Latest / The BioHub - by Avetix / Episode 240 - Inder Kaul - CMO at Draig Therapeutics

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Episode 240 - Inder Kaul - CMO at Draig Therapeutics · The BioHub - by Avetix

• 0:06
  Welcome back to the Biohub podcast by Avetics.
• 0:09
  Today I'm joined by Doctor Indakul, who is Chief Medical
• 0:13
  Officer at Drake Therapeutics. Now, India is a physician and
• 0:17
  clinical development leader whose career has spanned both
• 0:20
  biotech and large pharma. Before joining Drake, he held
• 0:24
  senior roles at Corona Therapeutics and BMS, where he
• 0:28
  helped lead the pivotal clinical programme behind CAR XT, which
• 0:31
  is now known as Cabente. He's bringing that experience to
• 0:35
  Drake, which is a clinical stage company developing a new
• 0:37
  generation of treatments for depression and others
• 0:40
  neuropsychiatric disorders. It's lead program, DT One O 1 is
• 0:45
  currently in food development for MDD alongside a broader
• 0:49
  pipeline targeting AMPA and GABA, A receptor in the.
• 0:53
  It's a pleasure to have you with me today.
• 0:56
  Pleasure is mine as well. Amazing.
• 0:59
  Well, let's let's jump into things in the, you know, you
• 1:02
  spend your career working on novel mechanisms in psychiatry,
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  notably, as I've just mentioned, with Karuna and Kabenti.
• 1:10
  What really drew you to Drake and to this next chapter within
• 1:13
  MDD? I think it was largely dregs
• 1:17
  science, you know, Dregs approach to delivering next
• 1:20
  generation treatments for neuropsychiatry disorders and
• 1:25
  that too through the development of, you know, highly targeted
• 1:28
  neuromodulators that hopefully redefine the existing treatment
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  paradigm and will enable people with neuropsychiatry disorders
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  to to live their best life. I think that's one thing.
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  The other thing is the problem is that I believe DT one O 1,
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  which is the molecule we have in development.
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  The problem is that we believe it will be able to deliver and
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  it will also deliver a differentiated next generation
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  positive Alistair Machulator of the amper receptors.
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  And that will be for 10s of millions of people with major
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  depressive disorders, particularly those whose needs
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  are unmet by the current standard of care, wherever that
• 2:11
  exists. And I'm also vested because of
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  the fact that I have a child who has MDD and has been suffering
• 2:19
  with it for the last 15 plus years.
• 2:22
  And whatever she has been exposed to counselling drugs and
• 2:27
  so on, it has not ameliorated her condition at all.
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  And, and I just hope that, you know, there are more and more
• 2:35
  options available for these kinds of people.
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  So having the, you know, someone in your own family also have it
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  makes me even more energized and committed to bringing this
• 2:51
  molecule over time to this NDT community.
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  Yeah, of course. And that that must have been
• 2:58
  really difficult for you to experience as a parent as well.
• 3:01
  It has been, yeah. So I mean for the for the
• 3:05
  listeners, can you give us just a short overview of the company,
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  the real science behind your lead asset and essentially the
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  specific problems within MDD that you're really trying to
• 3:17
  solve here? Absolutely.
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  I think you sort of started the podcast by saying that drag is a
• 3:24
  clinical stage by a pharmaceutical company and
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  that's absolutely true. DT 101, which again is the
• 3:33
  molecule, the Amphibam that we are developing, it's designed to
• 3:38
  provide a wider therapeutic window versus the generation
• 3:44
  molecules that were previously under development.
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  And this is to enable effective modulation of the amper receptor
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  without compromising the safety and tolerability.
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  So basically what we've done here is expanded or broadened
• 4:00
  the therapeutic index of this molecule compared to older
• 4:04
  generation drugs. It is designed to address the
• 4:10
  unmet critical needs in major depressive disorders.
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  And by that I mean, given the mix of action, we should be able
• 4:19
  to show improvement in cognitive impairment.
• 4:22
  It will demonstrate that it will have a fast onset of effect, the
• 4:28
  safety tolerability profile that we have observed so far.
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  But this molecule is, is very good and it will also have an
• 4:37
  antidepressant effect. Now we have done some studies
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  and some studies are ongoing. At this stage, we completed 2
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  studies in a phase one setting and where we saw, saw that the
• 4:53
  clinical evidence of safety and target engagement.
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  It was a pretty one of the phase one studies was in my humble
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  opinion, a pretty large one. And between the two phase one
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  studies together, we had roughly 100 healthy volunteers.
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  And in those trials, we were able to confirm that there was
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  CNS distribution, meaning that DT101 was getting distributed in
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  the central nervous system. And we did that through sampling
• 5:22
  of the cerebral spinal fluid. We also utilize what's called as
• 5:27
  a Magneto encephalography in that by that utilization we were
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  able to show that there was target engagement at the
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  receptor level. In addition to that AMPIPAM, the
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  company also has two additional molecules that are GABA
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  compounds. One we refer to as DT2O1.
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  It is a negative allosteric modulator of the A5 GABA
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  receptor and it has we believe best in class potential.
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  There's another molecule called DT3O1, which is a precision
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  alpha 2/3 GABAPAM and that we believe will have best in class
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  selectivity. So that's in nutshell what we
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  have in development. Yeah, I mean, it's a, it's a
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  really exciting pipeline. And I mean, so psychiatry in
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  general has really been crying out for new mechanisms over the
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  past 1020, thirty years. Scientifically then, what makes
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  amper receptor, you know, particularly interesting and how
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  could it offer something that is really differentiated from the
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  traditional antidepressants that are available today?
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  Yeah, I think it's important to recognize that the clinical data
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  converged has sort of demonstrated that restoring the
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  synaptic connectivity can can drive a meaningful
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  antidepressant effects as is seen with therapies such as
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  esketamine and some, you know and psychedelics.
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  Two of those psychedelic compounds recently reported
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  their results, others are in continue to be in development.
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  We also know that the amper receptor is a critical regulator
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  of mood synaptic plasticity as well as cognitive enhancement.
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  As I was mentioning earlier. We believe we'll be able to show
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  that we make a difference there. And you know as I mentioned
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  previously, prior drug development efforts have
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  suffered because of the narrow therapeutic margins which
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  ultimately led to the eventual discontinuation in the
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  development of those compounds. And you know it's also because
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  the modulation of the AMPA as well as the GABA receptor
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  signaling is highly complex and requires precision to be safe
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  and effective. I believe DTO one which is the
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  Drex compound overcomes this hurdle as A next generation
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  ampereceptor potentiator, which is designed to restore synaptic
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  connectivity in MDD so that we are able to deliver a
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  differentiated complete therapeutic profile.
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  It's going to be given orally. It's a once daily dosing regimen
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  to deliver rapid, robust and durable antidepressant effects,
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  while it also is hoped to improve the cognitive impairment
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  that folks with MDD have to a certain extent.
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  And then if you look across then the competitive landscape,
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  neurocrine are already slightly further ahead with a similar
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  mechanism. You know, they've already
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  produced positive phase two data.
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  How do you really view that external validation?
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  And in what areas do you feel that Drake can still
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  differentiate from Neurocrine's program?
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  Sure, clearly you know paradigm shift in your psychiatry.
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  Drug discovery is long overdue. There are currently about 70% of
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  the patients with MDD who do not respond to first line SSRIs, for
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  example. To me, Neurocrine's data is
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  validation of the AMP approach and an important advancement for
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  those who are living in the MDD and do not respond to the
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  existing treatment options they have.
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  Neurocrine's Savampitor had a broad, has a broad therapeutic
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  index, meaning the safety margin is there, the dose to drive
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  efficacy while you maintain tolerability.
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  And this data shows that this translates into a leading
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  clinical benefit with patients and with MDD.
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  As I mentioned previously, DT one O 1 similarly has a broad
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  therapeutic index, but we are different from Savampitor purely
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  given RPK and that by PK I mean the pharmacokinetics and our
• 10:09
  pharmacokinetics should be should allow us to differentiate
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  our molecule from neurocrans. What is special about our
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  pharmacokinetics? DT1O1 has a pulsatile
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  pharmacokinetics which is designed by on by purpose and it
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  is better mechanistically aligned with the underlying
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  biology of the synaptic plasticity.
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  Now this has been validated by recent data from compounds such
• 10:41
  as esketamine as well as psychedelics.
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  We believe that we will have the potential to be the best in
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  class in MDD given this differentiated profile, which
• 10:54
  will also allow us to deliver a fast acting and a stress fast
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  acting robust and durable antidepressant effect.
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  Again, for folks who have MDD with a likely benefit on the
• 11:09
  cognition, meaning improving their cognitive impairment.
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  I should stress here that DT 101 in its current development will
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  be a once daily overal dose. Yeah.
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  I mean we, we, we've touched there on neurocrine's particular
• 11:29
  phase two data. But if we look at Drake's phase
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  two studies that you are running, you're running 2IN MDD,
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  SO1 globally in monotherapy and then one purely just focused in
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  the US as an injunctive treatment.
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  Why was it particularly important to explore DT101 in in
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  both of these settings? Sure.
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  We, I we believe that this strategy of ours gives us
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  commercial and strategically optionality in a in a few
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  important ways. 1 The standards of care differ within the
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  overall MDT population. Some patients may be treated
• 12:10
  with an approved drug as minor therapy, while other patients
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  may receive it with additional drugs as background therapy.
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  A global monotherapy trial offers a clearer picture of DT
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  one O 1 and could deliver important validation of the
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  effect, the dose response, and other things without any
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  compounding background therapy. Moreover, there isn't any
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  biological rationale that Ampli Pams cannot function as
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  monotherapy in MDT. Furthermore, a significant
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  portion of the NDD patients post frontline generic SSRIs or SNTIS
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  are treated with monotherapy, which provides relevance for
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  evaluating Det one O 1 in the monotherapy setting.
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  Additionally, we wanted to conduct an agent trial to assess
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  how DD101 would function in this setting in an adjunct setting,
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  meaning on top of some other antidepressant cover to provide
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  a more comprehensive therapeutic profile and that would be, you
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  know, in patients with background therapies.
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  And you you've touched briefly on the PK profile of DT one O 1
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  and the potential for, you know, fast, durable antidepressant
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  effects with with really the hope of seeing separation early
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  in treatment. Why could early onset matter in
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  MDD? And what would you really need
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  to see to know that that signal is clinically meaningful rather
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  than it just being noise from? So I mentioned earlier that we
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  had a pretty large phase one trial and we were very
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  encouraged with the data that we saw from come out from that
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  phase one trial. And what that displayed was that
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  DT1O1 with the pulsatile PK profile enabled transient
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  receptor engagement. It aligned with synaptic
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  plasticity mechanisms and therefore our thereby it
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  reinforced its potential to deliver fast and durable
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  therapeutic effects. At Trek, our mission is to
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  transform the future of neuropsychiatry and enable
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  patients to live their best lives.
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  For those with MDD, everyday accounts and an earlier onset of
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  effect would be meaningful. An earlier onset effect is
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  usually referred to as within seven days.
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  The regulatory expectation is within seven days and it's an
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  important differentiator. While seven days is viewed as
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  the regulatory definition of fast onset, we are looking to
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  demonstrate in our situation an early onset which would be as
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  early as day four. Wow.
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  That's what we are exploring in our phase two trials and we are
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  very confident that our PK will allow us to unlock this fast
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  acting antidepressant effect given our mechanism.
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  Yeah, that would be a game changer for what's out there
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  currently within the therapeutic market.
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  Let's let's sort of step back from from Drake specifically and
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  focus on, you know, yourself and your and your expertise.
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  Depression trials in general are notoriously difficult to run
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  well, particularly because of placebo response, subjective
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  endpoints and the importance of trial methodology.
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  What does it really take to execute an MDD study properly,
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  and where do companies typically or or you know, potentially get
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  this wrong? Three things, Execution,
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  execution, execution. So so MDD trials succeed or fail
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  on execution discipline because the endpoints are subjective and
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  the placebo response if not addressed and watched out for,
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  can be high. And the goal is to reduce the
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  variability wherever it's possible.
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  I can give you a few examples for FOCUS and MDT trials.
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  One, the patient selection has to be rigorous.
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  Centralized diagnostic confirmation and independent
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  eligibility review help ensure the right patients are enrolled.
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  Now in clinical trials, you have a set number of things where you
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  say that does this subject have ABC, does the subject not have
• 16:59
  DEF and then you qualify or you become eligible for being in the
• 17:03
  trial. When I say patient selection has
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  to be rigorous, checking the boxes that are required is
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  important and essential. But I think more important is to
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  be able to evaluate and see if this particular subject or
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  patient is meeting the the spirit of the protocol, the
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  spirit of the study that you and I think that becomes very
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  important. And then there's a common
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  mistake, at least what I have observed in the neuropsychiatry
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  field, and that is that there's all, there's always a push for
• 17:37
  speedy recruitment, but that does dilute the patient quality.
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  So yeah, you might gain on speed.
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  You might be able to condense your timelines, but there could
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  be, you could be paying the price for that.
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  Number 2, you know, placebo response has to be and must be
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  actively managed. That in itself requires
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  disciplined screening here for site selection, limited
• 18:03
  unnecessary patient burden, whether it's the number of
• 18:07
  visits that you have during the duration of the trial or it is
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  the amount of data that you are trying to gather.
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  All of those things are found to be contributing to a high
• 18:22
  placebo response. And then finally, you know, the
• 18:24
  study conduct has to be consistent.
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  Another thing that is specific to neuropsychiatry is that you
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  know the raters. These are folks who elicit
• 18:36
  information from the subjects as well as the endpoints.
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  That's like when you claim that I I went the objectives.
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  They need tight control. Rating scales are only useful if
• 18:49
  the raters are well trained and there is consistency between the
• 18:54
  raters, whether it's inter rater or intra rater at that side and
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  that you know that it's calibrated and that it's
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  consistent across sites where I believe companies sometimes get
• 19:08
  it wrong. They prioritize speed over
• 19:10
  quality. I did sort of briefly mention
• 19:12
  this a little earlier under they're under control raters
• 19:18
  underestimated placebo response. And so I think they all
• 19:21
  contribute to minimizing your probability of success.
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  And if they're not controlled, you know, you, you, you can't be
• 19:30
  assured of that, that, that, you know, have a positive outcome.
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  Of course, that means the drug, you know, assumes the drug is
• 19:36
  working. I think additionally, there's a
• 19:38
  key challenge in drug development for psychiatric
• 19:41
  disorders and it's the lack of functional pharmaco dynamic
• 19:46
  biomarkers. Our phase one, as I mentioned
• 19:50
  earlier, was the first clinical study to use Meg, which is
• 19:54
  Magneto encephalography and we demonstrated functional brain
• 19:58
  responses to an investigational drug.
• 20:02
  We had incorporated in our phase one trial the MEC into repeat
• 20:09
  dose and single dose crossover components to clearly assess the
• 20:13
  effects of DT1O1R drags compound on the brain activity.
• 20:19
  A crossover design enabled within participant comparison
• 20:24
  across different dose levels and it also enabled increasing
• 20:30
  sensitivity to detect pharmacodynamic effects.
• 20:33
  Ultimately those data helped us to inform the dose and selection
• 20:39
  of our dose for our phase two trials, two of them ongoing. 1
• 20:44
  is a global one which is the the monotherapy trial.
• 20:50
  Another one is AUS based only domestic and that's the adjunct
• 20:55
  setting and be you know, these findings have helped us to
• 20:59
  advance the fields understanding of functional pharmacodynamic
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  biomarkers and how they can be used to measure trial
• 21:07
  effectiveness. Yeah, yeah.
• 21:11
  I mean, it's, it's exciting and I think, you know, your years of
• 21:15
  experience doing this have been a been a real key help to, to
• 21:18
  drag in terms of looking at study design.
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  But also, you know, the execution side of things you
• 21:23
  mentioned is, is so crucial when it comes to these depression
• 21:25
  studies. But beyond just treating the
• 21:29
  core symptoms of MDD, what else could a glutamate pathway
• 21:33
  molecule like DT1O1 offer, particularly around, you know,
• 21:37
  cognition, functional improvement, and potential life
• 21:41
  cycle opportunities across broader neuropsychiatric
• 21:44
  diseases? You know, I'll try to be as
• 21:52
  unbiased as I possibly can. You know this, this compound
• 21:56
  really has a tremendous degree of benefits hopefully to offer
• 22:02
  and it's not limited just to MDD.
• 22:04
  Some other areas that I could think about where this product
• 22:07
  could be developed would be related.
• 22:11
  One would be cognitive impairment and cognitive
• 22:14
  impairment that's associated with schizophrenia is a huge
• 22:17
  problem. And with not much to offer these
• 22:22
  patients to enhance their cognitive, that could be 1 area.
• 22:27
  Another area where this could be explored, and I'm just saying
• 22:31
  these things based on the mix of action and where we know that
• 22:34
  this drug can make a dent would be on the improving the symptoms
• 22:39
  that you see in folks with Alzheimer's disease.
• 22:42
  And by the way, all these things that I'm going to mention, the
• 22:46
  prevalence of these in the United States is in 7 billion,
• 22:50
  right? So it's not like an orphan
• 22:52
  state. It's like several million people
• 22:54
  have this problem that, you know, acute hyperactivity
• 23:01
  attention disorder would be another one.
• 23:04
  Autism or broadly we refer to as autism spectrum disorder could
• 23:09
  be another one. There is a problem that's
• 23:13
  prevalent certainly in the United States and other parts of
• 23:15
  the world called as opioid induced respiratory depression.
• 23:20
  The numbers there are not huge meaning people.
• 23:22
  The prevalence of that is a little shy of a million, but but
• 23:25
  nevertheless an important indication that could cause
• 23:28
  food. And then one other one that I
• 23:30
  can think about is called the fragile X syndrome, which is a
• 23:36
  genetic disorder that's caused by mutations in one of the genes
• 23:42
  and that leads to intellectual disability and behavioural
• 23:47
  challenges. It's also a leading cause for
• 23:50
  autism spectral disorder. There are about 7 to 10 million
• 23:55
  folks in the US with with this particular issue.
• 23:59
  Not a problem. Yeah.
• 24:01
  Absolutely, several indications could be could be pursued and
• 24:07
  whether that is, you know, part of the life cycle management or
• 24:11
  you know, you're going in parallel, you know it, it has a
• 24:15
  lot to offer this molecule. And I say that as in a very
• 24:19
  unbiased, unselfish way. I just as a physician thinking
• 24:23
  about the implications of, you know, what this drug could do.
• 24:27
  Yeah, and I'll, I'll certainly be keeping up with the progress
• 24:30
  that you're making. And I'm sure a lot of a lot of
• 24:32
  our listeners now will be as well as they've been, you know,
• 24:34
  started to become more and more excited about about DT one O 1.
• 24:39
  Just just to wrap things up here, then in the if, if you
• 24:42
  could have dinner with any scientist or innovator, past or
• 24:45
  present, who would it be and why?
• 24:48
  That's a tough one because I can only come up with one person.
• 24:51
  But you know, it would have to be my colleague, Professor Simon
• 24:55
  Ward, who is a founder or a cofounder of TREC and is also
• 25:00
  its chief scientific officer. In my 40 years in the industry,
• 25:06
  he has been the brightest scientist I have interacted
• 25:11
  with. He's someone who keeps me on my
• 25:14
  toes and keeps challenging me all the time.
• 25:17
  But, but at that, apart from the fact that he's a very bright
• 25:19
  guy, he also is someone who is very much committed and
• 25:26
  dedicated to bringing this molecule eventually into a
• 25:30
  commercial space and, and, and, and his desire to bring this
• 25:38
  molecule to fruition, the promise that this molecule holds
• 25:41
  is, is way beyond just superficial.
• 25:46
  What I have certainly appreciated about him is his
• 25:49
  ability to galvanized, you know, multifunctional teams towards
• 25:57
  the ultimate objective of demonstrating, you know,
• 26:01
  clinical efficacy and and safety and tolerability and hopefully
• 26:06
  offer the MDD community at large something that they will be
• 26:12
  happy with. This community has been crying
• 26:15
  for many years and it's time we come up with something.
• 26:19
  Yeah, no exciting. And yeah, I'm sure of of of of
• 26:23
  the different guests that we've had.
• 26:25
  You know, I thought people have mentioned that they will have
• 26:27
  dinner with them. I'm sure some would be one of
• 26:29
  the easier ones that we could set something up with.
• 26:31
  OK, sounds good to me. But look, absolute pleasure to
• 26:35
  have you join me today and I've really enjoyed our conversation.
• 26:39
  So did I. Thank you so much.
• 26:41
  No worries at all and thanks for everyone for tuning in.
• 26:43
  Make sure you stay tuned for any future episodes that are coming
• 26:46
  out. But for now, that's all from us.
• 26:48
  Thanks and goodbye. OK, bye, bye.