Pipeline

Pipeline

Illustration chart of stages

Preclinical virucidal effect on respiratory viruses

Testing the virucidal activity of a 3% LTX-109 formulation against
respiratory viruses after 1 hour contact time

  • The aim of these studies were to determine the antiviral activity of a 3% formulation of LTX-109 against Influenza A virus (IAV), SARS-CoV2 and
    Respiratory Syncytial Virus (RSV) after 60 seconds contact time.
  • The viruses were incubated with 3% LTX-109 for 60 seconds, and the virucidal activity was determined by quantifying the number of infectious virus units
    recovered.
  • Upon treatment with 3% LTX-109, over 2 log reduction in virus infectivity was detected compared to a negative control, after 60 seconds contact time. Cytotoxicity was observed under some conditions but did not affect the validity
    of the assays.
  • Under the conditions tested, 3% LTX-109 displays a virucidal activity of over 2 log, corresponding to over 99% reduction of RSV infectivity and SARS-CoV2 infectivity, and a virucidal activity of over 1 log, corresponding to over 90% reduction of IAV infectivity.

Results of in vitro testing of the virucidal activity of a 1% LTX-109 formulation against respiratory viruses after 1 hour contact time and 3% LTX-109 for 60 sec.

Results of in vitro testing of the virucidal activity of a 1% LTX-109 formulation against respiratory viruses after 1 hour contact time and 3% LTX-109 for 60 sec.

Figure 1: The image shows Lenti-virus-like particles with intact envelope (control) and dissolved envelope (1% LTX-109). Top pictures before treatment and bottom pictures after treatment.

Figure 2: The loss of morphological integrity of the virus post-treatment with LTX-109, note the capsid of the virion without envelope. Top pictures before treatment and bottom pictures after treatment.

HIGH RISK PATIENTS AND UNMET NEED – WHY AND WHAT WE AIM TO DO

 

In immunocompromized patients, Influenza is associated to a significantly higher number of radiographic abnormalities and severe complications, require more intensive care and mechanical ventilation.1

Prolonged influenza shedding is also observed in these patients which contributes to viral spread in the general population.

  • The population with highest risk of mortality are haematopoietic stem cell transplant2 (HSCT) patients, but also other conditions such as:
    – Hematologic malignancies and solid organ tumor patients
    – Patients who receive other immunosuppressive therapies
  • Furthermore, Influenza vaccines have highly variable efficacy that is hard to predict
  • High Influenza viral load titers seem to correlate with worse outcome and increased risk of mortality3
  • Current treatment options do not have a meaningful impact symptom duration4 in these patients. In addition, they are replication inhibitors as opposed to LTX-109s direct virucidal effect.

LTX-109, as a direct virucidal, will demonstrate reduction in hospitalisation, mortality and symptom duration in clinical trials in non-hospitalized early stage HSCT influenza patients as an add-on to standard of care.

 

  1. Influenza virus load in hospitalised patients, N Lee et al. Hong Kong Med J 2013 & The severity and risk factors for mortality in immunocompromised adult patients hospitalized with influenza-related pneumonia,Chen et al. 2021 
  2. Respiratory virus infections in stem cell transplant patients: the European experience. Biol Blood Marrow Transplant. Ljungman P.  Et al.  2001
  3. a) Viral Factors Associated With the High Mortality Related to Human Infections With Clade 2.1 Influenza A/H5N1 Virus in Indonesia  Pavestri et al 2020 Clinical infectious disease b) Every 10-fold increase in viral load results in 26% more patient deaths: a correlation analysis, Jiang et al. Int J Clin Exp Med 2019.  c) Influence of viral load in the outcome of hospitalized patients with influenza virus infection, Lalueza et al.
  4. 4 Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. T Jefferson et al. Cochrane Database of Systematic Reviews 2014https://www.ema.europa.eu/en/medicines/human/EPAR/xofluza

LTX-109 is rapidly bactericidal

The onset of LTX-109 activity is rapid and dependent on concentration. Increased concentrations of up to 8x MIC (minimum inhibitory concentration) for LTX-109, compared to Vancomycin and Dicloxacillin against Staphylococcus Aureus and compared to Penicillin and Erythromycin against Streptococcus Pyrogenes, showed that the bactericidal effect of LTX-109 is dependent on concentration with a faster effect at higher concentrations, compared to Vancomycin, Dicloxacillin, Penicillin or Erythromycin.

Rapid bactericidal effect on S. Aureus

LTX-109 acting on Staphylococcus aureus bacteria; Live (green) and dead (red). Time lapsing inminutes

Lack of resistance development

In general, compounds acting on the cell membrane have low propensity for developing resistance. The occurrence of spontaneous resistance towards LTX-109 was studied by plating a heterogeneous mixture of bacteria. Neither in wild type, MRSA nor glycol peptide resistant Staphylococcus aureus was any spontaneous resistance observed. No signs of resistance development have been observed in 5 different Staphylococcus aureus strains after 14 passages

MIC Value

The minimum inhibitory concentration (MIC) is the lowest concentration of a chemical, usually a drug, which prevents visible growth of a bacterium or bacteria. MIC depends on the microorganism, the affected human being (in vivo only), and the antibiotic or antimicrobial peptide itself.

CFU (Colony Forming Units) is a measure of number of bacteria. 1 Colony forming unit is one bacterium causing growth on plates with growth medium. The natural logarithmic scale Log10 is used to show change in CFU.

LTX-109 kills MRSA better than ‘Gold Standard’ drugs

  • Murine skin infection model (tape-stripping, ATCC 33591)
  • Read-out: bact growth +9 hours after teatment
  • Retapamulin is a topical antibiotic developed by GlaxoSmithKline. It is the first drug in the new class of pleuromutilin antibiotics to be approved for human use. It is marketed as an ointment under the brand names Altabax and Altargo.
  • Retapamulin was approved by the United States Food and Drug Administration in April 2007 for the treatment of bacterial skin infections such as impetigo. In May 2007, retapamulin received approval in the EU from the European Medicines Agency for the same indication.

  • Fusidic acid is an antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Pharma in Ballerup, Denmark and released for clinical use in the 1960s.

Completed clincal trials:

A first in man Phase I study to investigate tolerability and safety of topical LTX-109 in healthy subjects (Study C08-109-01)

      • Healthy volunteers
      • Phase I
      • 1, 2 and 5% LTX-109 3x daily for 5 days, placebo controlled
      • 3 x 6 subjects w/ intact skin, and 6 subjects with abraded skin (1%)

Safety conclusions
Application site reactions for 2% and 5% not significantly different from placebo. Negligible systemic uptake

Efficacy conclusions
No efficiency assessment performed.

A Phase I/IIa study to evaluate the safety, tolerability and efficacy of topical LTX-109 in subjects nasally colonized with methicillin-resistant/-sensitive Staphylococcus aureus (MRSA/MSSA; Study C10-109-02)
Clinicaltrials.gov

      • Nasal decolonization with MSSA or MRSA
      • Phase I / IIa
      • 1, 2 and 5% LTX-109 3x daily for 3 days, placebo controlled
      • 3 x 6 subjects; 12 with MSSA and 6 with MRSA

Safety conclusions
Predominantly mild (95%) AEs, also moderate (4%). Two unrelated severe AE (1%). 2% and 5%
caused more itching and burning

Efficacy conclusions
Statistically significant treatment effect on Log CFU for 2% and 5% on day 3 and 4. Re-colonization
weeks 2, 5 and 9.

A Phase I/IIa, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety and Exploratory Efficacy of 3% LTX-109 compared to Placebo for nasal decolonisation of Staphylococcus aureus (Study C21-109-06)
Clinicaltrials.gov

      • Nasal decolonization with MSSA or MRSA
      • Phase I / IIa
      • 3% LTX-109 4x in a day, 2 hours between applications, placebo controlled
      • 15 subjects

Safety conclusions
4 applications once every 2 h of a high-viscosity gel containing 3 % w/w was safe and well-tolerated by the study subjects. 19 AEs reported and 10 were assessed as possibly related, 1 was assessed as probably related, and 8 were assessed as unlikely related to the IMP.

Efficacy conclusions
The largest bacterial eradication rate in the active treatment group was observed at 6 h after the start of treatment (eradication in 8 out of 11 subjects). Four (4) out of 11 subjects in the active treatment group had MSSA eradicated at the end of the study (Day 22).

LTX-109 is as fungicidal as Amphotericin B
  • A study investigated the fungicidal activity of LTX-109 by determining minimum fungicidal concentration (MFC) and by Time-Kill Kinetics.
  • Amphotericin B is an antifungal medication used for serious fungal infections (which due to its extensive side effects, it is often reserved for severe infections
    in critically ill patients)
  • Results shows Time-Kill Curves, measures as percentages survival of 3 different fungus (log10 % survival after 24 hours)
  • The study concludes that LTX-109 is as fungicidal as Amphotericin B in Time-Kill experiments, an indicate that LTX-109 has a potential as treatment for fungicidal infections