Technology Overview & Status

Inimex Pharmaceuticals Inc.’s technology platform represents the next generation of innate immune modulation. The company is developing a new class of compounds called Innate Defense Regulators (IDRs), to treat infections and tissue damage. Preclinical data indicate that IDRs are active in models of a wide range of indications including life threatening bacterial infections and the severe side-effects of chemo- and radiation-therapy. The first drug in this class, poised to start a Phase 2 clinical trial, is IMX942 - a fully synthetic, five amino acid peptide with high aqueous solubility. Extensive in vivo preclinical studies have shown that IMX942 accelerates pathogen clearance and increases host survival in a broad spectrum of bacterial infections (including Gram positive and negative bacteria and both drug sensitive and resistant strains), while having no direct antibacterial activity. IMX942 also reduces tissue damage associated with chemotherapy, radiation, trauma and inflammation.

The Company has a strong IP position on IMX942 and related analogs. Intravenous IMX942 was well tolerated in a healthy volunteer Phase 1 trial. A Phase 2 protocol is complete and principal investigators have been engaged. The company’s first Phase 2 trial will evaluate the ability of IMX942, added to a standard antibiotic regimen, to accelerate the time to resolution in patients with severe acute bacterial skin and skin structure (ABSSSI) infections. The company will file an IND for this study in Q3 2011.

IDRs and Innate Defenses:

The innate immune response involves numerous signaling pathways and leads to a wide spectrum of biological responses. IDRs provide a novel approach to control of infection and tissue damage by binding to an intracellular adaptor protein, sequestosome-1, also known as p62, that has a pivotal function in signal transduction during activation and control of the innate defense system:

 

Sequestosome, p62:
  • expressed in most cell types;
  • downstream of pattern recognition receptors (e.g. TLR, NOD);
  • “signal integrator” in innate defense signaling pathways;
  • recently identified target for modulation of innate defenses

As host-directed agents, IDRs do not select for antibiotic resistance in pathogens. In vitro data indicates that the endothelium plays a significant role in IMX942 activity and animal studies show that IDRs selectively promote monocyte and macrophage recruitment to disease sites and accelerate resolution of disease. While IDR action depends on the presence of monocytes and macrophages, there is no dependence on the presence of either the adaptive immune system (e.g., T cells) or neutrophils. This suggests that IDRs may be effective in immunosuppressed patients.

Summary of animal studies:

Inimex’ extensive animal data set points to high potential for development of a broad spectrum of products. Inimex IDR compounds have been shown to:
ameliorate injury;

  • reduce inflammation;
  • fight both antibiotic sensitive and resistant infections;
  • complement antibiotics:
  • protect immune-compromised animals


More specifically:

  • IMX942 ameliorates tissue damage in models of chemotherapy and radiation induced mucositis as well as DSS induced colitis and has shown accelerated healing in a murine model of skin infection and injury.
  • Studies in murine models of bacterial infection have shown activity against a broad range of pathogens including MRSA, K. pneumoniae, E.coli, P. aeruginosa. and B. pseudomallei.
  • IMX942 enhances the activity of antibiotics administered at sub-optimal doses.
  • Studies in a model of MRSA bacteremia indicate that IMX942 is effective both therapeutically and prophylactically.
  • The peptide is most effective when administered by IV injection and has a very short plasma half- life.
  • When administered prophylactically in the MRSA model, a single dose of IMX942 is protective when injected up to 5 days before bacterial challenge, indicating a prolonged pharmacodynamic effect despite rapid plasma clearance.
Product Profile:
  • Safe for multiple IV administrations;
  • Rapid action - intracellular protein target is widely distributed in body tissues and modulates multi-cellular response cascades;
  • Rapidly cleared from circulation – early localization in mucosa;
  • Prolonged efficacy after single exposure, but no drug accumulation;
  • Broad-spectrum response to injury or pathogen challenge;
  • Independent of adaptive immune system – effective in immune-suppressed animals.
Clinical studies:

Phase 1 - Completed: IMX942 has been evaluated in a placebo-controlled Phase 1 clinical trial in healthy volunteers with both single ascending dose and multiple ascending dose components. The peptide showed a strong safety profile when administered IV over 7 days. Drug clearance in Man is rapid and similar to results seen in pre-clinical studies.

Phase 2 – 2H, 2011 start: Inimex is working with world-leading clinicians to evaluate IMX942 in a Phase 2 clinical trial in patients with severe ABSSSIs. The objective of this trial is to see if IMX942, when combined with standard antibiotic therapy, can shorten the time to resolution in these patients. This trial design takes advantage of both the anti-infective and tissue protective effects seen in pre-clinical studies. GMP manufacture of Drug Product is complete and FDA have indicated that that trial can proceed under the IND filed August 2011.