What was the primary motivation behind establishing Locus Biosciences?
The main challenge we wanted to address when co-founding Locus was the delivery of gene editing technologies, particularly surrounding CRISPR-Cas3. These technologies have incredible potential, but their safe and effective delivery into the human body remains a significant hurdle. We saw a unique opportunity in engineering phage to address this. Additionally, we identified a niche in combating antimicrobial resistance, a novel area for CRISPR technology application. Despite the complexities in the infectious disease sector, exacerbated by events like the COVID-19 pandemic, our work at Locus has been pivotal in demonstrating the power of our technology platform.
Can you explain the initial vision and strategy of Locus Biosciences?
Our initial vision was to shift from traditional, broad-spectrum antibiotics to targeted antibacterial approach for treatments. Historically, antibiotics have been used in a way that indiscriminately affects all bacteria in the body, not just the harmful ones. This approach neglected the importance of many species of “good” bacteria (the so-called healthy microbiome) on human health. Our goal was to pioneer precision antibacterials similar to precision gene therapies, starting in the realm of infectious diseases to validate our approach.
How does Locus Biosciences' work impact the field of precision medicine?
Our work is integral to the evolution of precision medicine. We began by targeting infectious diseases, an underserved field, and are now expanding into broader applications. For instance, we recently started a project targeting specific E. coli strains associated with Crohn's disease. Our approach could revolutionize Crohn’s patient treatment by addressing a possible root cause of inflammation, reducing the need for traditional anti-inflammatory drugs.
Ultimately, our aim is to develop targeted therapies against major pathogenic threats, as we believe precision in treating diseases caused or exacerbated by bacteria is crucial for the future of medicine.
Could you give examples of your precision therapies?
Our first-generation drugs work in conjunction with antibiotics, easing doctors into a new way of treating bacterial infections. We are working with the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, under a $150 million partnership, focusing on recurrent urinary tract infections caused by antimicrobial resistant (AMR) and multi-drug resistant (MDR) strains of E. coli. This is a significant issue, particularly for women, with over 10 million UTIs annually in the U.S. alone and a recurrence rate greater than 20%.
Our lead asset, LBP-EC01, is currently being tested concomitantly with trimethoprim/sulfametoxazole (TMP/SMX) in a two-part multicenter Phase 2 clinical trial. Based on positive results from the uncontrolled open-label Part 1 portion of this study, BARDA released $23.9 million under the contract to support the double-blind placebo-controlled Part 2. If successful, we expect this trial will provide important clinical validation for our platform for wider use against MDR infections and beyond.
What sets your approach apart from traditional antibiotic treatments?
Our approach is revolutionary in its precision. As previously mentioned, traditional antibiotics indiscriminately kill both the target pathogen and other species of “good” bacteria that are important for health. By killing only the pathogen, our products preserve the healthy microbiome, which is an important patient and commercial benefit. When a new antibiotic comes to market, doctors tend to hold it back for use only after other products have failed, which leads to poor commercial outcomes. The precision nature of our products creates a compelling benefit that is readily understood by patients, doctors, and payors, which we believe will translate into a much stronger commercial opportunity for Locus products than for recent antibiotic product launches.
How does your technology work at a molecular level?
Phages, the most abundant biological entities on Earth, maintain a predator-prey relationship with bacteria. This has limited phage therapy products in the past, because wild-type (natural) phages have challenges in completely eliminating the bacterial population in an infection. We engineer payloads into phage genomes to enhance their bactericidal efficacy. Our leading payload, CRISPR-Cas3, targets specific DNA sequences in the bacterial genome for degradation, causing damage that cannot be repaired by the bacterial cell and resulting in rapid cell death. Over the years, we have also added other payloads to our arsenal to complement CRISPR-Cas3.
Are there potential side effects of this technology?
Bacteriophage are everywhere – including the water we drink and the food we eat. They have also been used to treat bacterial infections for over 100 years. They fell out of favor in the West with the discovery of antibiotics in the mid-20th century but remained in use to treat infections in Eastern Europe and other parts of the world. Meanwhile, bacteriophage have also been widely used in agriculture and food processing, with several phage products enjoying Generally Regarded as Safe (“GRAS”) designation from the U.S. Food and Drug Administration. The likelihood of side effects for bacteriophage products is relatively low because phages cannot infect human cells; they only target bacteria. We will need to conduct well-designed controlled clinical studies to prove that our products are safe and effective for their intended uses, but the history of phage product use makes us optimistic.
How has the post-pandemic depressed investment climate affected Locus Biosciences?
The investment climate in anti-bacterials has been challenging for the past seven to eight years, influenced by the general lack of differentiation between new products and older generic antibiotics. COVID-19 exacerbated these challenges by causing an investment frenzy in antivirals and vaccines, leading to an overcrowded space with delayed programs for companies like ours. In 2019, we signed an $800 million deal with Johnson & Johnson, which was very successful in developing potential best-in-class products that were poised to enter clinical development. Unfortunately, this collaboration was disrupted when J&J shut down its infectious disease division post-COVID. This exemplifies the post-pandemic difficulties: a surge in investment, often misplaced, followed by a significant pullback. We hope that 2024 marks a turnaround, moving past this phase of irrational exuberance followed by irrational pessimism, as MDR is an urgent public health threat that we simply must address for the future of humanity.
Where do you see Locus Biosciences in three years?
In the next three years, I anticipate Locus Biosciences emerging as a leader in our field, buoyed by positive data from our superiority studies. This success should open doors for other clinical assets, giving us the opportunity to enter new therapeutic areas such as immunology for conditions like Crohn's disease and possibly central nervous system for conditions like autism.
We expect government support to continue playing a crucial role, given the incredible unmet medical need for treating emerging MDR threats and the woefully inadequate antibacterial pipeline. The path has been difficult, but recent financing challenges in biotech have thinned the competition, positioning us to lead a new era in precision anti-bacterials, paralleling the advancements in precision medicine and gene therapy. Our journey, challenging as it has been, positions us uniquely for breakthroughs in addressing the MDR epidemic.
