"Although each rare disease impacts a small population, the rare disease population is estimated to be 10% of the total population, meaning 25-30 million Americans have at least one rare condition."
What are the key molecules that make up ConSynance Therapeutics’ pipeline?
ConSynance is a clinical-stage virtual biopharmaceutical company focusing on rare diseases in the central nervous system, particularly those related to hypothalamic dysfunction. Our lead asset is CSTI-500, a small molecule first-in-class triple monoamine reuptake inhibitor (TRI), that I originally co-invented to treat depression before discovering its potentially benefit on patients with Prader-Willi syndrome (PWS) and hypothalamic obesity (HO). We recently received FDA approval to study CSTI-500 in PWS patients, which will mark the first clinical study involving this population. We plan to initiate the clinical trial in Q2 of 2022.
In 2021, we reached an asset purchase agreement with Harmony Biosciences for our second drug, (formerly CSTI-100, now renamed HBS-102). This potential first-in-class molecule with a novel mechanism of action has the potential to treat a variety of neurological disorders. ConSynance currently holds the license of this drug for the Greater China region, and Harmony has global commercialization rights outside of Greater China. Harmony is currently evaluating the potential of HBS-102 in a variety of rare neurological areas.
Can you explain the main symptoms of PWS and hypothalamic obesity?
PWS is a developmental genetic disorder caused by the inactivity of a section in paternal chromosome 15 that impacts the functioning of the hypothalamus, a region of the brain that maintains homeostasis in eating, sleeping, moods and behaviors. There are roughly 10,000-20,000 patients in the US and 250,000-500,000 patients worldwide with PWS, with incidence not associated with sex, race, or ethnicity. The hallmark symptom is a life-threatening, insatiable appetite called hyperphagia. Symptoms also include multiple hormonal dysfunctions and unique neuropsychiatric disorders such as repetitive and ritualistic behaviors, temper outbursts, skin picking, daytime sleepiness, depression and intellectual disabilities. There is currently no treatment for PWS, and the only approved drug for this population is a growth hormone to treat shortness.
Often called the “phenotypical cousin” of PWS, HO has very similar symptoms, including hyperphagia. Most often, this disorder arises either from a benign brain tumor, such as craniopharyngioma impacting the hypothalamus, or negative consequences from the surgical removal of this tumor.
How can CSTI-500 be used to treat Prader-Willi syndrome and Hypothalamic Obesity?
In HO and PWS, the major nuclei in the energy center of hypothalamus are damaged, dysregulating feeding behaviors and energy expenditure balance. CSTI-500 is an optimally balanced TRI targeting the downstream pathways of hypothalamus to the reward, executive, and autonomic centers, helping to restore the dysregulated signalling. Based on existing clinical evidence of “single” and “dual” reuptake inhibitors, CSTI-500 is also expected to improve the neuropsychic symptoms of these disorders.
What is your assessment of the current research and regulatory environment for rare diseases in the US?
There are over 7,000 rare diseases, and over 90% have no FDA-approved treatment. Although each rare disease impacts a small population, the rare disease population is estimated to be 10% of the total population, meaning 25-30 million Americans have at least one rare condition.
The Rare Disease Act has helped incentivize biopharmaceutical research to treat this population. Currently, 31% of drugs in biopharma companies' pipelines target rare diseases, compared to 18% in 2010. The US is the leading country for rare disease research thanks to its patient-centric ecosystem fostered by the government, patient advocacy groups, industry, research institutions, and the general regulatory environment. The US has the most favorable environment for rare disease research given the ability to take on high-risk endeavors that have the potential to transform the treatment of rare disease patients and significantly improve their quality of life. I am pleased to see a recent congressional hearing on “the Future of Medicine” includes bills that further improve the regulatory environment for rare disease therapeutics.
What trends are you most excited about in the CNS / neural research space?
One-third of rare diseases have a CNS or neural component. There are several innovative technologies advancing this field, particularly regarding gene therapy, including RNA-based technologies and cell therapies. Additionally, there is an uptick into research into the potential use of previously "forbidden" substances such as psychedelics and cannabinoids for the treatment of psychiatric and neurological disorders. I am also excited about the promise shown by AI and machine learning (such as AlphaFold), given their potential to dramatically shorten the drug discovery process. There are use cases for target identification, virtual screening, lead optimization, and drug design. These tools can map protein targets with structures previously impossible to precisely predict.
Looking ahead, what are your short-term goals for ConSynance?
Our primary goal for 2022 is to complete the first clinical trial for CSTI-500 in PWS patients. We also look forward to the advancement of HBS-102 by Harmony Biosciences and plan to examine other rare disease opportunities in the CNS space.