Developing Therapies for Chronic Diseases
Building a biotech startup for chronic inflammatory diseases, onboarding engineering teams, brain computer interfaces, employee stock options, jobs, events, and more
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Developing Therapies for Chronic Diseases
Some of the most challenging diseases of our time — atherosclerotic, neurodegenerative, metabolic, autoimmune diseases, etc. — may ride the same steed: inflammation. Inflammation, by definition, should be good. It is the way our body heals itself after injury. But chronic, unchecked, continually ramped-up inflammation leads to the opposite: chronic disorders in many forms.
Today, we discuss the work of Promakhos Therapeutics, a biotech startup that develops therapies for chronic inflammatory diseases. A duo of medical researchers from Harvard and MIT, backed by Y Combinator, with a mission to help our bodies control inflammation and heal. With Katerina Chatzi, CEO and founder, we talked about:
How inflammation becomes chronic and why inflammatory diseases are prevalent in our societies nowadays
Redefining how inflammatory diseases are cured by activating the immune system
The process from molecule design to developing new therapies
Challenges building a biotech startup
Katerina, I’d like to start with some context first. Why are chronic inflammatory diseases so prevalent in our societies nowadays? What are the conditions under which inflammation in our bodies — which I understand by definition should be good, right? As it’s how your body defends against viruses, bacteria, fungi, etc — becomes chronic?
KC: Inflammation is the body's natural defence mechanism against external threats and plays a critical role in the healing process following an injury. However, there are instances when this defence mechanism becomes overly active, leading to chronic inflammation marked by periods of exacerbation and remission. It's as though the body struggles to effectively heal or eliminate the underlying cause of the initial injury. Now, answering your question about why inflammation becomes uncontrolled;
Our immune system can be categorised into two main components:
The innate or fast immune system consists of cells that activate when our body faces a threat, like a microbe or a wound. These cells not only eradicate the threat, such as microbes, but also recruit additional cells and promote the growth of our own cells to aid in wound healing.
The adaptive or slow immune system is specialised to target and eliminate specific germs using antibodies and cells designed to recognise specific motifs that are found in certain microorganisms.
When the fast immune system fails to efficiently clear the area of invaders, the slow immune system takes over. However, this system tends to address one microbe at a time, which is inadequate when a more generalised clearing system is required. This leads to uncontrolled inflammation.
But why does the fast immune system fail? Interestingly, microbes play a pivotal role in training the fast immune system to function correctly. Changes in our microbiome, dietary habits, specific medications like anti-inflammatories, and a lack of exercise can all impact the proper functioning of our innate immune system.
Existing treatments for autoimmune diseases primarily suppress the slow immune system. We are taking a more direct approach by restoring the function of the fast immune system. Instead of simply blocking the slow immune cells responsible for the observed damage, our goal is to retrain the innate immune system to become robust enough to effectively resolve the issue at its source.
A lot to unpack here. Is the rise of ongoing inflammation in our bodies associated with the high numbers of chronic diseases in our societies nowadays? Cardiovascular, neurodegenerative, autoimmune diseases, etc.
KC: It is essential to realise that chronic inflammation is not a specific disease but a mechanistic process. Yes, it plays a central role in some of the most challenging diseases of our time. Still, we cannot put everything in one basket because every disease is different, affects different body tissues, and is treated differently. For example, for Alzheimer’s, the scientific community has made limited progress in the past years, whereas the opposite stands for cancer. For autoimmune diseases — an umbrella term for more than 80 different diseases such as rheumatoid arthritis, multiple sclerosis, ulcerative colitis, ankylosing spondylitis, etc., that occur when the body’s immune system attacks and destroys healthy body tissue by mistake — we haven’t really progressed in the last 20 years.
And I believe part of the problem is that these diseases are all treated with the same drugs, although they’re very different. As a result, only 20% of patients see some benefit in the long term. This is unacceptable. Autoimmune disorders today affect about one in ten individuals.
How is Promakhos redefining the way inflammatory diseases are cured?
KC: Current approaches to treating autoimmune diseases aim to suppress or “shut down” the slow immune system to make the patient feel better. They treat symptoms rather than addressing the root causes of the disease. The problem is that the disease usually re-appears after some time. We believe we need to do the opposite. We need to empower our innate immune system, not suppress it, to maintain a balance with our microbes and resolve inflammation. We believe that such a treatment can be curative.
We started Promakhos in 2021 with my co-founder, Jasper Neggers. I was a postdoc at Harvard and Jasper at a cross-collaborative institute of MIT and Harvard (Broad Institute). From our research over the past 15 years, we realised that autoimmune diseases are primitively treated, and there was a better way. We went through the Y Combinator startup accelerator in 2021 and have raised $2.5M since then. We decided to start with Crohn’s disease, an inflammatory bowel disease (IBD) affecting over 700,000 Americans that can affect any segment of the gastrointestinal tract. Symptoms include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Unfortunately, those with the disease are at greater risk of colon and small bowel cancer. There’s a huge unmet medical need for Crohn’s disease, as 80% of patients must undergo bowel surgery within ten years.
We believe the problem in autoimmune diseases like Crohn’s is a broken communication between our fast immune system and the microbes living in our gut. So, we are developing an oral drug that targets a receptor and regulates how the fast immune system interacts with the gut bacteria. Essentially, we aim to make the fast immune system of the gut respond better when there’s a threat (wound or infection). That’s why Promakhos was the right name for our startup, too. Promakhos meant “the first to enter a battle” in ancient Greece; it was also used to refer to the strongest/bravest men on the front line of an army to deter the enemy.
Consequently, by restoring the innate immune system, the slow immune system, which existing treatments try to suppress, is not overactivated anymore. We believe our approach is disease-modifying and will be curative, instead of something that just controls symptoms. After Crohn’s disease, we aim to modify our drug to treat Ankylosing spondylitis and Multiple sclerosis in the future.
What other means do you see complementary to your work for curing gastrointestinal diseases?
KC: Diet is vital. There are other approaches, such as microbiome transplantation, although we have many microbes, and finding the right combination is tough. But I think, as a principle, it’s towards the right direction of creating curative treatment. Any other strategies that focus on restoring the crosstalk between the gut microbes, the local immune system and wound healing are also likely to have potential.
Biotech is a field with a whole set of challenges. What steps does your work need to go through to develop new therapies?
KC: We already have a candidate molecule that will eventually become our drug. This molecule demonstrates specific properties such as going to the tissue of interest, binding to the receptor and eliciting a desirable pharmacological response. So far, the scientific community cannot do much without animal testing. We administer our drug at different doses to mice and larger animals and confirm it doesn’t cause toxicity or problems in their organs, excess inflammation, changes in the genetic material, etc. At the same time, we have to scale up our chemical process to reproducibly create large and pure amounts of our drug for patients. Our drug can already be administered by mouth after dissolving in water, but we can improve its stability and delivery by formulating it in a pill of standard pharmaceutical ingredients. Once we complete these tremendously extensive studies, we aim to start testing our drug in clinical trials in humans after initial approval from the regulatory agencies.
Clinical trials in humans usually begin with short-term studies in healthy individuals who take the drug to confirm its safety. Then, you can test it on patients. Overall, we will need more than 1,000 patients to show that a drug works in chronic inflammatory diseases such as Crohn’s disease; some will take the drug and others a placebo. These studies will run for about a year. So many patients are required as it’s critical to demonstrate that your drug shows a statistically significant difference over placebo.
And what do you think have been the biggest challenges in this journey so far?
KC: If you want to change the treatment paradigm by developing a curative treatment that will disrupt the standard of care, you must go from zero to one. This means you have to create a roadmap/playbook from scratch that everyone else can later follow to make treatments based on the new paradigm you set. So far, the playbook has been “We have a target; we try to suppress the immune system; we measure these biomarkers”. Now, we try to do the opposite: We activate the immune system and measure entirely different things. When you have something that disruptive, you obviously face resistance, right? Particularly from financiers of drug development who tend to be conservative. And building a biotech company is very capital-intensive. But without significant risk, there’s no big reward. On the contrary, the community of patients and doctors has been extremely enthusiastic about our work.
So, you have to keep pushing. It’s a game of persistence. Good ideas are rare; it’s worth going all in if you have one. In our case, it’s about having a unique understanding of how we can solve a very tough problem. This came through working in several scientific disciplines for many years and allowed us to view the problem in a different way than other people.
That was really insightful. Thank you so much, Katerina.
KC: My pleasure, Alex.
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