FP-045 (mirivadelgat): Fanconi Anemia; PH-ILD

FP-045 (mirivadelgat) 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 SAD/ MAD studies evaluating FP-045 in healthy volunteers in 2018. It was safe and well tolerated, and the pharmacokinetic profiles were in line with expectations. 
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374139

A Phase 1b/2 Fanconi Anemia study (FuschiA study) for FP-045 has been initiated.
https://clinicaltrials.gov/ct2/show/NCT04522375?term=Foresee+Pharmaceuticals&draw=2&rank=1)(Identifier: NCT04522375)。

Additionally, a Phase 2 clinical study in pulmonary hypertension associated with interstitial lung disease (PH-ILD) patients (Windward study) is in planning for initiation in 4Q2024.


Fanconi Anemia

Fanconi anemia (FA) is a rare inherited disease caused by genetic defects in the DNA repair protein group. The incidence of this disease is about 1/130,000 in the United States. The majority (60 – 70%) of FA is attributable to mutations of the FANCA gene.

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 lymphocytes and protects FANCA-deficient cells from 4-hydroxynonenal (4-HNE) induced damage in a dose-dependent manner. Aldehydes, such as 4-HNE, inhibit the growth of FANCA gene-deficient lymphocytes and cause DNA double-strand breaks, resulting in cell damage; 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 the progression of the disease. If successfully developed, FP-045 will become the first and only drug in the world for Fanconi anemia.

 

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) and it 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.

According to DelveInsight statistics, approximately 166,000 PH-ILD patients were diagnosed in key countries in 2021, among which approximately 87,000 patients were in the United States, while Europe and Japan had around 57,000 and 22,000 PH-ILD patients respectively. Furthermore, the global market value for PH-ILD in key countries was approximately US$1.263 billion in 2022, with an expected continued growth trend.

Recently, more and more evidence has shown that oxidative stress is crucial in the pathological remodeling of the pulmonary vasculature, and excessive lipid peroxidation is also a cause of abnormal proliferation of pulmonary artery endothelial smooth muscle cells. ALDH2 activators including Foresee’s FP-045 series of compounds have demonstrated compelling activity in pharmacological models of PH, HF and ILD through the activation of ALDH2, demonstrating disease modifying efficacy on lung fibrosis, heart hypertrophy and fibrosis as well as pulmonary and cardiac function.

FP-045 has the potential to become a first-in-class oral therapeutic for PH-ILD and eventually other forms of PH.