Latest / The BioHub - by Avetix / Episode 51 – Harith Rajagopalan - CEO & CO-Founder Fractyl Health

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Episode 51 – Harith Rajagopalan - CEO & CO-Founder Fractyl Health · The BioHub - by Avetix

• 0:04
  So welcome back to the episode of the Bio Hub.
• 0:07
  Today we're thrilled to be joined by Harif Rajikapalan,
• 0:10
  who's the CEO, Co founder of Fractal Health, a biotech
• 0:14
  company pioneering a new approach to treating the root
• 0:16
  causes of metabolic diseases like type 2 diabetes and
• 0:19
  obesity. Under his leadership, Fractal
• 0:22
  has grown from a bold idea into a clinical stage company
• 0:25
  tackling some of the biggest health challenges.
• 0:28
  So join us today is Harif. He talks us through his story,
• 0:31
  the obesity, space and fractals journey.
• 0:33
  So Harry, thanks so much for coming on.
• 0:36
  How are you? Excellent, Tom.
• 0:38
  Thanks. Nice to see you.
• 0:39
  Yeah, it's a it's a pleasure. So let's let's kick it off with
• 0:43
  a little bit about yourself then.
• 0:45
  So can you talk us through your journey and what inspired you to
• 0:49
  pursue a career in the biotech industry?
• 0:51
  Sure. I I never would have thought
• 0:53
  that I would be in the biotech industry.
• 0:54
  Honestly. I was an MDPHD scientist and a
• 0:58
  cardiologist at the Brigham Brigham and Women's Hospital in
• 1:01
  Boston when my dad and my uncle were diagnosed with type 2
• 1:06
  diabetes. And these are two like the smart
• 1:09
  people working hard, doing what they thought was the right thing
• 1:13
  in their lives, getting diagnosed with the disease.
• 1:15
  And I saw how they tried to keep taking their medicines and diet
• 1:20
  and exercise, but their disease kept progressing.
• 1:23
  And that really frustrated me, this notion that they were doing
• 1:26
  all of the right things, but the disease kept advancing and
• 1:30
  putting them at risk. And in my clinical practice as a
• 1:34
  cardiologist, I used to see a lot of people with type 2
• 1:37
  diabetes and cardiovascular disease and really got me
• 1:41
  thinking because of my personal experience with family members,
• 1:44
  like what is going on that's causing so many people to
• 1:46
  develop these diseases? And why are our medicines not
• 1:50
  fully solving the problem? And what I realized is, like, we
• 1:56
  have all of these medicines that we're using to try to manage the
• 1:59
  symptoms of obesity and type 2 diabetes and cardiovascular
• 2:03
  disease, but we're really not fixing what's fundamentally
• 2:07
  going wrong in the body that's causing people to develop and
• 2:10
  progress these diseases over time.
• 2:13
  And that's what began to inspire me to try to think about what is
• 2:16
  the root cause of obesity and type 2 diabetes in the body,
• 2:20
  Why? What is going wrong that is
• 2:23
  causing people to develop these diseases and what can we do
• 2:27
  about it? And it's that simple question
• 2:30
  that led us to begin to think radically differently about
• 2:35
  obesity and metabolic disease, and to start fractal health.
• 2:39
  OK. Also, and you mentioned it a
• 2:42
  little bit there, but can you share the origin story behind
• 2:45
  Fractal Health? Like why did, what was the
• 2:47
  inspiration behind its founding? You mentioned it a little bit
• 2:50
  there, but. Yeah.
• 2:52
  So I actually had a patient who was in my practice who underwent
• 2:56
  a surgery called bariatric surgery.
• 2:59
  And this was an individual whom we all felt really didn't care
• 3:04
  about his health. He was overweight, he had
• 3:07
  cardiovascular disease, he had type 2 diabetes, a number of
• 3:10
  sort of coexisting fellow travelling metabolic problems
• 3:16
  and efforts to admonish him by warning him of the dangers of
• 3:22
  disease progression and complications to try to eat
• 3:25
  healthier and be more adherent to his, you know, prescribed
• 3:31
  medicines. Really, we're not meeting with
• 3:35
  success. But he underwent A bariatric
• 3:39
  surgery. I went to see him in the
• 3:42
  hospital three days after the surgery and the hospital had
• 3:45
  delivered a tray with a hamburger and French fries for
• 3:51
  the guy three days out from this gut altering surgery.
• 3:55
  And he just pushed it away in front of me.
• 3:57
  And he said I'm not interested in this.
• 3:59
  This is not appealing to me anymore.
• 4:02
  And even by day three, this person with very poorly
• 4:06
  controlled type 2 diabetes had already had normal blood sugars
• 4:11
  and didn't need to restart his diabetes medicines.
• 4:15
  And then when I saw him in clinic again like 3 months
• 4:17
  later, he had begun to lose a substantial amount of weight.
• 4:21
  Now, this is like an incredible finding because you're doing
• 4:24
  this operation on the gut, you're not touching the
• 4:26
  pancreas, you're not touching the brain directly.
• 4:30
  And yet he doesn't have an appetite for unhealthy foods.
• 4:33
  He's losing weight without trying, and his blood sugar has
• 4:36
  totally normalized and he's not taking any of his medicines
• 4:39
  anymore. So it got me wondering, like,
• 4:41
  what is going on that this surgery did that's fixing
• 4:44
  something so profoundly fundamental to why he developed
• 4:48
  obesity and diabetes in the 1st place?
• 4:50
  And that led to the realization that the gut is a hugely
• 4:56
  important regulator of the body's metabolic control
• 5:00
  systems. And we are only beginning to
• 5:04
  scratch the surface in our understanding of how the gut
• 5:07
  talks to the brain in order to help the brain regulate blood
• 5:11
  sugar and body weight. But what we do know is that the
• 5:15
  gut plays a huge role. And what we also know is that
• 5:20
  high fat, high sugar diets cause changes to the lining of the
• 5:23
  gut, particularly in the first portion of the gut called the
• 5:26
  duodenum. That is causing a neural and a
• 5:30
  hormonal change in the body which leads to obesity and
• 5:34
  diabetes. So the founding idea was to
• 5:38
  actually go to friends and colleagues at a venture capital
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  firm and ask them what would be the clinical and economic value
• 5:48
  of figuring out a way to reverse obesity in type 2 diabetes by
• 5:53
  fixing its root cause in the gut rather than managing the
• 5:57
  symptoms for someone for the rest of their lives.
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  Turns out that like 50% of people have inadequately
• 6:03
  controlled disease with type 2 diabetes.
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  Most people with obesity, even though they have GLP one drugs
• 6:09
  today, stop taking those drugs within a year and so therefore
• 6:12
  really don't achieve clinical benefit from GLP one drugs.
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  And so there's this huge population of people who are
• 6:20
  living with the risk of progression of metabolic disease
• 6:24
  where they really could benefit from something that's changing
• 6:28
  the trajectory of disease by fixing the root cause.
• 6:31
  And that's what we're going after with the programs at
• 6:33
  Fractal Health. Interesting, cool.
• 6:37
  And I think, I mean in the obesity space at the moment,
• 6:40
  there's been some pretty big fundraising rounds over the past
• 6:43
  12 rounds in that market. I'm going to break this up, this
• 6:47
  next question into two different bits.
• 6:48
  So can you talk us through your perspective of the obesity space
• 6:52
  and why it is such a crowded market at the moment?
• 6:54
  And then the second point would be like the differentiation of
• 6:58
  fractal, like what sets you guys apart when looking to address a
• 7:03
  critical unmet need? Yeah, we'll be happy to.
• 7:06
  A few years ago Nova Nordis got Somaglitite approved first as
• 7:13
  Ozempic for type 2 diabetes and then we go V for obesity.
• 7:17
  And that then led to this massive explosion in the
• 7:23
  interest in GLP one drugs for the treatment of obesity which I
• 7:27
  would say has kick started this gold rush effect in biotech to
• 7:34
  try to find new approaches in obesity.
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  What we know are that these GLP One drugs are amazing medicines
• 7:42
  that mimic a natural hormone in the body called GLP One, but are
• 7:48
  weekly injectable therapies that can achieve a lot of weight
• 7:52
  loss. But what we also know is that
• 7:54
  these medicines are not perfect. They are hard to titrate.
• 7:59
  They take a long time to get up to a therapeutic dose, many,
• 8:03
  many months. They can cause a lot of side
• 8:06
  effects, and particularly a lot of people have a hard time
• 8:11
  getting up to a dose that works for them because they start to
• 8:14
  experience nausea or vomiting or other typically GI related side
• 8:19
  effects. And even though these drugs work
• 8:23
  really well in phase three clinical trials, they're not
• 8:26
  proving to work nearly as well in the real world because a lot
• 8:31
  of people can't get to the full dose or can't stay on these
• 8:34
  medicines lifelong. And the major problem that has
• 8:38
  emerged is that when people stop taking these GLP one drugs, they
• 8:42
  regain weight very, very rapidly and almost immediately lose
• 8:46
  whatever clinical metabolic benefit they had while they were
• 8:50
  on the drugs in the 1st place. So where do you see the
• 8:54
  landscape shifting? Like the unmet need is moving in
• 8:56
  a lot of different directions. Some people think that what we
• 8:59
  need are oral versions of these injectables that can move fast,
• 9:04
  and Eli Lilly is taking a lead in developing those.
• 9:07
  There are people who are looking at new mechanisms of weight loss
• 9:11
  that target different pathways, and that's another approach that
• 9:15
  people are taking. Where we are differentiated is
• 9:19
  that we've been asking how do you lock in these benefits in a
• 9:24
  way that doesn't force people to have to stay on medicines for
• 9:27
  the rest of their lives? If these medicines are as good
• 9:30
  as they are, which they clearly are, but people can't stay on
• 9:33
  them, can you change the body's Physiology so that they don't
• 9:37
  need to be on them anymore? And so with our lead asset,
• 9:41
  which is called Ravita, what we are doing is we are fixing the
• 9:46
  portion of the gut called the duodenum that I mentioned
• 9:48
  earlier that is a main driver of why people develop obesity in
• 9:52
  the 1st place. We are performing a 40 minute
• 9:56
  outpatient procedure delivered by a gastroenterologist that
• 10:01
  targets this region of the gut and aims to reset the abnormal
• 10:06
  metabolic signals that are coming from this portion of the
• 10:09
  gut that were caused by someone eating an unhealthy diet for all
• 10:13
  of their lives. It's kind of like wiping the
• 10:15
  slate clean by removing and replacing their duodenal lining
• 10:20
  so that the normal metabolic signals can be restored.
• 10:24
  And that product. Revita is in a pivotal study in
• 10:29
  the United States for weight maintenance after stopping GLP
• 10:33
  one drugs. That study's called Remain 1.
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  And it's an incredibly exciting clinical study because it's
• 10:40
  potentially the first therapeutic approach that would
• 10:44
  offer patients the ability to maintain body weight loss in a
• 10:49
  durable manner, even without needing to stay on medicines.
• 10:53
  Nothing like that exists today. And we've been enrolling this
• 10:57
  study. It's been moving incredibly
• 11:00
  fast. We first identified this
• 11:02
  opportunity in November of 2023. We've got an approval from the
• 11:08
  FDA just a few months later to begin this pivotal study.
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  And then by the summer of last year, the FDA had granted
• 11:16
  breakthrough device designation for Revita for weight
• 11:19
  maintenance after GLP 1 discontinuation.
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  The reason we think we got breakthrough designation is
• 11:24
  because people are now more concerned.
• 11:27
  But how do you maintain body weight loss for people who need
• 11:32
  to stop medicines? Then how do you get more body
• 11:35
  weight loss like the maintenance of the body weight has become
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  the big concern. We've been enrolling this trial
• 11:43
  since August and it's enrolled at historically fast rates.
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  And we're excited to say that we're nearly complete and
• 11:50
  enrolling the pivotal study and we're seeing some encouraging
• 11:53
  open label data so far. More open label data is coming
• 11:58
  in June. And then a key randomized data
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  set from the remain one study is expected in Q3.
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  That'll be the first randomized proof of whether Revita can
• 12:10
  achieve weight maintenance after stopping a GL P1 drug.
• 12:15
  And so we're very excited about that.
• 12:17
  Interesting. Good.
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  And I mean, you guys are now in the clinic, you're primarily
• 12:22
  focused on treating TT 2D and obesity.
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  You mentioned a little bit about the data then.
• 12:27
  Can you talk us through the pipeline as a whole and a little
• 12:31
  bit more just into the recent data that was announced?
• 12:35
  Absolutely. So the Ravita asset is our lead
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  asset and I mentioned the main studies that are going on, there
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  are open label studies and randomized studies in
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  discontinuation of GLP one drugs and weight maintenance
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  thereafter. What we just announced at the
• 12:51
  beginning of April are some early one month data from
• 12:55
  patients who had been on tirzepatide, which is one of
• 12:58
  these most powerful GLP one drugs, but then needed to stop
• 13:02
  the drug for whatever reason and then were followed thereafter.
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  And what we're beginning to see in patients who've been followed
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  at one and three months after stopping tirzepatide is that
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  they seem to be able to be protected from the type of
• 13:15
  weight regain that is normally associated with stopping
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  tirzepatide. And so what's very exciting
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  about that is it's the first glimpse into data that maybe
• 13:26
  there's a way to lock in weight loss without needing to stay on
• 13:30
  tirzepatide or similar drugs. Which I think is exciting
• 13:34
  because it provides hope to potentially millions of people
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  who just want to live a life at a lower weight without having to
• 13:42
  work at it constantly, which is what the disease of obesity
• 13:46
  means to them today. The thought of persistent
• 13:50
  ability to maintain a lower body weight, I think is a massive
• 13:55
  unmet need. I would argue it is the highest
• 13:58
  aspiration of people who struggle with obesity today and
• 14:02
  would have profound consequences for their metabolic risks down
• 14:07
  the line if you were able to allow them to keep a lower body
• 14:10
  weight just in a physiologic natural manner.
• 14:14
  Behind this, we have an incredibly exciting pipeline
• 14:18
  that essentially leverages our historical experience in
• 14:23
  developing advanced therapies targeting the gut.
• 14:26
  And we've got a platform for pancreatic gene therapy called
• 14:30
  Rejuva, which delivers AAV gene therapy directly into the
• 14:35
  pancreas. And we will be presenting an
• 14:39
  oral presentation at the upcoming gene and cell therapy
• 14:44
  meeting in May. What when, when we go, what
• 14:48
  we're going to show is the body of work that we have done
• 14:51
  preclinically to test a smart GLP one, a one time therapeutic
• 14:57
  administration of a gene therapy that allows the body to make GLP
• 15:02
  one in a way more physiologic manner than the drugs that are
• 15:06
  out there today. It's natural native human GLP 1
• 15:11
  and it is released from the pancreas as and when the body
• 15:15
  needs it and it mimics the body's own GLP 1, the same GLP
• 15:19
  one that you make or I make. And in preclinical studies so
• 15:23
  far, our one time GLP ONE has better durability and potency
• 15:30
  and we think is likely to be better tolerated than the GLP
• 15:35
  ones that exist today. So in Revita, we have a product
• 15:39
  that can offer a way to keep the weight off if you can't stay on
• 15:43
  AGLP 1. And with Verjuva, we've got
• 15:46
  something that will be entering the clinic in the very near
• 15:49
  future that is designed to maintain GLP One benefits for
• 15:54
  life. And we're very excited about
• 15:56
  both of them and the data that we've been generating with both,
• 15:59
  but also we're super excited about the upcoming catalyst from
• 16:02
  both of these programs in the coming quarters.
• 16:04
  Yeah, sounds exciting. And then this is I guess
• 16:08
  separate to the science of Fractal.
• 16:10
  But back to you. So this is the first time CEO
• 16:13
  and Co founder, how did you find it in the early stages of
• 16:17
  setting up Fractal? I know that was your first time
• 16:20
  as CEO, How how was that? And I guess the second bit, I
• 16:23
  speak to people all the time that I guess one day we'd like
• 16:27
  to be CEO or have their own company.
• 16:28
  What advice would you give to maybe open come in biotech
• 16:32
  entrepreneurs as well? Well, I will let me, I'll start
• 16:37
  with the second question, which is, you know, what advice do I,
• 16:39
  I would say I think it's really valuable to start with the
• 16:43
  problem that you're trying to solve and make sure that it's a
• 16:45
  deeply meaningful and personal problem for you like obesity and
• 16:49
  types of diabetes is for me because of what I told you about
• 16:52
  the founding of the company. And the second thing that I
• 16:56
  would say is that you have to understand yourself, what your
• 17:01
  strengths are and how those strengths can be brought to bear
• 17:05
  in order to help advance that idea in as selfless a way as
• 17:09
  possible. There are so many ways in which
• 17:12
  a founder can help ensure that a therapy becomes available to
• 17:16
  patients, depending on their background, their skills, and
• 17:19
  their experiences. That vision of what you can
• 17:22
  bring to patients and the change that you can bring that may help
• 17:26
  people live healthier, better lives is so crucially important
• 17:30
  and so valuable for a founder. But you can do that from a lot
• 17:32
  of different seats within the company based on whatever you're
• 17:35
  best at Now. What I learned through this
• 17:39
  process is that I'm so passionate about what we're
• 17:45
  trying to accomplish for patients that I couldn't imagine
• 17:48
  staying at the Brigham and doing my day-to-day work as a
• 17:51
  cardiologist. I had to pursue it full time and
• 17:55
  then I had to learn that the job of ACEO is to articulate a
• 18:01
  vision. The world that you're trying to
• 18:03
  create and the vision that we're trying to create is a world
• 18:07
  where people are leading healthier lives free of obesity
• 18:11
  and type 2 diabetes, where we're developing therapies that have
• 18:14
  the potential to prevent and reverse disease rather than
• 18:17
  simply manage them. I felt like that was a
• 18:19
  compelling enough vision for us and for the entire company.
• 18:23
  Then you got to rally people behind that vision.
• 18:25
  You got to rally dollars behind that vision.
• 18:27
  You got to make sure you're executing against that vision.
• 18:30
  And I feel like I've had to learn how to do those things
• 18:33
  because you don't really learn how to do those things when
• 18:35
  you're rounding on cardiovascular patients in the
• 18:37
  ICU every day. So it was a steep learning
• 18:40
  curve, but I'm really glad that I did it.
• 18:42
  Good. And this is a question that we
• 18:44
  always finish with on the Bio Hub.
• 18:46
  And I know I gave you a heads up on this, but.
• 18:48
  You did and I totally forgot what that heads up was, but so
• 18:52
  we'll see how it goes. Yeah, so it was.
• 18:55
  If you were to have dinner with three people, past or present,
• 18:59
  who would they be and why? They don't necessarily need to
• 19:02
  be biotech innovators, although they can if you like.
• 19:07
  But yeah, three people for dinner.
• 19:08
  Who would it be and why? Right.
• 19:10
  OK, so three people for dinner. I mean, I would love in the
• 19:13
  current world to have dinner with Elon Musk because I really
• 19:19
  want to understand how his brain functions.
• 19:24
  And whatever you might think about him, the fact that he has
• 19:30
  built so many incredibly successful businesses and been
• 19:36
  so bold in his vision is something that I deeply admire.
• 19:41
  So he's number one. A second person whom I'd like to
• 19:45
  have dinner with is the Dalai Lama.
• 19:51
  The reason I like to have dinner with him is because he's under
• 19:54
  tremendous pressure for his religion and the people who
• 19:57
  follow him, and he carries himself with like, such
• 20:00
  composure. And a sense of calm.
• 20:04
  He has figured out how to hack the stresses of life in a way
• 20:08
  that I think is, like, deeply inspiring.
• 20:11
  I think it would be great to have dinner with him.
• 20:15
  I'm going to pause and think about who my third one is.
• 20:16
  OK, give me a second. OK.
• 20:27
  I'd like to have dinner with my dad, who's no longer with us
• 20:30
  today and wasn't able to see the company that we've been building
• 20:34
  and the work that we've been doing that he inspired.
• 20:36
  And I would love to be able to bring him back and show him what
• 20:40
  we're doing and just share that with him.
• 20:44
  Yeah. Well, look there, there was 3
• 20:46
  terrific answers there. And I think just hearing not
• 20:50
  only the obesity space, but your personal journey to get to where
• 20:53
  you are today is, is super inspiring.
• 20:56
  So I think it's, it's been an absolute pleasure to have you on
• 20:58
  Harry. Thanks so much for for helping
• 21:00
  us out with it. Thank you.
• 21:02
  Appreciate it, Tom.