AEG35156 (DB06184): A Comprehensive Review of a Second-Generation XIAP-Targeting Antisense Oligonucleotide

1. Introduction to AEG35156 (DB06184)

Overview: AEG35156 as a Second-Generation Antisense Oligonucleotide (ASO)

AEG35156 (DrugBank ID: DB06184) is an investigational therapeutic agent classified as a second-generation synthetic antisense oligonucleotide (ASO).[1] These second-generation ASOs were engineered to overcome limitations of earlier ASO chemistries, primarily by incorporating chemical modifications that enhance their stability against nuclease degradation, improve binding affinity to target messenger RNA (mRNA), and potentially offer a more favorable toxicity profile.[4] Such improvements are critical for achieving therapeutic efficacy in a clinical setting. AEG35156 was specifically designed with the potential for antineoplastic activity by selectively interfering with the cellular expression of a key protein implicated in cancer cell survival and drug resistance.[1]

Therapeutic Target: X-linked Inhibitor of Apoptosis Protein (XIAP)

The molecular target of AEG35156 is the mRNA encoding the X-linked Inhibitor of Apoptosis Protein (XIAP), also known as Baculoviral IAP Repeat Containing 4 (BIRC4) or Inhibitor of Apoptosis Protein 3 (IAP3).[1] XIAP is recognized as one of the most potent endogenous inhibitors of apoptosis (programmed cell death). Its primary anti-apoptotic function is executed through the direct binding and inhibition of key executioner caspases, namely caspase-3 and caspase-7, as well as the initiator caspase-9.[1] By neutralizing these critical enzymes, XIAP effectively blocks the progression of both the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) apoptotic pathways, thereby promoting cell survival.

Rationale for Targeting XIAP in Cancer

The rationale for developing XIAP inhibitors like AEG35156 for cancer therapy is rooted in the observation that XIAP is frequently overexpressed in a wide spectrum of human malignancies.[1] This overexpression is not merely a correlative finding; it has been functionally linked to resistance to conventional cancer treatments, including chemotherapy and radiotherapy, and is often associated with more aggressive disease and poorer patient prognosis across various tumor types such as acute myeloid leukemia (AML), prostate cancer, pancreatic cancer, lung cancer, and breast cancer.[4]

Cancer cells frequently co-opt survival mechanisms, such as the upregulation of anti-apoptotic proteins like XIAP, to evade the cell death programs that chemotherapy and radiotherapy aim to induce. This upregulation forms a significant barrier to effective treatment. The therapeutic strategy underpinning AEG35156 is based on the premise that by specifically reducing the levels of XIAP, the inherent apoptotic threshold of cancer cells can be lowered.[1] This, in turn, is expected to sensitize them to the apoptotic signals triggered by intrinsic cellular stress or by co-administered cytotoxic therapies, thereby potentially overcoming chemoresistance. The widespread overexpression of XIAP across diverse cancer types and its fundamental role in apoptosis regulation positions it as a compelling therapeutic target. By aiming to dismantle this key survival mechanism, AEG35156 was envisioned to have broad applicability as a chemosensitizing agent, contingent upon the specific tumor's reliance on XIAP for its survival and resistance phenotypes.

2. Chemical Properties and Structure of AEG35156

A clear understanding of the chemical nature of AEG35156 is fundamental to appreciating its mechanism of action and pharmacokinetic behavior.

Nomenclature and Identifiers

AEG35156 is the primary generic name for this investigational drug, which is also widely known by its synonym GEM640 (or GEM 640, GEM-640).[1] Other reported synonyms include AEG 35156 and AEG-161.[10] Its unique DrugBank Accession Number is DB06184.[1] The Chemical Abstracts Service (CAS) Registry Number assigned to AEG35156 is 928841-57-0.[16]

Molecular Structure: Second-Generation Antisense Oligonucleotide (ASO)

AEG35156 is a 19-mer oligonucleotide, meaning it is composed of 19 nucleotide units.[4] It features a "mixed-backbone" or "gapmer" design, characteristic of many second-generation ASOs. This structure comprises a central 11-nucleotide DNA "gap" region, which is flanked on both its 3' and 5' ends by four 2'-O-methyl (2'-OMe) modified RNA residues.[4] The entire oligonucleotide backbone incorporates phosphorothioate linkages instead of the natural phosphodiester linkages.[4]

The design of AEG35156 was carefully optimized for specificity towards its XIAP mRNA target and for enhanced cellular potency.[15] A notable feature of its design is the absence of CpG dinucleotide motifs.[15] The 2'-OMe modifications in the RNA "wings" serve to increase the ASO's resistance to degradation by cellular nucleases and enhance its binding affinity (hybridization strength) to the target mRNA sequence. The phosphorothioate modification of the backbone further contributes to nuclease resistance, a critical factor for maintaining ASO integrity in vivo. However, phosphorothioate linkages can sometimes be associated with non-specific protein binding and certain toxicities. The central DNA "gap" is essential for the ASO's primary mechanism of action, as this DNA:RNA hybrid region is recognized and cleaved by the cellular enzyme RNase H. The intentional exclusion of CpG motifs is a strategic design choice to minimize or avoid potential immunostimulatory effects that are often triggered by unmethylated CpG sequences in phosphorothioate oligonucleotides, which can lead to unwanted side effects.[6]

Sequence Information

The precise oligonucleotide base sequence of AEG35156/GEM640 (e.g., the specific order of A, T, C, and G, and their modified counterparts) is not explicitly disclosed in the provided research materials.[4] Searches for patent information within these documents also did not yield the specific sequence.[4]

The absence of the exact base sequence is typical for proprietary investigational drugs. The sequence is the core intellectual property that defines the ASO's specificity for its target mRNA. While the general chemical architecture and design principles—such as targeting XIAP mRNA, the 19-mer length, the 2'-OMe/DNA gapmer structure, the phosphorothioate backbone, and the lack of CpG motifs—are described, the unique "code" of bases that directs it to XIAP mRNA remains confidential in these public domain documents. This highlights the distinction between scientific disclosure of a drug's class and mechanism and the protection of its core intellectual property. A complete understanding of its hybridization characteristics with XIAP mRNA would necessitate knowledge of this sequence.

The following table summarizes the key identifiers and structural features of AEG35156:

Table 1: AEG35156 - Key Identifiers and Structural Features

Feature	Description	Source(s)
Generic Name	AEG35156	1
DrugBank ID	DB06184	1
CAS Number	928841-57-0	16
Synonyms	GEM640, GEM 640, GEM-640, AEG 35156, AEG-161	1
Molecular Type	Second-Generation Antisense Oligonucleotide (ASO), Gapmer, Mixed-Backbone Oligonucleotide (MBO)	4
Length	19-mer	4
Backbone Chemistry	Fully Phosphorothioated	4
Flanking Modifications	Four 2'-O-methyl (2'-OMe) RNA residues at 3' and 5' ends	4
Core Type	11-nucleotide DNA "gap"	4
CpG Motif Status	Absent	15
Specific Sequence	Not publicly available in provided sources	4

3. Mechanism of Action

XIAP Inhibition: Selective Blocking of XIAP mRNA and Protein Expression

AEG35156 functions as an antisense oligonucleotide specifically engineered to hybridize with the messenger RNA (mRNA) encoding human XIAP.[1] Upon binding, it obstructs the normal translation process of this mRNA into XIAP protein. Consequently, the overall cellular production and levels of XIAP protein are diminished.[1]

Molecular Interactions: RNase H-Mediated Degradation

The "gapmer" design of AEG35156, featuring a central DNA segment flanked by modified RNA wings, is crucial for its primary mode of action. When AEG35156 binds to the complementary sequence on the XIAP mRNA, it forms a DNA:RNA heteroduplex in the "gap" region. This hybrid structure is a substrate for the endogenous cellular enzyme RNase H.[5] RNase H selectively cleaves the RNA strand of such hybrids, leading to the degradation of the XIAP mRNA. This targeted mRNA degradation effectively prevents the synthesis of new XIAP protein. The 2'-O-methyl modifications in the wings of the ASO protect it from nuclease attack and enhance its binding affinity to the target mRNA but do not themselves mediate RNase H cleavage.[6]

Cellular Consequences: Sensitization to Apoptosis and Overcoming Chemoresistance

The direct outcome of reduced XIAP protein levels is a lowering of the apoptotic threshold within cancer cells.[1] Since XIAP normally functions to suppress apoptosis by inhibiting caspases, its depletion renders cancer cells more vulnerable to apoptotic stimuli. These stimuli can originate from intrinsic cellular stress pathways or, significantly, from the action of cytotoxic anticancer drugs. Therefore, AEG35156 is intended to act as a chemosensitizing agent, restoring or enhancing the ability of conventional chemotherapies to induce cancer cell death and thereby overcoming a common mechanism of drug resistance.[1]

Synergistic Effects with Cytotoxic Drugs

A cornerstone of the therapeutic strategy for AEG35156 is its potential to work synergistically with existing cytotoxic drugs.[1] By diminishing XIAP levels, AEG35156 is expected to amplify the pro-apoptotic effects of chemotherapeutic agents, potentially allowing for lower doses of chemotherapy, reducing toxicity, or achieving efficacy in tumors that have become resistant.

Overview of XIAP: Role in Apoptosis and Cancer

XIAP is a prominent member of the Inhibitor of Apoptosis Protein (IAP) family, a group of proteins that are critical regulators of programmed cell death.[1] Structurally, XIAP contains three Baculovirus IAP Repeat (BIR) domains, a Ubiquitin-Associated (UBA) domain, and a C-terminal RING (Really Interesting New Gene) finger domain.[11] The BIR2 domain (along with its linker region) is primarily responsible for inhibiting effector caspases-3 and -7, while the BIR3 domain targets the initiator caspase-9.[1] This direct inhibition blocks both the intrinsic mitochondrial pathway and the extrinsic death receptor pathway of apoptosis. The RING domain endows XIAP with E3 ubiquitin ligase activity, allowing it to target proteins (including itself and caspases) for ubiquitination, which can lead to their degradation or modulation of their function.[1]

The function of XIAP is endogenously antagonized by proteins such as SMAC (Second Mitochondria-derived Activator of Caspases)/Diablo. Upon apoptotic stimuli, SMAC/Diablo is released from the mitochondria into the cytoplasm, where it binds to XIAP, displacing the inhibited caspases and thereby promoting apoptosis.[1] The overexpression of XIAP in many cancers disrupts this balance, favoring cell survival and contributing to resistance against therapies designed to kill cancer cells by inducing apoptosis.[1] Beyond apoptosis, XIAP is also implicated in regulating other cell death pathways like autophagy and necroptosis, and influences processes such as inflammation and copper homeostasis.[1]

Interestingly, while cytosolic XIAP is primarily recognized for its anti-apoptotic functions, emerging evidence suggests a more complex role involving its translocation to mitochondria. Under certain stress conditions, XIAP can localize to mitochondria and potentially modulate mitochondrial outer membrane permeabilization (MOMP), a critical step in the intrinsic apoptotic pathway that leads to the release of cytochrome c and SMAC/Diablo.[11] This mitochondrial activity of XIAP could be pro-apoptotic in some contexts, for instance, by interacting with Bax, a pro-apoptotic Bcl-2 family member, to facilitate MOMP.[11] This nuanced, context-dependent role of XIAP at the mitochondrial level adds a layer of complexity to XIAP-targeting strategies. If mitochondrial XIAP can, under certain circumstances, promote apoptosis, a therapy that globally reduces XIAP levels might inadvertently abrogate this pro-apoptotic function alongside its intended anti-apoptotic blockade. This complexity could contribute to the variable efficacy observed with XIAP-targeting agents and suggests that the net effect of XIAP downregulation might depend on the specific cellular context and the balance of XIAP's different subcellular functions.

The following table summarizes the multifaceted role of XIAP and the rationale for its targeting by AEG35156:

Table 2: Overview of XIAP Function and Rationale for Targeting

Aspect of XIAP	Description/Role	Implication for Cancer	Therapeutic Rationale for AEG35156	Key Source(s)
Caspase Inhibition	Directly binds and inhibits initiator caspase-9 and effector caspases-3 and -7.	Prevents cancer cell apoptosis, promoting survival.	Reduce XIAP to unleash caspase activity.	1
Role in Intrinsic Apoptosis	Blocks caspase cascade downstream of mitochondrial cytochrome c release.	Confers resistance to mitochondria-mediated apoptosis.	Sensitize cells to intrinsic apoptotic signals.	1
Role in Extrinsic Apoptosis	Inhibits caspases activated by death receptor signaling.	Confers resistance to death receptor-mediated apoptosis.	Sensitize cells to extrinsic apoptotic signals.	1
Overexpression in Cancer	Frequently upregulated in various tumor types.	Correlates with aggressive disease and poor prognosis.	Target an aberrantly expressed survival protein.	4
Link to Chemoresistance	High XIAP levels protect cancer cells from drug-induced apoptosis.	Major mechanism of resistance to cytotoxic therapies.	Overcome chemoresistance by lowering the apoptotic threshold.	1
Interaction with SMAC/Diablo	Endogenously inhibited by SMAC/Diablo, which displaces caspases from XIAP.	Cancer cells may have altered XIAP/SMAC balance favoring survival.	Reducing XIAP may shift balance towards apoptosis even with endogenous SMAC.	4
Mitochondrial Localization/Function	Can translocate to mitochondria; may modulate MOMP (potentially pro-apoptotic in some contexts).	Complex role; may influence mitochondrial apoptosis initiation.	Reducing XIAP may have multifaceted effects on mitochondrial apoptosis beyond just caspase inhibition.	11
E3 Ubiquitin Ligase Activity	RING domain mediates ubiquitination of various targets.	Modulates stability/function of proteins involved in apoptosis and signaling.	Reducing XIAP levels would also reduce its E3 ligase activity.	1

4. Preclinical Development and Evaluation

The preclinical assessment of AEG35156 provided the foundational evidence for its mechanism of action and therapeutic potential, paving the way for clinical trials.

In Vitro Studies

XIAP Knockdown Efficacy

In vitro experiments consistently demonstrated the ability of AEG35156 to reduce XIAP expression in various human cancer cell lines. Dose-dependent downregulation of XIAP mRNA was observed in cell lines derived from lung (H460), pancreas (Panc-1), ovary (A2780-cp), breast (MDA-MB-231), and prostate (PC-3) cancers.[9] The half maximal effective concentration (EC50) for XIAP mRNA reduction typically ranged from 8 to 32 nmol/L in these cell lines.[9] Correspondingly, a substantial decrease in XIAP protein levels, often exceeding 80%, was achieved following AEG35156 treatment.[9] Similar efficacy in reducing XIAP protein was also shown in primary AML patient samples treated in vitro.[36]

Induction of Apoptosis and Sensitization

The reduction in XIAP protein levels achieved by AEG35156 directly translated into enhanced sensitivity of cancer cells to apoptotic stimuli. For example, in Panc-1 pancreatic carcinoma cells, decreased XIAP expression correlated with increased sensitization to apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL).[9] More broadly, the inhibition of XIAP expression by AEG35156 was shown to enhance cancer cell apoptosis in various models.[4]

In Vivo Studies (Xenograft Models)

Antitumor Activity as a Single Agent

In human cancer xenograft models, AEG35156 demonstrated antitumor activity even when administered as a monotherapy. Potent activity relative to control oligonucleotides was observed in models of prostate cancer (PC-3), colon cancer (LS174T), and lung cancer (H460), although the H460 lung cancer model appeared somewhat refractory to single-agent AEG35156.[9] The observed antitumor effects consistently correlated with the suppression of XIAP levels within the tumor tissue, reinforcing the target engagement and mechanism of action in vivo.[9]

Synergy with Chemotherapeutic Agents

A significant finding from preclinical in vivo studies was the synergistic antitumor effect of AEG35156 when combined with conventional chemotherapeutic agents.

• Taxanes (Docetaxel, Paclitaxel): Combination therapy with taxanes, such as docetaxel or paclitaxel, yielded particularly striking results. In prostate (PC-3) and lung (H460) cancer xenografts, the addition of AEG35156 to taxane treatment led to complete tumor regressions in some instances.[9] This synergy was especially noteworthy because, at the doses used, neither AEG35156 nor the taxane alone was highly effective, indicating a potentiation of the chemotherapeutic effect by XIAP downregulation.
• Platinum Agents (Cisplatin, Carboplatin): In contrast to the robust synergy observed with taxanes, combinations of AEG35156 with platinum-based drugs (cisplatin in H460 xenografts and carboplatin in PC-3 xenografts) did not show significant additive or synergistic effects; these combinations were generally unproductive.[22] This differential outcome suggests that the ability of XIAP downregulation to sensitize cancer cells to chemotherapy is dependent on the specific mechanisms of action of the co-administered cytotoxic drug. While taxanes trigger apoptosis primarily through mitotic arrest, platinum agents induce DNA damage. The lack of synergy with platinum agents might imply that XIAP is not the primary bottleneck for apoptosis induced by these DNA-damaging agents in the tested models, or that other resistance or repair mechanisms dominate the cellular response to platinum-induced damage, irrespective of XIAP levels. This underscores the importance of understanding the specific apoptotic pathways engaged by different chemotherapies when designing rational combination strategies with IAP inhibitors.
• Other Combinations: Preclinical studies also indicated potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA) models, providing a rationale for clinical investigation in this indication.[10]

Pharmacokinetics and Safety in Animal Models

Pharmacokinetic and safety studies in non-human primates (cynomolgus monkeys) were conducted to support clinical development. Following continuous intravenous infusion, AEG35156 plasma concentrations rapidly reached steady-state in a dose-proportional manner and declined quickly after the infusion was stopped.[15] Metabolism was limited, with n-1 and n-2 metabolites (oligonucleotides shortened by one or two bases) being observed.[15] Significant accumulation of AEG35156 and its metabolites was noted in tissues, particularly the liver and kidney, which was roughly dose-proportional and showed some clearance after a recovery period.[15]

The safety profile in monkeys was generally acceptable. No significant clinical signs were observed at low or mid-doses. High doses led to some dose-dependent effects characteristic of phosphorothioate ASOs, including signs of immunostimulation (though AEG35156 lacks CpG motifs, which are common triggers for such effects).[15] Importantly, no significant complement activation, a potential concern with some ASOs, was observed. At high doses, elevations in plasma liver enzymes and histological changes in the liver and kidney were noted, consistent with drug deposition, but these were not considered likely to cause organ dysfunction.[15] A dedicated safety pharmacology study showed no adverse effects on cardiovascular, respiratory, or neurological parameters.[15] Additionally, a murine-specific variant of AEG35156 administered subcutaneously to mice demonstrated XIAP protein attenuation in circulating peripheral blood mononuclear cells (PBMCs) and bone marrow at doses below 10 mg/kg.[13]

The following table summarizes key preclinical findings for AEG35156:

Table 3: Summary of Key Preclinical Studies of AEG35156

Study Type	Model	Key Findings	Key Source(s)
In Vitro	Human cancer cell lines (H460, Panc-1, A2780-cp, PC-3, MDA-MB-231)	Dose-dependent XIAP mRNA reduction (EC50: 8-32 nM); >80% XIAP protein reduction.	9
In Vitro	Panc-1 pancreatic cells	Loss of XIAP protein sensitized cells to TRAIL-mediated apoptosis.	9
In Vitro	AML patient samples	Effective decrease in XIAP protein levels.	36
In Vivo	PC-3 prostate xenograft	Single-agent: dose-dependent tumor growth reduction (~80%), modest regression. Combination with docetaxel: significant enhancement, complete tumor regression. No synergy with carboplatin.	9
In Vivo	LS174T colon xenograft	Single-agent: dose-dependent tumor growth inhibition (~60%).	9
In Vivo	H460 lung xenograft	Single-agent: largely refractory. Combination with docetaxel: dramatic, synergistic tumor size reduction (~80%). No synergy with cisplatin.	9
In Vivo	Pancreatic cancer models	Potent activity in combination with gemcitabine.	10
In Vivo (Monkeys)	Cynomolgus monkeys (continuous IV infusion)	Dose-proportional plasma levels; rapid clearance from plasma; significant tissue accumulation (liver, kidney); limited metabolism. Acceptable safety profile; high-dose effects typical of PS-ASOs (immunostimulation, liver enzyme elevation).	15
In Vivo (Mice)	Mice (s.c. murine-specific variant)	XIAP protein attenuation in PBMCs and bone marrow at <10mg/kg.	13

5. Clinical Development of AEG35156

AEG35156 progressed into an extensive clinical development program, encompassing Phase I and Phase I/II trials across a range of hematological malignancies and solid tumors. It was evaluated both as a monotherapy and, more commonly, in combination with various standard-of-care cytotoxic agents, reflecting its primary rationale as a chemosensitizer.

Overview of Clinical Trial Program

Clinical investigations of AEG35156 spanned multiple cancer types, including acute myeloid leukemia (AML), hepatocellular carcinoma (HCC), chronic lymphocytic leukemia (CLL), B-cell lymphomas, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC), and other advanced refractory solid tumors.[1] The drug was administered via intravenous infusion, with various schedules and dose levels explored in combination with agents such as idarubicin/cytarabine (for AML), sorafenib (for HCC), gemcitabine (for pancreatic cancer), paclitaxel (for breast cancer), carboplatin/paclitaxel (for NSCLC), and docetaxel (for solid tumors).[1]

Pharmacokinetics in Humans

Human pharmacokinetic (PK) data were primarily derived from Phase I studies. In the first-in-man trial (NCT00096699 / NCT00385775), where AEG35156 was administered as a 7-day or 3-day continuous intravenous infusion (CIVI), plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased proportionally with the dose.[5] Cmax was typically achieved approximately 24 hours after the start of the infusion.[5] Following discontinuation of the infusion, an initial, rapid elimination half-life (t1/2α) of approximately 0.5 to 1.5 hours (or about 60 minutes) was observed, which appeared to be dose-independent, followed by a longer terminal elimination half-life (t1/2β) of around 24 hours.[5] Population PK modeling suggested a two-compartment model best described the data, with total clearance values of 5.3 L/h for the 7-day infusion schedule and 4.0 L/h for the 3-day schedule, which did not vary with dose.[5] These PK characteristics are generally consistent with those of other second-generation ASOs, which typically exhibit rapid distribution from plasma into tissues and subsequent elimination phases.[6]

Pharmacodynamics in Humans

Pharmacodynamic assessments focused on confirming target engagement (XIAP knockdown) and observing downstream effects on apoptosis.

• XIAP mRNA and Protein Knockdown: Evidence of XIAP mRNA downregulation in patient PBMCs or circulating leukemic blasts was a consistent finding across several trials, often showing a dose-dependent relationship.[5]
• In AML trials (e.g., NCT00130176, NCT01018069, NCT00363974), significant XIAP mRNA knockdown was achieved, with a median maximal knockdown of 90-100% in blasts from patients receiving 350 mg/m² of AEG35156. Most patients receiving ≥110 mg/m² showed >30% target knockdown.[10]
• In the Phase I solid tumor trial (NCT00096699 / NCT00385775), XIAP mRNA suppression in PBMCs peaked at 72 hours, with a mean suppression of approximately 21%.[5]
• Reductions in XIAP protein levels in patient samples were also documented, corroborating the mRNA knockdown.[5]
• Apoptosis Induction: Downstream of XIAP inhibition, markers of apoptosis induction were observed. These included elevated plasma levels of M30/M65 (fragments of cytokeratin 18 released during apoptosis), PARP cleavage, and increased activated caspase-3 levels.[5] Notably, in AML patients, apoptosis induction was reported to be most pronounced in the CD34+CD38- leukemic stem cell population, and this effect correlated with clinical response in some phase 2 patients.[32]

Clinical Efficacy (Summarized by Key Trials/Indications)

The clinical development of AEG35156 involved numerous trials across various cancer types. The outcomes were mixed, with some encouraging early signals but ultimately a failure to demonstrate consistent, robust efficacy leading to regulatory approval. A summary of key trials is presented in Table 4, followed by a narrative discussion.

Table 4: Summary of Key Clinical Trials of AEG35156

NCT Number(s)	Phase	Indication(s)	Combination Agent(s)	Key Efficacy Findings	Key Safety/Tolerability Findings	Status	Sponsor(s)	Key Source(s)
NCT00096699 / NCT00385775	I	Advanced Refractory Solid Tumors & Lymphoma	Monotherapy (7-day or 3-day CIVI)	Two unconfirmed PRs (breast, melanoma); 7 SDs. XIAP mRNA suppression (mean 21% in PBMCs). Decrease in circulating tumor cells in one lymphoma patient.	MTD: 125 mg/m²/d (7DI), ≤213 mg/m²/d (3DI). DLTs: elevated hepatic enzymes, hypophosphatemia, thrombocytopenia. Generally well-tolerated.	Completed	Cancer Research UK, Aegera Therapeutics	5
NCT00130176 / NCT01018069 / NCT00363974	I/II (pooled data from related AML studies)	Relapsed/Refractory Acute Myeloid Leukemia (AML)	Idarubicin, Cytarabine	Dose-dependent XIAP mRNA knockdown (median max 90-100% at 350 mg/m²). ORR higher at 350 mg/m² AEG35156: 15/32 (47%) CR/CRp vs 1/24 (4%) at lower doses. Notably, 10/11 (91%) refractory to 1 prior induction achieved CR/CRp with 350 mg/m² combo. Preferential apoptosis in CD34+38- AML stem cells correlated with response.	Generally well-tolerated. Two cases of Grade 3-4 peripheral neuropathy at 350 mg/m² after multiple doses (led to schedule change). Induction deaths (infection, renal failure) noted, similar between arms in some analyses.	Completed/ Terminated	Aegera Therapeutics, M.D. Anderson Cancer Center	10
NCT00882869	I/II (Ph II randomized)	Advanced Hepatocellular Carcinoma (HCC)	Sorafenib	Combination arm (AEG35156 + Sorafenib): mPFS 4.0 mo, mOS 6.5 mo, ORR 10% (Choi) / 16.1% (RECIST). Sorafenib alone: mPFS 2.6 mo, mOS 5.4 mo, ORR 0%. Benefit more apparent in dose-reduced subgroups.	Well-tolerated. One AEG35156-related SAE (hypersensitivity); two sorafenib-related GI SAEs.	Completed	Aegera Therapeutics	10
NCT00557596	I	Metastatic Pancreatic Ductal Adenocarcinoma (PDA)	Gemcitabine	MTD: AEG35156 500 mg + Gemcitabine 1000 mg/m² (d1,8,15 q28d). 5/14 (45%) patients had SD. Median PFS 58 days. Failed to show significant clinical activity.	Toxicities: neutropenia (G3/4, 6 pts), thrombocytopenia (G3, 2 pts), peripheral neuropathy (G3, 2 pts), fatigue (G3, 4 pts), ascites (G3, 2 pts), nausea/vomiting (G4, 2 pts). Neurotoxicity led to dose de-escalation recommendation.	Terminated	Aegera Therapeutics	1
NCT00768339	I/II	Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) & Indolent B-Cell Lymphomas	Monotherapy	Limited information on results. Trial terminated.	Not detailed in provided snippets.	Terminated	Aegera Therapeutics	1
NCT00558545	I/II	Advanced Breast Cancer	Paclitaxel	Limited information on results. Trial terminated.	Not detailed in provided snippets.	Terminated	Aegera Therapeutics	1
NCT00558922	I/II	Advanced Non-Small Cell Lung Cancer (NSCLC)	Carboplatin, Paclitaxel	Limited information on results. Trial terminated.	Not detailed in provided snippets.	Terminated	Aegera Therapeutics	1
NCT00372736 / NCT00357747	I	Advanced/Metastatic Solid Tumors	Docetaxel	Phase I dose-finding studies. MTD and safety established for combination. Details on specific efficacy not extensively provided in snippets.	Tolerable in combination with docetaxel.	Completed	NCIC Clinical Trials Group	1

• Acute Myeloid Leukemia (AML):
• In Phase I/II trials (NCT00130176, NCT01018069, NCT00363974), AEG35156 combined with idarubicin and cytarabine showed promising activity, especially in patients refractory to a single prior induction regimen. At the 350 mg/m² dose of AEG35156, a high complete response (CR) or CR with incomplete platelet recovery (CRp) rate of 47% overall, and 91% in patients refractory to one prior induction, was observed.[10]
• Pharmacodynamic studies confirmed dose-dependent XIAP mRNA knockdown, with preferential apoptosis induction in CD34+CD38- AML stem cells, which correlated with clinical response.[32]
• However, a subsequent randomized Phase II study (NCT01018069 or related analysis) comparing reinduction chemotherapy with or without AEG35156 (650 mg dose mentioned, possibly total dose or different schedule) in patients with primary refractory AML did not show an improvement in remission rates with the addition of AEG35156 (41% CR/CRp with AEG35156 vs. 69% in control arm, p=0.18).[38] This discrepancy highlights the challenges in translating promising early-phase signals into definitive Phase II/III benefits. The difference in AEG35156 dose/schedule and patient populations (e.g. number of prior refractory treatments) between these reports may contribute to the differing outcomes.
• Advanced Hepatocellular Carcinoma (HCC):
• In a randomized Phase II study (NCT00882869), AEG35156 (300mg weekly) combined with sorafenib was compared to sorafenib alone.[10]
• The combination arm showed a modest improvement in median progression-free survival (mPFS: 4.0 months vs. 2.6 months) and median overall survival (mOS: 6.5 months vs. 5.4 months). The objective response rate (ORR) was 10-16% in the combination arm versus 0% in the control arm.[10]
• Interestingly, patients in the combination arm who had treatment interruptions or dose modifications showed better PFS and OS, suggesting that an optimized dosing schedule might be critical.[10]
• Metastatic Pancreatic Ductal Adenocarcinoma (PDA):
• A Phase I trial (NCT00557596) combined AEG35156 (350 mg or 500 mg IV, 3 weeks on/1 week off) with gemcitabine (1000 mg/m²).[10]
• The MTD was AEG35156 500 mg with gemcitabine. While 45% of patients achieved stable disease, the median PFS was only 58 days. The study concluded that the combination failed to show significant clinical activity in advanced PDA.[10]
• Advanced Refractory Solid Tumors and Lymphoma (Monotherapy):
• The first-in-man Phase I trial (NCT00096699 / NCT00385775) evaluated AEG35156 as a monotherapy using 7-day or 3-day CIVI schedules.[5]
• The MTDs were 125 mg/m²/d (7DI) and ≤213 mg/m²/d (3DI). XIAP mRNA suppression was observed in PBMCs. Antitumor activity included two unconfirmed partial responses (breast cancer, melanoma) and stable disease in seven patients. A notable decrease in circulating tumor cells was seen in one lymphoma patient, coinciding with XIAP mRNA knockdown.[5]
• Other Solid Tumors (Combination with Docetaxel):
• Phase I trials (NCT00372736, NCT00357747) by NCIC Clinical Trials Group evaluated AEG35156 with docetaxel in patients with advanced/metastatic solid tumors. These studies established the MTD and safety of the combination, but detailed efficacy results are not extensively covered in the provided snippets.[31]
• Terminated Trials: Several other Phase I/II trials were initiated but subsequently terminated, often before completion or with limited reported outcomes. These included studies in:
• Relapsed/refractory CLL and indolent B-cell lymphomas (NCT00768339, monotherapy).[1]
• Advanced breast cancer with paclitaxel (NCT00558545).[1]
• Advanced NSCLC with carboplatin and paclitaxel (NCT00558922).[1] The reasons for termination are not always explicitly stated in the snippets but often relate to insufficient accrual, lack of efficacy, strategic decisions by the sponsor, or emerging toxicity. For instance, the pancreatic cancer trial (NCT00557596) was noted for failing to show significant clinical activity and encountering neurotoxicity.[10]

Safety and Tolerability in Humans

Across various trials, AEG35156, when administered as monotherapy or in combination, was generally described as well-tolerated, though specific dose-limiting toxicities (DLTs) and adverse events (AEs) were identified.

• Common Adverse Events: In the Phase I monotherapy trial, most AEs were grade 1-2 and included elevated liver enzymes (ALT, AST, GGT), lymphopenia, thrombocytopenia, neutropenia, leucopenia, and fatigue.[5]
• Dose-Limiting Toxicities (DLTs):
• In monotherapy (NCT00096699 / NCT00385775): Elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia were identified as DLTs.[5]
• In AML combination therapy (NCT00130176 and related studies): Two cases of Grade 3-4 peripheral neuropathy were observed at the 350 mg/m² dose of AEG35156 after multiple administrations, leading to a protocol amendment to limit the number of AEG35156 cycles.[10] Induction deaths due to infection or renal failure were also reported, though their direct attribution to AEG35156 versus the underlying disease and intensive chemotherapy was complex.[10]
• In pancreatic cancer combination with gemcitabine (NCT00557596): Toxicities included neutropenia, thrombocytopenia, peripheral neuropathy, fatigue, ascites, and nausea/vomiting. Perceived neurotoxicity led to a recommendation for dose de-escalation.[10]
• Serious Adverse Events (SAEs): In the HCC trial (NCT00882869), one AEG35156-related SAE of hypersensitivity was reported.[10]

6. Regulatory Status and Development History

Orphan Drug Designation

AEG35156 itself does not appear to have received orphan drug designation from the FDA or EMA based on the provided snippets. The snippets discussing orphan drug designation for "radgocitabine" [103] are not relevant to AEG35156. General information on EMA orphan drug processes is available [107], but no specific designation for AEG35156 is mentioned. Similarly, FDA orphan drug information provided [109] pertains to other compounds.

Developer and Discontinuation

• Original Developer(s): AEG35156 was developed by Aegera Therapeutics Inc..[4] Some early work or chemistry may have involved Hybridon, Inc. (later Idera Pharmaceuticals) given their expertise in ASO technology and mentions in early preclinical reports.[9] Aegera Therapeutics was founded in 2000 and was acquired by Pharmascience on May 27, 2011.[110]
• Idera Pharmaceuticals (formerly Hybridon): While Idera Pharmaceuticals (which became Aceragen in 2023 [112]) was a key player in ASO development, its direct continued development of AEG35156 specifically is less clear from the snippets after Aegera's acquisition. Idera's pipeline (later Aceragen's) shifted focus, for example, to IMO-2125 for melanoma and later to rare pulmonary and rheumatic diseases.[112] One snippet mentions Idera Pharmaceuticals in connection with AEG35156 as "terminated; failed to reach endpoints; neurotoxicity".[114]
• Discontinuation of Development: The clinical development of AEG35156 appears to have been discontinued. Many of its clinical trials were terminated.[1] The reasons for discontinuation are likely multifactorial, reflecting a common challenge in oncology drug development.

1. Limited Efficacy: Despite promising preclinical data and some positive early-phase clinical signals (especially in specific AML patient subsets and in combination with sorafenib for HCC), consistent and robust efficacy across broader patient populations or in later-phase trials was not sufficiently demonstrated.[10] For example, the pancreatic cancer trial with gemcitabine failed to show significant clinical activity [23], and a randomized Phase II AML study did not show improved remission rates with AEG35156.[38] The transient nature of target knockdown was also noted as a concern.[10]
2. Toxicity Concerns: While often described as "generally well-tolerated," specific toxicities did emerge, most notably peripheral neuropathy in AML patients receiving multiple doses of 350 mg/m² and in the pancreatic cancer trial, which led to dose de-escalation recommendations or protocol amendments.[10] Other DLTs like elevated liver enzymes and thrombocytopenia were also reported.[5]
3. Challenges in ASO Development: Antisense oligonucleotides, particularly earlier generations, faced challenges related to delivery, stability in vivo, off-target effects, and achieving sustained target engagement in tumors at tolerable doses.[6] While AEG35156 was a second-generation ASO with improvements, some of these inherent class-related challenges might still have played a role.
4. Strategic Business Decisions: The acquisition of Aegera Therapeutics by Pharmascience in 2011 [110] and subsequent shifts in Idera's (Hybridon's successor) focus could also have influenced the decision to discontinue the AEG35156 program, irrespective of purely scientific or clinical outcomes. Companies often re-prioritize their pipelines based on evolving market conditions, competitive landscapes, and internal strategic goals. The note about Idera Pharmaceuticals and AEG35156 being "terminated; failed to reach endpoints; neurotoxicity" [114] encapsulates these issues.

The journey of AEG35156 from promising preclinical candidate to clinical evaluation and eventual discontinuation reflects the arduous path of oncology drug development. While it demonstrated target engagement and some clinical activity, the overall risk-benefit profile and efficacy were likely insufficient to warrant further advancement in a competitive therapeutic landscape.

7. Discussion and Future Perspectives

The development of AEG35156 provides valuable lessons for the field of antisense oligonucleotide therapeutics and XIAP targeting in oncology. Preclinically, AEG35156 robustly demonstrated its intended mechanism of action: downregulation of XIAP mRNA and protein, leading to sensitization of cancer cells to apoptosis, and synergistic antitumor effects with certain chemotherapeutic agents, particularly taxanes.[9] The gapmer design with 2'-OMe wings and a phosphorothioate backbone aimed to optimize stability and RNase H-mediated target cleavage while minimizing CpG-related immunostimulation.[4]

In human trials, AEG35156 confirmed target engagement, with dose-dependent XIAP mRNA knockdown observed in patient cells.[5] Some encouraging clinical activity was noted, particularly in subsets of AML patients refractory to a single induction regimen when combined with chemotherapy [10] and in HCC when combined with sorafenib.[10] The preferential induction of apoptosis in CD34+CD38- AML stem cells was a particularly interesting pharmacodynamic finding.[32]

However, the overall clinical development program did not culminate in a successful therapeutic. Several factors likely contributed to this outcome. Firstly, the efficacy observed in early phases did not consistently translate into robust, statistically significant benefits in broader or randomized settings, as seen in one of the AML Phase II studies [38] and the pancreatic cancer trial.[23] The complexity of cancer biology, tumor heterogeneity, and the presence of multiple resistance mechanisms mean that targeting a single anti-apoptotic protein, even one as critical as XIAP, may not be sufficient in all contexts. The observation that AEG35156 showed strong preclinical synergy with taxanes but not with platinum agents underscores the context-dependent nature of its sensitizing effect.[22] This suggests that the specific apoptotic pathways engaged by the partner chemotherapeutic agent, and the tumor's reliance on XIAP to evade those specific pathways, are critical determinants of successful synergy.

Secondly, toxicity, particularly peripheral neuropathy at higher or cumulative doses, emerged as a concern.[10] While second-generation ASOs generally have improved safety profiles over first-generation compounds, off-target effects or class-specific toxicities can still limit their therapeutic window. The phosphorothioate backbone, while enhancing stability, is known to sometimes contribute to such toxicities through non-specific protein interactions.

Thirdly, the pharmacokinetics of ASOs, including tissue distribution and achieving sustained target knockdown within the tumor microenvironment at safe systemic exposures, remain ongoing challenges for the field.[6] While AEG35156 demonstrated target knockdown, the transient nature of this effect was noted in some reviews, potentially limiting its sustained biological impact.[10]

The evolving understanding of XIAP biology, including its potential dual roles in apoptosis regulation particularly concerning its mitochondrial localization and function [11], might also suggest that simple downregulation may not always yield the desired pro-apoptotic outcome uniformly across all cancer types or therapeutic combinations. If mitochondrial XIAP can, in some instances, promote MOMP, then its global reduction could have unintended consequences, potentially dampening certain pro-apoptotic signals even as it relieves caspase inhibition.

Future development of XIAP-targeting ASOs or other modalities could benefit from more sophisticated patient selection strategies, perhaps based on XIAP expression levels, the status of related apoptotic pathway components (e.g., SMAC, other IAPs, caspases), or genetic markers predicting reliance on XIAP for survival. Furthermore, advancements in ASO chemistry and delivery technologies continue to improve potency, specificity, and safety, potentially overcoming some of the limitations faced by earlier agents like AEG35156. Combination strategies will remain key, but these must be rationally designed based on a deep understanding of the interplay between the ASO target and the mechanism of the partner drug.

8. Conclusion

AEG35156 (DB06184, GEM640) was a rationally designed second-generation antisense oligonucleotide targeting XIAP, a critical inhibitor of apoptosis frequently overexpressed in cancer and associated with chemoresistance. Preclinical studies robustly supported its mechanism of action, demonstrating XIAP knockdown, apoptosis sensitization, and synergistic antitumor activity with specific chemotherapies, notably taxanes.

The clinical development program for AEG35156 was extensive, exploring its utility in various hematological and solid tumors, both as monotherapy and in combination. While target engagement (XIAP mRNA and protein knockdown) and some encouraging signals of clinical activity were observed in early-phase trials, particularly in certain AML patient populations and in HCC, these did not consistently translate into definitive efficacy in later-stage or broader randomized studies. Challenges encountered included limited efficacy in some settings (e.g., pancreatic cancer, some AML cohorts) and the emergence of dose-limiting toxicities such as peripheral neuropathy.

The discontinuation of AEG35156's development likely resulted from a combination of insufficient efficacy to justify further investment in the context of its therapeutic window, emerging toxicities, and the inherent complexities of ASO drug development and cancer therapy. Nevertheless, the study of AEG35156 contributed valuable knowledge regarding XIAP as a therapeutic target, the clinical behavior of second-generation ASOs, and the intricacies of combining targeted agents with chemotherapy. The experience with AEG35156 underscores the importance of rigorous preclinical validation of combination strategies, careful patient selection, and ongoing advancements in oligonucleotide chemistry and delivery to realize the full potential of antisense therapies in oncology.

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