Comprehensive Report on INM004: An Investigational Anti-Shiga Toxin Therapy for Hemolytic Uremic Syndrome

1. Executive Summary

INM004 (DrugBank ID: DB17791) is an investigational biotherapeutic agent developed by the Argentinian company Inmunova S.A..[1] It consists of polyclonal F(ab')2​ antibody fragments derived from equine immunoglobulins.[1] The therapy is designed to neutralize Shiga toxins (Stx1 and Stx2), the primary causative agents of Shiga toxin-producing Escherichia coli (STEC)-associated Hemolytic Uremic Syndrome (STEC-HUS).[5] By targeting the B subunits of these toxins, INM004 aims to prevent their binding to host cell receptors, thereby blocking toxin internalization and subsequent cellular damage, particularly in the kidneys.[6] STEC-HUS represents a significant unmet medical need, especially in pediatric populations where it is a leading cause of acute kidney injury.[5] Currently, treatment relies on supportive care, with no approved therapies specifically targeting the Shiga toxin.[2]

INM004 has progressed through preclinical development, demonstrating broad neutralizing capacity against various Shiga toxin variants in vitro and protective effects in animal models.[8] Phase 1 clinical trials in healthy adults established an acceptable safety profile and predictable pharmacokinetics supporting the planned dosing regimen.[10] A subsequent Phase 2 trial (NCT05569746) in pediatric patients with STEC-HUS confirmed the favorable safety profile, with only mild-to-moderate, transient adverse events deemed possibly related and no reports of serious hypersensitivity reactions like serum sickness or anaphylaxis.[5] While the Phase 2 trial did not meet its primary efficacy endpoint based on dialysis days with statistical significance, it showed non-statistically significant trends favoring INM004 in reducing the need for and duration of dialysis and accelerating kidney function recovery.[5] Based on these findings, INM004 is currently being evaluated in a large, multinational, randomized, double-blind, placebo-controlled Phase 3 trial (NCT06389474).[4] INM004 has received Orphan Drug designation from both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as well as Rare Pediatric Disease Designation from the FDA, highlighting its potential to address a critical gap in treating this severe pediatric condition.[4] The progression of INM004, despite non-significant Phase 2 efficacy results, reflects the high unmet need and the potential attributed to its targeted anti-toxin mechanism.

2. Introduction

2.1. Shiga Toxin-Producing E. coli Infections and Hemolytic Uremic Syndrome

Infections caused by Shiga toxin-producing Escherichia coli (STEC) are a significant public health concern, often acquired through the consumption of contaminated food or water.[2] While many infections result in self-limiting diarrhea, a subset of patients, particularly young children, develop Hemolytic Uremic Syndrome (HUS), a severe and potentially life-threatening complication.[5] HUS is clinically defined by the triad of microangiopathic hemolytic anemia (destruction of red blood cells), thrombocytopenia (low platelet count), and acute kidney injury (AKI).[5]

2.2. Epidemiology and Clinical Impact of STEC-HUS

STEC-HUS is recognized globally as a leading cause of AKI in children.[5] Certain regions, such as Argentina, report the highest incidence rates worldwide, with hundreds of cases occurring annually, primarily affecting children under five years old.[2] The disease carries substantial morbidity; even with recovery from the acute phase, a significant proportion of survivors may develop long-term sequelae, including chronic kidney disease (CKD), hypertension, and neurological deficits.[2] The mortality rate, although variable, underscores the severity of the condition.[7]

2.3. Pathogenesis: The Central Role of Shiga Toxins

The pathogenesis of STEC-HUS is primarily driven by Shiga toxins (Stxs) produced by the bacteria, making the systemic disease essentially a toxemia rather than a disseminated bacterial infection.[8] There are two main types, Stx1 and Stx2, with several subtypes. Stx2 is generally considered more virulent and is more frequently associated with severe HUS development.[8] These toxins share a common AB$_5$ structure, consisting of an enzymatically active A subunit responsible for cytotoxicity and a pentameric B subunit (StxB) that mediates binding to the glycolipid receptor globotriaosylceramide (Gb3) on the surface of host cells.[8] Gb3 receptors are prominently expressed on vascular endothelial cells, particularly in the kidneys and brain, explaining the primary organ systems affected in HUS.[8] Upon binding, the toxin is internalized, and the A subunit translocates to the cytoplasm where it inhibits protein synthesis by cleaving ribosomal RNA, leading to cell stress, apoptosis, and the characteristic microvascular damage and thrombosis seen in HUS.[8]

2.4. Current Management and Unmet Medical Need

Despite the severity of STEC-HUS, there are currently no specific therapies approved to counteract the effects of Shiga toxin or prevent the progression to HUS.[2] The mainstay of treatment remains supportive care, focused on managing fluid and electrolyte balance, controlling hypertension, providing transfusions for severe anemia or thrombocytopenia, and initiating renal replacement therapy (dialysis) for patients with severe AKI.[2] The use of antibiotics is controversial, as some studies suggest they might increase the risk of HUS development, possibly by enhancing toxin release from bacteria.[9] This lack of targeted treatment represents a critical unmet medical need for therapies that can directly neutralize Shiga toxin and mitigate its devastating consequences. The characterization of STEC-HUS as a toxemia provides a strong rationale for developing anti-toxin therapies. Since the disease process is initiated by toxin binding and subsequent cellular damage, early intervention with a neutralizing agent, before irreversible organ injury occurs, is theoretically the most effective strategy. This principle influences the design of clinical trials, emphasizing the need to enroll patients and administer treatment as early as possible following the onset of STEC infection or initial HUS symptoms.[10]

2.5. Introduction of INM004

INM004 is an investigational polyclonal antibody therapy developed by Inmunova S.A. specifically designed to address this unmet need.[2] It aims to neutralize circulating Shiga toxins, thereby preventing their interaction with target cells and potentially halting the progression of HUS.[2]

3. INM004: Drug Profile

Description: INM004 is a biopharmaceutical product formulated as a sterile, concentrated solution for intravenous infusion. It contains polyclonal F(ab')2​ fragments derived from the immunoglobulins of horses hyperimmunized against engineered Shiga toxin B-subunit antigens.[1]

DrugBank ID: DB17791.[1]

Synonyms: Known synonyms include Anti-Shiga toxin hyperimmune equine immunoglobulin F(ab')2​ fragment, INM 004, Neutralizing equine anti-Stx hyperimmune immunoglobulin F(ab')2​ fragment, ANTI SHIGA TOXIN, and Shiga antitoxin.[1]

Drug Type/Classification: INM004 is classified as a biotechnology-derived product, specifically a protein-based therapy. It falls under the categories of polyclonal antibodies (pAbs), F(ab')2​ fragments, immunoglobulins, immunoproteins, serum globulins, antitoxins, and potentially immunostimulants.[1]

Developer: INM004 was originated and is being developed by Inmunova S.A., a biotechnology company based in Argentina.[2] AdisInsight also lists Exeltis as a developer [4], although this collaboration is not widely mentioned in other available sources [2] and requires further confirmation.

The choice to use F(ab')2​ fragments instead of intact equine IgG is a significant aspect of INM004's design. Whole antibodies, especially those derived from non-human species, contain an Fc region that can trigger unwanted immune responses in patients, such as complement activation or binding to Fc receptors on immune cells, contributing to hypersensitivity reactions like anaphylaxis or serum sickness.[19] Enzymatic digestion to produce F(ab')2​ fragments removes most of the Fc portion while retaining the two antigen-binding arms (bivalency).[20] This modification reduces the molecular size, potentially improving tissue penetration, and significantly lowers the risk of Fc-mediated adverse effects and immunogenicity.[20] This design strategy likely contributes to the favorable safety profile observed in the early clinical trials of INM004, where serious hypersensitivity reactions typically associated with equine sera have not been reported.[5]

4. Mechanism of Action

INM004 exerts its therapeutic effect through direct neutralization of Shiga toxins (Stx1 and Stx2).[6]

Target: The specific molecular targets of INM004 are the pentameric B subunits (StxB) of both Stx1 and Stx2.[8] These subunits are crucial for the toxin's ability to bind to host cells.[8]

Binding and Neutralization: Being a polyclonal preparation, INM004 contains a mixture of F(ab')2​ fragments recognizing multiple different epitopes on the StxB structures of various toxin subtypes.[8] This broad recognition is advantageous given the antigenic variability among Shiga toxins produced by different STEC strains.[8]

Receptor Blockade: The primary mechanism of neutralization involves steric hindrance. By binding extensively to the StxB pentamer, the F(ab')2​ fragments physically block the sites required for the toxin to interact with its cellular receptor, globotriaosylceramide (Gb3).[8] Cryo-electron microscopy (cryo-EM) studies have visually confirmed that INM004-derived Fab fragments coat the Gb3-binding surfaces of both Stx1B and Stx2B.[8]

Prevention of Internalization and Toxicity: By preventing the initial binding step between the toxin and the Gb3 receptor expressed on endothelial cells (particularly in the kidney and brain) and other target cells, INM004 effectively stops the toxin from entering the cell.[8] This prevents the toxic A subunit from reaching the cytosol, where it would otherwise inhibit protein synthesis and trigger the cascade of events leading to cell damage, microvascular thrombosis, and the clinical manifestations of HUS.[8]

Polyclonal Advantage: The polyclonal nature of INM004 may offer an advantage over monoclonal antibodies by providing broader coverage against different Stx variants and potentially being effective even when toxins are bound to circulating components like neutrophils or microvesicles.[16]

This mechanism of action, targeting the very first step of toxin-cell interaction, represents an upstream intervention compared to current supportive therapies. It aims to prevent the pathogenic cascade from initiating or progressing, rather than managing the downstream consequences of established cellular damage. Consequently, the timing of INM004 administration relative to the onset of infection and toxin release is expected to be a critical determinant of its clinical efficacy.[10] Treatment initiated early, before substantial amounts of toxin have bound to and entered target cells, is likely to yield the greatest benefit.

5. Preclinical Development

The development of INM004 involved innovative protein engineering and rigorous preclinical evaluation.

Immunogen Design and Production: A key challenge in developing anti-StxB antibodies is the instability of the isolated StxB pentamer.[8] Inmunova addressed this by creating chimeric fusion proteins. They genetically fused the B subunits of Stx1 and Stx2 (Stx1B and Stx2B) to the highly stable, decameric lumazine synthase protein from Brucella spp. (BLS).[8] This BLS-Stx1B and BLS-Stx2B design successfully stabilized the StxB pentamers in their native conformation, exposing the relevant Gb3-binding epitopes, and significantly enhanced their immunogenicity.[8] This bioengineering solution was crucial for generating a potent immune response.

Immunization and Antibody Fragment Production: Horses were immunized with these chimeric immunogens to generate a hyperimmune serum rich in polyclonal antibodies against both Stx1B and Stx2B.[8] The serum was then processed using standard techniques (e.g., pepsin digestion) to cleave the whole IgG molecules and isolate the F(ab')2​ fragments, which constitute the active pharmaceutical ingredient of INM004.[16]

In Vitro Neutralization Studies: Preclinical in vitro assays confirmed that the resulting F(ab')2​ fragments possess high neutralizing capacity against a broad range of clinically relevant Stx1 and Stx2 variants.[8] This broad-spectrum activity is essential for a therapy intended to treat infections caused by diverse STEC strains.

In Vivo Efficacy Studies: Studies in mouse models provided crucial proof-of-concept for INM004's protective effect in vivo. Immunization with the chimeric immunogens conferred protection against lethal Stx challenge.[8] Furthermore, passive transfer of the antibodies (or serum from immunized animals) protected mice from the detrimental effects of experimental STEC infection, demonstrating that the antibodies can effectively neutralize the toxin as it is produced and released by the bacteria within the host.[8] These positive preclinical results, combined with the innovative immunogen design, provided a strong foundation for advancing INM004 into clinical trials.

6. Clinical Development Program

The clinical development of INM004 has progressed through Phase 1 and Phase 2 trials, with a pivotal Phase 3 trial currently underway.

6.1. Phase 1 Study (Healthy Adults)

• Design: A single-center, randomized, single-blind, placebo-controlled study was conducted in Argentina to evaluate the safety, tolerability, and pharmacokinetics (PK) of INM004 in 14 healthy adult volunteers.[11] Stage I involved single intravenous doses of 2 mg/kg or 4 mg/kg (3:1 randomization vs placebo). Stage II involved three daily intravenous doses of 4 mg/kg (5:1 randomization vs placebo).[10]
• Safety and Tolerability: INM004 was generally well-tolerated. Eight of the 14 participants (57.1%) experienced mild treatment-emergent adverse events (TEAEs), most commonly rhinitis, headache, and flushing, which resolved within 24 hours without intervention. No serious adverse events (SAEs) were reported. Four TEAEs were considered possibly related to the study drug.[11]
• Pharmacokinetics: Following infusion, peak plasma concentrations (Cmax) were reached within approximately 2 hours. Median Cmax values were 45.1 µg/mL for the 2 mg/kg single dose and 77.7 µg/mL for the 4 mg/kg single dose. The drug exhibited biphasic elimination with a terminal half-life (t$_{1/2}$) ranging from 30.7 to 52.9 hours. Systemic exposure increased proportionally with dose, and accumulation was observed with the repeated dosing regimen (geometric median Cmax 149 µg/mL and AUC 10,300 µg·h/mL after three doses).[10]
• Pharmacodynamics: Serum samples collected from participants demonstrated in vitro neutralizing activity against both Stx1 and Stx2, confirming the biological activity of the administered F(ab')2​ fragments.[10]
• Conclusion: The Phase 1 study demonstrated an acceptable safety and PK profile in healthy adults, supporting the progression of INM004 into Phase 2 trials in the target pediatric population.[10]

6.2. Phase 2 Study (Pediatric STEC-HUS, NCT05569746)

• Design: This was a multicenter, open-label trial conducted at 16 hospitals in Argentina, comparing INM004 plus standard of care (SoC) to a historical control group receiving SoC alone.[5] Propensity score matching (PSM) was employed to balance baseline characteristics, resulting in 52 patients per arm for efficacy analyses.[5]
• Patient Population: The trial enrolled children aged 1 to 12 years hospitalized with a diagnosis of STEC-HUS (defined by AKI plus evidence of hemolysis and/or thrombocytopenia) within 13 days of diarrhea onset.[13]
• Intervention: Patients in the treatment arm received two intravenous infusions of INM004 at a dose of 4 mg/kg, administered 24 hours apart, in addition to SoC.[5]
• Endpoints: The primary endpoints included safety, PK, and efficacy measured by the number of dialysis days. Secondary endpoints assessed other renal outcomes (e.g., proportion requiring dialysis, duration of dialysis >10 days, time to glomerular filtration rate normalization), extrarenal complications, hematological recovery, mortality, and length of hospital stay.[5]
• Safety Findings: INM004 demonstrated an adequate safety profile. Eight possibly related AEs were reported, all mild or moderate and non-serious. Importantly, no cases of anaphylaxis or serum sickness were observed.[5] (See Section 7 for more detail).
• Efficacy Findings: The study did not meet its primary efficacy endpoint with statistical significance. The median number of dialysis days was 4 in the INM004 arm versus 6 in the control arm (difference of 2 days, p=0.43). However, several secondary endpoints showed non-statistically significant trends favoring the INM004 group: fewer patients required dialysis (56% vs 67%, p=0.23), fewer required dialysis for more than 10 days (19% vs 27%, p=0.44), and time to GFR normalization appeared shorter (Hazard Ratio = 1.83). Platelet recovery was also slightly faster (median 7 vs 9 days).[5]
• Conclusion: While not demonstrating statistically significant efficacy, the Phase 2 trial confirmed the acceptable safety profile of INM004 in pediatric STEC-HUS patients and provided encouraging efficacy signals, particularly regarding kidney injury amelioration. These results supported the decision to proceed to a definitive Phase 3 study.[5]

6.3. Phase 3 Study (Pediatric STEC-HUS, NCT06389474)

• Design: A large, pivotal Phase 3 trial is currently underway. It is a multicenter, randomized, double-blind, placebo-controlled study employing an adaptive design.[4] The trial is actively recruiting participants across multiple sites in Argentina and Europe (including Belgium, France, Germany, Ireland, Italy, Netherlands, Poland, Spain, UK).[4]
• Patient Population: The study aims to enroll children aged 9 months to 18 years with a clinical diagnosis of STEC-HUS, presenting within 10 days of diarrhea onset.[6]
• Intervention: Participants are randomized to receive either two intravenous infusions of INM004 (4 mg/kg each) or a matching placebo, administered 24 hours apart, in addition to SoC.[6]
• Endpoints: The primary objective is to evaluate the efficacy of INM004 in improving renal function compared to placebo. Secondary objectives include assessing effects on mortality, extrarenal complications (neurological, cardiovascular, gastrointestinal), hematological parameters, duration of hospital stay, and overall safety and tolerability.[6]
• Status: Recruiting.[1]

The transition from an open-label, historically controlled Phase 2 design to a rigorous randomized, double-blind, placebo-controlled Phase 3 trial is a critical step. The Phase 3 design will provide more robust and definitive evidence regarding the efficacy of INM004 by minimizing potential biases associated with historical controls and open-label administration. The incorporation of an adaptive design also allows for pre-planned modifications based on interim analyses, potentially enhancing trial efficiency and the likelihood of detecting a true treatment effect if one exists.[6]

6.4. Other Trials

DrugBank lists two additional trials: a completed Phase 2 trial investigating INM004 for COVID-19 / Diarrhea-Associated HUS / HUS / Pediatric Kidney Disease, and a terminated Phase 2/3 trial focused on prevention of bloody diarrhea / HUS / Pediatric Kidney Disease / STEC infection.[1] Specific details regarding the purpose, design, results, or reasons for termination of these trials are limited in the available data.[1]

Table 1: Summary of Key INM004 Clinical Trials

Trial ID (if available)	Phase	Status	Population	Purpose	Key Endpoints (Primary listed first)	N (Enrolled)	Key Findings Summary
N/A	1	Completed	Healthy Adults	Safety, Tolerability, PK	Safety/Tolerability; PK parameters (Cmax, AUC, t$_{1/2}$); PD (in vitro neutralization)	14	Well-tolerated (mild AEs: rhinitis, headache, flushing; no SAEs). PK suitable for planned dosing, accumulation observed. Serum showed neutralizing activity.10
NCT05569746	2	Completed	Pediatric STEC-HUS (1-12 yrs)	Safety, Efficacy, PK	Safety Profile; PK; Efficacy (Dialysis Days); Secondary: Dialysis need/duration, GFR normalization, extrarenal complications, hematology, mortality, hospital stay	57 (Tx arm)	Adequate safety profile (8 possibly related mild/moderate AEs, no anaphylaxis/serum sickness). Efficacy: Non-significant trend for fewer dialysis days (4 vs 6) & improved renal outcomes.5
NCT06389474	3	Recruiting	Pediatric STEC-HUS (9 mos - 18 yrs)	Efficacy, Safety	Efficacy (Renal Function Improvement); Secondary: Mortality, extrarenal complications, hematology, hospital stay, safety	~250 (target)	Ongoing pivotal trial to definitively assess efficacy and safety.4
N/A	2/3	Terminated	Pediatric patients at risk of STEC-HUS	Prevention	Not specified	1	Terminated; reason not specified in available data.1
N/A	2	Completed	COVID-19 / Diarrhea-Assoc. HUS / HUS	Treatment	Not specified	1	Completed; results not detailed in available data.1

Abbreviations: AE, Adverse Event; AUC, Area Under the Curve; Cmax, Maximum Concentration; GFR, Glomerular Filtration Rate; HUS, Hemolytic Uremic Syndrome; IV, Intravenous; N, Number of participants; PK, Pharmacokinetics; PD, Pharmacodynamics; PSM, Propensity Score Matching; RCT, Randomized Controlled Trial; SAE, Serious Adverse Event; SoC, Standard of Care; STEC, Shiga toxin-producing Escherichia coli; t$_{1/2}$, Half-life; TEAE, Treatment-Emergent Adverse Event; Tx, Treatment.

7. Safety and Tolerability Profile

The safety and tolerability of INM004 have been assessed in both healthy adults and pediatric patients with STEC-HUS.

Overall Summary: Across Phase 1 and Phase 2 trials involving over 70 participants, INM004 has demonstrated a generally favorable safety profile.[5] The majority of reported adverse events (AEs) have been mild to moderate in intensity and transient.[11]

Phase 1 Findings (Healthy Adults): In the Phase 1 study (N=14), 57.1% of participants experienced TEAEs, with rhinitis, headache, and flushing being the most common. All TEAEs resolved within 24 hours without specific intervention. No SAEs were reported. Four TEAEs were considered possibly related to INM004.[11]

Phase 2 Findings (Pediatric STEC-HUS): In the Phase 2 study (N=57 treated), 103 AEs were reported in 38 patients. Eight AEs were deemed possibly related to INM004 by investigators; these included single instances of rash scarlatiniform, hypersensitivity, injection site reaction, hypotension, and oliguria, plus two instances of vomiting and three of increased liver enzymes.[5] All possibly related AEs were mild or moderate, non-serious, and non-severe. Investigators noted potential alternative causes (e.g., underlying STEC-HUS, concomitant conditions/medications) for all possibly related AEs.[13] Four SAEs occurred, but none were considered related to INM004. Ten events were classified as AEs of special interest (AESI), including the possibly related rash, hypersensitivity, injection site reaction, vomiting, hypotension, increased liver enzymes, and oliguria events; none of these were severe or serious except where attributable to the underlying HUS.[13] Crucially, no cases of anaphylaxis or serum sickness were reported.[13] The Data Safety Monitoring Board concluded the safety profile was adequate.[13]

Risks Associated with Equine F(ab')2​ Fragments: While INM004 has shown good tolerability, equine-derived antibody products inherently carry risks of hypersensitivity reactions.[19]

• Acute Hypersensitivity/Anaphylaxis: These reactions can be immediate and severe, potentially mediated by IgE or occurring de novo without prior sensitization. Patients with known allergies to horse protein are at higher risk. Standard management involves immediate discontinuation of the infusion and administration of emergency treatments like epinephrine, corticosteroids, and antihistamines.[19]
• Delayed Serum Sickness: This is a Type III hypersensitivity reaction typically manifesting within two weeks of exposure. Symptoms include rash, fever, joint pain (arthralgia), and muscle pain (myalgia). Monitoring for these signs and symptoms during follow-up is necessary.[19]

Mitigation and Monitoring: The use of F(ab')2​ fragments, lacking most of the immunogenic Fc region, is expected to reduce the risk of these reactions compared to whole equine IgG.[20] Clinical trial protocols include exclusion criteria for patients with known hypersensitivity to equine products.[13] Standard precautions for administering biological products, including close monitoring during and after infusion and availability of emergency treatment, are essential.[22]

The favorable safety profile reported thus far, particularly the absence of severe hypersensitivity events in the initial clinical studies, is encouraging. However, given that these reactions can be rare, the larger patient cohort in the ongoing Phase 3 trial will be critical for more definitively characterizing the incidence of hypersensitivity and serum sickness associated with INM004.[4] Confirmation of the low risk observed to date in a larger population is necessary.

Table 2: Summary of Adverse Events Reported in INM004 Clinical Trials

Trial Phase	Population	AE Category	Specific Event Examples	Incidence/Frequency	Severity	Relatedness (Possibly Related)	Notes
Phase 1	Healthy Adults	TEAE	Rhinitis, Headache, Flushing	8/14 subjects (57.1%) experienced ≥1 TEAE	Mild	4 TEAEs in unspecified subjects	All resolved within 24h; No SAEs reported.11
Phase 2	Pediatric HUS	Any AE	Various	103 AEs in 38/57 subjects	Varied	8 AEs in 7 subjects	4 SAEs occurred, none related to INM004. 10 AESIs occurred in 6 subjects.13
Phase 2	Pediatric HUS	Possibly Related AE	Rash scarlatiniform, Hypersensitivity, Vomiting (x2), Hypotension, Injection site reaction, ↑Liver enzymes (x3), Oliguria	8 AEs in 7/57 subjects	Mild / Moderate	Yes	None severe or serious. Alternative causes identified for all. No anaphylaxis or serum sickness reported.5
Phase 2	Pediatric HUS	SAE	Not specified	4 SAEs in unspecified subjects	Serious	No	None considered related to INM004.13
Phase 2	Pediatric HUS	AESI	Rash, Hypersensitivity, Vomiting, Hypotension, etc.	10 AESIs in 6/57 subjects	Mild / Moderate	Some (see Possibly Related AEs)	Details in Supplementary Tables 7 & 8.13 None severe/serious except potentially due to underlying HUS.

Abbreviations: AE, Adverse Event; AESI, Adverse Event of Special Interest; HUS, Hemolytic Uremic Syndrome; SAE, Serious Adverse Event; TEAE, Treatment-Emergent Adverse Event.

8. Regulatory Status and Designations

INM004 has received significant regulatory attention, reflecting the unmet need in STEC-HUS.

• Orphan Drug Designation (ODD): INM004 has been granted ODD by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).[4] The designation covers Haemolytic Uraemic Syndrome and/or Haemolytic Anaemia.[4] ODD is granted to therapies intended for rare diseases (affecting fewer than 5 in 10,000 people in the EU or 200,000 in the US) that are serious or life-threatening and lack satisfactory treatments. This designation provides incentives such as market exclusivity (typically 10 years in the EU, 7 years in the US) upon approval, fee reductions for regulatory procedures, and protocol assistance (scientific advice) from regulatory agencies.
• Rare Pediatric Disease Designation (RPDD): The FDA has also granted RPDD to INM004.[8] This designation is for drugs treating serious or life-threatening diseases primarily affecting individuals aged 18 years or younger. A key potential benefit of RPDD is eligibility for a Priority Review Voucher (PRV) upon marketing approval. A PRV can be used to obtain expedited FDA review for a subsequent drug application or can be sold to another company.
• Fast Track Designation: Available sources do not indicate that INM004 has received Fast Track designation from the FDA.[4] Fast Track is designed to facilitate the development and expedite the review of drugs intended to treat serious conditions and fill an unmet medical need.[24]
• Clinical Trial Endorsements: The clinical development program for INM004 has received endorsements or approvals to proceed from key regulatory bodies, including ANMAT in Argentina, the FDA in the US, and the EMA in Europe.[2]

The granting of ODD and RPDD provides substantial support for the development of INM004. These designations acknowledge the severity and rarity of STEC-HUS and the lack of existing treatments. The associated incentives, particularly market exclusivity and the potential for a PRV, significantly improve the commercial prospects and reduce the financial risks of developing a therapy for a small patient population, which is especially important for a company like Inmunova.[2]

9. Discussion and Future Directions

INM004 represents a targeted therapeutic approach for STEC-HUS, a condition with significant morbidity and mortality, particularly in children, and no currently approved specific treatments. Its development is based on a strong scientific rationale: neutralizing the causative Shiga toxins before they induce irreversible organ damage.[8]

Synthesis of Findings: Preclinical studies successfully demonstrated the feasibility of generating potent, broadly neutralizing polyclonal F(ab')2​ antibodies using innovative chimeric immunogens.[8] Phase 1 trials confirmed safety and established appropriate pharmacokinetics in adults.[11] The Phase 2 trial in pediatric patients further supported the safety profile, showing good tolerability with no major hypersensitivity issues identified in the cohort studied.[5] While Phase 2 efficacy endpoints were not met with statistical significance, the observed trends towards improved renal outcomes provided sufficient encouragement, given the high unmet need and safety data, to proceed to a large-scale Phase 3 trial.[5]

Potential Clinical Impact: If the ongoing Phase 3 trial demonstrates statistically significant efficacy and confirms the favorable safety profile, INM004 could become the first approved targeted therapy for STEC-HUS.[2] Its mechanism, acting upstream in the disease cascade, holds the potential to prevent or mitigate severe kidney injury and other systemic complications. The critical factor for maximizing clinical impact will likely be early administration following STEC infection or HUS onset, allowing the antibodies to neutralize toxins before substantial cellular binding and damage occur.[10]

Comparison to Other Approaches: INM004 utilizes polyclonal equine F(ab')2​ fragments. This contrasts with monoclonal antibody approaches (e.g., urtoxazumab, which targets Stx2) that have also been investigated.[7] Polyclonal antibodies offer the theoretical advantage of broader neutralization against various Stx subtypes and potentially recognizing toxins bound to other components.[16] However, they carry the inherent risks associated with animal-derived products, although the F(ab')2​ format mitigates some of these.[19] Monoclonal antibodies may offer greater consistency and potentially lower immunogenicity risk but might have narrower strain coverage unless multiple mAbs are combined.[15] Other strategies like toxin receptor decoys have also been explored preclinically.[15]

Limitations and Unanswered Questions: The primary limitation currently is the lack of definitive Phase 3 efficacy data. The non-significant trends in Phase 2 require confirmation in the ongoing, more rigorously designed RCT.[5] Long-term safety, particularly regarding potential immunogenicity with equine proteins (even fragments), needs continued monitoring. Defining the optimal therapeutic window for administration in real-world clinical practice, where diagnosis might be delayed, remains a challenge. While preclinical data suggests broad neutralization, efficacy across all clinically relevant STEC strains and Stx subtypes needs confirmation. The termination of an earlier prevention trial also raises questions about the feasibility of using INM004 prophylactically in high-risk situations versus therapeutically after symptom onset.[1]

Future Directions: The successful completion and positive outcome of the pivotal Phase 3 trial (NCT06389474) are paramount.[4] If results are favorable, Inmunova will likely proceed with regulatory submissions to the FDA, EMA, and other agencies, leveraging the existing Orphan Drug and Rare Pediatric Disease designations.[4] Post-approval research would likely focus on long-term outcomes, real-world effectiveness, and potentially exploring use in specific patient subgroups or different timings of administration. Establishing rapid diagnostic capabilities and clear treatment guidelines will be crucial for integrating INM004 effectively into clinical practice. The ultimate success of INM004 depends not only on demonstrating statistically significant efficacy in the Phase 3 setting but also on reinforcing its safety profile in a larger cohort and addressing the practical challenges of timely administration in clinical settings where rapid diagnosis and intervention can be difficult.

10. Conclusions

INM004 is a rationally designed, polyclonal equine F(ab')2​ anti-Shiga toxin therapy addressing a significant unmet medical need in the treatment of STEC-HUS. Its mechanism of action, neutralizing the causative toxins by blocking receptor binding, is well-supported by structural and preclinical data. Early-phase clinical trials have established an acceptable safety and tolerability profile, including in the target pediatric population, with predictable pharmacokinetics. While Phase 2 efficacy results showed positive trends but lacked statistical significance, the combination of a strong mechanistic rationale, favorable safety data, and high unmet need has justified progression to a large, multinational Phase 3 randomized controlled trial. Regulatory agencies have acknowledged the potential of INM004 through the granting of Orphan Drug and Rare Pediatric Disease designations. The ongoing Phase 3 trial is critical and will provide definitive evidence regarding the clinical efficacy and safety of INM004. If successful, INM004 holds the promise of becoming the first specific, disease-modifying therapy for STEC-HUS, potentially transforming the management and improving outcomes for affected children worldwide. However, successful implementation will also require addressing challenges related to timely diagnosis and administration in clinical practice.

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