Nasal Decolonization to prevent post-surgical infections.

Humans are the natural reservoirs for the bacterium S. aureus. 20-50% of healthy adults are colonized. Nasal colonization with S. aureus, is the single most important determinant of subsequent S. aureus infections and is a major risk factor for surgical site infections. The US, EU and the WHO all recommend decolonization of S. aureus prior to surgery. To reduce the likelihood of postoperative infections, it is particularly important to maintain nasal decolonization of S. aureus during the operation and for a few days after the operation. Currently, mupirocin is the drug of choice for nasal decolonization. But increasing mupirocin resistance indicate the potential loss of this method for preventing infections. Furthermore, decolonization therapy with mupirocin is currently not considered relevant for patients undergoing non-elective/sub-acute surgery. Hence, there is an unmet medical need for a new and highly effective drug with rapid mode of action and low propensity for resistance development to replace/complement mupirocin. Pharma Holdings' aim is to develop a safe, efficacious, and resistance-tolerant innovative antimicrobial agent for prophylactic decolonization of nasal Staphylococcus aureus with respect to non-elective/sub-acute high-risk surgery. In the project, the safety and decolonization effect of LTX-109 (3.0% hydrogel) was evaluated in two clinical studies. Furthermore, potential resistance to LTX-109 was studied in laboratory experiments. In the first part of the project period, the company carried out the resistance study as well as the first clinical study. The Arctic University of Norway/Center for new antibacterial strategies was responsible for carrying out the resistance study. The clinical study was conducted in the Phase I Unit at CTC AB in Sweden. The clinical study was conducted on 15 healthy volunteer carriers of S. aureus at a clinic in Sweden. 11 people received treatment with LTX-109 and 4 people received treatment with placebo. Both groups received 4 applications of LTX-109 over 6 hours. The results showed that the amount of S. aureus in the nose was greatly reduced in both groups. The reduction was more extensive in the group receiving treatment with LTX-109. At the same time, the study showed that recolonization resumed quite quickly in both groups. UiT/CANS carried out an extensive resistance study where the development of resistance in S. aureus against LTX-109 was studied. In the study, the effect of LTX-109 against both antibiotic-resistant and non-antibiotic-resistant S. aureus was studied, as well as the development of LTX-109 resistance over time. The results showed that LTX-109 has just as good an effect on antibiotic-resistant strains as on non-resistant strains. Furthermore, the study showed that despite long-term exposure to LTX-109, it was not possible to observe development in LTX-109 resistance in any of the S. aureus strains that were examined. The results are very encouraging and support that LTX-109 can be an important piece in the fight against resistant bacteria. The second part of the project was the implementation of a new clinical study on Nasal Decolonization of S. aureus. The study was carried out in collaboration with CTC AB in Sweden. In this study, the ambition was to change the treatment regimen with the aim of decolonization with a longer duration than observed in the first study. 25 carriers of S. aureus were treated, where 16 people received multiple (6 or 8) treatments with LTX-109 and 9 people received similar treatment with placebo. The results showed that all subjects had a reduction in the amount of S. aureus in the nose, with clearly the strongest reduction in those who received LTX109 treatment. The reduction in the amount of bacteria in people who received LTX-109 treatment was on average 99.9% only 6 hours after the treatment started. A reduction of approximately 99.9% was measured 2 days after the start of treatment, and on day 7 (5 days after the end of treatment) the reduction was still measured at 98%. In summary, the project has provided the company with valuable information. The results show that the use of LTX-109 is effective against antibiotic-resistant and non-antibiotic-resistant strains of S. aureus. At the same time, the study shows that the development of LTX-109 resistance in S. aureus is not possible to provoke, despite long-term trials. The conclusions drawn from the clinical studies are that multiple applications of LTX-109 nasal gel clearly results in a substantial, and probably clinically relevant, reduction in nasal S. aureus. Because of the LTX-109 effectiveness (>99% S. aureus reduction lasting for 7 days), rapid mode of action (>99% S. aureus reduction obtained 6 hours after start of LTX-application) and low propensity for resistance development the drug represents an interesting new decolonization option for patients with an unmet medical need undergoing non-elective/sub-acute surgery.

The key outcome of the project are two clinical study reports from the Phase II clinical trials, a preclinical report on in vitro study on LTX-109 resistance development in S. aureus strains, and advice from the European Medicines Agency (“EMA”) on the clinical development program. The results from the resistance study at CANS confirm that LTX-109 is effective against both MSSA and MRSA strains displaying a low MIC of 4-8 mg/L. Further, no spontaneous or adaptive resistance towards LTX-109 was detected. The conclusions drawn from the clinical studies are that multiple applications of LTX-109 nasal gel clearly results in a substantial, and probably clinically relevant, reduction in nasal S. aureus colony forming units. Because of the LTX-109 effectiveness (>99% S. aureus reduction lasting for 7 days), rapid mode of action (>99% S. aureus reduction obtained 6 hours after start of LTX-application) and low propensity for resistance development the drug represents an interesting new decolonization option for patients with an unmet medical need undergoing non-elective/sub-acute surgery. Pharma Holdings has started planning for the late-stage clinical development of LTX-109 as nasal decolonization drug for patients undergoing non-elective surgery. Based on advice/signals on from EMA the late-stage clinical development plan for LTX-109 nasal gel should be based on trials to demonstrate clinical benefit with reduction in post-operative infections as the primary endpoint.

Pharma Holdings (PH) is a biotechnology company, and its patented molecule LTX-109, is a cationic peptidomimetic which is a novel antimicrobial reagent acting directly on the bacterial cell membrane by inducing disruption and cell lysis. LTX-109 is extensively studied in non-clinical and clinical investigations and has demonstrated a very low propensity for resistance development. The aim of this study is to determine the S. aureus nasal decolonization efficacy of LTX-109 in a 3,0 % gel formulation versus placebo. The gel formulation or placebo will be applied topically to the anterior nares. The study will be a randomized, placebo-controlled, double-blinded trial enrolling approximately 40 persistent carriers in total. Patients will be sampled in their nose during and after treatment. Volunteers with persistent carriage of S. aureus including MRSA will be included. Persistent carriage will be defined as having at least 2 positive bacteria cultures, and the carriage status will be calculated according to the culture rule from nasal swabs. Nasal bacterial cultures will be investigated during and after treatment. Culture samples from nose and other body sites will be collected weekly up to 4 weeks after treatment start. The objective is to explore the efficacy of LTX-109 gel in an intensive regimen as evaluated by measuring the eradication rate of bacterial counts (number of subjects eradicated) as evaluated by measuring the eradication rate of bacterial counts. The study will be divided into to parts. Part one will be a Proof of Concept study enrolling approximately 16 persistent carriers of s. aureus. The study will be conducted by CTC AB/ClinSmart AB at a Phase I Unit facilities in Uppsala, Sweden. The primary objective is to explore the efficacy of LTX-109 gel in an intensive one day treatment regimen. Part two will be a Phase II study enrolling approximately 24 persistent carriers of s. aureus. The study will be conducted by CTC AB/ClinSmart AB, the Clinical Project will also be managed by CTC AB. The primary objective is to further explore the efficacy of LTX-109 gel in an intensive one day treatment, alternatively in a less intensive treatment regimen. The project duration is estimated to be three years.