Randomised Controlled Trial of pErhexiline on regreSsion Of Left Ventricular hypErtrophy (LVH) in Patients With Symptomatic Hypertrophic CardioMyopathy (RESOLVE-HCM)

Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart muscle condition affecting up to 1 in 200 of the general population. It results from mutations in genes encoding components of the contractile apparatus in the heart muscle cell (myocyte). These mutations result in increased energy cost of force production for the myocyte which then cumulatively causes a myocardial energy deficit. This myocardial energy deficit is then thought to lead to cardiac hypertrophy ('left ventricular hypertrophy' or LVH) in HCM.
LVH leads to impairments in heart muscle function, heart muscle oxygenation and microvascular blood flow and is the chief driver of patient symptoms in HCM. These symptoms consist of chest pain, shortness of breath, dizziness, fainting episodes or palpitations. Occasionally, the disease may cause sudden cardiac death (SCD). HCM is the most common cause of SCD in young people including competitive athletes. In addition, HCM has been found to result in significant global deterioration in health-related quality of life.
Treatment of HCM has focused on relief of symptoms by drugs such as ß-blockers which slow the heart rate and improve heart function. However, symptom relief is often incomplete and there is no evidence on the benefit of ß-blockers or related medications to reverse LVH. Perhexiline, a potent carnitine palmitoyl transferase-1 (CPT-1) inhibitor shifts myocardial metabolism to more efficient glucose utilisation and rectifies impaired myocardial energetics. It is currently used to treat angina in patients with coronary artery disease. There is some preliminary evidence that Perhexiline may aid in the improvement of symptoms in patients with HCM. However, the effect of any form of therapy on potential regression of LVH in HCM remains unexplored.
In this randomised double-blind placebo-controlled trial, the investigators will use state of the art cardiac imaging, principally advanced echocardiography and Cardiovascular Magnetic Resonance (CMR) to study the effects of perhexiline on LVH, cardiac function, and oxygenation in symptomatic patients with HCM. The investigators hypothesize that perhexiline will favourably reduce LVH and improve myocardial oxygenation by improving myocardial energetics, and that these putative morphological and functional changes can be accurately measured utilizing echocardiography and CMR. If this pilot study supports the hypothesis, then it will pave the way for a major randomised controlled trial to definitely determine the role of Perhexiline in HCM.

Start Date01 Dec 2020

Sponsor / Collaborator

Flinders University

ACTRN12620000785909

/ Not yet recruitingPhase 2

Randomised controlled trial of pErhexiline on regreSsion Of Left Ventricular hypErtrophy in patients with symptomatic Hypertrophic CardioMyopathy (RESOLVE-HCM)

Start Date01 Sep 2020

Sponsor / Collaborator

Flinders Medical Centre

NCT02862600

/ TerminatedPhase 2

A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on the Efficacy, Safety and Tolerability of Perhexiline in Patients With Hypertrophic Cardiomyopathy and Moderate to Severe Heart Failure With Preserved Left Ventricular Function

The purpose of this study is to evaluate the effect of perhexiline on exercise performance (efficacy) and safety in patients with hypertrophic cardiomyopathy and moderate-to-severe heart failure following dosing for 16 weeks.

Start Date01 Aug 2016

Sponsor / Collaborator

HEART METABOLICS LTD

100 Clinical Results associated with Perhexiline Maleate

100 Translational Medicine associated with Perhexiline Maleate

100 Patents (Medical) associated with Perhexiline Maleate

946

Literatures (Medical) associated with Perhexiline Maleate

01 May 2025·Advanced Healthcare Materials

3D Microtumors Representing Ovarian Cancer Minimal Residual Disease Respond to the Fatty Acid Oxidation Inhibitor Perhexiline

Article

Author: Muñoz‐Galvan, Sandra ; Rai, Lena ; Artibani, Mara ; Aggarwal, Aneesh ; Yang, Xingyun ; Jin, Yongcheng ; Albukhari, Ashwag ; Kumar, Ravinash Krishna ; Bayley, Hagan ; Zhou, Linna ; Zhang, Yujia ; Ahmed, Ahmed Ashour ; Mukherjee, Nobina ; Ma, Shaohua ; Mikhailova, Ellina

Abstract:

The poor survival of ovarian cancer patients is linked to their high likelihood of relapse. In spite of full apparent macroscopic clearance, tumor recurrences arise from cells that are resistant to primary chemotherapy in the form of minimal residual disease (MRD). MRD exhibits distinct molecular drivers from bulk cancer and therefore necessitates alternative therapeutic strategies. However, there is a lack of 3D models that faithfully recapitulate MRD ex vivo for therapy development. This study constructs microfluidics‐based 3D microtumors to generate a clinically‐relevant model for ovarian cancer MRD. The microtumors recapitulate the non‐genetic heterogeneity of ovarian cancer, capturing the “Oxford Classic” five molecular signatures. Gene expression in the 3D microtumors aligns closely with MRD from ovarian cancer patients and features the upregulation of fatty acid metabolism genes. Finally, the MRD 3D microtumors respond to the approved fatty acid oxidation inhibitor, perhexiline, demonstrating their utility in drug discovery. This system might be used as a drug‐testing platform for the discovery of novel MRD‐specific therapies in ovarian cancer.

02 Jan 2025·Expert Opinion On Drug Safety

Risk of drug-induced delirium in older patients- a pharmacovigilance study of FDA adverse event reporting system database

Article

Author: Li, Jiayu ; Zhou, Ying ; Jia, Boying ; Zhou, Shuang ; Wan, Liyan ; Cui, Yimin

BACKGROUND:

Drug-induced delirium is known risk factors associated with increased morbidity and mortality in older patients. The objective was to evaluate the risk of drug-related delirium in older patients based on the FDA Adverse Event Reporting System (FAERS).

RESEARCH DESIGN AND METHODS:

Delirium reports in older patients (age ≥65) extracted from the FAERS database using Open Vigil 2.1. The reported odds ratio and the proportional reported ratio were calculated to detect the adverse reaction signal of delirium. Combined with published evidence, suspected drugs were categorized as known, possible, or new potential delirium-risk-increasing drugs.

RESULTS:

Of the 130,885 reports (including 28,850 delirium events and 1,857 drugs) analyzed for this study, 314 positive signal drugs were detected. Positive signal drugs are mainly concentrated on the drug of nervous system, cardiovascular system , alimentary tract and metabolism and anti-infectives for systemic use. Of the positive signal drugs, 26.11% (82/314) were known delirium-risk increasing drugs, 44.90% (141/314) were possible and 28.98% (91/314) were new potential.

CONCLUSION:

Drug-induced delirium risk is prevalent in older patients, according to the FAERS. The risk level of drug-induced delirium should be taken into account to optimize drug therapy in clinical practice.

01 Jan 2025·Acta Pharmaceutica Sinica B

GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery

Article

Author: Wang, Qun ; Lu, Jinyuan ; Chen, Zexi ; Wu, Xinyi ; Chen, Luonan ; Cao, Wen ; Liao, Xuyang ; Tian, Saisai ; Zhang, Jinbo ; Zhang, Weidong

Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

News (Medical) associated with Perhexiline Maleate

02 Jan 2024

·www.fiercebiotech.com

Old heart drug halts growth of pancreatic cancer in organoid and mouse models

An image of cancer organoid cells treated with perhexiline maleate. The red in the image is a marker of cell death, indicating where the cells were destroyed by the drug. Scientists have shown that an old heart drug can inhibit growth of one of the most common and lethal forms of pancreatic cancer, at least in preclinical models. In a study published Dec. 26 in Cell Stem Cell, researchers from Weill Cornell Medicine showed that perhexiline maleate—a calcium channel blocker used to treat angina—could stifle the growth of KRAS-G12D-mutated pancreatic ductal adenocarcinoma in human organoid models that had been transplanted into mice. Its mechanism of action could form the basis of future drugs. Perhexiline maleate, prescribed as Pexid or Pexsig, was used as an anti-angina treatment until the 1980s, when it was sidelined in most countries due to its side effect profile, a review article by researchers at the University of Adelaide explains. While the drug was never approved for use in the U.S., it is still used by clinicians in New Zealand and Australia. It works by shifting the metabolism of fatty acids and carbohydrates in a way that helps the heart process oxygen more efficiently, thus reducing the symptoms of angina. Scientists first demonstrated perhexiline’s anti-cancer potential in 1984, when they showed that it could sensitize leukemia cells to chemotherapy. Since then, it has shown to not only boost chemo but also to inhibit growth on its own in cell lines and mouse models of breast, lung, brain, liver and other cancers with a variety of different gene mutations. In the new study, the researchers didn’t set out to test perhexiline maleate specifically. They started by setting up an automated drug screening system that looked at the efficacy of different drugs on organoids made from mouse pancreatic cells that had been engineered with the many different types of mutations associated with pancreatic ductal adenocarcinoma, including a mouse version of KRAS-G12D. Organoids are three-dimensional cell cultures grown from stem cells that function like the tissue of the organ they represent. Of the 6,000 compounds tested, perhexiline maleate emerged the winner. The drug was able to not only stop all of the cancerous organoids from growing, but even destroyed some of them altogether. It also appeared to have no effect on healthy, non-mutated organoid cells. The researchers then tested perhexiline maleate on mice transplanted with the same type of organoids, along with another group that received human-derived cancerous organoids. The drug inhibited the growth of the cells in both of those models, along with a separate set of human-derived pancreatic cancer organoids with different types of KRAS mutations. When the researchers compared gene patterns between treated and untreated organoids, they noticed that the KRAS-G12D mutation was boosting the production of cholesterol in the mutated cells. Perhexiline maleate was counteracting that effect, thereby stopping the cancerous organoids from growing, by inhibiting a protein involved in cholesterol synthesis called SREBP2. While this wasn’t news to the researchers, as cholesterol is well known to play a role in cancer progression and synthesis, it did mark the first time that scientists had shown that targeting it could be effective against pancreatic ductal adenocarcinoma with KRAS-G12D mutations. The fact that it worked in human organoids with other types of KRAS mutations could mean that the treatment mechanism is less vulnerable to being overcome by cancer resistance, the researchers noted in a press release. In the same release, the scientists added perhexiline maleate itself will not be used as an anti-cancer agent, as the risk of side effects—namely liver and nerve damage—is too high. Instead, researchers will likely tinker with its chemical structure to come up with a candidate that has the same anti-cancer effects without the drawbacks.

Drug Approval

27 Dec 2023

·www.sciencedaily.com

Scientists use organoid model to identify potential new pancreatic cancer treatment

A drug screening system that models cancers using lab-grown tissues called organoids has helped uncover a promising target for future pancreatic cancer treatments. A drug screening system that models cancers using lab-grown tissues called organoids has helped uncover a promising target for future pancreatic cancer treatments, according to a new study from researchers at Weill Cornell Medicine. In the study, published Dec. 26 in Cell Stem Cell, the scientists tested more than 6,000 compounds on their pancreatic tumor organoids, which contain a common pancreatic cancer-driving mutation. They identified one compound -- an existing heart drug called perhexiline maleate -- that powerfully suppresses the organoids' growth. The researchers discovered that the cancer-driving mutation in the organoids forces the abnormally high production of cholesterol, which the drug largely reverses. "Our findings identify hyperactive cholesterol synthesis as a vulnerability that may be targetable in most pancreatic cancers," said study co-senior author Dr. Todd Evans, vice chair for research in surgery, the Peter I. Pressman MD Professor in Surgery, and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. "This study also highlights the value of using genetically well-defined organoids to model cancer and discover new treatment strategies," said co-senior author Dr. Shuibing Chen, director of the Center for Genomic Health, the Kilts Family Professor Surgery and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. The other co-senior author was Dr. Fong Cheng Pan, a research assistant professor in the department of surgery at Weill Cornell Medicine during the study. The study's co-first authors were postdoctoral researcher Dr. Xiaohua Duan, instructor Dr. Tuo Zhang, and a visiting fellow, Dr. Lingling Feng, all at Weill Cornell Medicine during the study. A Tumor Organoid-Based Screening System Organoids have become popular tools for studying tissues in health and disease. They can be made from human or animal tissue, they can recreate much of an organ's complex architecture, and they can be genetically engineered for precision modeling. Organoids can also model specific tumor types with their cancer-driving gene mutations. Indeed, when these tumor organoids are derived from human tissue, they have the potential to model human cancers better than any animal model. In the study, the researchers set up an organoid-based automated drug-screening system for the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) -- one of the most untreatable and lethal of cancers. The organoids, made from normal mouse pancreatic tissue, were engineered to contain various sets of mutations known to drive human pancreatic tumors. All the organoids contained KrasG12D, the mouse version of a cancer-driving mutant gene found in most cases of PDAC. The researchers tested a library of more than 6,000 compounds, including FDA-approved drugs, on the organoids, identifying several that could substantially disrupt their growth. The best of these was perhexiline maleate, an older drug used to treat the heart condition called angina. A modest dose of the drug blocked growth in all the KrasG12D-containing organoids, destroying some of them outright within days, while having no adverse impact on healthy organoids lacking the mutation. The drug had similar effects against mouse and human PDAC-derived tumor organoids transplanted into mice, and in human tumor organoids carrying other types of Kras mutation. By comparing gene activity patterns in treated and untreated organoids, the researchers found that cancer-associated mutant Kras greatly boosts the production of cholesterol in organoid cells, and that perhexiline maleate opposes this effect by inhibiting a key cholesterol metabolic pathway regulatory factor called SREBP2. Cholesterol as an Emerging Cancer Target The discovery of cholesterol's role was not entirely surprising, since cholesterol is an essential building-block used in making new cells, and a promoter of cell survival; it is already known to be an important sustainer of malignant growth for some other tumors, including lung tumors. Now, the results suggest that targeting it may be an effective new treatment strategy against PDAC. Perhexiline maleate's effectiveness in human organoids harboring several different Kras mutations also suggests that turbo-charged cholesterol synthesis can be a general treatment target in KRAS-mutant cancers. "We hope that our cholesterol-targeting strategy will be independent of particular KRAS mutations and will make it hard for treated tumors to evolve resistance," said Dr. Evans, who is also a member of the Sandra and Edward Meyer Cancer Center . Perhexiline maleate is unlikely to be used as-is for treating PDAC. Although it is still prescribed as an angina drug in Australia and some other countries, it can have serious side effects, including liver damage and peripheral nerve damage -- which is why it was withdrawn from several European markets in the 1980s, and was never approved in the United States. "We want a better compound for cancer treatment," said Dr. Chen. The simplicity of the drug's chemical structure suggests that it probably can be modified to improve its potency, safety, bloodstream half-life and other properties, she said. The team now plans to use perhexiline maleate as a starting point for the development of a more refined candidate PDAC drug, and as a laboratory tool for studying cholesterol synthesis in PDAC and other cancers.

31 Aug 2023

·www.biopharmadive.com

Sanofi appoints a venture investor to R&D head as executive team expands

Dive Brief:Sanofi has found a new head of research and development in Houman Ashrafian, who currently serves as a scientific advisor at SV Health Investors. His start date is Sept. 11.The appointment fills a spot vacated by John Reed, who left Sanofi early this year for a similar position at Johnson & Johnson. Ashrafian is a cardiologist by training and, according to SV Health, co-founder of seven of the firms still-active companies. He also sits on the boards of five of those companies, as well as four others.Ashrafians hiring came alongside an announcement of a larger expansion to Sanofis executive team. The French pharmaceutical giant said it added a head of business operations and a chief digital officer, and now has an interim head for its specialty care business unit, as the former head, Bill Sibold, plans to leave to pursue an external opportunity.Dive Insight:Sanofis R&D activities changed significantly during the five years Reed oversaw them. Formerly best known for its work in heart and diabetes research, the company has more recently been prioritizing areas like cancer, the immune system and rare diseases.Ashrafian will soon be in charge of Sanofis busy pipeline. In February, the company said it was expecting results from 27 early- to mid-stage clinical trials sometime over the following 15 months.Ashrafian brings a wealth of expertise as a scientist and in bringing high value transformational medicines from discovery to market, said Paul Hudson, Sanofis CEO, in a statement.With Houmans leadership and deep understanding of science, we aspire to make our R&D transformation sustainable, Hudson added.Before joining SV Health in 2016, Ashrafian co-founded a U.K.-based drug development firm, Heart Metabolics. According to SV Health, that company successfully repositioned a drug called perhexiline, which has been tested as a potential treatment for several heart conditions, including cardiomyopathy and chronic heart failure.Ashrafian also previously served as head of the clinical science group at UCB Pharma.Joining him on Sanofis board will be Madeleine Roach, Sanofis newly appointed head of business operations. Roach left AstraZeneca for Sanofi last year, coming on as head of internal audit and risk management. Her new role is effective Oct. 1.Sanofis freshly minted chief digital officer, Emmanuel Frenehard, is also an internal hire. Frenehard has been at the company for three years, holding various leadership roles related to digital activities. In his new appointment, which is effective immediately, he will be responsible for advancing Sanofis digital transformation as well as its data and technology strategy.Sanofi said Dietmar Berger, whos been leading the companys R&D team on an interim basis since Reeds departure, will continue to serve in his roles as chief medical officer and global head of development. '

Executive Change

100 Deals associated with Perhexiline Maleate

External Link

KEGG	Wiki	ATC	Drug Bank
D05442	Perhexiline Maleate	C08EX02	DB01074

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Angina Pectoris	-	-	-

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiomyopathy, Hypertrophic	Phase 1	Australia	Heart Metabolics Ltd.	-
Pancreatic Ductal Adenocarcinoma	Preclinical	United States	Weill Cornell Medicine	06 Jan 2024

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02862600 (CTgov)	Phase 2	Heart Failure \| Cardiomyopathy, Hypertrophic, Familial	35	Perhexiline+Use of bioanalytical assay to monitor plasma levels of perhexiline	hfvjgorbcp(fiueshiqrt) = vbscdelrik kxhjjzefty (kayesrknwm, tfvwnesesl - xevkxiolgx) View more	-	31 Aug 2017
NCT00845364 (Pubmed \| Eur J Cardiothorac Surg)	Phase 2/3	-	286	Perhexiline	lweerfwxpk(xoynozhrxk) = gzeuhzjmwy uewbltgxhp (vgtlhzugek )	Negative	01 Mar 2015
NCT00845364 (Pubmed \| Eur J Cardiothorac Surg)	Phase 2/3	-	286	Placebo	lweerfwxpk(xoynozhrxk) = udxaqgbdcr uewbltgxhp (vgtlhzugek )	Negative	01 Mar 2015

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