Latest / The BioHub - by Avetix / Episode 169 - nChroma Bio - Melissa Bonner (CSO) & Jenny Marlowe

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Episode 169 - nChroma Bio - Melissa Bonner (CSO) & Jenny Marlowe · The BioHub - by Avetix

• 0:06
  So welcome back to another episode of the Bio Hub.
• 0:08
  Today we're delighted to be joined by two extraordinary
• 0:11
  leaders from in Chroma Bio, a company who are at the forefront
• 0:15
  of cutting edge genetic medicines.
• 0:17
  Today we have the pleasure of welcoming him on Jenny Marlow,
• 0:20
  who's the Chief Development Officer and Melissa Bonner,
• 0:23
  who's the Chief Scientific Officer.
• 0:25
  Jenny Lee's development in Chroma Bio translating
• 0:28
  breakthrough science into clinical reality, guiding
• 0:30
  therapies from research for trials and towards patients.
• 0:34
  And Melissa leads the scientific vision driving innovation in
• 0:38
  gene therapy and epigenetic medicine and helping shape the
• 0:42
  company's approach to tackling some of the most complex
• 0:45
  diseases. Today.
• 0:47
  We'll discuss in Chroma's pipeline and their lead program
• 0:51
  the next scientific, clinical and organizational milestones
• 0:54
  over the next 12 to 24 months at the company and maintaining
• 0:58
  culture as the company grows. So guys, thanks so much for
• 1:02
  coming on. How are you?
• 1:04
  Doing well. Thank you.
• 1:05
  Thanks for. Having us, yeah, I really.
• 1:06
  Thank you for. Having us, how are you?
• 1:08
  Yeah, good. It's a pleasure to have you on
• 1:10
  as well. I've been super excited for
• 1:12
  this, so appreciate you guys making the time.
• 1:15
  So let's just start off with a little bit about both of your
• 1:18
  backgrounds and, and journeys through the field.
• 1:20
  So could you just walk us through your journey into life
• 1:23
  sciences and drug discovery? And I'd love to hear a little
• 1:27
  bit about what first sparked your interest in science and the
• 1:29
  path that that ultimately LED you into biotechnology.
• 1:34
  Melissa, let's just start with you and then Jenny will go with
• 1:37
  you after. Yeah, so I have worked in the
• 1:41
  lab since I was 15. I actually used to work in an
• 1:46
  environmental chemistry lab when I was in high school, and that
• 1:50
  really kind of sparked my interest in lab work.
• 1:53
  And I really had a fascination with biology.
• 1:57
  So it was a really natural path for me to pursue science in this
• 2:02
  way. I've been doing specifically
• 2:05
  cell and gene therapy for over 20 years.
• 2:08
  I, you know, was introduced to the concept of cell and gene
• 2:12
  therapy when I was doing my graduate work and fell in love
• 2:16
  with it. And I, I really just am so
• 2:18
  excited about the potential power of these types of
• 2:21
  technologies and what they can do for patients who have very
• 2:25
  limited or if, if potentially none, no alternatives.
• 2:30
  And, you know, I was fortunate to be part of Bluebird Bio as my
• 2:35
  first industry experience. And you know, that was a really
• 2:38
  kind of transformational experience for me, like learning
• 2:42
  kind of the drug development lens in, in industry and, you
• 2:48
  know, being part of, you know, such amazing medicines that made
• 2:52
  it to patients. And I'm hoping to continue that
• 2:55
  here at Encroma. Amazing.
• 3:01
  So, yeah, I think my story starts similarly.
• 3:04
  I loved biology. And so, you know, I focus all of
• 3:08
  my sort of educational efforts as much as I could.
• 3:11
  Even starting in high school, I took every biology class that
• 3:13
  was possible and across all fields, frankly, including I
• 3:16
  remember one of my favorite classes was a botany class that
• 3:19
  I took for for a semester. So it was obvious to me that I
• 3:22
  was going to study biology and stay in that in that space.
• 3:26
  But what I was going to do with it, to be honest, I had, I
• 3:29
  really, I had no idea. I was just following what I
• 3:32
  enjoy doing. And I got to college and I
• 3:34
  thought, well, maybe I'll go to medical school, you know, And
• 3:37
  then I was in my intro biology class and there were a couple
• 3:41
  professors there and they started talking about working in
• 3:43
  the lab. And I thought, well, that sounds
• 3:45
  interesting. Maybe I should give that a shot.
• 3:47
  So that was sort of my bifurcation right there from
• 3:50
  thinking about medical school. I have no idea if I would have
• 3:52
  done that or not, but I started working in the lab and that was
• 3:55
  sort of what sent me down that that path of like, I actually
• 3:58
  like doing science. This is really cool.
• 4:02
  But it really was. I, I took a toxicology class at
• 4:05
  the very end of my undergraduate career.
• 4:08
  And it really was that that ultimately led me to frankly,
• 4:11
  where I am now. I love that class.
• 4:14
  And I was looking for a job after undergrad and I saw this
• 4:18
  advertisement in the paper for a research assistant position in a
• 4:22
  toxicology lab at the University of Cincinnati.
• 4:25
  And so I took that, took that job for that reason.
• 4:28
  It was also a molecular biology lab.
• 4:30
  So it wasn't, it wasn't sort of a, a typical kind of toxicology
• 4:34
  endeavor. It really was focused on
• 4:36
  molecular biology, biochemistry, cell biology, etcetera, with
• 4:39
  applications and, and tox. So ultimately that is the piece
• 4:44
  that led me to, to pharma. I didn't know anything about the
• 4:47
  biotech industry. I was, you know, I knew a little
• 4:50
  bit of people working in the industry from the, you know, the
• 4:54
  lab I was working in, but ultimately that was the, the
• 4:57
  path that got me to Novartis. My first job was at Novartis
• 5:01
  Pharmaceuticals in mechanistic toxicology, and that's where I
• 5:06
  learned about drug development. As Melissa said, you know, we
• 5:08
  all have the that moment in time where, you know, we, you know,
• 5:13
  there's not a whole lot of ways to learn drug development
• 5:15
  outside of actually being in it. And Novartis was what taught me
• 5:19
  about drug development. And I love being at that
• 5:21
  intersection, frankly, of research and development.
• 5:23
  And that's what mechanistic talks allowed me to do.
• 5:26
  I was frankly work at all stages of the drug development pipeline
• 5:29
  from discovery programs all the way to programs that were
• 5:32
  frankly in the marketplace already.
• 5:35
  And so there was that development path and that focus
• 5:37
  on cell biology, molecular biology that led me to frankly
• 5:41
  the same field as Melissa, where I started working on more cell
• 5:44
  and gene therapy projects and realizing the excitement that
• 5:47
  was in that field, the potential that those therapies had.
• 5:50
  And I also ended up at Bluebird Bio.
• 5:51
  That's where I first met Melissa and ran translational
• 5:54
  development there for, for about 4 1/2 years before I left to
• 6:00
  work at another gene therapy company.
• 6:03
  I ultimately ended up at, at Solid Biosciences as, as CSO
• 6:06
  there and about two years ago came to Chroma as Chief
• 6:09
  development Officer. So always sort of riding that,
• 6:12
  you know, edge between frankly research and development and
• 6:16
  working in the translational development space in the early
• 6:18
  clinicals POC space has been my passion for for quite a while.
• 6:23
  Nice, amazing. And you mentioned you both bid
• 6:25
  at Bluebird bio. We've actually had a number of
• 6:27
  ex Bluebird people on on the podcast.
• 6:29
  We've had Jason Cole and Allison Finger and Rob Rob Ross guys,
• 6:34
  people I'm sure you all probably know quite well.
• 6:36
  But alongside all of them, you also were working at Bluebird
• 6:40
  with and Chroma CEO Jeffrey Walsh.
• 6:43
  Can you just tell us a bit about your your time at Bluebird Bio
• 6:48
  and then just how, how you think the gene editing industry has
• 6:51
  has evolved since then? Yeah.
• 6:55
  Do you want to go first? Mostly.
• 6:56
  You were there longer than I was, so I.
• 6:58
  Was there for 9 years. I mean, again, like I mentioned
• 7:02
  previously, I, I, I learned so much at Bluebird.
• 7:07
  You know, to what Jenny said previously, until you are
• 7:10
  actually doing drug development, it is actually pretty hard to
• 7:15
  conceptualize what it looks like and what it needs to look like
• 7:18
  if you're doing it correctly. I think there's there's learning
• 7:22
  about doing something, but actually going through and
• 7:24
  getting that experience is invaluable.
• 7:28
  And so when I started a Bluebird, I started as an entry
• 7:31
  level scientist. I was working on projects
• 7:33
  directly related to all of our hematopoietic stem cell based
• 7:38
  therapies, trying to understand how we could increase
• 7:41
  transaction efficiency of hematopoietic stem cells.
• 7:45
  Ultimately we were able to identify something that led to
• 7:49
  us making ACMC change and you know, ultimately led to the
• 7:54
  outcomes that we then saw that led to both Zintaglo and Lagenia
• 8:00
  where that the change was implemented.
• 8:02
  I worked really closely with, you know, our CMC colleagues.
• 8:06
  You know, my team stands the gamut developing assays to
• 8:11
  support, you know, characterization and, and
• 8:14
  ultimately release assays and, you know, understanding kind of
• 8:20
  how our drug works in patients and and nuances kind of related
• 8:24
  to various genetic backgrounds of some of the the patients that
• 8:28
  we treated and how that affected ultimately the potency of the
• 8:33
  drug. Bluebird, as I'm sure anyone who
• 8:37
  follows the space, you know, obviously is now genetics,
• 8:41
  biotherapeutics, but you know, years ago when it was still
• 8:45
  Bluebird, you know, it, it went through kind of a lot of a
• 8:48
  roller coaster of of transitions throughout the years.
• 8:54
  You know, we were on the cutting edge of a field and a space
• 8:59
  where really no one had ever gone before.
• 9:02
  We were in uncharted territory. We encountered a lot of the
• 9:09
  issues that were thought to have been theoretical at the time.
• 9:14
  Everything's theoretical until you see it for the first time,
• 9:17
  and we were able to navigate a lot of challenges in the field.
• 9:22
  I think ultimately one of the things that Bluebird did very
• 9:25
  well was transparency and disclosure of our data and our
• 9:30
  understanding of how, you know, various aspects kind of shaped
• 9:37
  either kind of the potency of the drug or the safety of the
• 9:40
  drug. And I think that ultimately is
• 9:41
  going to help and has helped others with development of their
• 9:45
  products as well. And you know, super involves
• 9:50
  with the approvals for in particular as in Ted Lowens,
• 9:54
  Sky, Sona. That experience was probably one
• 9:58
  of the highlights of my career thus far.
• 10:01
  I mean, it was just really fun. It was one of the most
• 10:04
  challenging times just from like the the sheer amount of work and
• 10:11
  the stress and the pressure, but doing it with a group of people
• 10:14
  that I was doing it with, it made it just one of the most fun
• 10:18
  times as well. That's actually one of the
• 10:21
  things I reflect about when I think about my time at Bluebird
• 10:24
  is how, you know, some the times where I was under the most
• 10:28
  amount of pressure and stress honestly turned out to be the
• 10:32
  things that I think about most fondly because I was doing it
• 10:35
  with people that I truly loved working with.
• 10:39
  And we were all in it because we were so focused on how do we
• 10:44
  understand this and how do we kind of, you know, make things
• 10:48
  ultimately as best outcomes as possible for patients.
• 10:51
  Like we all had a very kind of similar mindset and approach.
• 10:55
  So I mean, Bluebird really kind of transformed for me my career
• 11:00
  and, and my outlook on, on CGT cell and gene therapy now
• 11:04
  ultimately, right. Like how does that relate to
• 11:07
  gene editing? I think they, the Bluebird kind
• 11:08
  of really led the field and opened up the space for a lot of
• 11:11
  other companies like ourselves at Encroma now to to now kind of
• 11:16
  solve for other kind of gaps in the cell and gene therapy space.
• 11:19
  And, you know, without somebody having kind of kind of gone out
• 11:23
  and defined the edge of that field, right, there wouldn't be
• 11:26
  space for others to follow. So I think that that Bluebird
• 11:30
  really helped shape the field for for all of us, regardless of
• 11:33
  whether or not you actually are, you know, a former member of the
• 11:36
  flock. We loved our bird con.
• 11:40
  We did, we did, yeah. And I would, I would just
• 11:44
  emphasize a few of the things that Melissa said and maybe
• 11:47
  think about it also just around your specific question of, you
• 11:50
  know, how has gene therapy gene editing.
• 11:53
  I mean, we weren't much in gene editing, frankly, it was really
• 11:55
  cell therapy, autologous cell therapy was the largely the
• 11:58
  focus of Bluebird, right. And I think, you know, again,
• 12:01
  while I think we had, you know, almost, you know, incredibly
• 12:07
  short period of time, maybe it was unprecedented.
• 12:09
  I'm not entirely sure the number of approvals that that company
• 12:11
  had regulatory approvals in an incredibly short period of time
• 12:14
  in a completely new area was absolutely amazing and again
• 12:19
  incredibly difficult. As Melissa said.
• 12:22
  The the challenge though we remember again all very, very
• 12:25
  fondly as well. But I think, you know, those
• 12:28
  regulatory approvals have translated into variable, I
• 12:32
  would say, you know, commercial success.
• 12:34
  And I think that's rooted frankly in the fact that, you
• 12:38
  know, we were developing, you know, single therapies for
• 12:41
  single patients, right? And again, while they work
• 12:44
  incredibly well, it's an incredibly complicated product
• 12:48
  to actually bring to bear to large numbers of patients.
• 12:52
  And I think that has been some of that.
• 12:54
  You know, those lessons of that reality have translated into the
• 12:59
  focus that the field has had on now making therapies that could
• 13:04
  be broadly applicable to, you know, I mean, again, a medicine
• 13:07
  that can be given to many, many people, but yet do the same
• 13:10
  thing as some of these some of these cell therapies.
• 13:13
  So like the in vivo car T space, for example, is a prime example
• 13:17
  of of that, right? And how that core technology can
• 13:20
  now translate in a way that will potentially be able to benefit
• 13:25
  many more patients and in a way that is much more economically
• 13:28
  viable as well. So that's how I think things
• 13:30
  have evolved and the focus of the field has evolved.
• 13:34
  But in the end, it's all about I think the core mission that we
• 13:36
  had at Bluebird, which was bringing meaningful therapies to
• 13:40
  patients. That's ultimately what drives
• 13:42
  this industry, right, in the improvements that we're talking
• 13:45
  about. The way the science evolves, it
• 13:47
  evolves that way for a reason. And that's because of patient
• 13:50
  need, right? And trying ultimately to bring
• 13:52
  science to bear for patients in a way that not only, you know,
• 13:57
  the not only the healthcare system could sustain, but you
• 14:00
  know, economies, etcetera. And that these therapies can
• 14:03
  ultimately go global, right, in a way that some of again, the
• 14:07
  therapies at Bluebird, I think that was going to be quite
• 14:09
  difficult to actually realize. Yeah, amazing.
• 14:12
  And yeah, I've heard a lot about how how amazing it was at
• 14:17
  Bluebird just from various people that I mentioned, but
• 14:19
  others as well just just love the time there at Bluebirds.
• 14:22
  So yeah, just to dive in. So in Chroma you, you've both
• 14:27
  been at the company since its founding date in 2020 for all,
• 14:31
  Could you just talk us through the mission, I guess at a high
• 14:33
  level of a mission and the goals of the company and why the
• 14:37
  company was set up by what were you guys set out trying to
• 14:40
  achieve as well? Yeah.
• 14:42
  And Chroma was actually formed by the merger of two parent
• 14:45
  companies, so Envelope Therapeutics and Chroma Medicine
• 14:48
  in December of 2024. And the vision at the time was
• 14:52
  to combine the non viral delivery platform technology
• 14:55
  that comes from the Envelope therapeutic side with the
• 14:58
  epigenetic cargo strategies from the Chroma Medicine side in
• 15:01
  order to design best in class drugs for patients.
• 15:05
  And Chroma made an important transition in January of this
• 15:08
  year treating our first patient in our ongoing trial evaluating
• 15:12
  Chroma 1001 and chronic hepatitis B.
• 15:16
  And this makes us now a clinical stage organization and our focus
• 15:20
  really is on execution for patients.
• 15:23
  Yeah, amazing. And just both, could you both
• 15:27
  just talk us through what your roles look like in practice and
• 15:30
  how you guide your teams as well and how how did that work from
• 15:34
  when he did merge the company together?
• 15:36
  Was the people that came came across from both companies?
• 15:39
  Just just talk us through how you, both of your roles and
• 15:41
  teams look like. Yeah.
• 15:44
  So maybe just reflecting on the merger a little bit.
• 15:47
  I mean, it's it's complicated to do even a small company merger
• 15:51
  and you know, it comes with an incredible amount of turmoil for
• 15:55
  the teams of uncertainty. It always comes also with a
• 15:58
  reduction frankly of the overall teams and that's difficult and
• 16:03
  it was difficult frankly on on all of us.
• 16:07
  I think the, the biggest challenge we potentially had was
• 16:12
  the fact that, you know, in December of 2024, we had our eye
• 16:16
  on regulatory filings for Chroma 1001, just about nine months or
• 16:22
  10 months with something around that time.
• 16:25
  And frankly, I don't think anybody in the team thought we
• 16:28
  could do. I thought we could actually go
• 16:30
  through this, this upheaval, you know, letting people go, trying
• 16:34
  to bring these two companies together, figure out what the
• 16:36
  heck are we doing? What is this anyway, you know,
• 16:39
  as an organization and yet still keep what was the most important
• 16:43
  thing we could keep going for the company a a potential
• 16:46
  clinical asset, keep it going in the in the already a very
• 16:50
  aggressive timelines that we had laid out.
• 16:52
  So we did it obviously. So that's the one thing I would
• 16:55
  say that, you know, that's, that's something that I think
• 16:57
  all of us are incredibly proud of that we were able to go
• 17:01
  through that, that sort of relative upheaval with the team
• 17:05
  and still maintain that focus and still maintain, you know,
• 17:10
  frankly, the hard work it really takes to get these kinds of
• 17:14
  things over that development milestone and, and into clinical
• 17:18
  trial approvals. So that's sort of one thing I
• 17:21
  would say in terms of how we did that as a team.
• 17:25
  And we'll just, I mean, there, there are obviously many
• 17:27
  functions within the company that had to do this.
• 17:29
  But for Melissa and I, I will, this is my personal opinion and
• 17:33
  you could add to this, but Melissa and I, I think had a
• 17:36
  relatively easy time personally in doing this because we
• 17:41
  actually had very similar roles and parallel roles at Bluebird.
• 17:45
  So I have been running translational development.
• 17:47
  She had been running the rare disease research function.
• 17:50
  And we kind of operated it in the same way that we do now
• 17:53
  until in terms of division of roles overlap, we kind of had
• 17:56
  gotten all that mess out of our systems at Bluebird and we kind
• 18:00
  of could hit the ground running. And I think that really was a
• 18:02
  tremendous benefit to our teams as well because we could not
• 18:05
  only say that, but stand there with confidence and saying, hey,
• 18:08
  we know what we're doing here, guys.
• 18:10
  We know how to take this forward.
• 18:12
  We know how to best help these teams to operate as a cohesive,
• 18:18
  as a cohesive unit. I don't know if you had no I.
• 18:20
  Agree. I mean, like, I know we're, we
• 18:22
  also, we know each other well. We've worked together for years
• 18:26
  and so, you know, there wasn't like any sort of learning curve,
• 18:29
  like how do I communicate with this person?
• 18:31
  And and you know, we, we generally know kind of where
• 18:34
  each other stands and in terms of any, any, any question,
• 18:38
  right, we kind of know which, which page each other is on.
• 18:42
  And so, yeah, I agree. I think that really helped the
• 18:44
  teams. But I I would also under score
• 18:46
  that mergers are not easy at all.
• 18:50
  I I would say it took, I think it was like a solid 6 months
• 18:53
  solid 6 months. I think I made a comment to
• 18:55
  Jenny of like, wow, it actually feels like we're one team.
• 18:59
  Yeah, and and the whole time, right, like, you know, coming
• 19:03
  from from I was on the envelope therapeutic side of this.
• 19:05
  So getting thrown into oh, and we're filing the CTA.
• 19:08
  You're like, cool, So what are what, what, what is this getting
• 19:17
  thrown into that? It was like, I mean, really I, I
• 19:21
  think for a lot of us, we were, we were very much in the mode
• 19:24
  of, you know, building the plane while flying it.
• 19:27
  And I agree, I don't think any of us thought we were going to
• 19:30
  be able to keep that timeline. And and so could not be prouder
• 19:35
  of the team that was able to actually get that across the
• 19:39
  goal line because it was a large.
• 19:43
  Feat Yes, it was. Yeah, I can, I can imagine.
• 19:49
  So you just mentioned the LEAD program then Chroma 1001 which
• 19:52
  is in clinical testing to target hepatitis B, which is a
• 19:57
  significant unmet medical need. Could you just talk us through
• 20:01
  like what makes this disease area particularly well suited to
• 20:05
  in Chroma's approach and what are you trying to achieve from
• 20:09
  the from the? The trial and also just tell us
• 20:11
  about the the compound and any relevant preclinical data that
• 20:15
  that you guys have published as well?
• 20:18
  Sure. Yeah, I can.
• 20:19
  I can walk through that. So Chroma 1001, it's an
• 20:22
  epigenetic editor and it is as a drug product, it is a lipid
• 20:28
  nanoparticle that contains an mRNA that actually expresses
• 20:32
  that epigenetic editor and a guide RNA to take it to its
• 20:35
  target site. So that's kind of the the the
• 20:37
  gist of what the product is and I'll go into the details in in
• 20:40
  just a minute. So with Chromozoazor one, we're
• 20:43
  trying to address a a serious complication and long term
• 20:48
  complication of infection with the hepatitis B virus and that's
• 20:52
  called chronic hepatitis B Chronic hepatitis B is a very
• 20:57
  common disease. There are about 250 million
• 21:00
  estimated people in the world that have chronic hepatitis B.
• 21:05
  There are about a million new infections in the world a year,
• 21:08
  and there are roughly 1,000,000 people who actually die of
• 21:11
  complications of chronic hepatitis B.
• 21:13
  Those are largely related to liver cancers and to liver
• 21:18
  cirrhosis. The unmet need is significant in
• 21:22
  chronic hepatitis B because there currently is no cure,
• 21:25
  unlike other viruses like HCV, for example, where there is now
• 21:28
  a cure. There are vaccines for hepatitis
• 21:32
  B, but once you have chronic hepatitis B, there is no cure.
• 21:36
  There are treatments and those treatments are largely related
• 21:41
  to inhibition of viral replication.
• 21:44
  So nucleoside inhibitors or nucleoside analogs actually,
• 21:49
  which is a small molecule that people take on a daily basis to
• 21:52
  suppress viral replication is the primary treatment regimen
• 21:55
  for chronic hepatitis B. It rarely results in patients
• 22:00
  being cured of their chronic hepatitis B.
• 22:02
  There are about 1% of patients on nucleoside analogs that
• 22:05
  actually spontaneously cure. So why is chronic hepatitis B or
• 22:11
  why is hepatitis B virus, I should say, so difficult to, to,
• 22:15
  to cure? We believe that one of the
• 22:18
  primary reasons is that chronic hepatitis B, it's a stealthy
• 22:22
  virus and it actually establishes itself as a
• 22:25
  reservoir in hepatocytes of of human livers.
• 22:28
  And that reservoir comes in two forms.
• 22:31
  There's a form of episomal DNA that is referred to as CCCDNA
• 22:36
  that is essentially the source of viral replication.
• 22:38
  So that's the full viral genome of the hepatitis B virus that
• 22:42
  replicates and essentially causes patients to eventually
• 22:47
  develop chronic hepatitis B. There's another form of the DNA
• 22:51
  as well, where that episomal form of the DNA essentially gets
• 22:55
  broken and integrates into a patient's DNA in hepatocytes.
• 23:00
  And it is these two forms of DNA that essentially sustain the
• 23:04
  ability of hepatitis B to remain within the liver and to remain
• 23:08
  essentially masked from both the immune system, for example, and
• 23:13
  also the vast majority of therapies that have been tried
• 23:16
  against the virus. So we think that's for primary
• 23:19
  reason, because it is very rare that a therapy is able to
• 23:23
  actually target both forms of that HVVDNA.
• 23:27
  And as I said, it's that episomal form of the DNA that's
• 23:30
  responsible for viral replication, maintaining the
• 23:32
  virus in an infected patient. But that integrated form of DNA
• 23:38
  also expresses viral antigens. And those viral antigens seem to
• 23:42
  have a property that actively suppresses the immune system of
• 23:46
  the infected of an infected patient.
• 23:48
  So if you can't actually tackle both forms of that virus, once a
• 23:52
  patient comes off of any therapy that they might be on, the virus
• 23:55
  essentially become comes back again, right?
• 23:58
  It never really goes away. It's always kind of there in
• 24:01
  stealth mode. So what we think we can do with
• 24:04
  chroma 1001, and as I said, it's an RNA construct with a guide
• 24:08
  RNA. It's all packaged into a lipid
• 24:10
  nanoparticle. Lipid nanoparticles are very
• 24:13
  well suited to targeting the liver in their native state.
• 24:17
  Lots of companies are developing ways to try to get them to go
• 24:20
  other places targeted RNP, as I mentioned already, you know, in
• 24:23
  vivo Carty, that's one of the ways that they are actually
• 24:27
  affecting that is to use targeted lipid nanoparticles.
• 24:31
  Our nanoparticles are not targeted.
• 24:32
  They don't need to be. They go to the liver naturally,
• 24:36
  right? And that's where our target is.
• 24:38
  And so that is actually really well suited for for this
• 24:41
  particular indication. And as I said also the mRNA
• 24:44
  expresses a protein that we call an epigenetic effector.
• 24:48
  This epigenetic effector essentially is a multi American
• 24:53
  construct, multi American protein.
• 24:55
  It has a binding domain for DNA and that's where this guide RNA
• 25:00
  and this what we call a dead cast 9 protein actually takes it
• 25:05
  to a site in the hepatitis B genome and then it has a domain
• 25:10
  on it that actually methylates DNA.
• 25:13
  And so it is that methylation piece of the effector protein
• 25:18
  that actually essentially decorates the the DNA of
• 25:21
  hepatitis B with methylmarks and silences expression from that
• 25:26
  hepatitis B DNA. And it does it on both that
• 25:28
  episomal form, that CCCDNA as I mentioned, and it does it on the
• 25:33
  integrated form of DNA. We have lots of preclinical
• 25:35
  data. We have cell models, we have
• 25:37
  human cell models of integrated DNA.
• 25:39
  We have human cell models of of episomal DNA.
• 25:42
  We have infected cells that we've tested.
• 25:44
  We have animal models of episomal DNA.
• 25:47
  We have animal models of integrated DNA.
• 25:49
  In all of those various preclinical models, we are able
• 25:53
  to effectively silence expression of both forms of that
• 25:58
  DNA. And it is fundamentally because
• 26:00
  of that, because we think we can tackle both forms of that DNA
• 26:03
  that we think that this product has the potential to ultimately
• 26:09
  potentially cure patients of their chronic hepatitis B.
• 26:14
  Maybe just to say one more thing about why we think this way of
• 26:18
  silencing the HPV genome is potentially the right way to do
• 26:24
  it. There are other ways to
• 26:26
  obviously edit genomes, right? You already mentioned sort of
• 26:29
  classic genome editing, right, with Cast 9, our base editors,
• 26:33
  etcetera, where you can actually disrupt transcription through
• 26:37
  cutting the DNA. With epigenetic editing, we do
• 26:41
  not cut the DNA. And as I mentioned, we
• 26:44
  essentially are decorating that DNA with methylmarks and that
• 26:46
  keeps the genome quiet. It keeps it from essentially
• 26:50
  being able to transcribe RNA and ultimately make proteins because
• 26:55
  of that lack of cutting. We think that's a major
• 26:57
  advantage that we have as a platform.
• 27:00
  We believe that is a safer way to silence genes in general.
• 27:04
  But specifically for a disease like chronic hepatitis B where
• 27:07
  you have, again, you're going to have multiple integration sites
• 27:10
  in hepatocytes of infected humans and you're going to have
• 27:13
  the presence of that CCDNA. Cutting that DNA multiple times
• 27:17
  we believe is an inherently unsafe way to do this, frankly.
• 27:21
  And that epigenetic editing is going to be the safer way to
• 27:24
  silence, to silence HBV transcription and again,
• 27:28
  ultimately we think potentially cure chronic hepatitis B.
• 27:32
  Amazing 'cause I'm so exciting. And Melissa, maybe you could
• 27:36
  just talk us through the the rest of the pipeline.
• 27:39
  Could you maybe just give us an insight into and and the
• 27:43
  thoughts on how the company's prioritizing some of the other
• 27:46
  programs as it builds out the portfolio and maybe any
• 27:50
  additional therapeutic areas that you guys have focused on as
• 27:52
  well? Just just talk us through some
• 27:54
  of the other programs that you guys have.
• 27:56
  Yeah, happy to. So in addition to Chroma 1001,
• 28:00
  we are also advancing A next generation epigenetic silencer
• 28:04
  for hepatitis B as well. The expectation is that at some
• 28:09
  point we will have exceed the therapy window for some
• 28:14
  patients. And in order to ensure that we
• 28:17
  have a therapy that could be applied to the broad patient
• 28:22
  population which is you know represented by patients that are
• 28:26
  heterogeneous in in their disease.
• 28:29
  We are coming up with A next generation strategy for chronic
• 28:35
  hepatitis B in addition to Chroma 1001.
• 28:38
  Following on that, we actually have two distinct epigenetic
• 28:42
  silencer platform technologies. One is called CRISPR off.
• 28:47
  And this I think is what people kind of tend to think of when
• 28:50
  you, you know, are casually sitting around thinking about
• 28:52
  epigenetic silencers, right? It contains as we all do, as we
• 28:55
  all do, yes. So it contains like Jenny
• 28:59
  described the DNA binding domain and methylation domain and it
• 29:03
  can also contain something called a transcriptional
• 29:06
  effector domain. That methylation domain for
• 29:09
  crisper off tends to be a fusion of two kind of important
• 29:14
  proteins or or pieces of them I should say DNMT 3L and DNMT 3A.
• 29:19
  We have a second technology called CHARM, which utilizes a
• 29:24
  little bit of a different strategy for that methylation
• 29:26
  domain. And what this ultimately results
• 29:29
  in is an epigenetic silencer that's about 20% smaller than
• 29:35
  the crisper off silencer. Because this silencer is
• 29:39
  smaller, it is now amenable to delivery through modalities
• 29:43
  where the crisper off silencer is not.
• 29:47
  Namely one of those is an AAV. So charm can be packaged into an
• 29:53
  AAV and and you can utilize AAV to get various bio distribution
• 29:58
  profiles. So beyond our focus on hepatitis
• 30:02
  B, we are also utilizing the charm construct and thinking
• 30:07
  about AAV delivery specific to the central nervous system for
• 30:11
  various neurological indications.
• 30:13
  We have not publicly named any specific program to date.
• 30:18
  In addition to this, one thing that we have noticed for some
• 30:22
  loci, the charm constructs sometimes is more potent than
• 30:26
  the crisper off and and vice versa.
• 30:28
  It's a little bit. It needs to be empirically
• 30:31
  determined. We have an incredibly potent
• 30:35
  molecule that is able to silence PCSK 9 and we can achieve
• 30:40
  saturating pharmacology at .5 Megs per K, which is
• 30:43
  significantly lower than what anyone else is publicly
• 30:47
  described. And you know we are really
• 30:50
  excited about utilizing that for cardio metabolic disease.
• 30:56
  And lastly, we have a technology that actually allows us to
• 31:00
  Multiplex and actually go after multiple different target sites
• 31:04
  simultaneously. And of course do this with
• 31:07
  traditional gene editing as well.
• 31:09
  With traditional gene editing, you run the risk of, for
• 31:12
  example, chromosomal translocations if you're
• 31:15
  simultaneously cutting two different pieces of DNA.
• 31:19
  With epigenetic silencing, you can do a Multiplex where you are
• 31:23
  specifically methylating and silencing without cutting
• 31:27
  simultaneously multiple target sites.
• 31:29
  And we've demonstrated with this with up to five target sites
• 31:33
  simultaneously. We have a another kind of like
• 31:36
  nuanced way where we can simultaneously methylate and
• 31:41
  silence one target site and using the same effector, we can
• 31:45
  actually either cleave and and resolve through an insertion
• 31:50
  deletion event or base edit a second target site.
• 31:54
  And we call this polyfunctional editing.
• 31:56
  And this really allows us to expand our target landscape of
• 32:00
  interest. And we're thinking about this
• 32:01
  again through the lens of largely cardio metabolic disease
• 32:04
  currently. And if you look at like the
• 32:06
  landscape that that you guys are in and I never like to use the
• 32:10
  word competing because I think ultimately what you guys are
• 32:12
  doing is for patients. But who would like the companies
• 32:15
  that are in a similar sort of space to you guys that I guess
• 32:18
  you are sort of up against or is this quite an uncharted field
• 32:22
  that you guys are operated in? Like who are those companies?
• 32:25
  Epigenetics. Is hot.
• 32:26
  Yeah, there's quite a few. We are not.
• 32:29
  Alone I any. Yeah, yeah, I thought.
• 32:32
  So. Yeah.
• 32:34
  Yeah, we have a few, we have a few competitors even in the
• 32:37
  chronic hepatitis B space as well.
• 32:40
  So, but there are many companies now and epigenetic editing
• 32:44
  there's there are companies focused in CNS indications for
• 32:48
  example. There are others focused in
• 32:51
  liver indications as we have been and you know broadening out
• 32:55
  from from there. So yeah, we're definitely not
• 32:58
  alone. We have very much direct
• 33:01
  competition and we have some indirect competition as well.
• 33:03
  What I will say for chronic hepatitis, BI mentioned some of
• 33:07
  our preclinical data. I didn't sort of mention sort of
• 33:10
  the specifics of how it might compare to others that are, you
• 33:13
  know, competing in the same space.
• 33:14
  We think we have the the best epigenetic editor that is out
• 33:18
  there and not even avogenic editor, I would say gene editor
• 33:21
  in general in terms of the ability to to silence a
• 33:24
  particular locus. Melissa mentioned our PCs canine
• 33:28
  asset that I think that data frankly is, is unprecedented
• 33:32
  again as far as what we've seen in the public domain.
• 33:36
  And also we have shown our same editor for chronic hepatitis B
• 33:40
  clearly shows again in preclinical data superiority to
• 33:44
  our direct competition. So we were feeling pretty good
• 33:47
  about how our products are going to play out in the clinic and I
• 33:50
  would just. Add that, I think that it's
• 33:52
  actually great that so many entities are getting into
• 33:55
  epigenetics because we really feel that 2026 in particular is
• 34:00
  going to be a milestone year for this type of technology.
• 34:03
  There are now kind of a critical mass of clinical programs
• 34:08
  ongoing across patients, across therapeutic areas and the data
• 34:13
  that we expect will be coming out throughout the year.
• 34:17
  And and you know, we're also obviously looking forward to our
• 34:20
  own clinical data. We think it's really going to
• 34:23
  help shape this field and drive it and kind of bolster the
• 34:25
  momentum behind epigenetics moving forward.
• 34:29
  Amazing. As you guys look ahead to the
• 34:32
  next 12 to 24 months, just talk us through what the next sort of
• 34:36
  milestones that you guys are looking forward to, whether
• 34:38
  that's from a scientific, clinical or just general
• 34:42
  organizational milestones. Maybe you have a fundraising or
• 34:45
  partnering side that you guys are most excited about over the
• 34:48
  next year or two? Sure, yeah.
• 34:50
  So I think. For this year, there is no doubt
• 34:53
  that our most exciting milestones are going to come
• 34:56
  from our Carmel 1001 clinical program.
• 34:59
  So Melissa already mentioned that we got the year off to an
• 35:02
  exciting start by entering the clinic in the 1st place.
• 35:04
  We dosed our first patient in January.
• 35:07
  We have clinical trial approvals in the UK and New Zealand, in
• 35:13
  Hong Kong and in France now and we're continuing to move through
• 35:19
  our dose escalation plan for the beginning of our phase one
• 35:22
  trial. So as we get towards the, I
• 35:24
  would say the end of 2026, we expect some of that data to
• 35:28
  start to come to fruition and start to really understand how
• 35:32
  chroma 1001 is working in chronic hepatitis B patients.
• 35:37
  What I will also say is that we really have a strong network
• 35:42
  right now of highly engaged Kols, highly engaged Pis that
• 35:46
  have helped guide our strategy both into the clinic and now as
• 35:50
  we are in the clinic. And we're all excited us and and
• 35:54
  our partners in the space to execute this trial to see how
• 35:59
  this data plays out. And again, we expect to be
• 36:02
  seeing this towards towards the end of 26 really as we continue
• 36:06
  dose escalation. So in addition to that and
• 36:10
  Alyssa mentioned our next generation efforts for chronic
• 36:13
  hepatitis B as well. We are eager to see the results
• 36:17
  of those optimization efforts as our preclinical data package
• 36:21
  grows for our potential next generation asset as well.
• 36:26
  And then on the corporate development side, we're Melissa
• 36:29
  already mentioned, we are definitely excited to see the
• 36:32
  growing interest in epigenetic silencing.
• 36:34
  The number of active partnering conversations that we have going
• 36:37
  across the park pipeline continues to increase as more
• 36:40
  and more people are seeing the you know the growing interest in
• 36:46
  the field. The fact again that we're going
• 36:48
  to have a lot of different clinical data inflection points
• 36:51
  across epigenetic editing programs throughout this year.
• 36:55
  So you know, partnerships obviously for us would offer
• 36:58
  strategic acceleration, the expansion of capabilities and
• 37:01
  we're going to continue to evaluate opportunities like that
• 37:04
  over the next 12 to 24 months. Amazing.
• 37:06
  And just talk us through how you guys are thinking about building
• 37:10
  and maintaining a strong company culture as as the business
• 37:14
  grows. It's obviously I imagine there's
• 37:15
  been a bit of change in in size and all of that since the
• 37:18
  company was founded. But yeah, just talk us through
• 37:20
  how you're thinking about maintaining company culture,
• 37:22
  particularly for scientists who are working at the cutting edge
• 37:25
  of new technologies as well. Yeah, we are in a really
• 37:30
  fortunate position in that we have a a fantastic team here at
• 37:34
  Encroma. And you know, we consistently
• 37:37
  emphasize the importance of how we show up for one another and,
• 37:41
  and you know how that extends and, and what we do with regard
• 37:45
  to research and how we kind of keep the communities that we
• 37:50
  hope to treat front of mind. Our core values highlight the
• 37:54
  importance of collaboration, curiosity, kindness and being
• 37:57
  relentless in the pursuit of bringing hope to patients.
• 38:01
  And these really aren't just words on a piece of paper.
• 38:03
  We're really proud of the way that our team brings them to
• 38:06
  life each day. And I think that's a great
• 38:07
  example. And actually, this is something
• 38:09
  that I think we brought with us from our Bluebird experience as
• 38:11
  well, which was also a company highly focused on kind of
• 38:15
  emphasizing a strong culture. You know, we, we conducted a, an
• 38:22
  auction. Oh yes, that was.
• 38:25
  To benefit SO. Much appetitis B foundation and
• 38:28
  you know we we literally asked everybody like come up with
• 38:32
  something that you're going to throw in and we'll bid on each
• 38:34
  other's stuff right and and it rains like it was a big range of
• 38:39
  things here. I mean it's like I'll make you
• 38:40
  some cookies to like you know, Jenny and I pretty hotly tried
• 38:47
  to outbid each other and I am still maybe holding it against
• 38:50
  her a little bit. I won that she outbid me on what
• 38:56
  was it dumplings for a week one of our.
• 38:58
  Scientists put into the auction homemade dumplings for a week,
• 39:02
  and it was definitely. Yeah, I it, it was worth every
• 39:06
  penny I paid, you know? What if, you know, you know, we
• 39:13
  do fun things like that, right? I mean, I think we, we really
• 39:15
  focus on trying to tie, you know, our kind of activities
• 39:20
  that we conduct as a community to relieve the patient
• 39:23
  population that we hope to serve.
• 39:24
  And, and I think that really demonstrates kind of how we
• 39:29
  embody these values and, and make them real for each other.
• 39:33
  And, and I think that, you know, it's, it's, that's what it's all
• 39:37
  about. I mean, we, you spend a lot of
• 39:39
  time and your effort and your focus, you know, dedicated to
• 39:44
  roles like this throughout the organization and getting these
• 39:48
  drugs to patients. And, you know, you should, in an
• 39:51
  ideal world, have fun doing it and have the purpose.
• 39:55
  So I think we're really fortunate to be in that
• 39:57
  position. Yeah, for sure.
• 40:01
  You guys have obviously had the ability to have led large teams
• 40:05
  and that are tackling incredibly complex biological problems.
• 40:10
  Just talk us through about some of the lessons that you've
• 40:12
  learned about biotech leadership.
• 40:13
  I can imagine there's probably been quite a lot, but how do you
• 40:17
  create an environment where scientists can do their best
• 40:20
  work as well? Yeah, maybe I can answer. 1st
• 40:23
  and then Melissa can can add on. So I think there are the things
• 40:28
  I, I think about and I think that have, you know, worked for
• 40:31
  for me and, and my teams over the years.
• 40:33
  And some of it, I mean, I will say is not, I mean, it's, it's
• 40:37
  obvious and some in some ways, right.
• 40:39
  I don't think I'll say anything that that others haven't said
• 40:42
  before, but I think cultivating talented, motivated people, I
• 40:48
  think means giving them room to explore, to experiment and to
• 40:52
  build things on their on their own right and to maybe go in
• 40:57
  different directions that aren't within their core purview
• 41:01
  either. Right.
• 41:02
  And, and I think folks knowing that they have that option, that
• 41:07
  they have that opportunity to explore and learn and grow
• 41:10
  constantly. And not just about the science,
• 41:12
  but again, about the, there's so many different roles we can take
• 41:15
  on a scientist and biotech. And, and they're all interesting
• 41:18
  in their own ways. And I think folks knowing that
• 41:21
  they have that opportunity that they have the support to, to do
• 41:24
  that kind of exploration, I think really keeps talented
• 41:28
  folks together, frankly. I think also cultivating open
• 41:32
  and honest debate, transparency, input into big decisions and
• 41:37
  folks knowing that their voice means something in the room is
• 41:40
  obviously important. You know, and again, I think I
• 41:44
  think we make our best decisions, frankly, as as a
• 41:47
  group and not as as individuals. And so to ensure that folks have
• 41:52
  that opportunity to have their voices heard, you never know
• 41:54
  what you're going to hear. And I have my mind changed all
• 41:57
  the time by having these types of conversations.
• 42:00
  I think also Melissa referred to this already in terms of for the
• 42:04
  culture piece. I think building team spirit and
• 42:06
  connection is so important as we're doing this great work.
• 42:09
  I don't believe that we can do our best work if we don't have a
• 42:13
  relationship with the people around us.
• 42:15
  We spend way too much time in these jobs to not #1 like the
• 42:20
  people we're with know them as, as, as humans, right?
• 42:24
  As people who, you know, we all have problems outside of these
• 42:27
  four walls, right? And those problems affect
• 42:29
  sometimes what we're doing here. And it's important that we can
• 42:33
  express those things and that we know something about what, you
• 42:35
  know, what's happening in, in everyone's lives.
• 42:37
  So those are the, the kinds of teams and relationships that
• 42:41
  that I try to build in any, any place that I'm at with any team
• 42:45
  that I'm that I am, you know, privileged to, to lead.
• 42:51
  Yeah, I. Think, I think Jenny summed it
• 42:52
  up really well. I think for me and it like I
• 42:55
  would just add, right, I like to, and I think you do this too,
• 42:57
  right? Surround ourselves by people who
• 42:59
  are smarter than myself, right? I, I, I don't want to be the
• 43:03
  smartest person in the room. Like we should be scared if
• 43:05
  that's the case. Like I, I think I want to
• 43:08
  continually be surrounded by very smart people.
• 43:11
  And I will just ask the questions to try to be able to
• 43:14
  put the, the pieces together and, and help everybody kind of
• 43:18
  move, you know, in, in lockstep, in a, in a singular direction.
• 43:24
  And that's kind of how I view like our roles, right, as really
• 43:28
  just guidance more than anything else.
• 43:29
  And, and, you know, really just doing this job with the people
• 43:34
  that you like to do it with is, is fundamentally the most
• 43:36
  important aspect because it's, we could be doing a lot of
• 43:41
  things and, you know, it's, it's, it's really fun to do it
• 43:45
  with people who are also kind of so, so tied to the mission of
• 43:51
  what we do. Yeah, for sure.
• 43:54
  And this is a question that we always finish with on the
• 43:57
  podcast as well. And yeah, if you 2, are going to
• 44:00
  host a dinner party, if you could each invite three people,
• 44:05
  whether they're scientists, innovators or historical figures
• 44:08
  or whoever you like, to a dinner conversation about the future of
• 44:12
  science and medicine, who would you choose?
• 44:15
  And and what would you want to learn from them?
• 44:18
  I guess this. Is by far the most pressure
• 44:21
  filled question that that you have asked us so far.
• 44:25
  I, I will admit I did think about it quite a bit before
• 44:29
  actually joining today. And I, there are literally a
• 44:33
  million different answers one could give and they would all be
• 44:35
  great answers. I thought a little bit about our
• 44:40
  field and what we're trying to do in the history of our field.
• 44:42
  I mean, one of the things that I thought about is, you know, I've
• 44:44
  been working in some way, shape or form as a, a safety
• 44:48
  scientist, as a translational developer, etcetera, with lipid
• 44:51
  nanoparticles for the better part of it's going on 20 years
• 44:55
  now actually. And, you know, I thought about
• 44:58
  Bob Langer and his history in this field and he's, you know,
• 45:02
  fundamental to what we're all doing today in terms of, you
• 45:06
  know, not only the, the foundational science that he and
• 45:09
  his lab have have done, but the companies that he's founded.
• 45:12
  I mean, the, the, the proliferative work that he's
• 45:15
  done in the field of lipidarum particles is amazing.
• 45:18
  And it would be, I think great to have that conversation about
• 45:22
  where is where is this headed right now that we're actually
• 45:25
  seeing what seemed to be some, you know, I think significant
• 45:28
  not only progress, but we're on the verge of real success with
• 45:32
  actually drugs that will impact a lot of patients that are lipid
• 45:38
  nanoparticle based. So that's one person I thought
• 45:40
  about. Then the other person, you know,
• 45:41
  we're obviously an mRNA based drug as well.
• 45:44
  And I thought about Caitlin Carico and that the foundational
• 45:48
  role that she's played in terms of where we're at with mRNA
• 45:51
  based drugs. But also, I think the, you know,
• 45:55
  significant hurdles it's fair to say that she faced as a, as a
• 46:01
  with a career in science, right? And what that was like to to
• 46:06
  push through that and then get the kind of recognition that
• 46:09
  she's got sort of at the not the end of her career, but the late
• 46:13
  in her in her career as a result of you know, the vaccines
• 46:17
  etcetera. And then the last.
• 46:20
  Person I thought about. I read an article a couple of
• 46:22
  months ago about written by David Hung who was the CEO and
• 46:26
  Medivation sold for $14 billion sometime in the early teens,
• 46:31
  whatever of the the 20, I don't know, 14 something like that.
• 46:35
  Unbelievable success, right, What so many of us in, in
• 46:39
  biotech are are hoping for in terms of the success of one of
• 46:42
  our products. And then he went to be the CEO
• 46:44
  Axe Van and it was kind of the opposite kind of story, right?
• 46:47
  And I just, you know, I think failure is part of our business
• 46:52
  and probably more often than the not.
• 46:55
  And you know, many of us never get to see a product to the
• 46:58
  market. We've been lucky enough to see
• 46:59
  several now in our in our career.
• 47:01
  But many scientists don't frankly and to, you know, I
• 47:06
  think have a conversation with somebody who's seen such raging
• 47:09
  success and frankly such abject failure all within, you know, a
• 47:13
  few years of each other. I think it's part of the DNA of
• 47:17
  our work, frankly, and part of what we all need to I think,
• 47:21
  hear about and absorb and learn how people move through both
• 47:24
  success and failure in this business.
• 47:27
  So that's that's my answer. My answer is I just.
• 47:30
  Hope to get an invite to her dinner.
• 47:34
  I think it'll be a good one. Amazing.
• 47:39
  But look, guys, thanks so much for coming on and, and helping
• 47:42
  us out with this. It was a it was a pleasure to
• 47:44
  have you on and just learn a little bit more about your your
• 47:47
  journeys through the field and a bit more into in Chrome.
• 47:50
  It sounds super exciting what you guys are building.
• 47:53
  So I'm looking forward to seeing the the next milestones that
• 47:55
  come out over over the next few months and and years.
• 47:59
  So it was a pleasure. So thanks again, guys.
• 48:02
  Mike Wireless, thanks. For having us, yeah, we
• 48:04
  appreciate being on.