. Metastatic Pancreatic Cancer [19]
2. Acute Myeloid Leukemia (AML) [57]

• European Medicines Agency (EMA):
• Orphan Drug Designation: The EMA also recognized the drug's potential in several rare diseases, granting orphan status for:

1. Pancreatic Cancer [18]
2. Acute Myeloid Leukemia (AML) [18]
3. Burkitt's Lymphoma [18]
4. Biliary Tract Cancer [23]

This extensive list of regulatory designations serves as a powerful proxy for the perceived scientific promise of Devimistat. However, the subsequent clinical failures highlight a systemic challenge in drug development. Regulatory incentives designed to accelerate promising drugs can amplify the strategic and financial impact of a late-stage failure, creating a high-stakes environment where early promise, if not ultimately validated, can lead to a more profound and public collapse. The Devimistat story is a cautionary tale about the importance of critically evaluating scientific and translational risks, even in the face of strong regulatory encouragement.

7.2 Developer and Current Status

• Developer: Devimistat was developed by Rafael Pharmaceuticals, Inc., a company focused on the growing field of cancer metabolism.[18] In May 2022, the company announced a corporate name change to Cornerstone Pharmaceuticals, Inc..[62]
• Current Development Status: Following the definitive failures of the two pivotal Phase 3 trials in pancreatic cancer and AML, the development program for Devimistat has been significantly re-focused. The highest phase of development reached was Phase 3 for these two indications, and development for MDS has been discontinued.[6] However, the company has not abandoned the asset. As of August 2023, there were three ongoing clinical trials and continued preclinical work exploring new combinations and indications.[23] A key ongoing study is a Phase 2 trial (NCT05733000) investigating Devimistat in combination with hydroxychloroquine and either 5-FU or gemcitabine in patients with advanced, chemo-refractory solid tumors.[23] The company also anticipated a data readout from the Phase 2 trial in biliary tract cancer (NCT04203160) in late 2023.[23]

Regulatory Agency	Designation Type	Indication
U.S. FDA	Orphan Drug	Pancreatic Cancer 8
	Orphan Drug	Acute Myeloid Leukemia (AML) 8
	Orphan Drug	Myelodysplastic Syndromes (MDS) 8
	Orphan Drug	Peripheral T-cell Lymphoma (PTCL) 8
	Orphan Drug	Burkitt's Lymphoma 8
	Orphan Drug	Soft Tissue Sarcoma (Clear Cell Sarcoma) 48
	Orphan Drug	Biliary Tract Cancer 54
	Fast Track	Metastatic Pancreatic Cancer 19
	Fast Track	Acute Myeloid Leukemia (AML) 57
EMA	Orphan Drug	Pancreatic Cancer 18
	Orphan Drug	Acute Myeloid Leukemia (AML) 18
	Orphan Drug	Burkitt's Lymphoma 18
	Orphan Drug	Biliary Tract Cancer 23

Section 8: Critical Analysis and Future Outlook

The development trajectory of Devimistat, from a highly lauded "first-in-class" metabolic inhibitor with spectacular early results to a definitive failure in two pivotal Phase 3 trials, offers critical lessons for the field of oncology. This final section synthesizes the available evidence to deconstruct the reasons for this failure and to evaluate the potential future for Devimistat and the broader class of cancer metabolism inhibitors.

8.1 The Promise and Peril of Targeting Cancer Metabolism: Deconstructing the Failure

The stark disconnect between the promising early-phase data and the negative Phase 3 outcomes cannot be attributed to a single cause but likely results from a combination of complex biological factors that were not fully appreciated or were underestimated during development.

• Metabolic Plasticity and Resistance: The central premise of Devimistat was to induce catastrophic metabolic collapse by blocking two key TCA cycle entry points. However, a defining characteristic of cancer is its remarkable adaptability.[63] It is highly plausible that upon inhibition of PDH and KGDH, tumors in many patients were able to rewire their metabolism to utilize alternative fuel sources, such as fatty acids (via beta-oxidation) or acetate, to sustain the TCA cycle and generate ATP and biomass.[12] This metabolic flexibility represents a formidable intrinsic resistance mechanism. Furthermore, the drug's very short pharmacokinetic half-life and the resultant intermittent dosing schedule may have provided tumors with sufficient time between infusions to recover from the metabolic insult and activate these compensatory pathways, ultimately rendering the therapy ineffective.
• Tumor Heterogeneity: The specific metabolic phenotype that confers sensitivity to Devimistat—namely, a rigid co-dependence on both glucose and glutamine entry into the TCA cycle via the specifically "reconfigured" PDH and KGDH regulatory systems—is unlikely to be a universal feature of all pancreatic cancers or AMLs. The small, often single-center, early-phase trials may have inadvertently selected for a patient population with this precise vulnerability, leading to anomalously high response rates. When the drug was tested in large, global Phase 3 trials, the inherent biological heterogeneity of the patient population would have diluted this effect to the point of statistical insignificance.[9] Without a predictive biomarker to enrich for sensitive tumors, the trials were likely destined to fail in an unselected population.
• The Limits of Preclinical Models: While the preclinical xenograft and cell line models provided a strong and logical rationale for clinical testing, they may have failed to capture the full metabolic complexity and plasticity of human tumors within their native microenvironment. Factors such as nutrient availability, hypoxia, and interactions with stromal cells in the tumor microenvironment can profoundly influence cancer metabolism in ways that are not fully recapitulated in simplified models, potentially leading to an overestimation of the drug's real-world efficacy.

8.2 The Path Forward for Devimistat

Despite the major setbacks in its lead indications, the development of Devimistat is not entirely moribund. The focus has shifted toward more nuanced strategies and different disease contexts where its unique mechanism may yet find a niche.

• Exploring New Combinations: The ongoing Phase 2 trial combining Devimistat with hydroxychloroquine (an autophagy inhibitor) represents a mechanistically rational, second-generation hypothesis.[46] It is known that metabolic stress can induce a pro-survival autophagic response in cancer cells. If Devimistat's action triggers such a response, then concurrently blocking autophagy with hydroxychloroquine could restore or enhance its anti-tumor activity. This approach targets not only the primary metabolic pathway but also a key resistance mechanism.
• Niche Indications: The encouraging, albeit secondary, survival signals observed in the Phase 1b/2 trial for biliary tract cancer suggest that there may be specific tumor types where the metabolic dependency on the PDH/KGDH axis is more pronounced and less plastic.[16] Future efforts could focus on identifying these niche indications through extensive preclinical screening and biomarker analysis.
• The Imperative for Biomarkers: The ultimate future for Devimistat, if one exists, will almost certainly depend on the successful identification and validation of a predictive biomarker. Such a biomarker would need to identify patients whose tumors possess the specific metabolic vulnerabilities that make them susceptible to Devimistat's mechanism of action. Without this, any further large-scale clinical development in unselected populations would be ill-advised.

8.3 Broader Implications for the Field of Metabolic Oncology

The story of Devimistat serves as a crucial and cautionary tale for the entire field of cancer metabolism therapeutics. It highlights several key principles that must be addressed to improve the success rate of this promising class of drugs.

• Confronting Metabolic Plasticity: The failure of Devimistat underscores that simply inhibiting a central metabolic enzyme or pathway may be insufficient to kill cancer cells, which can often adapt and find alternative routes to survive.[11] Future strategies must anticipate and counter these resistance mechanisms, likely through rational combination therapies that block both the primary target and the predicted escape pathways.
• The Primacy of Biomarker Co-development: The Devimistat experience makes a powerful case that for metabolic inhibitors, predictive biomarkers are not a luxury but a necessity. The traditional clinical trial paradigm of testing in broad, unselected populations may be fundamentally unsuited for this class of agents. Biomarker strategies must be integrated from the earliest stages of clinical development to identify the right patients for the right drug, thereby de-risking late-stage trials and avoiding costly failures.
• Advancing Therapeutic Strategies: The field must move beyond single-pathway inhibition. The future of metabolic oncology likely lies in more sophisticated approaches, such as multi-target agents, combinations that induce synthetic lethality between metabolic pathways, or therapies that modulate the metabolism of the tumor microenvironment to enhance the efficacy of immunotherapies. While Devimistat did not succeed as initially hoped, the lessons learned from its development will be invaluable in guiding the next generation of therapies that target the metabolic engine of cancer.

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