Origami Therapeutics developing treatments for neurodegenerative diseases with ML and computational chemistry

AI, machine learningAI, machine learning

Beth Hoffman, Origami Therapeutics CEO, talks about how the company enlists machine learning and computational chemistry to develop ways to treat neurodegenerative diseases, in response to emailed questions.

Why did you start Origami Therapeutics?

I started Origami Therapeutics because I saw an opportunity to develop a different approach to treating neurodegenerative diseases by using protein correctors and degraders. I was at Vertex Pharmaceuticals for more than 7 years, leading their drug discovery efforts, which ultimately led to the development of the current blockbuster cystic fibrosis drugs, Orkambi® (lumacaftor/ivacaftor) and Kalydeco (ivacaftor). 

Prior to Vertex, I was scientific executive director at Amgen, where I built and guided their neuropsychiatric drug discovery group, a new disease area. I was also elected to the Scientific Advisory Board for Amgen Ventures to evaluate Series A and Series B investment opportunities. I was also previously Head of Neuroscience at Eli Lilly, where I established a new research group and oversaw strategic planning and execution on our novel targets portfolio. 

By combining my expertise gained in neuroscience drug development at Amgen and Eli Lilly with my experience at Vertex developing protein “correctors” for cystic fibrosis, Origami was founded. Leveraging my experience in discovering transformational therapies for cystic fibrosis that modulate CFTR conformation, our focus is to treat neurodegeneration by directly modulating pathogenic proteins.

Beth Hoffman

What does the company do? 

Based in San Diego, Origami is developing a pipeline of precision protein degraders and correctors to treat neurodegenerative diseases caused by toxic protein misfolding, beginning with Huntington’s Disease (HD). We are discovering compounds using our precision technology platform Oricision™ focused on high-value targets, with the potential to deliver more potent therapies and to address the >80% of proteins that evade inhibition and have been “undruggable” by traditional approaches. 

We are also pioneering the adoption of spheroid brain cell cultures, a 3-D cell culture system of multiple brain cell types to create patient-derived cells models of neurological disease. Origami is using machine learning and computational chemistry to optimize small molecules that prevent mutant huntingtin (mHTT) pathology in human neurons.

What sets your company apart?

Most of the industry’s current programs in protein degradation are in oncology. At Origami, we are developing a novel pipeline of small molecule, disease-modifying protein degraders and corrector therapeutics for neurodegenerative diseases. 

Origami’s discovery platform, Oricision™, enables the discovery and development of both protein degraders and conformation correctors, allowing us to match the best drug to treat each disease using AI and machine learning driven, patient-derived disease models including brain organoids (or spheroids) to enhance translation to the clinic.

In oncology, companies are targeting a protein that, when eliminated, causes the cancer cell to die. For neurological diseases, we don’t want brain cells to die, so we must find a means to reduce the toxic protein in a way that protects and saves a patient’s nerve cells, preserving healthy, thriving cells and preventing dysfunction. 

Origami is taking a fundamentally different approach to protein degradation, a more elegant approach that spares functional proteins while selectively eliminating toxic misfolded forms. Our competitive advantage is we’re developing a novel pipeline of small molecules that target the underlying cause of disease, beginning with mutant huntingtin protein (mHTT), the only validated target for HD.

Oral delivery enables non-invasive treatment throughout the body, and early peripheral blood-based biomarkers guide timing for brain biomarker assessment. Our lead candidate ORI-113 targets toxic misfolded mHTT for elimination via natural degradation pathways with the goal of sparing HTT function. Conformation correctors prevent/repair protein misfolding, eliminating toxic effects while preserving HTT function. 

What specific need are you addressing in healthcare/ life sciences?

Since many neurodegenerative diseases are caused by protein misfolding, there is a significant opportunity to develop drugs that address the underlying cause of the disease using a mechanism that could halt, potentially reverse, and hopefully prevent the disease entirely.

We believe that neuroscience investment is seeing a huge renaissance moment right now, and there is a huge opportunity with increased pharma interest and growth in this space, in areas of significant unmet medical need such as in HD, Alzheimer’s disease, Parkinson’s disease, and other disorders. 

At what stage of development is your lead product?

Our lead compound ORI-113 is in pre-clinical development for Huntington’s disease, a huge unmet medical need for patients, where no FDA approved drugs slow, halt, prevent or reverse disease progression. The currently approved drugs only partially treat motor symptoms of HD, with significant side-effects. 

We selected HD as our lead indication since it is a monogenic, dominantly inherited fatal neurodegenerative disease characterized by a triad of symptoms: motor, psychiatric and cognitive impairment. Typically diagnosed between 30 and 50 years of age, HD is a systemic disease with dysfunction observed throughout the body, including immune, cardiovascular, digestive and endocrine systems as well as skeletal muscle.

There are large 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 the right patients for our future studies, we have diagnostics to evaluate how well they respond to the treatment and we can relatively quickly know if our drug is working.

HD is an orphan disease with 71,000 symptomatic patients in the U.S. & Europe and 250,000 individuals at risk for inheriting the gene that causes HD, 50% of whom are anticipated to be gene-positive. The worldwide patient population is estimated at 185,000.

Do you have clinical validation for your product?

Our lead candidate ORI-113 for HD is currently in preclinical development. 

What are some milestones you have achieved?

We have conducted a proprietary high throughput screen (HTS), hit expansion/ hit-to-lead, our initial mechanism of action (MoA) studies which show that our molecules suppress mHTT toxicities. We’ve also secured a broad IP portfolio. Our team is based in Biolabs San Diego, where we have a wet lab and have built a scientific and research team. 

What’s next for the company this year? 

We are currently in the process of raising our seed financing round. The seed funding will advance our lead protein degrader into lead optimization for HD and additional programs. Currently, we are selecting the optimal protein degrader to advance into pre-clinical studies for HD and initiating programs for additional indications.

We are evaluating several molecules and select the best one with the aim of choosing a clinical candidate compound in 12-18 months. Besides the degrader molecules, we expect to advance conformation correctors, which restore protein function by fixing the misfolded structures. 

Photo: Andrzej Wojcicki, Getty Images

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