Jeff Aronin's Paragon Biosciences and its portfolio companies have seen great growth in the first two quarters of 2022 on its mission to find innovative treatments for rare and debilitating diseases for which therapeutic solutions have been elusive.  To accomplish its mission, Paragon has cultivated bioscience companies with technological expertise in three major areas, cell and gene therapy, optimized protein design, and state-of-the-art biotechnology.  These companies include Castle Creek Biosciences, CiRC Biosciences, Emalex Biosciences, Evozyne, and Harmony Biosciences.

Highlights from 2022 include a new alliance and license agreement between Evozyne and Takeda to advance multiple research avenues, an expansion of Emalex Bioscience's central nervous system platform with a new licensing agreement, and the recent procurement and funding of in vivo technology by Castle Creek Biosciences to expand its gene therapy pipeline.  In the wake of positive pediatric Tourette syndrome study findings, Emalex has begun to present its data at medical conferences.

Evozyne is Evolving with Takeda

The new agreement between Evozyne and Takeda builds upon an earlier agreement between the two companies in January 2021 that specifically targeted protein engineering to enhance gene therapies for inborn errors of metabolism and lysosomal storage disease.  The new licensing agreement will cover designer proteins to be integrated into cutting-edge gene therapies targeting as many as four rare disease mechanisms.

Evozyne's unique platform wields AI and machine learning to recreate the evolutionary process using underlying assumptions about how evolution works.  Closed loop circuits analyze high throughput gene products and automated assays to simulate the creative power and performance of evolutionary adaptations in a laboratory setting.  In this way, completely unique proteins can be developed that sidestep therapeutic barriers by transforming existing proteins under evolutionary conditions.

Under the terms of the agreement, Takeda will sponsor Evozyme with upfront and research funding payments in the double digit million-dollar range in exchange for exclusive licensing rights to deliverables as part of their gene therapy program.  The portfolio company will then be able to acquire up to $400 million in compensation if future developmental, regulatory, and commercial milestones are met in addition to tiered royalties for any commercial product that develops from the partnership.

A Big "Wake Up" Year for Harmony

As part of its first quarter 2022 financial results release, Harmony Biosciences disclosed more than $500 million in cumulative net revenue since its WAKIX® (pitolisant) launch.  2021 was Harmony's first full year of profitability, achieving $22.7 million in net income it its fourth quarter.  Year-over-year net revenue grew 43%, reaching $85.3 million in the first quarter of 2022.

WAKIX® is a first-in-class medication administered once per day that has been FDA approved to treat excessive daytime sleepiness (EDS) or cataplexy in adults suffering from a sleep disorder called narcolepsy.  Features of the narcolepsy include EDS even after enough sleep at night and involuntary episodes of sleep onset at inappropriate times during the day.  Around 70 percent of narcoleptics also suffer from cataplexy, a phenomenon of sudden loss of the ability to move during wakefulness, which should only occur during rapid-eye-movement (REM) sleep, the part of sleep where dreaming occurs.  

Pitolisant is thought to work by increasing the activity of neurons that release histamine.  It inhibits the histamine 3 (H3) receptor, an autoreceptor that decreases production and release of histamine when it senses histamine levels rising, a phenomenon known as feedback inhibition.  The drug operates by dampening this inhibition, thereby raising histamine levels.  Histamine is a chemical messenger in the brain that activates parts of brain that keep you awake during the day and inhibits parts of the brain that make you sleepy at night and shut off your motor control during REM sleep.  

In the second half of 2022, Harmony is planning to release interim results from a phase 2 proof-of-concept trial evaluating the effectiveness of pitolisant in treating EDS and other key features in the rare genetic syndrome, Prader Willi syndrome.  Interim results from a phase 3 trial evaluating the effectiveness of pitosolant in treating EDS and nonmotor features of the rare neuromuscular disorder, myotonic dystrophy, are planned for release in 2023.

Castle Creek Now Commands a Dual-Technology Platform

Due to its oversubscribed preferred stock offering, Castle Creek Biosciences has secured $112.8 million in financial capital.  The company plans to use to the funds to complete its Phase 3 study investigating a new potential ex vivo therapy for recessive dystrophic epidermolysis bullosa (RDEB), a currently untreatable, frequently deadly, rare genetic skin condition characterized by painful blisters.  Funding will also enable Castle Creek to pursue work on its in vivo candidate for hereditary tyrosinemia tye 1 (HT1), for which it has submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration.

HT1 is a rare genetic disorder affecting the metabolism of the amino acid, tyrosine, that causes injury to the liver as well as the kidneys and peripheral nerves.  Ex vivo technology differs from in vivo technology in that cells are first removed from an individual's body and then they are returned after genetic manipulation.  In vivo technology directly inserts engineered genes into a person's body, such as with a genetically modified virus.  Castle Creeks now can leverage the capabilities of both these technologies to expand its therapeutic pipeline.

Castle Creek's in vivo technology platform was made possible earlier this year following its acquisition of Novavita Thera, Inc., a preclinical stage company devoted to developing therapies for liver and metabolic diseases.  In conjunction with the acquisition, two new important appointments were announced: Joseph Lillegard, MD, PhD, as chief scientific officer and Robert A. Kaiser, PhD, DABT, as vice president of preclinical development.  Drs. Lillegard and Kaiser will spearhead Castle's Creek's joint research venture with the Mayo clinic to find and advance effective gene therapy candidates to treat two devastating, rare connective tissue diseases, osteogenesis imperfecta (often called brittle bone disease) and classical Ehlers-Danlos syndrome.

Emalex is Taking Its Topline Results to Medical Conferences

Taking full advantage of the American Academy of Neurology's (AAN) annual meeting venue, Emalex Biosciences gave an abstract presentation on interim results for its phase 2B study (D1AMOND Study) evaluating the efficacy and safety of the investigational new drug, ecopipam (EBS-101) in treating Tourette syndrome (TS) sufferers in the pediatric age range.  Analysis of study data obtained last November showed a 30% decrease in tics in the treatment group compared to placebo, a clinically meaningful effect size that reached statistical significance.  Headache, drowsiness, sluggishness, anxiety, and restlessness were the most common treatment-related adverse reactions.  

A disorder with childhood onset that can persist into adulthood, TS is characterized by unwanted repetitive movements or sounds, called motor and vocal tics.  Ecopipam is a first-in-class selective antagonist of the D1 family of dopamine receptors, which includes subtypes D1 and D5.  This contrasts with most typical and atypical antipsychotics that primarily act at the D2 receptor.  

The selective action at the D1 receptor averts certain side effects, including parkinsonism (characterized by slow, low amplitude movements, stiffness, and resting tremor) and weight gain, that can occur with other antipsychotic medications.  Emalex is organizing a phase 3 study on ecopipam for pediatric TS with a planned start date in 2022.  The company is also evaluating the efficacy and safety of ecopipam in treating childhood-onset fluency disorder (stuttering) in adults.

To broaden its central nervous system (CNS) therapeutic pipeline, Emalex has negotiated a licensing agreement with East Carolina University to explore ecopipam's potential therapeutic application to restless legs syndrome with augmentation (RLSa).  The primary feature of this condition, also known as Willis-Ekbom disease, is an overwhelming impulse to move one's legs stemming from a feeling of discomfort.  Symptoms worsen at night and can significantly disturb sleep.  RLS is the most prevalent movement disorder, affecting around 5%-10% of the general population according to the International Parkinson and Movement Disorder Society.   Conventional therapies, particularly dopamine agonists (agents that increase dopamine activity), exacerbate symptoms, a phenomenon known as augmentation.

CiRC's Lab is Growing 

The most recent addition to Paragon's portfolio of companies, CiRC Biosciences is continuing to conduct pre-clinical research studies on prospective cell therapy treatments to preserve and restore vision in advanced retinitis pigmentosa and geographic atrophy age-related macular degeneration.  Its scientific team has grown and has just finished moving to 400 N. Aberdeen in Chicago, where a large lab has been constructed. 

Geographic atrophy age-related macular degeneration (dry AMD) is the number one cause of permanent vision loss in those aged 65 and older and lacks any effective treatment, and advanced retinitis pigmentosa (RP) is a cluster of rare genetic mutations that destroy the retina over time leading to symptoms that advance from tunnel vision to complete loss of sight.

A biotech entrepreneur, Jeff Aronin founded Paragon Biosciences, where he serves as chairman and CEO.  He has had over thirty years of experience serving a leadership role in the medical life sciences space.  Aronin just recently won business accolades that included a platinum award for Entrepreneur of the Year by the TITAN Business Awards and a gold Stevie® Award from the American Business Awards® as Entrepreneur of the Year.  While affirming his commitment to finding solutions for "some of society's most challenging problems," he credited his successes to his team: "These recognitions belong to the hard-working scientists and other employees that make up the Paragon family."