Beth Hoffman Origami Therapy CEO, talk How companies use machine learning and computational chemistry to develop treatments for neurodegenerative diseases in response to email questions.
Why did you start Origami Therapeutics?
I started Origami Therapeutics because I saw an opportunity to develop a different approach to treat neurodegenerative diseases by using protein correctors and degradation agents. I worked at Vertex Pharmaceuticals for more than 7 years, leading their drug discovery work, which eventually led to the development of the current blockbuster cystic fibrosis drugs Orkambi® (lumacaftor/ivacaftor) and Kalydeco (ivacaftor).
Before joining Vertex, I was the scientific executive director of Amgen, where I established and directed their neuropsychiatric drug discovery group, which is a new disease field. I was also selected as a member of the scientific advisory board of Amgen Ventures, responsible for evaluating Series A and Series B investment opportunities. I also served as the head of neuroscience at Eli Lilly, where I established a new research group and oversaw the strategic planning and execution of our new target portfolio.
By combining my expertise in neuroscience drug development with Amgen and Eli Lilly with my experience in Vertex developing protein “correctors” for cystic fibrosis, Origami was founded. Using my experience in discovering cystic fibrosis conversion therapy that modulates the conformation of CFTR, our focus is to treat neurodegeneration by directly modulating pathogenic proteins.
Beth Hoffman
What does the company do?
Headquartered in San Diego, Origami is developing a series of precise protein degradants and correctors to treat neurodegenerative diseases caused by the misfolding of toxic proteins starting with Huntington’s disease (HD). We are using Oricision™, a precision technology platform focused on high-value targets, to discover compounds that have the potential to provide more effective treatments and resolve more than 80% of proteins that evade inhibition and are “unable to make drugs” through traditional methods.
We are also the first to adopt spherical brain cell culture, a 3D cell culture system containing multiple brain cell types to create patient-derived neurological disease cell models. Origami is using machine learning and computational chemistry to optimize small molecules to prevent mutant huntingtin (mHTT) pathology in human neurons.
What makes your company unique?
Most of the current protein degradation projects in the industry are in the field of oncology. At Origami, we are developing a new pipeline of small molecules, disease-modifying protein degradation agents, and neurodegenerative disease corrector therapies.
Origami’s discovery platform, Oricision™, can discover and develop protein degradants and conformation correctors, allowing us to match the best drugs to treat each disease. Driven by artificial intelligence and machine learning, Patient-derived disease models Including brain organoids (or spheres) To strengthen clinical translation.
In the field of oncology, the company is targeting a protein that, when eliminated, will cause cancer cells to die. For neurological diseases, we don’t want brain cells to die, so we must find a way to reduce toxic proteins, thereby protecting and saving patients’ nerve cells, protecting healthy, thriving cells and preventing dysfunction.
Origami is using a completely different method of protein degradation, which is a more elegant method that preserves functional proteins while selectively eliminating toxic forms of misfolding. Our competitive advantage is that we are developing a new small molecule pipeline targeting the root cause of the disease, starting with mutant huntingtin (mHTT), which is the only verified HD target.
Oral administration can achieve systemic non-invasive treatment, and early biomarkers based on peripheral blood guide the timing of brain biomarker evaluation. Our main candidate, ORI-113, targets the toxic misfolded mHTT, which is eliminated through the natural degradation pathway, with the goal of retaining the HTT function. The conformation corrector can prevent/repair protein misfolding and eliminate toxic effects while retaining the HTT function.
What are your specific needs in the healthcare/life sciences field?
Since many neurodegenerative diseases are caused by protein misfolding, there is an important opportunity to develop drugs to address the root cause of the disease, using a mechanism that can prevent, possibly reverse, and hopefully prevent the disease completely.
We believe that neuroscience investment is currently ushering in a huge revival. With the increase and growth of the pharmaceutical industry’s interest in this field, there is a huge presence in areas with serious unmet medical needs such as HD, Alzheimer’s disease, and Parkinson’s disease. opportunity. obstacle.
At what stage of development is your leading product?
Our lead compound ORI-113 is in the preclinical development stage of Huntington’s disease, which is a huge unmet medical need of patients. Among them, there is no FDA-approved drug that can slow, prevent, prevent, or reverse the progression of the disease. Currently approved drugs only partially treat the motor symptoms of HD and have significant side effects.
We chose HD as our main indication because it is a single-gene, dominantly inherited, fatal neurodegenerative disease, which is characterized by a triad of symptoms: motor, mental, and cognitive disorders. HD is usually diagnosed between 30 and 50 years of age. It is a systemic disease with dysfunctions observed throughout the body, including immune, cardiovascular, digestive and endocrine systems, and skeletal muscles.
There are a large number of HD patient registries in North America and Europe, so we can select patients at a very precise stage of the disease. In addition to being able to select suitable patients for our future research, we also have diagnostic tools to assess their response to treatment, and we can know whether our drugs are effective relatively quickly.
HD is an orphan disease. In the United States and Europe, 71,000 symptomatic patients and 250,000 people are at risk of inheriting the gene that causes HD, and 50% of them are expected to be genetically positive. The number of patients worldwide is estimated to be 185,000.
Is your product clinically validated?
Our main candidate for HD, ORI-113, is currently in the preclinical development stage.
What are your milestone achievements?
We have performed proprietary high-throughput screening (HTS), hit extension/hit lead, and our initial mechanism of action (MoA) studies have shown that our molecule inhibits mHTT toxicity. We have also acquired a broad portfolio of intellectual property rights.Our team is located San Diego Biolab, We have a wet laboratory there and established a scientific research team.
What is the next step for the company this year?
We are currently raising our seed round of financing. The seed funding will push our lead protein degradants into the lead optimization of HD and other projects. At present, we are selecting the best protein degradants to advance the preclinical research of HD and initiate plans for other indications.
We are evaluating several molecules and selecting the best one, with the goal of selecting a clinical candidate compound within 12-18 months. In addition to degrading molecules, we also hope to advance conformation correctors to restore protein function by repairing misfolded structures.
Photo: Andrzej Wojcicki, Getty Images
