Triangle gene editing firms CEO: There is a revolution occurring in medicine – WRAL TechWire

RESEARCH TRIANGLE PARK The Triangle continues to emerge as a hotbed of life science and biopharmaceutical technologies, along with a global evolution in medicine,Paul Garofolo, the cofounder and chief executive officer for Locus Biosciences, tells WRAL TechWire.

There is a revolution occurring in medicine. We are evolving from the days where we discovered small molecules that produced a favorable result in a large number of patients, likely with some level of side effects, to precision medicines that directly address the problem for the intended patient, he says. It started with antibodies and other biologic therapies that revolutionized Oncology and Immunological diseases. It is moving towards cell and gene therapies where the technology is proving itself in ultrarare diseases, and much like their predecessor technologies, will move toward more broad-based applications over time.

And Locus expects to be a part of the future of medicine, having grown its workforce to 75 employees since the companys founding in 2015, after Garofolo had the CRISPR-Cas3 technology upon which the companys research is built introduced to him by a student at North Carolina State University.

Theres growth ahead, as well, said Garofolo, as the company expects to reach 100 employees in 2022, and recently landed a $25 million credit facility to expand the companys in-house manufacturing capabilities and drug discovery program.

Paul Garofolo. Locus Biosciences image.

Were unique in biopharma in that we are clinical stage and revenue generating, said Garofolo. We generate revenue from our partnerships with two of the top five global pharmaceutical companies and contracts with BARDA and CARB-X, which together provide a combination of milestone payments, R&D cost reimbursement, and manufacturing revenue.

Those partnerships, the first of which was signed in 2019 with Janssen Pharmaceuticals, also known as Johnson & Johnson, are worth as much as $1 billion.

That partnership with Johnson & Johnson yielded Locus $20 million up front and up to $798 million in potential development and commercial milestones, as well as royalties on product sales, said Garofolo, with the goal of the partnership being the development and manufacturing ofcrPhage products targeting two key bacterial pathogens.

The company signed a contract with the Biomedical Advanced Research and Development Authority (BARDA) in September 2020 that enabled the company to advance a $144 million precision medicine program to develop LBP-EC01, a crPhage product, to combat recurrent urinary tract infections caused by E. coli,, and later that year, the company inked a deal worth $15 million to develop a product to combat antibiotic-resistant K. pneumoniae infections through Phase 1 of clinical development with the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X).

Garofolo told WRAL TechWire that he and his wife provided the initial funding for the company, then raised a seed round of $1.5 million in 2016, a $19 million Series A round in 2017, a convertible note of $20 million in 2020, and then the recent $25 million credit facility earlier this year. That positions the company for the future, Garofolo noted, adding that this access to valuable growth capital supporting the expansion of our discovery platform engine and in-house manufacturing capacity [will be] used to address critical unmet medical needs.

WRAL TechWire spoke with Garofolo about the company, and about the future of life science and biopharma. A lightly edited transcript of the conversation appears below.

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TW: Tell us more about Locus Biosciences, its six programs, and the companys position in the marketplace.

Garofolo: Locus is the worlds leading developer of products based on CRISPR-Cas3 systems. Were unique in biopharma in that we are clinical stage and revenue generating. As described above, we generate revenue from our partnerships with two of the top five global pharmaceutical companies and contracts with BARDA and CARB-X, which together provide a combination of milestone payments, R&D cost reimbursement, and manufacturing revenue.

Locus has one clinical program underway, and up to five more in urinary tract, respiratory and bloodstream infections anticipated to enter the clinic by 2023.

Locuscompletedthe worlds firstplacebo-controlled Phase 1bclinical trial of a CRISPR Cas3-enhanced bacteriophage product targetingE. coliin UTIs. The results demonstrated safety and tolerability for LBP-EC01, and the trial met all its primary and secondary endpoints. We are working towards initiating the LBP-EC01 Phase 2 study inearly 2022. In October 2020, Locus announced a contract with the Biomedical Advanced Research and Development Authority (BARDA) to support Phase 2 and Phase 3 clinical trials and other activities required to seek FDA approval of LBP-EC01.

In 2019, Locus announced an agreement with Janssen Pharmaceuticals, Inc. for an exclusive, worldwide research collaboration and license to develop, manufacture and commercialize two products generated using Locuss recombinant CRISPR-Cas3 engineered bacteriophage (crPhage) platform for the treatment of respiratory tract infections which cause significant morbidity and mortality. The collaboration focuses on developing unique bactericidal disease-modifying crPhage products. These products will treat serious respiratory tract infections and infections in other areas of the body.

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TW: Whats the difference betweenCRISPR-Cas9 and CRISPR-Cas3 in the context of CRISPR technology overall?

Garofolo: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is the adaptive immune system of bacterial cells, capable of capturing and incorporating an invaders DNA into the bacterias genome to fend off future attacks.

When reprogrammed, as Locus has done, CRISPR enzymes like Cas3 and 9 can be used to edit or destroy DNA, making it a very useful tool for gene therapy, antibacterials, and other applications.

CRISPR-Cas3 is the most common CRISPR-Cas system in nature. Cas3 is a powerful exonuclease that permanently degrades chromosomal DNA beyond repair with high specificity, leading to rapid death of the target bacterial cell. Cas3s DNA degrading effect is distinct from the more widely-known Cas9 which causes a clean break in the DNA that can be repaired by the cell.

While others use CRISPR-Cas9 to edit DNA in human cells and other organisms, Locus is concentrating its efforts on removing deadly pathogens from the human body. CRISPR-Cas3, loaded into a bacteriophage delivery vehicle (other gene therapy companies use AAV), is the ideal system to target DNA to destroy a bacterial cells genome beyond repair.

Simply put, Cas3 acts like a Pacman that gobbles up tens of thousands of DNA base pairs while Cas9 acts like a pair of scissors that make a precise cut in one place.

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TW: The company describes on its website and in press statements two product lines, precision bacteriophage products and also engineered bacteriophage therapies. Tell us more about each, and the science behind the product lines.

Bacteria are directly associated with many human diseases. Bacteriophages, or phages, are naturally occurring viruses that infect and kill bacteria. Bacteriophage have been used as antibacterial therapy for more than 100 years. However, natural phages are not typically effective enough on their own to treat serious infections in humans. Locus believes its precision engineered bacteriophage platform has the potential to fundamentally change the way bacteria-related diseases are treated.

Our team of scientists collects natural bacteriophagethe natural predator of bacteriawith the best disease-fighting characteristics. Then, leveraging artificial intelligence and machine learning algorithms, Locus Biosciences identifies the best cocktail of bacteriophages to target a particular bacterial species that causes a specific disease. Next, we engineer these bacteriophages with CRISPR-Cas3, which drastically increases their ability to fight bacteria and treat diseases without killing the good bacteria the body needs without applying selective pressure to other bacteria that increases AMR (antimicrobial resistance)

Through its unique bacteriophage discovery, synthetic biology and manufacturing platform, Locus is developing two innovative categories of biotherapeutics to address significant unmet medical needs: precision products to fight deadly infections, including those caused by multi-drug resistant bacteria; and engineered bacteriophage therapies that utilize bacteria resident in the body to deliver therapeutic molecules, while leaving the rest of the microbiome intact. Both categories are engineered bacteriophage. The former, are CRISPR Cas3-enhanced bacteriophage (crPhage) that exquisitely eradicates bacteria. While developing crPhage we became experts in engineering bacteriophage, where we can now deliver any protein or peptide therapeutic we desire.

The incidence of antibiotic-resistant infections is growing rapidly with large-scale use of antibiotics. This is a particular concern with the overuse of antibiotics during a viral pandemic, such as those caused by H1N1 influenza or SARS-CoV-2.

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The need for new precision antibacterial therapies that selectively kill target bacteria while leaving good bacteria in the body unharmed is widely recognized. The development of non-traditional therapies that possess alternative properties to conventional small-molecule antibiotics represents a unique opportunity to advance the field of medicine and provide new treatment options to patients with antimicrobial-resistant infections which are a growing concern for our nations health security.

Furthermore, the one bug, one drug precision approach our platform employs, has significant implications for bacterial infections in patients receiving novel therapeutics for conditions such as cancer. Lifesaving checkpoint inhibitors, for example, which are used across several cancer types, are negatively impacted by antibiotic use in these fragile patients. By specifically targeting only the pathogen of interest, Locus precision medicines avoid negatively affecting patient responses to these important therapies.

Within immunology and oncology, the association between disease and bacteria is becoming clearer each day. Locus platform enables the company to directly remove bacteria driving/exacerbating disease while delivering biotherapeutics that can ameliorate disease pathogenesis.

Here we leverage the microbiome to manufacture the biotherapeutics inside the human body at the site of the disease, increasing the effective dose at the target site while decreasing systemic exposure. All designed to improve outcomes while decreasing side effects.

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TW: Whats the current state of the industry and the sector, and what does the future hold, in 2022 and beyond?

Garofolo: There is a revolution occurring in medicine. We are evolving from the days where we discovered small molecules that produced a favorable result in a large number of patients, likely with some level of side effects, to precision medicines that directly address the problem for the intended patient. It started with antibodies and other biologic therapies that revolutionized Oncology and Immunological diseases. It is moving towards cell and gene therapies where the technology is proving itself in ultrarare diseases, and much like their predecessor technologies, will move toward more broad-based applications over time.

2022 will continue to see the explosive advancement of gene therapy and gene editing technologies that results in new companies and investments across the industry. As these technologies advance through the clinic in the years to come, we will see them applied more broadly to address genetic diseases that affect broader patient populations. We are already seeing the move from muscular dystrophy to sickle cell disease and beyond. From Locus, you will see our team take our CRISPR-Cas3 enhanced bacteriophage into a Phase 2 trial targeting urinary tract infections caused by E. coli a disease that affects millions of people each year in the US alone.

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TW: What can you tell us about how the companys geographic location in the Triangle means for future opportunity?

The Locus manufacturing platform is the lynchpin of our success in progressing bacteriophage products by enabling internal control over the timing, quality and speed at which we can take drugs to the clinic. We leverage our teams deep manufacturing experience as well as our geography, as NC is an ideal manufacturing location due to the local economics and talent pool.

Our world-class 10,000 square foott modular cGMP biologics manufacturing facility meets the standards of the US (FDA), Europe (EMA), Japan (PMDA), and several other countries and regions, to enable the manufacture of our precision medicines while providing the capability to also manufacture gene therapy vectors and other advanced biologics. Our facility design allows for parallel production of multiple drug substances simultaneously, in isolated production suites, without risk of cross-contamination. It is optimized for viral vector manufacturing, including bacteriophage, adenovirus, AAV, and other vectors. Taken together, our facility and proprietary production processes allow for all viral products manufactured by Locus to meet or exceed US and international regulatory standards for parenterally administered drug products for clinical and commercial use.

The modular design also allows us to change-out or upgrade existing equipment that moves Locus from being able to produce clinical trial material to producing multiple early-stage commercial products in parallel; all while maintaining the same footprint.

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Triangle gene editing firms CEO: There is a revolution occurring in medicine - WRAL TechWire