Latest / The BioHub - by Avetix / Episode 157 - Harold Bernstein - President, R&D Maze Therapeutics

Transcript

Episode 157 - Harold Bernstein - President, R&D Maze Therapeutics · The BioHub - by Avetix

• 0:06
  So welcome back to another episode of the Bio Hub, a
• 0:09
  podcast brought to you by Avetics.
• 0:11
  Today I'm joined by Doctor Harold Bernstein, President of
• 0:15
  R&D of May's Therapeutics, a company at the forefront of
• 0:18
  using Human Genetics to build precision medicines for kidney,
• 0:21
  cardiovascular and metabolic diseases.
• 0:24
  Harold is one of those rare leaders who has done it all
• 0:27
  decades in academia, senior roles at Merck, Vertex and Bio
• 0:31
  Marim. He's a physician, scientist, an
• 0:34
  educator and a mentor. And now he's helping steer mazes
• 0:37
  genetic driven pipeline during a pivotal moment for the company.
• 0:41
  In this conversation, we talk about his academic roots, his
• 0:45
  career journey, mentorship, how Maze is succeeding in a tough
• 0:49
  market and the big picture vision for where position
• 0:52
  genetics is heading. So let's get into it.
• 0:54
  Pleasure to have you Harold. How are you?
• 0:57
  Good. And thanks, Max.
• 0:58
  It's great to be with you today. Amazing.
• 1:01
  So yeah, let's let's start with those academic routes.
• 1:04
  So you spent decades straddling both industry and academia.
• 1:09
  How have you managed to keep 1 foot in in each world?
• 1:13
  You know, Max, I think historically the crosstalk,
• 1:17
  let's say, between academic science and medicine and
• 1:20
  biopharma has really been a significant driver of innovation
• 1:24
  in the US. And obviously each institution
• 1:28
  is essential. And I don't think the public
• 1:30
  always realizes how each contributes to advancing human
• 1:34
  health. But the colleagues I've had in
• 1:36
  both spheres really do see this and they respect it.
• 1:40
  And you know, while my the focus of my current career has been on
• 1:45
  making new therapies on the industry side, I really value
• 1:49
  the perspective that, you know, as you say, straddling these two
• 1:53
  institutions have afforded me and that carries through to the
• 1:57
  organizations that I lead. I encourage the people I work
• 2:00
  with really to stay close to their academic roots and develop
• 2:05
  new relationships that not only support the endeavors of our
• 2:09
  academic colleagues, but provide them with the perspective of a
• 2:13
  drug developer. Look, your your career is taking
• 2:15
  you through Merck, Vertex, Bio Marin and then leading roles
• 2:19
  across early development, you know, translational medicine and
• 2:22
  global clinical strategy. Looking back, what what were the
• 2:26
  key inflection points that shape the DDUR today?
• 2:31
  I think one of the most important benefits I've had
• 2:34
  really has been encouraging mentors who have made me think,
• 2:38
  you know, I, I had great teachers in high school and
• 2:41
  college who are really committed to their students.
• 2:44
  And then I, I had a graduate advisor who is incredibly driven
• 2:48
  and demanding, but he really taught me to learn from, from
• 2:52
  everyone and anyone that I was working with, You know, in my
• 2:56
  first industry role at Merck, I found mentors who really
• 3:00
  understood where I was coming from because I'd already been in
• 3:03
  academia for decades. And they really were helpful in,
• 3:06
  in my making this transition. You know, one of those
• 3:11
  individuals in particular would ask me, you know, how I wanted
• 3:15
  to have an impact five years from now.
• 3:18
  And then once I was there, because I've kept in touch with
• 3:21
  him over the years, he he always asked that question.
• 3:25
  It's basically, you know, what do you need to learn?
• 3:27
  What experiences do you need to have to be ready when that
• 3:31
  opportunity comes along for you? And I think these inflection
• 3:35
  points tended to come as I took each role, focusing on different
• 3:40
  aspects of the research and development process.
• 3:44
  Now, of course, I'm leveraging everything I've learned and
• 3:48
  really expanding my understanding of how you
• 3:50
  integrate that into building a company.
• 3:54
  Yeah. And I think what was pretty
• 3:57
  interesting about your background is just the, the pure
• 3:59
  depth and broadness of it. You know, I mentioned early
• 4:02
  development, translational medicine, clinical strategy, but
• 4:05
  there's there's other areas as well, right.
• 4:08
  And what what's the importance of of having that broad
• 4:11
  expertise, especially when coming to a company like Maze as
• 4:14
  well? I think it's important, you
• 4:18
  know, no matter where you are in the process of, you know,
• 4:23
  discovering and developing new potential medicines, you have to
• 4:28
  sort of understand what's the end game?
• 4:31
  What what are you trying to bring to patients?
• 4:34
  What do they need? And then all along the way
• 4:36
  you're basically building evidence that gives you
• 4:39
  confidence that what you're working on is going to get you
• 4:42
  there. And so, you know, I think, you
• 4:46
  know, when I talk to people who are earlier in their careers,
• 4:51
  and especially, you know, the teams that I'm working with now,
• 4:55
  it's really important to me that they're not only, you know, are
• 4:57
  developing subject matter expertise in their own
• 5:01
  particular discipline, but they have this broader view.
• 5:06
  And then of course, in an early company, it, you know it, it's
• 5:10
  helpful to start to develop an enterprise level because you
• 5:14
  also have to match what you're doing in your mission to improve
• 5:19
  health with your ability to sort of keep that effort going.
• 5:25
  Yeah, I I also mentioned mentorship in my introduction.
• 5:30
  And you've mentored however many scientists, decisions and early
• 5:36
  career leaders over over the years.
• 5:40
  What What do you wish the younger generation coming into
• 5:42
  biotech understood about building a meaningful and and a
• 5:46
  sustainable career? You know, historically, there
• 5:52
  had been a big wall between academia, academia and industry.
• 5:57
  Maybe it wasn't as high on the West Coast in the United States,
• 6:02
  but, you know, overtime partnerships have really helped
• 6:05
  to lower these. So I think there's a lot better
• 6:07
  understanding. And I also think that, you know,
• 6:11
  current generations who are coming into biotech and are in
• 6:14
  biotech are really more proactively focused on their own
• 6:18
  professional development. And So what I, you know, what I
• 6:22
  think is, you know, you have to find the right colleagues who
• 6:25
  are going to help you grow. You have to find the environment
• 6:28
  that, you know, values creativity and allows you to
• 6:31
  take an appropriate, you know, amount of measured risk.
• 6:35
  And then, of course, you know, collect mentors and advisors
• 6:39
  along the way who can really help you evaluate the
• 6:42
  opportunities as they come your way to see whether, you know
• 6:46
  one, are they subjectively good opportunities, but also, how are
• 6:50
  they going to help you build your ability to have an impact?
• 6:54
  Yeah. For sure, like just talking
• 6:58
  about the mentorship as well, like how much do you value that
• 7:01
  yourself? Like you, you obviously have
• 7:03
  been a mentor, but you talked about looking for mentors as
• 7:07
  well earlier. Oh, yeah.
• 7:10
  I, I continue to carry with me, you know, many of the mentors
• 7:15
  I've had along the way and you know, and I look for, you know,
• 7:21
  mentorship amongst my current colleagues and I think I, I
• 7:26
  benefit from that. It's all about you.
• 7:29
  That initial experience I had in Graduate School where my advisor
• 7:34
  said, look, you know, you should have an open mind and be
• 7:39
  learning from everyone that you're working with.
• 7:43
  And I think that's that's been very helpful.
• 7:47
  For sure. I think a lot of people talk
• 7:50
  about that and the importance of it.
• 7:52
  I think to be honest, no, none more than than you in the way
• 7:56
  you talk about mentorship. And I mean, people obviously
• 8:00
  normally go the other way and say, look like it's, it's really
• 8:03
  important to have mentors. But for you, you understand
• 8:06
  that. So it's like you're looking for
• 8:07
  people to mentor, which I think is actually like a really lovely
• 8:10
  thing and it's actually really good to see.
• 8:15
  But let's talk about Maze. I think what you're doing is is
• 8:19
  extraordinary at the moment. Like, let's first talk about
• 8:23
  what initially drew you into the company and then also what makes
• 8:27
  this platform and a mission different from anything you've
• 8:30
  worked on before. You know, I love that question,
• 8:34
  Max, because I love talking about Maze, you know, with
• 8:39
  respect to the platform, which we call Compass.
• 8:42
  Like we've all watched the field of genetics evolve over time,
• 8:47
  but it's really been daunting to find ways to apply what we're
• 8:51
  learning toward improving the human condition.
• 8:54
  And so I think, you know, we all admit that the the promise has
• 8:58
  not really been fully realized. But you know, what attracted me
• 9:02
  to Maze was, you know, we're finally in a moment at Maze
• 9:07
  where we're using modern genetics and the type of data
• 9:11
  that's now being becoming available, like specifically,
• 9:15
  you know, match genetic with clinical data and even
• 9:18
  metabolomic data to really approach therapeutics for common
• 9:23
  diseases like chronic kidney disease and metabolic syndrome.
• 9:28
  You know, at Mays, we've developed our Compass platform
• 9:32
  to deliver what we like to call genetically informed therapies
• 9:36
  for diseases that may not have a clear genetic cause.
• 9:40
  So what we're really doing is we're leveraging human genetic
• 9:45
  variation, what we can learn about that to understand disease
• 9:50
  biology better and formulate medicines that really
• 9:55
  recapitulate what genetics is showing us.
• 10:00
  This really moves beyond the genome wide association data
• 10:04
  that we're familiar with to identifying series of bi
• 10:08
  directional gene alleles that include variants that either
• 10:13
  protect or confer risk with a given gene.
• 10:17
  And then we then take these variants into the lab to
• 10:20
  determine their function, you know, something we call this
• 10:23
  variant functionalization. And we've also been investing in
• 10:27
  some AI and machine learning methods to call these variants,
• 10:30
  in other words, to prioritize the ones that are most likely to
• 10:34
  be informative. And you know, as as you're
• 10:37
  probably aware, some recent meta analysis have shown that when
• 10:40
  you have a significant bi directional allelic series,
• 10:45
  you're up to four times more likely to have an approvable
• 10:48
  medicine. So, you know, once we have the
• 10:52
  genetics as the foundation for a target and and a therapeutic
• 10:57
  hypothesis, we then use, you know, the the array of current
• 11:01
  drug discovery techniques, including, you know, high
• 11:04
  throughput screen augmented by computational methods and also
• 11:09
  newer structural methods like CRY, OEM and HDX to develop
• 11:13
  small molecules that phenocopy the effects of these protective
• 11:18
  variants. Now you know, this is where we
• 11:23
  think we've been able to be successful in just about every
• 11:27
  program that we've been able to move forward at Maze.
• 11:33
  Yeah. And you can see that from an
• 11:34
  outsider's perspective, and it's exciting, right?
• 11:39
  And another part of it is that there's very few small biotechs
• 11:44
  working on kidney disease at the moment.
• 11:47
  What what shaped the decision for Maze to focus initially on
• 11:50
  kidney disease? You know, it comes down, comes
• 11:55
  down to patient need. Kidney disease truly is a silent
• 11:58
  killer. Most people have in some way
• 12:01
  been touched by kidney disease in either their own experience
• 12:05
  or those of people they know. Chronic kidney disease is
• 12:09
  recognized as a growing health crisis.
• 12:12
  It affects nearly 800 million adults worldwide.
• 12:17
  Recently, I think it was shown it's the 9th leading cause of
• 12:20
  death. And in some countries, you know,
• 12:22
  the waiting list for a kidney transplant, the current
• 12:25
  definitive therapy can be more than four years.
• 12:29
  And yet there's been very little innovation in developing
• 12:32
  medicines focused on kidney disease.
• 12:36
  Most of the innovation has has come based on observations of
• 12:40
  drugs targeting other diseases like type 2 diabetes.
• 12:45
  And precision medicine is really in its infancy where kidney
• 12:48
  disease is concerned. So, you know, given all that, we
• 12:53
  also recognize that kidney disease is well suited to our
• 12:56
  approach as there's some very well validated clinical measures
• 13:01
  that tell us how severe the disease is and how it's
• 13:04
  progressing. And we can use these clinical
• 13:07
  measures in combination with genetics to identify those
• 13:12
  allelic variants I talked about that confer risk or protection.
• 13:16
  So, you know, it may as we're leveraging human genetic
• 13:21
  variation to both in gain insight into, you know, kidney
• 13:24
  disease biology as well as inform our drug discovery
• 13:28
  efforts. And we really believe that right
• 13:32
  now, this is how much of the prior investment in
• 13:35
  understanding genetics in the human genome is really going to
• 13:38
  pay off for human health. Yeah, so, so why do you think
• 13:44
  other biotechs aren't moving in or or thinking about kidney
• 13:47
  disease? I, I think they are.
• 13:51
  I think we're starting to see some movement.
• 13:53
  I think, you know, for a long time it's been pretty daunting
• 14:00
  to develop drugs for kidney disease.
• 14:03
  You know, there's a lot of biology, but the biology alone
• 14:07
  maybe isn't sufficient. The other thing is the
• 14:09
  requirements for getting a drug approved and demonstrating, you
• 14:14
  know, how it helps patients has been difficult because it's
• 14:17
  required, you know, large lung trials because of the nature of
• 14:23
  the endpoints you're looking at. But I think more recently, as
• 14:26
  we've seen in kidney diseases like I get and, and you know,
• 14:31
  FSGS, focal segmental glomerulosclerosis, there's been
• 14:36
  recognition that there are definitely some endpoints that
• 14:40
  could really accelerate the study of drugs.
• 14:45
  And so of course, as we look towards our own development
• 14:48
  programs, we're looking towards these to to seek ways that we
• 14:53
  could accelerate development as well.
• 14:57
  Yeah. And you guys, I mean as we're
• 15:00
  having this conversation actually the market is turning
• 15:02
  and looking in a much better place.
• 15:04
  But high majority of your your build has been in in a tough
• 15:08
  market and you've built quite a bit of momentum as of recent.
• 15:13
  What do you think's allowed the company to move forward when
• 15:15
  when so many others have really struggled?
• 15:19
  Yeah. Well, first just, you know,
• 15:20
  acknowledging that it's really great to see that investment in,
• 15:27
  you know, early programs, new platforms is starting to pick up
• 15:31
  again. I really think that, you know,
• 15:33
  our country is a real driver of innovation.
• 15:36
  And so it's good to see that the environment is now starting to
• 15:40
  return towards supporting that. I think for us at Mays.
• 15:44
  And, and it has been sort of a rough few years.
• 15:47
  I think, you know, my colleagues in in Mays's leadership have
• 15:52
  really maintained exquisite focus.
• 15:55
  You know, we're working in specific therapeutic areas like
• 15:58
  kidney and metabolism that haven't greatly benefited from
• 16:02
  the application of genetics in the past.
• 16:06
  But as I said you know, but there are objective clinical
• 16:09
  measures with which to monitor disease progression that really
• 16:13
  allow us to apply our specific approach at looking at genetic
• 16:17
  variation match to how a disease progresses.
• 16:22
  And this is already happening is with our programs targeting you
• 16:26
  know, April O1 mediated kidney disease as well as the
• 16:31
  transporter SLC 6A-19 for broader chronic kidney disease
• 16:36
  and PKU you know a rare metabolic disorder.
• 16:39
  You know, we're focused on small molecules to leverage our in
• 16:44
  house expertise and and you know, using established
• 16:49
  development approaches that we know how to accelerate so well.
• 16:55
  It's tempting to go into many different modalities as a, as a
• 17:00
  small company, we're really leaning into our strengths here.
• 17:05
  And of course, we're also constantly listening to our
• 17:08
  stakeholders, including patients, providers, health
• 17:12
  authorities and the and funders to tell us, you know, what they
• 17:17
  want, what they're excited about supporting.
• 17:20
  I think taken together and our ability to really, you know,
• 17:24
  execute on what we say we're going to do has really helped us
• 17:28
  and, and and sustained us during the rough period.
• 17:32
  Yeah, for sure. How much just like the team and
• 17:37
  the story come into it as well, especially when talking to
• 17:42
  investors and potential investors.
• 17:45
  Yeah. I think, you know, one of the
• 17:49
  things we've managed to do especially and sort of building
• 17:52
  out, you know, mazes R&D effort specifically on the development
• 18:00
  side. Now that we have, you know,
• 18:02
  several clinical programs, we really brought in people who've
• 18:09
  not only had experience in small companies, but also in big
• 18:15
  pharma. And that gives all of us across
• 18:18
  the board sort of a view towards not just how to make an asset,
• 18:24
  but how to make a drug. And I think that's recognized.
• 18:28
  I think people, you know, have more confidence that as a team,
• 18:32
  we're able to do this. We're we're able to, you know,
• 18:36
  identify, you know, good targets, develop good drugs and
• 18:42
  we know how to develop them and ultimately get them to patients.
• 18:47
  Yeah, 100%. And then when you zoom out like
• 18:51
  what what's the long term vision for me is how, how big can this
• 18:55
  approach to Human Genetics in precision medicine really get?
• 19:01
  You know we get, we get that question a lot.
• 19:04
  You know, we're very much focused on our near term data
• 19:07
  readouts right now. We're we were very excited by
• 19:10
  our phase one clinical data that we shared in last September.
• 19:13
  Rightly so. Yeah, we were able to use non
• 19:16
  invasive biomarkers to demonstrate proof of mechanism
• 19:19
  for MZ 782 in two diseases. This is really giving us the
• 19:26
  confidence of the about the potential for our SLC 6A-19
• 19:30
  inhibitor to treat patients not only with PKU, but patients
• 19:35
  challenged by chronic kidney disease.
• 19:39
  And you know we're revving up now to share clinical data
• 19:42
  toward the end of this quarter from our phase two program
• 19:45
  called Horizon with MZ 829, which has the potential really
• 19:51
  to be the first demonstration of this mechanism in a broad
• 19:56
  population of patients with APLO 1 mediated kidney disease.
• 20:01
  Beyond that, you know, our pipeline continues to be focused
• 20:04
  on other kidney diseases as well as diseases driven by altered
• 20:08
  metabolism, obesity, where we think our approach could
• 20:12
  continue to have, you know, really big impact.
• 20:17
  That's cool. That's yeah.
• 20:18
  So there's there's all the modalities that you could
• 20:21
  potentially move into with what what you're doing.
• 20:24
  Yes, except you know for now again as a small company I think
• 20:28
  we're you know, we're focused on our strength which is in small
• 20:34
  molecule drug discovery. And again, you know, right now,
• 20:39
  I think the, the clinical data that we have access to really
• 20:43
  supports us going after these therapeutic areas, you know,
• 20:50
  some other therapeutic areas where it's not so clear.
• 20:52
  It's a little bit harder to apply this idea of matching
• 20:56
  genetic variance with, you know, clinical outcomes.
• 21:00
  But of course, as the science comes along and perhaps more
• 21:05
  work is done there, for example, in neuroscience, eventually we
• 21:10
  might be able to apply there. But for right now, it's really,
• 21:14
  you know, the ideal areas where we can kind of move towards
• 21:18
  genetically informed therapies for common disease.
• 21:21
  Really, you know, I think the there's a lot of value in
• 21:25
  looking in the kidney metabolism and cardiovascular areas.
• 21:32
  Yeah, for sure. And then look, we, we, we come
• 21:36
  to our final question, which is the question I finish on with
• 21:39
  everyone. If you could have dinner with
• 21:42
  any scientist or innovator, past or present, who, who would it be
• 21:45
  and why? Harold.
• 21:50
  You know, certainly family and friends that I'd like another
• 21:53
  dinner with, but I don't think that's what you mean.
• 21:57
  You know, I was thinking about this and right about the time I
• 22:02
  was deciding to make the transition from academia to
• 22:05
  industry, I was reading this great book called The Idea
• 22:10
  Factory that recounts the history of Bell Labs.
• 22:14
  It really illustrated the way industry can move innovative
• 22:17
  ideas to people with a certain urgency.
• 22:20
  And I think that reading that book was probably among the most
• 22:23
  thought provoking influences that ultimately encouraged me to
• 22:27
  leave academia and pursue pursue a career in biopharma.
• 22:31
  You know, that sense of urgency to have an impact.
• 22:36
  So, you know, one of the individuals that figured really
• 22:40
  prominently in the early days of Bell Labs was a guy named Mervyn
• 22:45
  Kelly. He was a physicist and engineer.
• 22:48
  He not only LED Bell Labs through this period of
• 22:50
  incredible innovation, but he really modernized, like the
• 22:55
  integration of research with, you know, development and
• 22:59
  application. You know, the creativity led to
• 23:02
  discoveries that really change life as as it was known back
• 23:07
  then, probably before you and I were born.
• 23:09
  But still like the transistor, you know, computer operating
• 23:14
  systems, fiber optics. And so, you know, as I've taken
• 23:18
  on this role at Maze, I thought a lot about, you know, how to
• 23:22
  get everyone within the very, very disciplines of research and
• 23:27
  development, talking, sharing ideas with each other, working
• 23:32
  together to to sort of move new medicines along.
• 23:36
  And I think hearing about how Mervyn Kelly integrated this
• 23:40
  team of physicists, I think they're engineers, business
• 23:43
  people, sometimes working with the US government, how they
• 23:47
  could work together really inspired me at that time.
• 23:50
  So probably I would choose Mervyn, Kelly and maybe still my
• 23:55
  parents. I love that answer.
• 23:57
  So, so good. Look, thank you so much for
• 24:00
  coming on, Harold. It was an absolute pleasure.
• 24:04
  You know, I want to thank you, Max, not only for the
• 24:06
  opportunity to share these thoughts, but, you know, I'm
• 24:09
  really grateful for the opportunities I've had.
• 24:13
  And, you know, I get excited about providing up those
• 24:16
  opportunities for others who are coming up, and I'm also looking
• 24:20
  forward to more of them. So thanks very much.
• 24:22
  And you know what that shows? You know, we talked about
• 24:24
  mentorship earlier and like which way the market like yeah,
• 24:28
  for sure, like the way you talked about, thank God the
• 24:30
  market is shifting sort of thing is is amazing.
• 24:34
  So lot pleasure to have you on Harold.
• 24:36
  Please everyone like and subscribe to the bio hub and and
• 24:39
  thank you so much again.