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Founder Spotlight #36: Beth Hoffman @ Origami Therapeutics

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Origami Therapeutics is a biotech company developing novel protein degrader therapeutics with a proprietary drug discovery platform which holds the promise for disease-modification in neurodegenerative diseases, beginning with Huntington’s Disease. We are pioneering the next-generation precision small molecules targeting disease-causing proteins.

Beth Hoffman is Founder, President, & CEO @ Origami Therapeutics. She brings more than 25 years experience of CNS drug discovery and has developed over 30 assets that have advanced into the clinic in cystic fibrosis, metabolic diseases, neurology, pain, and psychiatry. Prior to Origami, she was Vice President, Discovery Biology for Vertex Pharmaceuticals, where she generated and launched first-in-class blockbuster drugs in cystic fibrosis (Kalydeco, Orkambi, Symdeko, Trikafta). She expanded the market for Orkambi helping increase sales to over $1 billion, and also generated a novel non-opioid pain therapeutic and other protein folding programs at Vertex. Dr. Hoffman received an A.B. in Molecular Biology from Wellesley College and a Ph.D. in Cell Biology from Johns Hopkins University. She is a member of the Board of Trustees for the Huntington’s Disease Society of America as well as a Scientific Advisor for the Tau Consortium focusing on alleviating diseases associated with tau pathology, such as Alzheimer’s Disease. She is also on the Board of Biofrontera (NASDAQ:BFRI).

Personal Spark

What prompted you to pursue a career in Life Sciences? Was there a specific moment in time or influence you can remember? What drives you to work in this space?

I took my first biology course in 9th grade and loved the subject straight away. My mom encouraged me to apply for an NIH-run program in Biochemistry, a summer camp for high school students to experience real research. This experience accentuated my interest in biosciences and, particularly, in the field of neuroscience. I have always been interested in the brain and cognition-related disciplines and for a while I was thinking of going to medical school but ended up getting a Ph.D. instead. I was convinced that academia could be a powerful way to impact patients’ health through fundamental research.

How did you get your training, if any to be able to build your company?

My liberal arts education, combined with my personal interests in different subjects, always encouraged me to diversify my training and then use my broad background to synthesize new ideas and, ultimately, solve problems. I did not expect to go to industry as this was not a path many graduate students followed at that time. However, through my work at NIH first as a postdoc and then as a tenure-track investigator, I encountered such an opportunity. Dr. Steve Paul, who headed the National Institute of Mental Health went to Eli Lilly and Co. and convinced me to follow him. I was initially reluctant, but this was exactly the kind of work I wanted to be doing: not only impactful but also cross-functional — that was my sweet spot. I have stayed in pharma and biotech ever since. Combined with the deep scientific expertise I developed through leading cystic fibrosis drug discovery and development at Vertex, my industry experience uniquely positioned me to identify and pursue opportunities for building Origami Therapeutics.

Can you tell us a little bit about your background & career thus far? What were you doing before you started running a high potential, venture-backed startup?

Prior to founding Origami Therapeutics, 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 for Amgen at the time. I was also elected to the Scientific Advisory Board for Amgen Ventures to evaluate Series A and Series B investment opportunities. Previously I was Head of Neuroscience at Eli Lilly and Co., where I established a new research group and oversaw strategic planning and execution on our portfolio of drugs working through new mechanisms.

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.

Company Overview

What problem is your company solving? How did you become motivated to tackle this particular problem?

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 pipeline of novel small molecules that target the underlying cause of disease, beginning with mutant huntingtin protein (mHTT), the only validated target for HD.

What does your 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.

Now in technical language, what are the specifics of what your company does?

Our lead candidate ORI-113, a protein degrader, targets toxic misfolded mutant huntingtin protein for elimination via natural degradation pathways with the goal of sparing normal huntingtin function. Conformation correctors prevent/repair protein misfolding, eliminating toxic effects while preserving huntingtin protein function. Our small molecules permit oral delivery which enables non-invasive treatment throughout the body. Our research also identifies early peripheral blood-based biomarkers that help guide the timing of functional assessment.

Why does your solution matter for the world when you get it right?

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 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.

Genesis

What is your company’s founding story? How did everything come together?

Until recently, neurodegeneration was a stagnating field in pharma R&D — no progress was being made, and companies were pulling out of clinical trials. I identified opportunities for transferring the scientific knowledge gained in cystic fibrosis programs and have had vast experience in putting compounds in the clinic (over 30 compounds by then). I thought it was my responsibility to try to make a difference in the field.

Was there a specific moment when you knew you should pursue this as a business idea? If so, what was it?

One thing I learned in industry is going after low-hanging fruit, for something practical once you have a chance to do so. In technical terms, this means going for something relatively de-risked as a business and with a high probability of technical success. To do this, you need to understand enough biology to generate clinical candidates, but then also understand which patients to recruit and what exactly to measure in clinical trials. Monogenic neurodegenerative diseases, just like the monogenic disease Cystic Fibrosis, fit this description today. At the same time, unlike alternative genetic therapeutics, small molecules have fewer delivery issues for targeting the brain; such therapeutics are more accessible at the point of care and their effects are ‘reversible’ upon the termination of use. We, thus, moved forward to building small-molecule-based treatments to monogenic neurodegenerative diseases.

Timing is everything — how did you know the timing was right?

Vertex was not particularly interested in neurodegeneration but had a program in Huntington’s disease. Through that, I understood the science and got involved with the community by volunteering with the Huntington’s Disease Society of America to better understand the patients and their immediate needs. At the same time, we had developed a profound understanding of small molecules therapeutics through our efforts in cystic fibrosis. It was then time to merge these two distinct areas of expertise.

Accomplishments

What are some of the notable milestones your company has achieved thus far?

We have conducted a proprietary high throughput screen (HTS), followed by hit expansion/ hit-to-lead work. Our initial mechanism of action (MoA) studies have shown that our molecules suppress mutant huntingtin toxicities in patient-derived nerve cells. We’ve also secured a broad IP portfolio for our molecules. We have built a scientific research team based in Biolabs San Diego.

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, the community of HD researchers has 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.

What are some of the biggest hurdles ahead?

Currently, we are selecting the optimal protein degrader to advance into pre-clinical studies for HD and initiating programs for additional indications. We will need to demonstrate oral activity and effects on the target in the brain in relevant animal models.

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

Pay It Forward

What are some of the traits that make a great founder? What type of risk profile/archetype does someone need to have to be a founder in your opinion?

An experienced team, and scientific validation of the platform.

What are some of the traits that make a great founder? What type of risk profile/archetype does someone need to have to be a founder in your opinion?

I think you need to start with a stellar idea and be passionate about it in order to make it happen. Your product also has to meet an unmet medical need for patients. To ensure this, you need to be talking to people, syndicating approaches, and bringing your champions on board to work together in a productive way.

You also have to be flexible and be able to pivot. If that’s uncomfortable, this is a strong indication against starting a company.

Finally, sometimes we forget about being humble and being open-minded about things you don’t know. Again, if you don’t like learning new things, this might not be a good business for you.

For folks coming out of academia, what advice would you share?

No one knows everything. Often founders have to learn either the science or the business side better.

What advice for managing and hiring a great team can you share?

Be authentic, treat people the way you would like to be treated.

Your team needs to share common motivation but have complementary yet overlapping skillsets. This way, everyone has something they contribute — their background, diversity of thought, diversity of experience, and training — and can trust each other to operate together. Teamwork is based on trust; you need to build it and maintain it, as it is very hard to regain if the trust is lost.

You should also encourage people to speak their minds and accept that despite the fact that it won’t always work out, they need to keep trying and pushing to make breakthroughs. Finally, you need to be observant and open-minded. It’s important not to come in with expectations for the outcome of an experiment, as science does not work this way. This means you and your team have to be enjoying this journey of searching for answers together.

Other

Anything else you would like to add?

We were recently accepted to Y-combinator and 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.

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❤️ Thanks Sasha Eremina for your help in putting this together :)

Alix Ventures, by way of BIOS Community, is providing this content for general information purposes only. Reference to any specific product or entity does not constitute an endorsement or recommendation by Alix Ventures, BIOS Community, or its affiliates. The views expressed by guests are their own and their appearance on the program does not imply an endorsement of them or any entity they represent. Views and opinions expressed by Alix Ventures employees are those of the employees and do not necessarily reflect the view of Alix Ventures, BIOS Community, affiliates, and content sponsors.

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