FP-045: Fanconi Anemia; 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.

FP-045 has successfully completed single and multiple ascending dose Phase 1 studies. Its safety and tolerability are insured, pharmacokinetic properties are in line with expectations. For detailed study design, please visit:
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374139

The data from the study would be use for the dose selection and study design for subsequent proof-of-concept studies testing the effect of FP-045 in different indications. Foresee selected FP-045 as a lead compound for clinical development from a series of ALDH2 activator drugs and prodrugs.
FP-045 is free to proceed into Phase 1b/2 Fanconi anemia clinical trial in September, 2020. The clinical trial is being initiated currently. For detailed study design, please visit:
https://clinicaltrials.gov/ct2/show/NCT04522375?term=Foresee+Pharmaceuticals&draw=2&rank=1
(Identifier: NCT04522375)。

In addition to Fanconi Anemia (FA), Foresee continues to evaluate and research FP-045 in other possible indications.


Fanconi Anemia

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. Between 80% of patients will develop bone marrow failure in their second decade of life. Up to 98% of patients will develop symptoms related to blood abnormalities and a variety of 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 important in maintaining the development of blood cells in Fanconi anemia patients and as such may be a useful treatment for patients with incipient bone marrow failure. At present, there is no medicine on the market to cure Fanconi anemia or slow down the progression of the disease. If successfully developed, FP-045 will become the first and only drug in the world for Fanconi anemia.

Cardiovascular, Renal and Metabolism (CVRM)


Cardiorenal metabolic conditions are a group of interconnected disorders affecting the heart, kidneys and endocrine system. In aggregate, 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). Our 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 disorder. Our efforts in this area also aim to thwart 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 mostly 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 pain in the leg (or less common in 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 as well as 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 (Apr., 2022). 70% of people who have leg amputations due to PAD die within 3 years.

Currently, medical treatment of PAD is designed to reduce mortality and to relieve symptoms. However, new therapies are needed to relieve symptoms. Our approach using ALDH2 activators to developing a novel therapy for PAD is based upon accumulating evidence that these patients have a profound mitochondriopathy, which is presumably 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.