FP-045: Fanconi Anemia; Pulmonary hypertension associated with interstitial lung disease (PH-ILD); Cardiovascular, Renal and Metabolism (CVRM); Peripheral artery disease (PAD)
FP-045 is a potent and highly selective aldehyde dehydrogenase (ALDH2) activator, highly soluble and orally available. ALDH2 is a key mitochondrial regulator of toxic aldehyde metabolism, and it plays an important role in the metabolism of toxic aldehydes produced by ethanol metabolism and other oxidative stress.
Foresee has completed a Phase 1 study evaluating FP-045 a single ascending dose and multiple ascending doses (SAD/ MAD) in healthy volunteers study titled: A Single-Center, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Dose Escalation Study to Evaluate the Safety/Tolerability and Pharmacokinetics of FP-045 Administered Orally to Normal, Healthy Volunteers(https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374139). Based on the outcome of this study, the safety, tolerability, and pharmacokinetic properties of FP-045 were promising and met the expectation for the study drug.
A Phase 1b/2 Fanconi Anemia study for FP-045 is currently being initiated. The study entitled: “A multi-center, Phase 1/2 study to determine the Optimal Biologic Dose (OBD) and to evaluate the safety, tolerability, PK, and preliminary activity of FP 045 when administered orally in young adult/adolescent and pediatric patients with Fanconi anemia”(https://clinicaltrials.gov/ct2/show/NCT04522375?term=Foresee+Pharmaceuticals&draw=2&rank=1)(Identifier: NCT04522375)。
In addition to Fanconi Anemia (FA), Foresee plans to evaluate and research FP-045 in other possible indications.
Fanconi anemia (FA) is a rare inherited disease caused by genetic defects in the DNA repair protein group. The majority (60 – 70%) of FA is attributable to mutations of the FANCA gene. FA is often characterized by physical abnormalities, bone marrow failure, and/or an increased risk of malignancy. The incidence of this disease is about 1/130,000 in the United States.
The most significant early manifestations of FA are hematologic abnormalities. 80% of patients will develop bone marrow failure in their second decade. Up to 98% of patients will develop symptoms related to blood abnormalities and various disorders; most will develop cancer.
In vitro, FP-045 increases ALDH2 activity in FANCA-deficient cells and protects FANCA-deficient cells from damage due to exposure to toxic reactive aldehyde. FP-045 will protect cells from these toxic aldehydes and maintain healthy cell growth. These data support that ALDH2 activity may be necessary for maintaining the development of blood cells in Fanconi anemia patients. As such, it may be a valuable treatment for patients with incipient bone marrow failure. Currently, there is no medicine on the market to cure Fanconi anemia or slow the progression of the disease. As Foresee advances the development of FP-045 as a potential therapy for FA, this could become the first available worldwide for Fanconi anemia patients.
Pulmonary hypertension associated with interstitial lung disease (PH-ILD)
Pulmonary hypertension (PH) is a group of patients with abnormally high mean pulmonary arterial pressure (mPAP). PH is a complex and devastating disease that causes progressive vasoconstriction and vascular remodeling of the distal pulmonary arteries. According to the World Symposium on Pulmonary Hypertension (WSPH), pulmonary hypertension is categorized into 5 groups. It is estimated that patients of Group 3 pulmonary hypertension account for about 9% of the overall pulmonary hypertension patients according to the statistics of the World Health Organization (WHO). Group 3 PH includes PH due to hypoxia (low oxygen levels), intertitial lung disease and/or chronic lung disease.
Recent evidence has supported that oxidative stress is critical in the anthological remodeling of the pulmonary vasculature. Excessive lipid peroxidation is also a resource to cause abnormal proliferation of PASMCs. The (FP-045) compound series, developed by Foresee, has been demonstrated to show robust effect in detoxifying aldehyde by increasing ALDH2 activity, so it has the potential to develop as new drug for pulmonary hypertension.
Foresee is currently working on advancing FP-045 clinical development to patients who have Pulmonary hypertension associated with interstitial lung disease (PH-ILD). More information about the progress of the program will be shared in the near future.
Cardiovascular, Renal and Metabolism (CVRM)
Cardiorenal metabolic conditions are a group of interconnected disorders affecting the heart, kidneys and endocrine system. These conditions are the leading cause of deaths worldwide, accounting for up to 20 million deaths annually. Conditions within this group include coronary artery disease, heart failure, chronic kidney disease, and type 2 diabetes, among many others.
Components of the cardiorenal metabolic disease are central obesity, insulin resistance, hypertension, metabolic dyslipidemia (low HDL, high triglycerides and increased small dense LDL particles), proteinuria, and/or reduced glomerular filtration rate (GFR< 60 ml/min) (Adam Whaley Connell and James R. Sowers J Am Soc Hypertens. 2014 Aug; 8(8): 604–606). Foresee’s scientists are designing potential new therapies based on an emerging understanding of the biology behind the problem, for example, oxidative stress, mitochondria health, and ALDH2 activity.
In the early animal testing, our drug candidate FP-045 has been shown to be able to treat cardiorenal metabolic disorders. Our efforts in this area target the damaging reactive oxygen species, common in cardiorenal and metabolic diseases, to prevent mitochondria disorder and alleviate heart/renal failure.
Peripheral Artery Disease (PAD)
Peripheral Artery Disease (PAD) is a disease that affects mainly the lower extremities. It has also been referred to as Peripheral Vascular Disease (PVD) or Peripheral Artery Occlusive Disease (PAOD). The most common clinical manifestation of PAD is Intermittent Claudication (IC). IC is a pain in the leg (or less common in the thigh, buttock, or back) that occurs on exercise and is relieved by rest. It is caused by an inadequate blood supply to the legs due to blockage of arteries. Current treatment aims to modify the underlying cardiovascular risk factors and relieve symptoms, including exercise rehabilitation, revascularization, and medical treatment.
Peripheral artery disease is one of the leading causes of amputations in the U.S.； it causes the blood vessels to narrow, reducing blood flow to the limbs, especially the legs. While 8.5 million people in the U.S. have been diagnosed with PAD, as many as 20 million may have it, according to J&J (April 2022). 70% of people with leg amputations due to PAD die within three years.
Currently, medical treatment for PAD is designed to reduce mortality and relieve symptoms. However, new therapies are needed to alleviate symptoms. Our approach using ALDH2 activators to develop a novel therapy for PAD is based upon accumulating evidence that these patients have a profound mitochondrial diseases, which are could be caused by bouts of ischemia-reperfusion (I-R) induced by walking that leads to oxidative injury to the mitochondria in the ischemic muscle. Driven by this new paradigm, we have proposed that improving aldehyde clearance ameliorates the ongoing mitochondrial injury in PAD.