Common "driver pathogens" in many emerging infectious and chronic diseases represent a large opportunity for impact.
Spirochetes
Spirochetes are a biologically sophisticated gram-negative bacteria. They are a deeply-branching phylum of bacteria initially delineated by their serpentine shape and periplasmic flagella. Their unusual cellular ultrastructure, motility mechanism, metabolic pathways, capacity for gene regulation and ability to modulate and evade the immune system make them a challenging opponent. They are invasive, mobile, immunosuppressive and difficult to detect, culture and treat. When an infection is left untreated or unresolved (>6 mos), they often lead to immune system malfunction, lasting microbiome changes and chronic illness. All of which produce an outsized negative impact on patients, families and the healthcare system.
Spirochete-driven Diseases
Examples of spirochetal diseases: Lyme disease (Borrelia burgdorferi), syphilis (Treponema pallidum), yaws (Treponema pallidum pertinue), advanced periodontal disease (Treponema denticola and Fusobacterium) and leptospirosis (Leptospira). Each of the above pose immense, and growing, global threats to human and animal health.
Fusobacterium
Fusobacterium nucleatum (Fn) is an opportunistic, gram-negative bacteria commonly found in the oral cavity. Fn is known to cause periodontal disease but is also associated with a growing number of systemic diseases, ranging from cancer and women’s health issues to Alzheimer’s disease.
The associations between poor oral health and chronic systemic disease have been suspected for years. However, more recent research suggests that Fn, if left unchecked, can manipulate the immune system and travel outside the oral cavity, ala a Trojan horse. Fusobacterium plays a primary role in this activity but is not often alone in the process, collaborating with other microbes, like Treponema denticola (a spirochete), to effect its pathogenic action in distant tissues.
Fusobacterium-driven Diseases
Fusobacterium nucleatum (Fn) has been associated with a host of cancers, most notably, colorectal cancer (CRC) and oral cancer (OSCC). In CRC, Fn promotes tumor development by recruiting immune cells to the tumor, which creates an inflammatory environment. Fn also promotes CRC development through toll-like receptor signaling and microRNA expression. The presence of Fn has been linked to poor prognosis in a host of other tissue proliferative and inflammatory disorders, including: breast, bladder, pancreatic, and esophageal cancers. It has also been linked with debilitating women’s health issues, such as, endometriosis, infertility, pre-term birth and still birth.
Our Platform
Flightpath Biosciences uses advanced drug discovery tools to identify optimal antimicrobial therapeutic candidates to vastly improve drug targeting and safety, reduce off-target impacts on the microbiome, speed the time-to-market and reduce the risk of antibiotic resistance.
In parallel, our data science and bioinformatics partners are working hard to understand host and microbiome genetics and transcriptomics to further define the impact of our drugs on the patient’s immune system, microbiome and overall health. We believe this will lead us to new data, novel discoveries and additional targeted therapeutic candidates.
Science Driven & Data Supported
FP-100
Our breakthrough, orally bioavailable, narrow-spectrum bactericidal antibiotic leverages a unique transport mechanism (not present in mammalian cells) and a known mechanism of action to inhibit protein synthesis in gram-negative spirochetes and fusobacterium. Flightpath has demonstrated selectivity in vitro and efficacy in vivo versus standard-of-care broad spectrum antibiotic therapies. Toxicity has been evaluated at multiple ascending doses and in multiple animal species without biologically relevant events.
Manufacturing Scale-up
Flightpath has conducted extensive technology transfer to achieve product manufacturing yields similar to that of standard broad-spectrum antibiotics (e.g. penicillin). We are now manufacturing at clinical and commercial scale and completing final GMP drug substance and drug product manufacturing activities.
Sparing the Microbiome
FP-100 is a narrow-spectrum antibiotic with a favorable microbiome profile.
Standard-of-care broad-spectrum antibiotics are known to cause blooms of Enterococcus and gastroinstestinal dysbiosis that could lead to immune dysregulation, chronic diseases and health problems beyond the infection being treated (e.g. asthma, allergies, anxiety, cancer, depression, diabetes, etc). Patients with chronic Lyme disease often report having muscle and joint pain, psychological and / or neurological issues and immune system difficulties possibly associated with use of multiple, long-term, broad-spectrum antibiotics.
Drug Discovery
Flightpath and its collaborators are committed to advancing additional antimicrobial discovery research in non-traditional areas of pathogen-driven diseases with high unmet medical need.
Relevant Disease Statistics
New Lyme disease diagnoses each year (US)
New cases of adult and congenital syphilis (US)
47% of adults have periodontal disease (US)
Deaths from colorectal cancer every year (US)
New colorectal cancers diagnosed last year (US)
Males are more at risk of getting and dying from colorectal cancer than females
Women are affected by endometriosis (WW)
Hysterectomies performed per year (US)
Average cost of a hysterectomy
Diseases in Focus
Lyme Borreliosis
Lyme disease is the most common vector-borne disease in the United States. Lyme disease is caused by spirochetal bacteria Borrelia burgdorferi and rarely, Borrelia mayonii. It is transmitted to humans through the bite of infected blacklegged ticks. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system.
Endemic “Tropical” Treponematoses
A nonvenereal infectious disease caused by the spirochetal bacteria, Treponema pertenue, which is related to syphilis. Yaws is a disorder which is common in children and is characterized by skin and bone lesions. It is rarely found in the United States but is common among children in the humid tropics of Africa, South and Central America, the West Indies, and the Far East. See FDA’s Tropical Disease Priority Review Voucher Program for more information.
Periodontal Disease
Many periodontal disease conditions such as: the early stage of periodontitis, acute pericoronitis (infection under the gum tissue covering a partially erupted tooth), as well as necrotising ulcerative gingivitis (severe inflammation of the gum more common in immunocompromised patients) are caused by Treponema denticola, a subgingival oral spirochete and Fusobacterium Nucleatum. Advanced disease is also known as Vincent’s disease, fusospirochetal gingivitis or Trench mouth
Adult and Congenital Syphilis
Congenital syphilis is caused by a spirochete bacteria (Treponema pallidum) and acquired by the fetus from the mother. Pregnant women with syphilis may have a reduction in estrogen while serum progesterone levels may increase. Symptoms may include inflammation of the umbilical chord, rash, fever, low birth weight, high levels of cholesterol, aseptic meningitis, anemia, monocytosis, enlarged liver and spleen, jaundice, shedding of skin on palms and soles, convulsions, mental retardation, periostitis, rhinitis, hair loss, inflammation of the eye’s iris and pneumonia.
Leptospirosis (Weil syndrome)
Leptospirosis is an infectious disease that affects humans and animals caused by the spirochetal bacteria, Leptospira. Humans become infected through contact with water, food or soil containing urine from infected animals such as dogs, cats, cattle, horses, pigs, and, especially, rodents. Symptoms include high fever, chills, muscle aches, headache, vomiting, diarrhea, and jaundice. Early detection is important as the disease can cause serious complications if not treated early, including kidney damage (nephrosis), meningitis (inflammation of the tissue around the brain or spinal cord), respiratory distress and/or liver failure.
Cancer (colorectal cancer)
Colorectal cancer is the second most deadly cancer, killing over 52,000 people a year. Increasing evidence indicates Fusobacterium nucleatum, an opportunistic oral pathogen is one of the factors causing colorectal cancer. Fusobacteria are often found in healthy mouths, living in balance with other bacteria in the oral microbiome. It is considered opportunistic because in certain conditions it quickly grows out of control and causes damage to the human host.
Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System
Women’s Health (Endometriosis)
Endometriosis affects 190M women globally. In the US, there are ~600k hysterectomies per year at a cost to the healthcare system of between $30K-50K each. Notwithstanding cost and morbidity, endometriosis is also a major cause of infertility.
Recently, Muraoka et al at Nagoya University in Japan discovered a potential cause of endometriosis – a Fusobacterium Nucleatum (Fn) infection in the endometrial lining.
This work adds to research findings from many other institutions demonstrating possible links between Fn and infertility, pre-term birth and still birth.