Our Science

OVERVIEW

Lakewood-Amedex Biotherapeutics has discovered a novel class of antimicrobial agents called the Bisphosphocin^® class which possess ground-breaking properties that have the potential to provide a significant contribution in fighting the Antimicrobial Resistance (AMR) crisis.

Our lead candidate, Nu-3, is formulated as a topical gel, offering several advantages for the treatment of skin infections:

• Rapid and potent antimicrobial action
• Broad-spectrum activity, including against resistant bacterial strains.
• No expected resistance development

Nu-3 is well-suited for topical delivery, which has key advantages over systemic treatments:

• Targeted delivery at the infection site, overcoming circulation challenges in diabetic patients
• Minimal systemic exposure, reducing side effects while allowing for sufficient concentrations at the infection site

Nu-3 is initially being developed for the treatment of mildly Infected Diabetic Foot Ulcers (iDFU).

SCIENTIFIC APPROACH

Bisphosphocin^® compounds are novel, small nucleotide derivatives that exert antibacterial activity by targeting bacterial cell membranes, causing rapid bacterial cell death.

Mechanism of Action – Rapid Destabilization of Bacterial Cell Walls
The Bisphosphocin^® class of compounds targets bacteria through a pH and concentration dependent destabilization of the bacterial cell membrane, typically achieving this effect in under one minute of exposure.

Broad Antimicrobial Spectrum
Bisphosphocin^® compounds exhibit broad-spectrum antibacterial activity against gram positive, gram negative, and the most relevant resistant bacterial strains such as MRSA, VRE and other resistant pathogens. The antimicrobial properties of Bisphosphocin^® compounds are also notably effective against biodefense pathogens, thereby potentially playing an important role in national security and public health.

Rapid Antibacterial Effects
In time kill experiments where bacteria are exposed to the Bisphosphocin^® class of compounds the action is rapid, with total cell death occurring within minutes at higher concentrations and lower pH values.

For example, Nu-3 kills 10⁵ E. coli bacteria within 10 minutes at 25 mg/ml (2.5% solution) and leads to complete eradication in less than 10 minutes at higher concentrations.

Effects on Biofilm
Biofilms are used by bacteria to evade antibiotics and survive in hostile conditions and have been identified as a major problem associated with chronic, recurrent, and resistant infections. The majority of standard-of-care antibiotics have reduced efficacy against bacteria that have entered a non-replicating state, commonly referred to as dormancy. Recent research has proven that Bisphosphocin^® compounds are effective at killing bacteria even when present in a biofilm environment where bacteria are in a dormant state.

No Resistance Development
The rapid membrane antimicrobial mode of action of Bisphosphocin^® compounds is key to overcoming resistance development by bacteria. This property has been supported by laboratory experiments using a serial passage of E. coli and MRSA in the presence of Nu-3 for 21 days.

Minimal Systemic Exposure and Side Effects
The Bisphosphocin^® class of compounds is designed for application at the site of infection. In addition to the advantage of being able to target the infection directly, the local application limits systemic exposure and avoids most or all systemic side-effects. This includes severe allergic reactions and gastrointestinal side effects that would otherwise occur through disruption of the intestinal microbiome.

Lakewood-Amedex Biotherapeutics Inc. has demonstrated that local Bisphosphocin^® compound application produces limited systemic exposure in several animal models including a large animal porcine toxicology study where Nu-3 was applied to the wounds, in a twice-a-day regimen, for 14 days. Systemic exposure in this study was very low and short-lived with no adverse effects on any organ system. Quantitative testing (pharmacokinetics) of systemic exposure in humans is planned in a future clinical trial.

Antimicrobial Spectrum

Bisphosphocin^® compounds exhibit a broad-spectrum antibacterial activity against gram positive, gram negative, and the most relevant resistant bacterial strains such as MRSA and other resistant pathogens. A partial list of bacteria that are susceptible to Nu-3 and other Bisphosphocin^® compounds is shown in Figure 3 (bacteria shown in red are AMR organisms). Research indicates that the antimicrobial properties of Bisphosphocin^® compounds are effective against several biodefense pathogens, thereby potentially playing a role in national security and public health.

INTELLECTUAL PROPERTY

Lakewood-Amedex Biotherapeutic’s broad antimicrobial technology platform is well protected by a broad intellectual property portfolio comprising 98 patents, 69 of which have been allowed, with the remaining (29) being pending applications.

The key patent filings provide protection through at least 2038, and the most recent patent applications will extend protection through 2044, once issued. Our patents cover composition-of-matter of the Bisphosphocin^® class and other related classes of compounds; formulations of Nu-3; use patents for the Bisphosphocin^® class; and process patents for the class.

PUBLICATIONS

Perri M.B., Dale R., Zervos M.J., In Vitro Activity of an Investigation Nucleic Acid Antibacterial Compound Nu-2 against Multidrug-Resistant Bacteria, Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999, Sep 26-29; 39: 339 (abstract no. 1811).

Dale R.M.K., Schnell G., Wong J.P., Therapeutic Efficacy of “Nubiotics” against Burn Wound Infection by Pseudomonas aeruginosa, Antimicrobial Agents and Chemotherapy, 2004, 2918–2923.

Dale R.M.K., Schnell G., Zhang R.J.D., Wong J.P., Therapeutic efficacy of aerosolized liposome­encapsulated nubiotic against pulmonary Pseudomonas aeruginosa infection, Therapy, 2007, 4(4).

Cao S., Sun L.-Q., Wang M., Antimicrobial activity and mechanism of action of Nu-3, a protonated modified nucleotide, Annals of Clinical Microbiology and Antimicrobials, 2011, 10:1.

Akiyoshi D., Dilo J., DiTullio P., Novel Bisphosphocin Nu-3 Demonstrates Rapid Killing of Bacteria-Encased in Biofilm In vitro, D. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, 2013, Sept 10-13.

Wong J.P., DiTullio P., Parkinson S., Bisphosphocins: novel antimicrobials for enhanced killing of drug-resistant and biofilm-forming bacteria, Future Microbiol., 2015, 10(11), 1751–1758.