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Bone & Joint Infections (BJI) occur in various conditions such as hematogenous and chronic osteomyelitis, open fractures, and joint replacement surgery.
Staphylococcus sp. is the main infectious agent responsible for BJI. The current standard of treatment consists in prolonged systemic antibiotic therapy, frequently combined with surgery.

However, BJI have a significant rate of treatment failure because they are particularly difficult to treat due to local conditions (necrotic areas, bacteria sequestration in bone tissue, acidic pH, anaerobia, calcium, etc.) and biofilms production (exopolysaccharide matrix) which reduce the efficacy of antibiotics administrated through systemic delivery. The WHO priority pathogens list for R&D of new antibiotics includes S. aureus.

To avoid pharmacokinetics peaks-and-throughs that might result in the survival and eventual development of the most resistant bacteria, infusions of antibiotics are usually preferred, implying that the patients will stay in the hospital for weeks. Daptomycin represents one of the major anti-staphylococcal antibiotics used, but its administration is exclusively by intravenous route which causes side effects.

Staph-EX

is a new formulation of daptomycin and consists in daptomycin-loaded lipid nanocapsules (LNC) dispersed in a thermosetting aqueous gel containing free daptomycin. The entrapment efficiency is of 100%. Staph-Ex was developed to achieve high local daptomycin concentrations for long periods of time following single local administration during surgery in case of BJI.

In vivo evidence

The results below have been published in Antimicrobial Agents and Chemotherapy journal as Editor’s Pick.

Efficacy

In a Methicillin-Resistant Staphylococcus aureus (MRSA) osteomyelitis rabbit model. A single dose of Staph-EX allows complete eradication of MRSA in bone and bone marrow compartments:

significantly more effective than intravenous antibiotics administered for 4 days (Fig.1),

even 14 days post single-dose administration of Staph-EX (Fig. 2),

and no variant resistant to daptomycin was detected.

Figure 01.

Bone
Bone Marrow

MRSA osteomyelitis rabbit model comparing a single dose of Staph-EX and intravenous (IV) antibiotics for 4 days; local S. aureus infection calculated in Log10.Colony Forming Units (CFU);

IV VAN/vancomycin 20x mimicking the human dose; IV LZD/linezolid human equivalent 600mg (12 hours); IV CPT/ceftaroline human equivalent 600mg (12 hours); IV DPT/daptomycin human equivalent 6mg for (12 hours); Staph-EX: single local administration. *p<0.001 Staph-EX versus all groups.

Figure 02.

Bone
Bone Marrow

MRSA osteomyelitis rabbit model comparing a single dose of Staph-EX versus untreated group. Local S. aureus infection calculated in Log10.Colony Forming Units (CFU)
*p<0.001 Staph-EX versus control.

Biodistribution

Following local administration of a single dose of Staph-EX, high daptomycin concentrations were maintained over a period of 14 days in both bone and bone marrow. Except for plasma at day 1 where very small concentrations were observed briefly, in all other tissues and at all observation times daptomycin concentration was below the detection limit by HPLC (Fig. 3).

Staph-EX allows a controlled-release of daptomycin with persistent high concentrations of drug in the infected tissues and limited diffusion into of other tissues. This observation is consistent with the excellent therapeutic efficacy noted in the two previous experiments. At all observation points the local concentrations in bone & bone marrow were largely in excess of the MIC for MRSA (0.5 µg.mL-1) up to 14 days.

Figure 03.

Day 1
Day 4
Day 14

Daptomycin concentrations in bone marrow, bone, plasma, spleen, kidneys, and muscles after asingle local administration of Staph-EX in a MRSA osteomyelitis rabbit model.
* Daptomycin concentration in μg (micrograms) per gram (g) or milliliter (mL) of tissue. MIC: Minimum Inhibitory Concentration – for Daptomycin MIC = 0.5 μg.mL-1

Figure 04.

Staph-EX
Placebo
Untreated

Histopathologic analysis of Staph-EX in a rat experimental model.

Tolerance

Staph-EX and placebo (without daptomycin) were implanted into rat femoral condyle defects. Histological analyses were done 4 days following the implantation of the gels comparatively to a control group (untreated) (Fig. 4).

Bone histology did not reveal significant difference between Staph-EX, placebo, and control groups.

No difference in animal weight and no observable macroscopic lesions of the heart, lungs, liver, spleen, and kidneys.

Next Steps

We are currently looking for a pharma partner and raising a round of seed to complete the pre-clinical development of Staph-EX and file an IND (IMPD/UE) within two years. The IND (IMPD)-enabling studies comprise two main parts: Chemistry, Manufacturing-Controls (CMC) and Safety Assessment.

The preclinical development strategy of Staph-EX is based on:

Both the FDA “Guidance for Industry: Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route” and the EU “Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms”;
A Scientific Advice (SA) from EMEA: on March 2022, the SAWP (Scientific Advice Working Party) and the CHMP (Committee for Medicinal Products for Human Use) agreed our regulatory development plan.

In accordance with the guidelines and the SA, the IND (IMPD)-enabling safety studies will be limited to a loco-regional animal safety study (tolerability) in rodent species.