October 31, 2024 • 41 mins
Sam Clark, founder and CEO of Terran Biosciences, shares his insights with BioBoss host John Simboli about leadership in biopharma and how Terran is working to develop therapeutics and technologies for patients with neurological and psychiatric diseases.
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John Simboli (00:00):
Today, I'm speaking with Sam Clark, founder
and CEO of Terran Biosciences,headquartered in New York.
Welcome to BioBoss, Sam.
Sam Clark (00:09):
Thanks for having me.
Excited to be here.
John Simboli (00:11):
How did you find yourself in that role as founder
and CEO at Terran Biosciences?
Sam Clark (00:17):
Well, it really goes back to growing up. There were a
number of people in my immediatefamily and close friends who
were struggling with severemental illnesses, bipolar
disorder, as well asneurodegenerative conditions,
Alzheimer's disease. So justbeing affected by that, I really
wanted to better understandtreatments. How can we help
people develop bettertreatments? So when I went to
(00:40):
MIT and I studied neuroscienceto better understand the brain,
and then I went to ColumbiaUniversity, where I did my MD
and my PhD. But it was duringthat time for the MD when I
realized that the treatmentsthat we have just aren't that
great. They leave a lot to bedesired, whether through lack of
efficacy or side effects, andthere's really a lack of new,
(01:02):
innovative treatments. You know,if you think about
schizophrenia, for example,almost all of the antipsychotics
have roughly the same mechanismof action since the 1960s,you
know, just slight variance. Andyou know, we're just seeing this
year, the potential for thefirst approval of something with
the new mechanism. But ingeneral, the principle was, for
neuroscience, there isn't a lotof new options. So I really
(01:25):
wanted to help people bydeveloping kind of new
treatments. But then at the sametime, I was looking at other
biotechs, and I said, you know,there's a risk aversive attitude
in a lot of these biotechs,where they go for safer
mechanisms. So it's, you know, Iwant to, I was noticing, I said
at the time, you know,Instagram, Snapchat, Facebook,
they were all making enormousprogress in Silicon Valley. But
(01:48):
on the biotech side, I justsaid, we don't really have that
parallel of a fast moving, youknow, biotech that's not risk
averse, that's able to tacklethose impossible challenges. And
so I founded Terran with thegoal of building a platform
company that would take adifferent approach to
development of neuropsychiatrictherapeutics.
John Simboli (02:08):
As you made that decision to found Terran and to
become the CEO, based on yourpersonal experience and your
education and your thinkingabout the industry, did you
consider in those early stages,maybe I'll create this, but I
won't be the founder. I won't bethe CEO. That's sometimes the
case. It's an idea, but you findthe person you want to carry
(02:28):
that forward. Or did you knowfrom the beginning, I should do
this?
Sam Clark (02:32):
So when I founded the company, I wanted to push the
ideas forward. And peopleactually had discussed that same
idea with me, the idea that, youknow, when a venture group comes
in and gives you funding,they'll put their own team in.
You can be the science advisor,or maybe, you know, something
where you're not really runningthe company. And I always
(02:52):
wonder, well, why is that thecase? And that's the case, they
say, well, they want to bring insomeone who's more skilled at
the business aspects. But thebusiness aspects, actually, I
think you can pick up quitequickly. It's really having that
strong science background that Ithink has really enabled us to
move forward faster than othercompanies in the space, because
(03:13):
I stay involved in every aspectof the business. And instead,
you know, I'm inventor on over200 patent applications we put
through. I'm the invent, onlyinventor on the world's first
new forms of psilocybin, MDMA,long acting and other inventions
that we've made at Terran thathave been granted now by the
patent office. And so in doingthat, I think it actually gave
(03:34):
me an advantage. But there wasdefinitely some pushback when I
was starting to found thecompany for people saying, well,
we don't typically see someonedo this. But at the same time, I
had been reading a lot ofbiographies and studying and
said, look, in Silicon Valley,the founders take the company
forward. So in biotech, we cando that too. And it really has
(03:55):
worked out quite well.
John Simboli (03:56):
In those early stages, had you considered the
possibility of taking your ideato an existing, to a biopharma
company, to a pharma company,and having it developed under
your guidance, but within thatframework?
Sam Clark (04:09):
I thought about it for sure, but that leads to a
number of downsides. If you justsell off the idea immediately to
Big Pharma, then it may getshelved. You know, priorities
often change. And the otherthing is, the ideas we were
developing at Terran were notsafe ideas. This wasn't the case
of, hey, we have another, youknow, oncology drug with the
(04:32):
same mechanism that's beenapproved, slightly better
pharmacokinetics. These wereassets that we believe had the
potential to reallyrevolutionize the treatment of
neurological conditions thatalready had human data, but had
been discontinued by big pharmabecause they couldn't solve
certain problems. So it wasalready a big risk taking them
on and a challenge. And so whatI did was founded a company
(04:55):
where you can, we would build ateam of highly trained
operators. And then pull onworld experts so that we could
move forward to solve theseproblems. So in that sense, it
wouldn't have been the best fitto go straight to companies,
because the pitch would be,well, Big Pharma failed to
develop these, you know, andwe're pushing these high risk
assets forward. It's not thetypical approach. And then to
(05:17):
your other point, what abouttypical VC funding? The problem
there is that it's singularlyfocused. Companies they like to
invest in the most are typicallysingle asset focused companies
where the company's only doingone thing. Now we've seen a bit
of a switch recently withcompanies like Cerevel and
Neumora, and now the rise ofmore neuro platform companies,
(05:38):
and we see ourselves moving inthat direction as well. But you
know the past, it's largely beensingle asset focus, and it still
mostly is today.
John Simboli (05:47):
So those scientific problems that you
were fascinated by and wanted totry to address, that you
described for me at the verybeginning, as you got into it, a
few weeks, a few months into it,did you find yourself following
that path of things that youwanted to pursue within Terran,
or did those evolve? Did youknow what you didn't know? Is
(06:08):
another way of asking thequestion.
Sam Clark (06:10):
Some of this goes back to what I was studying
during my PhD years. During myPhD years, I was studying and
publishing on a receptor in thebrain called the kappa opioid
receptor. Now we have threeopioid receptors in the brain,
kappa, mu and delta. And mu iswhat you think about when you
think about opiates. They killpain, things like oxycodone,
(06:32):
Vicodin, all those prescriptionopiates act on the mu opioid
receptor. And same with drugs ofabuse, like heroin, a mu opioid
receptor. But there's anotherreceptor called kappa that's
very effective in killing painas well. The thing that makes it
interesting is that big pharmatried to target that receptor
because it has no potentialanimal models for abuse, so they
(06:55):
developed selective kappaagonists that would turn on the
receptor as the next generationof analgesic drugs to kill pain.
The problem is, people who tookthose became psychotic,
experienced terriblehallucinations. So they said,
well, this receptor may belinked to psychosis. And then,
interestingly, there was anatural plant called salvia
(07:16):
divinorum that also was selectedfor the kappa opioid receptor
and also would cause people toexperience hallucinations. But
one of the uniquecharacteristics about these is
that people described in manyreports hearing voices, which is
unusual because many drugs thatinduce psychedelic trips don't
really contain those componentsof hearing voices or really
(07:41):
fully formed delusions. Now,then it got even more
interesting when I dug into theliterature and I said, Wait a
minute, in schizophrenia, thereare a number of drugs that, in
the past, were shown to makeschizophrenia worse. One of
those was called ketamine. Atthe time it said, Well, you
know, ketamine acts on areceptor called the NMDA
receptor. But if, when youreally dig into it, you saw
(08:05):
there's a number of publicationswhere it showed it also acts on
the Kappa receptor and wouldcause patients with
schizophrenia to experienceworsening of voices,
hallucinations. So then I dugeven further, and I did this big
meta analysis of kappa opioidantagonists. Now, there were no
selective ones that were evertested, but there were more than
(08:27):
40 trials of non selectiveopioid antagonists through the
60s, 70s and 80s and early 90sin schizophrenia, and some of
those reported amazing resultswith a new mechanism at ending
schizophrenic hallucinations andimproving even the negative
symptoms, the social withdrawal,the cognitive symptoms. And so
the meta analysis showed therewas a significant effect on the
(08:49):
positive symptoms and a help onthe negative. But when I went to
try to develop this into a drug,initially, this is back in the
PhD years, that's when I foundout, well, it's actually very
hard to get funding for newdrugs. Nobody wants to fund the
old drugs because they say,well, there's no IP and, you
know, there's a lot of things.
It doesn't necessarily, it's notjust whether drugs effective,
(09:10):
it's whether there's patents,it's whether it's fully
druggable, it's whether you canmanufacture it. And so there's
so many other factors at play.
It's whether you can get itapproved by the FDA and the
regulatory side. That's when Icame across. So I realized,
okay, this is much morechallenging, but that's when we
came across another drug calledidazoxan from big pharma. And
(09:33):
this was a drug that PierreFabre in France had developed
all the way through Phase Threefor Parkinson's tremor. Now the
thing is, in Parkinson's tremor,it wasn't that effective, but it
was very safe. However, at thesame time, it was in trials at
the National Institute of MentalHealth in the United States, in
a collaboration forschizophrenia. And it was the
(09:55):
first adjunctive treatmenttested where you can add it on
to existing antipsychoticregimens, and it would double
the efficacy. And the thing is,it wasn't until years later that
we saw this in depression withthe drug Abilify, where you
could have an adjunctivetreatment that really became a
blockbuster and helped a lot ofpatients. So in that sense,
idazoxan had that potential. Theproblem was it had to be given
(10:19):
up to three times a day, everyday, and they said, look, it's
so short acting that it's notcommercially viable to have this
three times daily drug. And eventhen, it was closer to a four
times daily drug with a two hourhalf life. And so all the trials
were discontinued. Pierre Fabrehad largely exited neuroscience.
(10:40):
The drug was shelved, and it wasterrible, because at the time,
the doctor who ran the trials,who later invested in Terran and
is on our science advisoryboard, said patients and their
families were calling begging tobe put back on that drug, but
there was nothing they could do,because manufacturing had been
discontinued. So our scienceadvisory board made me aware of
(11:03):
that compound. We then went toFrance, met with Pierre Fabre,
licensed on the rights to thatdrug, completed all
manufacturing, made a once dailyform, put it back in the clinic
where it's showing a great oncedaily profile. Got the green
light from the FDA, then to moveit forward pending the results
of pharmacokinetic bridgingstudy into the larger trial with
(11:25):
patients with schizophrenia. Andit's by bringing back that
forgotten asset that had thepotential to be very effective
that already was very effectivein patients with schizophrenia,
and by solving that impossibleproblem that wasn't able to be
solved at the time the drug wastoo short acting. That's where
we really hope to make adifference. So to answer your
(11:45):
question, at the time, I didn'tknow about idazoxan, but I knew
about these ideas of forgottendrugs like kappa opioid receptor
antagonists and things that hadgreat efficacy but had hit
snags, and thus were not at thetime being funded by traditional
venture groups.
John Simboli (12:03):
Can you share any thoughts about how you develop
the process for knowing when tomake a decision versus when to
rely on someone on your team tohelp you make a decision?
Sam Clark (12:12):
The structure of Terran, and this is where we get
into the uniqueness of the modelis very different than most
biopharma companies. I'vestructured it after the tech
companies of Silicon Valley, andin that sense, we have a very
small team of highly trainedoperators. So I have a number of
ideas that I want to work on thecompany, and we have a small
(12:33):
team of operators that help keepeverything organized. But in
order to actually execute any ofthese ideas, we need the world's
best minds around the table, andso what we do is we build out
individual teams of worldexperts. Now this leads to a
more flat, hierarchicalstructure in the company. It's
not one of those pyramid topdown management where I'm
(12:56):
fundraising and telling thegeneral plan, and then you have
some managers under there, andsenior managers and VPs and
whatnot, and they trickle down,and then information trickles
up. In that sense it's flat. SoI'll be on, for example, the
manufacturing calls. I'll bepresent in all the clinical
calls, you know, I'll be in theweeds on everything, and I'll be
(13:17):
aware immediately whensomething's not getting done or
something, the train's going offthe tracks, and we have really
good operators that will keepeverything organized, but then
we have the best minds in theworld on individual teams who
are able to solve theseproblems. For example,
initially, before we had fullyimplemented this model, we had
people around the table thattried to fix cytosoxan but
(13:38):
didn't have the expertise. Itwasn't until we found someone
who had done this many timesbefore and had potentially more
long acting, once daily oraldosing formulations than almost
anyone in the industry who cameon board had done this many
times before. We built a teamaround them that was able to
take this drug forward andfinally fix it. So in that
(13:59):
sense, the way we have a rule atTerran where everything has to
be backed up by evidence. Sowhen nobody's allowed to say,
Oh, just trust me on this. Andthat goes for any aspect;
manufacturing, clinical trials,anytime we reach a difficult
decision, you know, people haveto bring on, bring expertise to
the table like, you know, weshould take this path based on
(14:21):
this feedback from FDA or basedon these other trials that have
been done in the past, this isthe best route. Nobody's allowed
to say, Oh, just, trust me, Ithink we should do this. I have
20 years of experience, so justlet me make this decision, but
at the same time, you know, I'mnot the one who's going to be
saying, you know, I'll make, youknow, like we always will bring
(14:42):
on regulatory help, for example,we'll bring on external
expertise to guide into thefinal decisions that then I'll
ultimately have to make. But Iwon't override the experience.
That's where we pull on externalexperience to make the guide the
decisions that I ultimately do.
John Simboli (14:59):
Did you find knowing when, in the end, you
had to make a decision, did thatfeel like a natural progression,
or is that something to belearned as a new CEO?
Sam Clark (15:06):
So ultimately, I have to make all the final decisions.
It's something that youdefinitely get better at over
time, and then you pick up, andthe best thing is having many
advisors around the table. Imean, if you think about it,
throughout history, any time youhave someone who has to lead a
group of people, the best thingis having that group of advisors
(15:30):
advising you. And so I try tobring on as much external
expertise. And the mostimportant thing is knowing when
you don't know something, andwhen you realize that you don't
know something, we move veryfast at Terran to find someone
who knows the answer. Sothere'll be, we can identify,
oh, you know, we have thisproblem. We realize when the
(15:50):
current team members also don'thave the solution, and we go as
fast as we can through ourentire network to find someone
who has the solution to thatproblem. And we've been very
successful using that fastmoving model. And once we have
that, then we can make thedecisions.
John Simboli (16:04):
If someone your team were to be asked the
question, well, what's Sam'smanagement approach? That might
or might not be how you woulddescribe it, but can you
estimate how others would say,oh, yeah, this is how he goes
about dealing with the team.
Sam Clark (16:18):
Well, I like to stay very highly involved with the
team, so we'll be chatting everyday is spent with the core team
of operators every morning. Sowe're in constant communication,
both in decision making as wellas, you know, planning. And I
generally have a lot of ideasthat I want to do each day. So
I'll help, you know, make surethe team's on schedule to
achieve those. And sometimesgive out new goals, new plans,
(16:41):
or readjust quickly if I thinkthe priorities change. So it's a
lot of top down information, butthe team handles it very well
and course corrects. And we'llcourse correct and change
sometimes, many times a week,I'll be making decisions to
pivot quickly, and I have a teamof operators that'll immediately
implement those changes. Sothere's not a management style
(17:05):
where I'll say, Hey, this iswhat we need to do. Go do it,
check in with me in two days.
Then we'll do another thing.
It's daily feedback and dailycourse correction. But I want to
draw a distinction. It's notmicromanagement, where people
have to babysit each individualdecision, like task. I trust the
(17:26):
team to be able to achieve thosetasks, to, you know, to
accomplish those goals andtasks, I give them. It's just
that we move so quickly that thetasks may change rapidly, and
there may be new tasks andalterations to those tasks. So I
don't have to babysit theirexecution of the task, but I do
have to be very much alert tomove and change very quickly.
(17:51):
And that's, I think, how we'vehad our greatest successes.
John Simboli (17:54):
Can you recall as a young child, eight, nine, ten,
whatever is a formative time foryou. Do you remember what it was
that you set your sights on? Whoknows where these things come
from, generally from parents,I'm sure. But do you remember
what path you saw in your lifeand does have anything to do
with what you're doing now?
Sam Clark (18:11):
You know, it's a combination of things. There was
a time when I was around age 10when I wanted to be a doctor and
I wanted to learn about thebody, but at the same time, it
was really mainly aroundexploration. I was always
exploring things, readingthings, you know, trying to
understand new things. And, youknow, this was during the time
in the all this new technologycoming out, you know, the
(18:31):
internet was just reallystarting to take off. And
computers, and, you know, thefirst laptops were, you know,
just being, you know, developed.
This is before smartphones, soand then the idea, also, besides
that too, is I would go out.
This was during also a time whenyou would, you would just go get
on your bike and go out, hangout your friends, and you'd bike
(18:52):
neighborhoods. You'd bikethrough the woods, you'd bike
through parks. You would just goand nobody was checking up on
you. You know, you come home fordinner. And the thing is, it
there was, it's not a kind of ahelicopter mentality we have
now. So you're out thereexploring and seeing things and
thinking things and readingbooks and and really just
dreaming. And that was the ideaI wanted to explore. And so I
(19:13):
think that's what we're doingnow in Terran, we're exploring
the brain. We're developing newpsychedelics. It's the final
frontier of neuroscience. Sowe're really, I think that's a
natural progression of thosetimes.
John Simboli (19:24):
When you go for that nutshell, 30 second very
brief kind of who is TerranBiosciences, how do you like to
answer that?
Sam Clark (19:32):
Terran is a platform company, so we do a number of
things, for example, in thepsychedelic space, one of the
largest manufacturers of GMP, Imean, for human use
psychedelics. We've created morenew psychedelics, we believe
than any other group so far withnew modifications to the trip.
We create psychedelics withoutthe trip. We also create
(19:54):
traditional neuro assets likeidazoxan for schizophrenia and
other antipsychotics. And wehave software, AI enabled
software, as a medical device toaid in the provided juncture
information aid in the diagnosisof neurological and psychiatric
conditions. And so in thatsense, you know, Terran is a
(20:15):
platform company with a suite ofoptions to help people with
neuro and psychiatricconditions.
John Simboli (20:21):
I imagine it's it often happens that you're at an
investor conference, or in someother kind of format, where
someone you give that briefdescription, and you're about to
go on, and then you're realizingpeople may have substituted a
preconception for what it isthat you're doing. It just
happens that's kind of part ofthe game. So my question is, in
this early stage are, is thereany kind of pattern that you see
(20:43):
where you think, oh, people seemto think it's this, but I have
to help them understand it'sthat.
Sam Clark (20:49):
Sometimes, and that's usually when people will get
fixated on one aspect of whatTerran does. So they'll say, ah,
Terran is psychedelics, orTerran is just software as a
medical device, you know, orit's just antipsychotics, and
they're missing the big picture.
Or, even more recently, becausewe had some high profile patents
publish with the goal of thosepatents actually being that we
(21:11):
can bring cheap, affordable, 505b2 medications to the market.
You get the traditional kind ofsummaries in forums or press
saying, okay, is Terran justtrying to snap up IP in the
space for no reason? Or theycan't possibly develop this many
drugs, what's the purpose?
Missing the picture of usingthose in order to bring cheap,
(21:34):
affordable medications via theFDAs accelerated 505 b2 path and
so sometimes people don't takethe time to really dig in and
see the full picture, but, youknow, we're very excited to
always tell them about it andmove this forward.
John Simboli (21:50):
It's been my experience that when people do
get that clarification, oftenthe next question is, well, how
can a relatively new companythat is building itself take on
something of this importer ofthis scale, and how do you help
them understand that?
Sam Clark (22:05):
Well we've been able to cut costs enormously. We run
very lean with that small teamof operators that cuts out a ton
of personnel costs that would betypical for biopharma. And then
we use the consultant model,where we have those world
experts come on and help solvethose problems, but those are,
you know, around specificproblems. So it's not you're not
(22:27):
carrying, you know, constant,you know, payments when projects
are completed. And so we're ableto really run very lean.
John Simboli (22:35):
Is there something you could share with our
audience about mechanisms ofaction that will help people to
understand what you're goingafter?
Sam Clark (22:42):
So let's talk about two of our lead therapeutic
assets. So one I talked aboutbefore idazoxan, that drug that
is adjunctive in schizophrenia.
That was one of the world'sfirst selective alpha two
antagonists. Now that's areceptor in the brain that helps
modulate dopamine release. Now,antipsychotics block certain
(23:07):
dopamine receptors on thedownstream neurons. That means
the postsynaptic side after aneuronal synapse happens that
postsynaptic side downstreamsignaling. But the upstream side
is not modulated. Idazoxanmodulates dopamine from a higher
level up, one level up from whattypical antipsychotics do and
(23:29):
atypicals do, and by adding thatdual control, you're able to
provide additional potential forefficacy. And it showed amazing
efficacy in phase two trialsalready. Then on this
psychedelic side, what we dothere? Well, one, we just make
traditional psychedelics withimprovements, the world's first
(23:51):
orally active DMT, long actingMDMA, things like that. But one
of the leads is a psychedelicwhere we've removed the trip.
Now, the way that works is thatscientists looked at
psychedelics that had shownefficacy, LSD, psilocybin, DMT,
and they said, Look, these acton a lot of receptors in the
brain. But we also know thatonly one of the more than 20
(24:14):
targets they hit is responsiblefor the trip, the
hallucinations. That's theserotonin 2a receptor. So these
scientists said, what wouldhappen if we combine the
psychedelic with a selectiveserotonin receptor blocker? And
they did that, and they foundthat in animal models, it was
(24:39):
able to remove the behavioraleffects of the trip but maintain
the therapeutic efficacy. Sothen we move that into a human
study where we showed thatpsychedelic without the trip
still maintain all of thefunctional changes on the brain
measured with functional MRI.
(25:03):
And so we had partnered withSanofi, where we exclusively
licensed their large neuralprograms, Eplivanserin and
Volinanserin. These are two ofthe most selective serotonin 2a
receptor antagonists known. Theyhad already been tested in
15,000 patients over 100clinical trials, we got the
exclusive worldwide rights todevelop those compounds. We're
(25:25):
combining them with ourpsychedelics now and pushing
those forward towards theclinic, where we hope to develop
a take home psychedelic withoutthe trip, where you can get the
antidepressant or anti anxietybenefits without having to
experience a trip. We're notanti tripitarian. It can
absolutely benefit certainpeople, but we believe that
(25:46):
without the trip, you have thepotential to benefit all those
extra people who can't affordthe trip, or can't take the time
for it, or scared by it, ordon't want it, and really
improve the market at lowercosts so that we can democratize
access for as many people aspossible.
John Simboli (26:03):
Do you want to also talk with me about the
software side of yourdevelopment?
Sam Clark (26:07):
This goes back to a biomarker called neuromelanin.
Now, all of our brains havedopamine, and dopamine gets
metabolized a little bit, breaksdown every day and it binds to
iron in the brain. Now, when itdoes that, it forms a metabolic
product called neuromelanin. Nowall of our brains just build up
(26:28):
neuromelanin across ourlifespan, but in certain
neurological conditions likeParkinson's, we lose our
neuromelanin, and in otherconditions like schizophrenia,
we gain additional neuromelanin.
Now for more than 20 years,scientists have studied
neuromelanin and they've shownthat it's a great in the
literature, it's been publishedas a great potential diagnostic
biomarker for Parkinson'sprognostic ability to predict
(26:51):
early detection, and also, andalso for schizophrenia and
depression and Alzheimer'sdisease, almost a Swiss Army
knife of biomarkers. The problemwas it was never FDA cleared,
because there was no way tofully automate the measurement
and standardize betweenscanners. Each scanner would
(27:12):
measure a little differently.
This is on a standard MRI, bythe way. So a team at Columbia
University got together. Theydeveloped algorithms, academic
algorithms, in academic piece ofsoftware called MATLAB that was
able to do that. Then welicensed those algorithms from
Columbia, reprogrammed them intoa cloud based system that could
(27:36):
integrate with any hospitalworldwide and passed all the
cybersecurity testing and thentook it to the FDA, and
historically, got this clearedas the first medical device, and
currently the only that islabeled for the measurement of
neuromelanin MRI analysis, andthat now brings that biomarker
(27:57):
that doctors have called to beincluded In the standard of care
for many years. This brings itto the clinic for the first
time, and also shows that wewere able to take an academic
convention that typically wouldjust stay in the realm of
academia, and bring it all theway to the FDA, reprogram it to
FDA standards and get it FDAcleared. And so it really ties
(28:20):
into Terran's mission ofcollaborating with academics. It
shows we have a track record ofsuccess, and it shows we were
able to overcome that nearimpossible problem, which is 20
years of recommendations and noFDA clearance until Terran was
able to do it for the firsttime.
John Simboli (28:36):
Can just tell me a little bit about the benefit for
patients of it?
Sam Clark (28:39):
Neuromelanin, in the literature has been published as
having a number of potentialbenefits. So right now, our FDA
clearance allows this softwareto be used to provide adjunctive
information that, wheninterpreted by a trained
neuroradiologist, could beuseful in determining diagnosis.
(28:59):
Now, if we go into literature,what is the recommendations from
different studies show, and whatthey're really comparing it to
is a technology called theDaTscan. Now this is separate
from our label. We're justtalking about the literature
right now. But what's happenedis that in the diagnosis of
Parkinson's disease, patients,some of the time they'll so
(29:20):
they'll come in, they havesymptoms, and they'll go, they
nearly 100% of the time theywill receive an MRI, and that's
not to diagnose Parkinson's,it's to rule out other
conditions, brain tumors,stroke, other things. Then a
percentage of the time they'llgo get a what's called a
DaTscan, which involves aninfusion of radioactive radio
tracer, high dose iodine, takesmany hours, can take up to five
(29:43):
hours, and can have sideeffects, and it involves an IV
so that can involve pain, and itdoes expose to radiation. Now,
neuromelanin imaging in theliterature has been used in
clinical studies, and theconclusion of some of those
clinical studies was that it wasjust as effective at providing
(30:05):
that diagnosis for Parkinson'sas SPECT imaging DaTscan, and it
was able to be done in just fiveminutes on a standard MRI that
patient already receives with nocontrast. Means no IV infusion,
no radiation, just five extraminutes. Now, what we are doing
is we are giving doctors accessto neuromelanin imaging where
(30:28):
they can use it how they want toget that adjunctive information,
and use that to help in the aidin their various evaluations.
And we believe, based onrecommendations in literature
that this could really be a bigbenefit to patients. There's
also other studies done by ourcollaborators, Dr Guillermo
(30:49):
Horga, who showed that it couldhelp predict treatment
resistance in schizophrenia,Kenneth Wengler, who developed
new algorithms to harmonize datasets, and Clifford Cassidy, who
showed that it could helppredict, this is neuromelanin
I'm talking about, andneuromelanin imaging could help
predict who will developneuropsychiatric symptoms from
(31:09):
Alzheimer's disease, which couldthen lead to better patients
treatment, as well as helppredict post traumatic stress
disorder and otherneuropsychiatric conditions,
substance use disorder and otherconditions as well. And so those
studies from our collaborators,which use the same algorithms
used in NM 101, that's theacademic version, have really
(31:32):
pushed forward the field, andshowing how neuromelanin imaging
could benefit patients.
John Simboli (31:37):
Is there a way to talk about how the pipeline as a
whole expresses your vision forwhat you're looking to do?
Sam Clark (31:44):
It's really about, it's the diversity of the
pipeline, about building those,solving those impossible
problems. So we've got idazoxanfor schizophrenia, we've got the
psychedelic without the trip.
But it's also about bringingcost effective medications that
are affordable for patients,that are not overpriced, and
tackling industries where thepatient may be priced out of
(32:08):
having access, that's somethingthat's very important to me ever
since seeing my family membersaffected by mental illness and
friends and the struggle to getmedications that may be on brand
and difficult or withoutinsurance. And we are pushing
that forward very quickly inpsychedelics. So there's two
sides of psychedelics. One isthat new drug that we're
(32:30):
developing that doesn't have thetrip and but another thing we're
hitting very hard right now iswe're pushing forward
psychedelics towards the 505 b2pathway, and I want to explain
how we've set up the company forsuccess here. Many companies are
developing psychedelics forvarious indications, so we've
(32:53):
got companies developingpsilocybin, LSD, MDMA, DMT,
five-methoxy DMT, methalone, andmany others. And those are all
compounds in the psychedelicspace. Now, those are all old
compounds. Psilocybin hasbenefited humanity for 1000s of
years. LSD has been around agood 60 plus years. And you
(33:16):
know, MDMA was invented in 1912and so the idea is that, you
know, these are compounds thatwe had heard initially, some of
these companies say, Look, we'regoing to lock them down in
patents around the we can't lockthem down in patents on the
composition of matter thatbiopharma typically get because
(33:37):
it's expired. The compounds areold. So what do we do? They
said, Well, what we'll do is wewill, we realize that there's a
little bit of a second levelhere, and that is that the FDA
is very strict in EMA aboutregulating the salt form that
your your compound is. Sodevelop a drug, it has to be
(34:00):
usually in some sort of salt orcrystal called a salt, and then
a crystal is the polymorph. Andwhy is that important? Well,
it's important because if youhave the wrong polymorph, some
of them are not soluble. Theydon't dissolve. And we saw that
with an HIV drug previously,where it switched to the wrong
polymorph. They didn't realizeit, and suddenly the pills
(34:22):
weren't dissolving in thepatient's stomachs anymore. So
the FDA said, Okay, we got toregulate this very strictly. You
have to control your polymorph.
Well, these other companies haverealized, well, if we own the
patents on all of thepolymorphs, we can control the
compound for example, psilocybinwas only thought to form three
(34:46):
polymorphs period. So, you know,people are saying, well, if one
company controls threepolymorphs, they'll be able to
have a monopoly on psilocybin.
And thus, for 20 years, therewon't be any generics, because
any generic would have to useone of the only three polymorphs
available. So we said, we'regonna we're gonna solve this
because we're gonna need tobring 505 b2 and I just want to
explain for your listeners, the505 b2 path means that five
(35:09):
years after someone gets thedrug approved, that's not on
patent, the FDA allows you totake all that phase three data,
and as long as you show you havea bioequivalent drug that could
be as little as a tiny phase onebridging study, you get to use
all that phase three data putyour drug on the market, and now
patients have access toessentially a generic, cheaper
(35:32):
drug. So we said we are notgoing to allow psychedelics to
be locked up in 20 yearexclusivity. You know, long and
we're not what we're talkingabout, all these old
psychedelics. You can't lockthem up in 20 year
exclusivities, where patientsdon't get access. People have a
brand new, special psychedelicthey invented. Sure, that's a
(35:53):
different story, but we'retalking about good old classic
psychedelics, LSD, whatnot. SoTerran went out there first, and
we completed more salt andpolymorph screens than any group
in history for psychedelics. Andnow Terran has been granted the
world's first new forms ofpsilocybin, psilocybin
hydrochloride, psilocybinedisylate. This is granted to
(36:16):
Terran now by the patent officeas the world's first new form,
and that's one of my inventionsand for new form and polymorph,
and that enables us to getaround any blocking IP on those
old polymorphs, because ours aretotally different. And that
means if someone goes forwardand develops an old polymorph
(36:36):
and gets a 20 year patent on itand gets it FDA cleared, the FDA
allows 505 b2s all the time withdifferent salts and polymorphs.
You just have to showbioequivalency. Terran will be
right there at the five yearmark with our psilocybin. And we
already have full GMPmanufacturing. We're
manufacturing at scale already,so we're ready to go for that.
(36:58):
We're already providing theclinical trials in Europe and
non clinical we created thefirst new forms of LSD. We
created new forms of derivativesof DMT. We created new forms of
the first new form of MDMA. Wasjust recently granted, MDMA
hemifumaratete, to TerranBiosciences, and so by doing
that, we're going to guaranteethat patients will have access
(37:20):
to these cost effectivemedications, and they won't be
priced out of the market. We'retaking risks at Terran, where we
are not afraid of risk, and sowe took big bets and risks to
develop assets and other thatwere highly effective for
diseases that other companiessaid that it's too difficult.
We're not going to touch it. Wejumped in there and we got it
(37:40):
done. You know, neuromelanin, 20years nobody was able to get
approved. We got it approved,you know, now that's going to
the market where it can benefitpatients and finally, give
doctors access, you know,psychedelics, you know, people.
That's been a contentious area,where people are trying to
really, you know, carve outcompanies and develop drugs that
could be priced way out of themarket, enormous therapy costs.
(38:03):
And Terran will be right therewith the multiple 505 b2s, where
we can give affordable meds topatients and not taking another
risk and jumping in there. We'renot afraid of that, of that
controversy, when it's abouthelping patients. People are
suffering right now from mentaland neurological conditions, and
we're going to move we're goingto move as fast as we can to
help them.
John Simboli (38:25):
Sam, thanks for speaking with me today.
Sam Clark (38:27):
Thank you.
Today, I'm speaking with Sam Clark, founder
and CEO of Terran Biosciences,headquartered in New York.
Welcome to BioBoss, Sam.
Sam Clark (00:09):
Thanks for having me.
Excited to be here.
John Simboli (00:11):
How did you find yourself in that role as founder
and CEO at Terran Biosciences?
Sam Clark (00:17):
Well, it really goes back to growing up. There were a
number of people in my immediatefamily and close friends who
were struggling with severemental illnesses, bipolar
disorder, as well asneurodegenerative conditions,
Alzheimer's disease. So justbeing affected by that, I really
wanted to better understandtreatments. How can we help
people develop bettertreatments? So when I went to
(00:40):
MIT and I studied neuroscienceto better understand the brain,
and then I went to ColumbiaUniversity, where I did my MD
and my PhD. But it was duringthat time for the MD when I
realized that the treatmentsthat we have just aren't that
great. They leave a lot to bedesired, whether through lack of
efficacy or side effects, andthere's really a lack of new,
(01:02):
innovative treatments. You know,if you think about
schizophrenia, for example,almost all of the antipsychotics
have roughly the same mechanismof action since the 1960s,you
know, just slight variance. Andyou know, we're just seeing this
year, the potential for thefirst approval of something with
the new mechanism. But ingeneral, the principle was, for
neuroscience, there isn't a lotof new options. So I really
(01:25):
wanted to help people bydeveloping kind of new
treatments. But then at the sametime, I was looking at other
biotechs, and I said, you know,there's a risk aversive attitude
in a lot of these biotechs,where they go for safer
mechanisms. So it's, you know, Iwant to, I was noticing, I said
at the time, you know,Instagram, Snapchat, Facebook,
they were all making enormousprogress in Silicon Valley. But
(01:48):
on the biotech side, I justsaid, we don't really have that
parallel of a fast moving, youknow, biotech that's not risk
averse, that's able to tacklethose impossible challenges. And
so I founded Terran with thegoal of building a platform
company that would take adifferent approach to
development of neuropsychiatrictherapeutics.
John Simboli (02:08):
As you made that decision to found Terran and to
become the CEO, based on yourpersonal experience and your
education and your thinkingabout the industry, did you
consider in those early stages,maybe I'll create this, but I
won't be the founder. I won't bethe CEO. That's sometimes the
case. It's an idea, but you findthe person you want to carry
(02:28):
that forward. Or did you knowfrom the beginning, I should do
this?
Sam Clark (02:32):
So when I founded the company, I wanted to push the
ideas forward. And peopleactually had discussed that same
idea with me, the idea that, youknow, when a venture group comes
in and gives you funding,they'll put their own team in.
You can be the science advisor,or maybe, you know, something
where you're not really runningthe company. And I always
(02:52):
wonder, well, why is that thecase? And that's the case, they
say, well, they want to bring insomeone who's more skilled at
the business aspects. But thebusiness aspects, actually, I
think you can pick up quitequickly. It's really having that
strong science background that Ithink has really enabled us to
move forward faster than othercompanies in the space, because
(03:13):
I stay involved in every aspectof the business. And instead,
you know, I'm inventor on over200 patent applications we put
through. I'm the invent, onlyinventor on the world's first
new forms of psilocybin, MDMA,long acting and other inventions
that we've made at Terran thathave been granted now by the
patent office. And so in doingthat, I think it actually gave
(03:34):
me an advantage. But there wasdefinitely some pushback when I
was starting to found thecompany for people saying, well,
we don't typically see someonedo this. But at the same time, I
had been reading a lot ofbiographies and studying and
said, look, in Silicon Valley,the founders take the company
forward. So in biotech, we cando that too. And it really has
(03:55):
worked out quite well.
John Simboli (03:56):
In those early stages, had you considered the
possibility of taking your ideato an existing, to a biopharma
company, to a pharma company,and having it developed under
your guidance, but within thatframework?
Sam Clark (04:09):
I thought about it for sure, but that leads to a
number of downsides. If you justsell off the idea immediately to
Big Pharma, then it may getshelved. You know, priorities
often change. And the otherthing is, the ideas we were
developing at Terran were notsafe ideas. This wasn't the case
of, hey, we have another, youknow, oncology drug with the
(04:32):
same mechanism that's beenapproved, slightly better
pharmacokinetics. These wereassets that we believe had the
potential to reallyrevolutionize the treatment of
neurological conditions thatalready had human data, but had
been discontinued by big pharmabecause they couldn't solve
certain problems. So it wasalready a big risk taking them
on and a challenge. And so whatI did was founded a company
(04:55):
where you can, we would build ateam of highly trained
operators. And then pull onworld experts so that we could
move forward to solve theseproblems. So in that sense, it
wouldn't have been the best fitto go straight to companies,
because the pitch would be,well, Big Pharma failed to
develop these, you know, andwe're pushing these high risk
assets forward. It's not thetypical approach. And then to
(05:17):
your other point, what abouttypical VC funding? The problem
there is that it's singularlyfocused. Companies they like to
invest in the most are typicallysingle asset focused companies
where the company's only doingone thing. Now we've seen a bit
of a switch recently withcompanies like Cerevel and
Neumora, and now the rise ofmore neuro platform companies,
(05:38):
and we see ourselves moving inthat direction as well. But you
know the past, it's largely beensingle asset focus, and it still
mostly is today.
John Simboli (05:47):
So those scientific problems that you
were fascinated by and wanted totry to address, that you
described for me at the verybeginning, as you got into it, a
few weeks, a few months into it,did you find yourself following
that path of things that youwanted to pursue within Terran,
or did those evolve? Did youknow what you didn't know? Is
(06:08):
another way of asking thequestion.
Sam Clark (06:10):
Some of this goes back to what I was studying
during my PhD years. During myPhD years, I was studying and
publishing on a receptor in thebrain called the kappa opioid
receptor. Now we have threeopioid receptors in the brain,
kappa, mu and delta. And mu iswhat you think about when you
think about opiates. They killpain, things like oxycodone,
(06:32):
Vicodin, all those prescriptionopiates act on the mu opioid
receptor. And same with drugs ofabuse, like heroin, a mu opioid
receptor. But there's anotherreceptor called kappa that's
very effective in killing painas well. The thing that makes it
interesting is that big pharmatried to target that receptor
because it has no potentialanimal models for abuse, so they
(06:55):
developed selective kappaagonists that would turn on the
receptor as the next generationof analgesic drugs to kill pain.
The problem is, people who tookthose became psychotic,
experienced terriblehallucinations. So they said,
well, this receptor may belinked to psychosis. And then,
interestingly, there was anatural plant called salvia
(07:16):
divinorum that also was selectedfor the kappa opioid receptor
and also would cause people toexperience hallucinations. But
one of the uniquecharacteristics about these is
that people described in manyreports hearing voices, which is
unusual because many drugs thatinduce psychedelic trips don't
really contain those componentsof hearing voices or really
(07:41):
fully formed delusions. Now,then it got even more
interesting when I dug into theliterature and I said, Wait a
minute, in schizophrenia, thereare a number of drugs that, in
the past, were shown to makeschizophrenia worse. One of
those was called ketamine. Atthe time it said, Well, you
know, ketamine acts on areceptor called the NMDA
receptor. But if, when youreally dig into it, you saw
(08:05):
there's a number of publicationswhere it showed it also acts on
the Kappa receptor and wouldcause patients with
schizophrenia to experienceworsening of voices,
hallucinations. So then I dugeven further, and I did this big
meta analysis of kappa opioidantagonists. Now, there were no
selective ones that were evertested, but there were more than
(08:27):
40 trials of non selectiveopioid antagonists through the
60s, 70s and 80s and early 90sin schizophrenia, and some of
those reported amazing resultswith a new mechanism at ending
schizophrenic hallucinations andimproving even the negative
symptoms, the social withdrawal,the cognitive symptoms. And so
the meta analysis showed therewas a significant effect on the
(08:49):
positive symptoms and a help onthe negative. But when I went to
try to develop this into a drug,initially, this is back in the
PhD years, that's when I foundout, well, it's actually very
hard to get funding for newdrugs. Nobody wants to fund the
old drugs because they say,well, there's no IP and, you
know, there's a lot of things.
It doesn't necessarily, it's notjust whether drugs effective,
(09:10):
it's whether there's patents,it's whether it's fully
druggable, it's whether you canmanufacture it. And so there's
so many other factors at play.
It's whether you can get itapproved by the FDA and the
regulatory side. That's when Icame across. So I realized,
okay, this is much morechallenging, but that's when we
came across another drug calledidazoxan from big pharma. And
(09:33):
this was a drug that PierreFabre in France had developed
all the way through Phase Threefor Parkinson's tremor. Now the
thing is, in Parkinson's tremor,it wasn't that effective, but it
was very safe. However, at thesame time, it was in trials at
the National Institute of MentalHealth in the United States, in
a collaboration forschizophrenia. And it was the
(09:55):
first adjunctive treatmenttested where you can add it on
to existing antipsychoticregimens, and it would double
the efficacy. And the thing is,it wasn't until years later that
we saw this in depression withthe drug Abilify, where you
could have an adjunctivetreatment that really became a
blockbuster and helped a lot ofpatients. So in that sense,
idazoxan had that potential. Theproblem was it had to be given
(10:19):
up to three times a day, everyday, and they said, look, it's
so short acting that it's notcommercially viable to have this
three times daily drug. And eventhen, it was closer to a four
times daily drug with a two hourhalf life. And so all the trials
were discontinued. Pierre Fabrehad largely exited neuroscience.
(10:40):
The drug was shelved, and it wasterrible, because at the time,
the doctor who ran the trials,who later invested in Terran and
is on our science advisoryboard, said patients and their
families were calling begging tobe put back on that drug, but
there was nothing they could do,because manufacturing had been
discontinued. So our scienceadvisory board made me aware of
(11:03):
that compound. We then went toFrance, met with Pierre Fabre,
licensed on the rights to thatdrug, completed all
manufacturing, made a once dailyform, put it back in the clinic
where it's showing a great oncedaily profile. Got the green
light from the FDA, then to moveit forward pending the results
of pharmacokinetic bridgingstudy into the larger trial with
(11:25):
patients with schizophrenia. Andit's by bringing back that
forgotten asset that had thepotential to be very effective
that already was very effectivein patients with schizophrenia,
and by solving that impossibleproblem that wasn't able to be
solved at the time the drug wastoo short acting. That's where
we really hope to make adifference. So to answer your
(11:45):
question, at the time, I didn'tknow about idazoxan, but I knew
about these ideas of forgottendrugs like kappa opioid receptor
antagonists and things that hadgreat efficacy but had hit
snags, and thus were not at thetime being funded by traditional
venture groups.
John Simboli (12:03):
Can you share any thoughts about how you develop
the process for knowing when tomake a decision versus when to
rely on someone on your team tohelp you make a decision?
Sam Clark (12:12):
The structure of Terran, and this is where we get
into the uniqueness of the modelis very different than most
biopharma companies. I'vestructured it after the tech
companies of Silicon Valley, andin that sense, we have a very
small team of highly trainedoperators. So I have a number of
ideas that I want to work on thecompany, and we have a small
(12:33):
team of operators that help keepeverything organized. But in
order to actually execute any ofthese ideas, we need the world's
best minds around the table, andso what we do is we build out
individual teams of worldexperts. Now this leads to a
more flat, hierarchicalstructure in the company. It's
not one of those pyramid topdown management where I'm
(12:56):
fundraising and telling thegeneral plan, and then you have
some managers under there, andsenior managers and VPs and
whatnot, and they trickle down,and then information trickles
up. In that sense it's flat. SoI'll be on, for example, the
manufacturing calls. I'll bepresent in all the clinical
calls, you know, I'll be in theweeds on everything, and I'll be
(13:17):
aware immediately whensomething's not getting done or
something, the train's going offthe tracks, and we have really
good operators that will keepeverything organized, but then
we have the best minds in theworld on individual teams who
are able to solve theseproblems. For example,
initially, before we had fullyimplemented this model, we had
people around the table thattried to fix cytosoxan but
(13:38):
didn't have the expertise. Itwasn't until we found someone
who had done this many timesbefore and had potentially more
long acting, once daily oraldosing formulations than almost
anyone in the industry who cameon board had done this many
times before. We built a teamaround them that was able to
take this drug forward andfinally fix it. So in that
(13:59):
sense, the way we have a rule atTerran where everything has to
be backed up by evidence. Sowhen nobody's allowed to say,
Oh, just trust me on this. Andthat goes for any aspect;
manufacturing, clinical trials,anytime we reach a difficult
decision, you know, people haveto bring on, bring expertise to
the table like, you know, weshould take this path based on
(14:21):
this feedback from FDA or basedon these other trials that have
been done in the past, this isthe best route. Nobody's allowed
to say, Oh, just, trust me, Ithink we should do this. I have
20 years of experience, so justlet me make this decision, but
at the same time, you know, I'mnot the one who's going to be
saying, you know, I'll make, youknow, like we always will bring
(14:42):
on regulatory help, for example,we'll bring on external
expertise to guide into thefinal decisions that then I'll
ultimately have to make. But Iwon't override the experience.
That's where we pull on externalexperience to make the guide the
decisions that I ultimately do.
John Simboli (14:59):
Did you find knowing when, in the end, you
had to make a decision, did thatfeel like a natural progression,
or is that something to belearned as a new CEO?
Sam Clark (15:06):
So ultimately, I have to make all the final decisions.
It's something that youdefinitely get better at over
time, and then you pick up, andthe best thing is having many
advisors around the table. Imean, if you think about it,
throughout history, any time youhave someone who has to lead a
group of people, the best thingis having that group of advisors
(15:30):
advising you. And so I try tobring on as much external
expertise. And the mostimportant thing is knowing when
you don't know something, andwhen you realize that you don't
know something, we move veryfast at Terran to find someone
who knows the answer. Sothere'll be, we can identify,
oh, you know, we have thisproblem. We realize when the
(15:50):
current team members also don'thave the solution, and we go as
fast as we can through ourentire network to find someone
who has the solution to thatproblem. And we've been very
successful using that fastmoving model. And once we have
that, then we can make thedecisions.
John Simboli (16:04):
If someone your team were to be asked the
question, well, what's Sam'smanagement approach? That might
or might not be how you woulddescribe it, but can you
estimate how others would say,oh, yeah, this is how he goes
about dealing with the team.
Sam Clark (16:18):
Well, I like to stay very highly involved with the
team, so we'll be chatting everyday is spent with the core team
of operators every morning. Sowe're in constant communication,
both in decision making as wellas, you know, planning. And I
generally have a lot of ideasthat I want to do each day. So
I'll help, you know, make surethe team's on schedule to
achieve those. And sometimesgive out new goals, new plans,
(16:41):
or readjust quickly if I thinkthe priorities change. So it's a
lot of top down information, butthe team handles it very well
and course corrects. And we'llcourse correct and change
sometimes, many times a week,I'll be making decisions to
pivot quickly, and I have a teamof operators that'll immediately
implement those changes. Sothere's not a management style
(17:05):
where I'll say, Hey, this iswhat we need to do. Go do it,
check in with me in two days.
Then we'll do another thing.
It's daily feedback and dailycourse correction. But I want to
draw a distinction. It's notmicromanagement, where people
have to babysit each individualdecision, like task. I trust the
(17:26):
team to be able to achieve thosetasks, to, you know, to
accomplish those goals andtasks, I give them. It's just
that we move so quickly that thetasks may change rapidly, and
there may be new tasks andalterations to those tasks. So I
don't have to babysit theirexecution of the task, but I do
have to be very much alert tomove and change very quickly.
(17:51):
And that's, I think, how we'vehad our greatest successes.
John Simboli (17:54):
Can you recall as a young child, eight, nine, ten,
whatever is a formative time foryou. Do you remember what it was
that you set your sights on? Whoknows where these things come
from, generally from parents,I'm sure. But do you remember
what path you saw in your lifeand does have anything to do
with what you're doing now?
Sam Clark (18:11):
You know, it's a combination of things. There was
a time when I was around age 10when I wanted to be a doctor and
I wanted to learn about thebody, but at the same time, it
was really mainly aroundexploration. I was always
exploring things, readingthings, you know, trying to
understand new things. And, youknow, this was during the time
in the all this new technologycoming out, you know, the
(18:31):
internet was just reallystarting to take off. And
computers, and, you know, thefirst laptops were, you know,
just being, you know, developed.
This is before smartphones, soand then the idea, also, besides
that too, is I would go out.
This was during also a time whenyou would, you would just go get
on your bike and go out, hangout your friends, and you'd bike
(18:52):
neighborhoods. You'd bikethrough the woods, you'd bike
through parks. You would just goand nobody was checking up on
you. You know, you come home fordinner. And the thing is, it
there was, it's not a kind of ahelicopter mentality we have
now. So you're out thereexploring and seeing things and
thinking things and readingbooks and and really just
dreaming. And that was the ideaI wanted to explore. And so I
(19:13):
think that's what we're doingnow in Terran, we're exploring
the brain. We're developing newpsychedelics. It's the final
frontier of neuroscience. Sowe're really, I think that's a
natural progression of thosetimes.
John Simboli (19:24):
When you go for that nutshell, 30 second very
brief kind of who is TerranBiosciences, how do you like to
answer that?
Sam Clark (19:32):
Terran is a platform company, so we do a number of
things, for example, in thepsychedelic space, one of the
largest manufacturers of GMP, Imean, for human use
psychedelics. We've created morenew psychedelics, we believe
than any other group so far withnew modifications to the trip.
We create psychedelics withoutthe trip. We also create
(19:54):
traditional neuro assets likeidazoxan for schizophrenia and
other antipsychotics. And wehave software, AI enabled
software, as a medical device toaid in the provided juncture
information aid in the diagnosisof neurological and psychiatric
conditions. And so in thatsense, you know, Terran is a
(20:15):
platform company with a suite ofoptions to help people with
neuro and psychiatricconditions.
John Simboli (20:21):
I imagine it's it often happens that you're at an
investor conference, or in someother kind of format, where
someone you give that briefdescription, and you're about to
go on, and then you're realizingpeople may have substituted a
preconception for what it isthat you're doing. It just
happens that's kind of part ofthe game. So my question is, in
this early stage are, is thereany kind of pattern that you see
(20:43):
where you think, oh, people seemto think it's this, but I have
to help them understand it'sthat.
Sam Clark (20:49):
Sometimes, and that's usually when people will get
fixated on one aspect of whatTerran does. So they'll say, ah,
Terran is psychedelics, orTerran is just software as a
medical device, you know, orit's just antipsychotics, and
they're missing the big picture.
Or, even more recently, becausewe had some high profile patents
publish with the goal of thosepatents actually being that we
(21:11):
can bring cheap, affordable, 505b2 medications to the market.
You get the traditional kind ofsummaries in forums or press
saying, okay, is Terran justtrying to snap up IP in the
space for no reason? Or theycan't possibly develop this many
drugs, what's the purpose?
Missing the picture of usingthose in order to bring cheap,
(21:34):
affordable medications via theFDAs accelerated 505 b2 path and
so sometimes people don't takethe time to really dig in and
see the full picture, but, youknow, we're very excited to
always tell them about it andmove this forward.
John Simboli (21:50):
It's been my experience that when people do
get that clarification, oftenthe next question is, well, how
can a relatively new companythat is building itself take on
something of this importer ofthis scale, and how do you help
them understand that?
Sam Clark (22:05):
Well we've been able to cut costs enormously. We run
very lean with that small teamof operators that cuts out a ton
of personnel costs that would betypical for biopharma. And then
we use the consultant model,where we have those world
experts come on and help solvethose problems, but those are,
you know, around specificproblems. So it's not you're not
(22:27):
carrying, you know, constant,you know, payments when projects
are completed. And so we're ableto really run very lean.
John Simboli (22:35):
Is there something you could share with our
audience about mechanisms ofaction that will help people to
understand what you're goingafter?
Sam Clark (22:42):
So let's talk about two of our lead therapeutic
assets. So one I talked aboutbefore idazoxan, that drug that
is adjunctive in schizophrenia.
That was one of the world'sfirst selective alpha two
antagonists. Now that's areceptor in the brain that helps
modulate dopamine release. Now,antipsychotics block certain
(23:07):
dopamine receptors on thedownstream neurons. That means
the postsynaptic side after aneuronal synapse happens that
postsynaptic side downstreamsignaling. But the upstream side
is not modulated. Idazoxanmodulates dopamine from a higher
level up, one level up from whattypical antipsychotics do and
(23:29):
atypicals do, and by adding thatdual control, you're able to
provide additional potential forefficacy. And it showed amazing
efficacy in phase two trialsalready. Then on this
psychedelic side, what we dothere? Well, one, we just make
traditional psychedelics withimprovements, the world's first
(23:51):
orally active DMT, long actingMDMA, things like that. But one
of the leads is a psychedelicwhere we've removed the trip.
Now, the way that works is thatscientists looked at
psychedelics that had shownefficacy, LSD, psilocybin, DMT,
and they said, Look, these acton a lot of receptors in the
brain. But we also know thatonly one of the more than 20
(24:14):
targets they hit is responsiblefor the trip, the
hallucinations. That's theserotonin 2a receptor. So these
scientists said, what wouldhappen if we combine the
psychedelic with a selectiveserotonin receptor blocker? And
they did that, and they foundthat in animal models, it was
(24:39):
able to remove the behavioraleffects of the trip but maintain
the therapeutic efficacy. Sothen we move that into a human
study where we showed thatpsychedelic without the trip
still maintain all of thefunctional changes on the brain
measured with functional MRI.
(25:03):
And so we had partnered withSanofi, where we exclusively
licensed their large neuralprograms, Eplivanserin and
Volinanserin. These are two ofthe most selective serotonin 2a
receptor antagonists known. Theyhad already been tested in
15,000 patients over 100clinical trials, we got the
exclusive worldwide rights todevelop those compounds. We're
(25:25):
combining them with ourpsychedelics now and pushing
those forward towards theclinic, where we hope to develop
a take home psychedelic withoutthe trip, where you can get the
antidepressant or anti anxietybenefits without having to
experience a trip. We're notanti tripitarian. It can
absolutely benefit certainpeople, but we believe that
(25:46):
without the trip, you have thepotential to benefit all those
extra people who can't affordthe trip, or can't take the time
for it, or scared by it, ordon't want it, and really
improve the market at lowercosts so that we can democratize
access for as many people aspossible.
John Simboli (26:03):
Do you want to also talk with me about the
software side of yourdevelopment?
Sam Clark (26:07):
This goes back to a biomarker called neuromelanin.
Now, all of our brains havedopamine, and dopamine gets
metabolized a little bit, breaksdown every day and it binds to
iron in the brain. Now, when itdoes that, it forms a metabolic
product called neuromelanin. Nowall of our brains just build up
(26:28):
neuromelanin across ourlifespan, but in certain
neurological conditions likeParkinson's, we lose our
neuromelanin, and in otherconditions like schizophrenia,
we gain additional neuromelanin.
Now for more than 20 years,scientists have studied
neuromelanin and they've shownthat it's a great in the
literature, it's been publishedas a great potential diagnostic
biomarker for Parkinson'sprognostic ability to predict
(26:51):
early detection, and also, andalso for schizophrenia and
depression and Alzheimer'sdisease, almost a Swiss Army
knife of biomarkers. The problemwas it was never FDA cleared,
because there was no way tofully automate the measurement
and standardize betweenscanners. Each scanner would
(27:12):
measure a little differently.
This is on a standard MRI, bythe way. So a team at Columbia
University got together. Theydeveloped algorithms, academic
algorithms, in academic piece ofsoftware called MATLAB that was
able to do that. Then welicensed those algorithms from
Columbia, reprogrammed them intoa cloud based system that could
(27:36):
integrate with any hospitalworldwide and passed all the
cybersecurity testing and thentook it to the FDA, and
historically, got this clearedas the first medical device, and
currently the only that islabeled for the measurement of
neuromelanin MRI analysis, andthat now brings that biomarker
(27:57):
that doctors have called to beincluded In the standard of care
for many years. This brings itto the clinic for the first
time, and also shows that wewere able to take an academic
convention that typically wouldjust stay in the realm of
academia, and bring it all theway to the FDA, reprogram it to
FDA standards and get it FDAcleared. And so it really ties
(28:20):
into Terran's mission ofcollaborating with academics. It
shows we have a track record ofsuccess, and it shows we were
able to overcome that nearimpossible problem, which is 20
years of recommendations and noFDA clearance until Terran was
able to do it for the firsttime.
John Simboli (28:36):
Can just tell me a little bit about the benefit for
patients of it?
Sam Clark (28:39):
Neuromelanin, in the literature has been published as
having a number of potentialbenefits. So right now, our FDA
clearance allows this softwareto be used to provide adjunctive
information that, wheninterpreted by a trained
neuroradiologist, could beuseful in determining diagnosis.
(28:59):
Now, if we go into literature,what is the recommendations from
different studies show, and whatthey're really comparing it to
is a technology called theDaTscan. Now this is separate
from our label. We're justtalking about the literature
right now. But what's happenedis that in the diagnosis of
Parkinson's disease, patients,some of the time they'll so
(29:20):
they'll come in, they havesymptoms, and they'll go, they
nearly 100% of the time theywill receive an MRI, and that's
not to diagnose Parkinson's,it's to rule out other
conditions, brain tumors,stroke, other things. Then a
percentage of the time they'llgo get a what's called a
DaTscan, which involves aninfusion of radioactive radio
tracer, high dose iodine, takesmany hours, can take up to five
(29:43):
hours, and can have sideeffects, and it involves an IV
so that can involve pain, and itdoes expose to radiation. Now,
neuromelanin imaging in theliterature has been used in
clinical studies, and theconclusion of some of those
clinical studies was that it wasjust as effective at providing
(30:05):
that diagnosis for Parkinson'sas SPECT imaging DaTscan, and it
was able to be done in just fiveminutes on a standard MRI that
patient already receives with nocontrast. Means no IV infusion,
no radiation, just five extraminutes. Now, what we are doing
is we are giving doctors accessto neuromelanin imaging where
(30:28):
they can use it how they want toget that adjunctive information,
and use that to help in the aidin their various evaluations.
And we believe, based onrecommendations in literature
that this could really be a bigbenefit to patients. There's
also other studies done by ourcollaborators, Dr Guillermo
(30:49):
Horga, who showed that it couldhelp predict treatment
resistance in schizophrenia,Kenneth Wengler, who developed
new algorithms to harmonize datasets, and Clifford Cassidy, who
showed that it could helppredict, this is neuromelanin
I'm talking about, andneuromelanin imaging could help
predict who will developneuropsychiatric symptoms from
(31:09):
Alzheimer's disease, which couldthen lead to better patients
treatment, as well as helppredict post traumatic stress
disorder and otherneuropsychiatric conditions,
substance use disorder and otherconditions as well. And so those
studies from our collaborators,which use the same algorithms
used in NM 101, that's theacademic version, have really
(31:32):
pushed forward the field, andshowing how neuromelanin imaging
could benefit patients.
John Simboli (31:37):
Is there a way to talk about how the pipeline as a
whole expresses your vision forwhat you're looking to do?
Sam Clark (31:44):
It's really about, it's the diversity of the
pipeline, about building those,solving those impossible
problems. So we've got idazoxanfor schizophrenia, we've got the
psychedelic without the trip.
But it's also about bringingcost effective medications that
are affordable for patients,that are not overpriced, and
tackling industries where thepatient may be priced out of
(32:08):
having access, that's somethingthat's very important to me ever
since seeing my family membersaffected by mental illness and
friends and the struggle to getmedications that may be on brand
and difficult or withoutinsurance. And we are pushing
that forward very quickly inpsychedelics. So there's two
sides of psychedelics. One isthat new drug that we're
(32:30):
developing that doesn't have thetrip and but another thing we're
hitting very hard right now iswe're pushing forward
psychedelics towards the 505 b2pathway, and I want to explain
how we've set up the company forsuccess here. Many companies are
developing psychedelics forvarious indications, so we've
(32:53):
got companies developingpsilocybin, LSD, MDMA, DMT,
five-methoxy DMT, methalone, andmany others. And those are all
compounds in the psychedelicspace. Now, those are all old
compounds. Psilocybin hasbenefited humanity for 1000s of
years. LSD has been around agood 60 plus years. And you
(33:16):
know, MDMA was invented in 1912and so the idea is that, you
know, these are compounds thatwe had heard initially, some of
these companies say, Look, we'regoing to lock them down in
patents around the we can't lockthem down in patents on the
composition of matter thatbiopharma typically get because
(33:37):
it's expired. The compounds areold. So what do we do? They
said, Well, what we'll do is wewill, we realize that there's a
little bit of a second levelhere, and that is that the FDA
is very strict in EMA aboutregulating the salt form that
your your compound is. Sodevelop a drug, it has to be
(34:00):
usually in some sort of salt orcrystal called a salt, and then
a crystal is the polymorph. Andwhy is that important? Well,
it's important because if youhave the wrong polymorph, some
of them are not soluble. Theydon't dissolve. And we saw that
with an HIV drug previously,where it switched to the wrong
polymorph. They didn't realizeit, and suddenly the pills
(34:22):
weren't dissolving in thepatient's stomachs anymore. So
the FDA said, Okay, we got toregulate this very strictly. You
have to control your polymorph.
Well, these other companies haverealized, well, if we own the
patents on all of thepolymorphs, we can control the
compound for example, psilocybinwas only thought to form three
(34:46):
polymorphs period. So, you know,people are saying, well, if one
company controls threepolymorphs, they'll be able to
have a monopoly on psilocybin.
And thus, for 20 years, therewon't be any generics, because
any generic would have to useone of the only three polymorphs
available. So we said, we'regonna we're gonna solve this
because we're gonna need tobring 505 b2 and I just want to
explain for your listeners, the505 b2 path means that five
(35:09):
years after someone gets thedrug approved, that's not on
patent, the FDA allows you totake all that phase three data,
and as long as you show you havea bioequivalent drug that could
be as little as a tiny phase onebridging study, you get to use
all that phase three data putyour drug on the market, and now
patients have access toessentially a generic, cheaper
(35:32):
drug. So we said we are notgoing to allow psychedelics to
be locked up in 20 yearexclusivity. You know, long and
we're not what we're talkingabout, all these old
psychedelics. You can't lockthem up in 20 year
exclusivities, where patientsdon't get access. People have a
brand new, special psychedelicthey invented. Sure, that's a
(35:53):
different story, but we'retalking about good old classic
psychedelics, LSD, whatnot. SoTerran went out there first, and
we completed more salt andpolymorph screens than any group
in history for psychedelics. Andnow Terran has been granted the
world's first new forms ofpsilocybin, psilocybin
hydrochloride, psilocybinedisylate. This is granted to
(36:16):
Terran now by the patent officeas the world's first new form,
and that's one of my inventionsand for new form and polymorph,
and that enables us to getaround any blocking IP on those
old polymorphs, because ours aretotally different. And that
means if someone goes forwardand develops an old polymorph
(36:36):
and gets a 20 year patent on itand gets it FDA cleared, the FDA
allows 505 b2s all the time withdifferent salts and polymorphs.
You just have to showbioequivalency. Terran will be
right there at the five yearmark with our psilocybin. And we
already have full GMPmanufacturing. We're
manufacturing at scale already,so we're ready to go for that.
(36:58):
We're already providing theclinical trials in Europe and
non clinical we created thefirst new forms of LSD. We
created new forms of derivativesof DMT. We created new forms of
the first new form of MDMA. Wasjust recently granted, MDMA
hemifumaratete, to TerranBiosciences, and so by doing
that, we're going to guaranteethat patients will have access
(37:20):
to these cost effectivemedications, and they won't be
priced out of the market. We'retaking risks at Terran, where we
are not afraid of risk, and sowe took big bets and risks to
develop assets and other thatwere highly effective for
diseases that other companiessaid that it's too difficult.
We're not going to touch it. Wejumped in there and we got it
(37:40):
done. You know, neuromelanin, 20years nobody was able to get
approved. We got it approved,you know, now that's going to
the market where it can benefitpatients and finally, give
doctors access, you know,psychedelics, you know, people.
That's been a contentious area,where people are trying to
really, you know, carve outcompanies and develop drugs that
could be priced way out of themarket, enormous therapy costs.
(38:03):
And Terran will be right therewith the multiple 505 b2s, where
we can give affordable meds topatients and not taking another
risk and jumping in there. We'renot afraid of that, of that
controversy, when it's abouthelping patients. People are
suffering right now from mentaland neurological conditions, and
we're going to move we're goingto move as fast as we can to
help them.
John Simboli (38:25):
Sam, thanks for speaking with me today.
Sam Clark (38:27):
Thank you.
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