July 14, 2025 • 54 mins
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On this week's episode, Roger Cone, Ph.D., Founder and Chair of the Scientific Advisory Board at Courage Therapeutics, talks about discovering obesity-related protein receptors in the brain, how he spun his academic discoveries out into a biotech company developing new obesity drugs, the need for obesity treatments with fewer side effects than currently available GLP-1 therapies, and the value of pairing scientific leadership with a strong business partner as CEO.
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Welcome back to the Business ofBiotech.
I'm your host, Ben Comer, chiefeditor at life science leader,
and today I'm speaking with Dr.
Roger Cone, founder and chairof the scientific advisory board
at Courage Therapeutics, apre-clinical company focused on
obesity and eating disorders.
Courage Therapeutics'intellectual property is based
(01:05):
on Rogers' discoveries anddecades of research into the
melanocortin system, a pathwaycrucial to eating behaviors and
energy homeostasis.
Rogers is a professor at theUniversity of Michigan and has a
number of other roles andresponsibilities at UM's Life
Sciences Institute andBiosciences Initiative.
Courage Therapeutics is aUniversity of Michigan spinout
(01:29):
and the third company Roger hasfounded, so we'll find out what
he's learned from thoseexperiences, what role Courage
Therapeutics might play in thewhite-hot obesity space and how
he approaches company leadershipas a founding scientist.
Thanks so much for being here,Roger.
Roger Cone, Ph.D. (01:46):
Thank you, Ben.
Ben Comer (01:48):
I want to start with a little bit of your background
and experience and I guess,first of all I'm curious about
how you set out on the path ofresearching how the body
regulates hunger, caloric intakeand energy expenditure and
other related eating disorders.
Roger Cone, Ph.D. (02:10):
Well, great question, and, like so many
other things in science, therewas a bit of serendipity
involved.
Many, many years ago, I wasengaged in cloning G-protein
coupled receptors, just whencloning cloning began, actually,
and and?
that was the what mid eighties,early eighties late eighties,
(02:31):
late eighties, late eighties Iwas cloning receptors, GPCRs,
and they had just the technologyfor identifying and cloning
GPCRs had just been developed.
And we cloned the MSH receptor,the receptor in your
melanocytes that regulatespigment production.
We cloned the ACTH receptor,the receptor in your adrenal
(02:56):
gland that regulates the stresshormone, the glucocorticoids
that your body produces.
And then we found that therewere three other receptors in
that same family.
Those first two receptors werehighly related.
We found three more highlyrelated receptors in the family.
We had no idea.
Nobody knew what they did,They'd never been seen before
(03:18):
and they were orphans in thatregard, and so we just gave them
numbers MC3, MC4, and MC5.
And so we just gave themnumbers MC3, MC4, and MC5.
We proceeded to delete themfrom mice and we proceeded to
develop agonists and antagoniststo find what the orphans did.
And MC3 and MC4 were in thebrain and we ultimately
discovered that MC3 and MC4 werecritical to feeding behavior
(03:41):
and the regulation of bodyweight.
And I've studied thosereceptors ever since.
Yeah, could you give me a senseof just what that was like when
you made that discovery of theorphans and, you know, started
working on the, you know, theknockout mouse models?
I mean, as someone who won'thave a chance to make a
discovery like that, I'm justcurious about you know how you
(04:02):
might describe what it felt liketo actually first make the
discovery and then go and start,you know, exploring those
receptors and what they couldpotentially do.
Yeah, it was a fantastic time inmy career.
At that time there was not asingle human obesity gene known,
(04:22):
or not a single obesity geneknown, and what happened was
that, and the way that wediscovered that the MC4 was
involved in energy homeostasiswas that there were five
monogenic obesity models in themouse at Jackson Labs, the lab
that produces all the mousestrains that most people work
(04:44):
with, and over the years theyhad found five super obese mice,
that in which the obesitysyndrome was monogenic.
They knew from genetic studies.
It was passed on by a singlegene, and the five obesity
strains were called OBDB forobesity and diabetes, called
(05:10):
OB-DB for obesity and diabetes,ob-db, fatty tubby and agouti.
And we had some clues that theagouti animal might have
something to do with themelanocortin peptides, because
this mutation not only made theanimals morbidly obese, it also
converted their coat color fromblack to yellow, and so we knew
(05:31):
that there was a gene that wasimpacting both body weight,
which is controlled by the brain, and pigmentation, which is
controlled by the melanocytes,and here we had a receptor
family with, you know, onemember critically important in
pigment production and anothermember in the brain with unknown
activity, and so we tested thehypothesis that maybe this
defect was affecting both themelanocortin-1 and 4 receptors,
(05:51):
the MSH receptor and the orphan,and indeed we were able to
prove that the Agouti mutationis a mutation which blocks both
the MSH receptor and the MC4receptor in the brain at the
same time.
Well, within a year of ourdiscovery of that which we
published in one of the topjournals, Nature, within a year
(06:15):
of the discovery of that, humangeneticists working with early
obese kids had discovered thatthe most common cause of
monogenic obesity in kids wasdue to mutations in the MC4
receptor, Philippe Froguel inFrance and Stephen O'Rahilly in
England published thosediscoveries.
(06:36):
So not only was it incrediblyexciting to find one of the
first obesity genes, butliterally within a year or so,
human geneticists discoveredthat what was true in the mouse
was true in people as well.
Ben Comer (06:51):
And when you say monogenic obesity, you're
talking about obesity that canbe directly attributed to a
single gene mutation.
Is that correct, correct?
What percentage I guess, ifpercentage I guess of, of, if
you had to kind of ballpark it,of overall obesity, would you
say is, uh, is monogeneic.
Roger Cone, Ph.D. (07:12):
Uh well, I don't have to ballpark it.
There's been a lot of researchon that from geneticists like
Steve O'Reilly and uh he'sdemonstrated that the prevalence
of obesity due to mutations inthe MC4 receptor is very common.
It's as high as one in athousand individuals has early
(07:32):
onset obesity due to mutationsin the MC4 receptor.
Ben Comer (07:37):
And this is something that you can discover through
genotyping a patient, I assumewhether they have that mutation
or not.
Roger Cone, Ph.D. (07:43):
It's not uncommon now if children present
with early onset severe obesity, it's not uncommon for
endocrinologists to request someDNA sequencing to find out if
they have a leptin mutation oran MC4 mutation corresponding to
those mouse models I talkedabout, because there's different
treatments available dependingon the genetic background for
(08:06):
this severe syndromic obesity.
Ben Comer (08:09):
So these discoveries and this research was started
off in the late 80s with youknow, at your lab.
And where were actually?
Where were you based at thattime?
I don't think you were at theUniversity of Michigan yet,
right?
Roger Cone, Ph.D. (08:24):
Correct, I was at the Vollum Institute at
Oregon Health SciencesUniversity.
Ben Comer (08:28):
Okay, all right, and you have been continuing this
research ever since then and I'mcurious about you, know what
you might say has kept youinterested and kept you focused
on this area, you know, forupwards of 30 years.
Roger Cone, Ph.D. (08:45):
Well, I got fascinated by the mechanisms
underlying energy homeostasis.
Energy homeostasis most peopledon't think about that.
You know, when we think abouthomeostatic systems, we think
about things like bodytemperature.
You know, we're all basicallyat 98.6 unless we get a fever.
We think about blood oxygen,things like that, sleep-wake
(09:10):
cycles.
You know, we think about thingslike that when we think about
physiological homeostasis.
Many people don't understandthat your long-term fat stores
are also controlledhomeostatically by the brain and
critically, involving thecentral melanocortin circuits
and hormones such as the fathormone leptin, which tells the
(09:30):
brain how much long-term energyyou have on board.
So three basic forms of energythat we use every day glucose in
our bloodstreams, glycogen inour liver and fat in the fat
cells.
Typically, your blood glucoseis good for a few hours.
(09:52):
Then you start tapping intoliver glycogen, start burning
liver glycogen if you skip a fewmeals and then, within a few
days, you start burning fat.
So fat is our long-term energystore and, evolutionarily, in
(10:13):
all vertebrates andinvertebrates for that matter
those energy stores areconserved and the brain has
developed very sophisticatedmechanics for conserving the
amount of fat that you have.
Now you would ask then well, whydo people become obese if those
fat levels are stored?
They are conservedhomeostatically, like the
(10:35):
temperature in the room, and Ihave two answers to that.
First of all, if you actuallylook at how people become obese,
it's incredibly tinyincremental gains in fat mass
that occur over a long period oftime.
In fact, if over 20 years,typically you get out of school
(10:56):
and 20 years later you're 20pounds overweight or whatnot,
that's only a pound per yearthat you're putting on on
average, or basically 3,500kcals in a year, 10 kcals in a
day.
That's the equivalent ofstoring one potato chip worth of
energy more per day than you'reburning the.
(11:27):
You know 40% of Americans beingoverweight or obese.
Even in the light of that, thebrain is still doing a really,
really good job of conservingyour long-term fat stores.
So that process is incrediblycomplex and 30 years later I'm
still trying to solve criticalissues to understand how the
brain regulates body weight.
Ben Comer (11:43):
So the freshman 15 that you hear about probably
takes a full year it's the fullfreshman year to get you to that
15-pound increase.
Roger Cone, Ph.D. (11:54):
Oh yeah, at least.
Ben Comer (11:56):
All right, I wanted to ask you a question.
Obviously, there is a lot ofdiscussion, a lot of interest, a
lot of excitement about theGLP-1 therapies and their
ability to help people loseweight and a number of other
things as well.
I wonder what you might say assomeone who's worked, you know,
(12:18):
kind of broadly, not in the GLPspace specifically, but more
broadly in this larger metabolicspace, I guess I'll call it.
What would you say about howthe obesity research field has
changed or evolved since youknow you started working in it,
maybe like before the discoveryand promotion of GLP-1s, and now
(12:41):
kind of where it stands today?
Roger Cone, Ph.D. (12:44):
So it's been a really remarkable period of
time in the history of scienceto see the field go.
When I started out from a placewhere we didn't have a single
obesity gene and there were noobesity therapeutics that really
worked.
You know, phentermine andfen-phen was used molecules that
(13:05):
block fat uptake for the gutbut had terrible side effects.
So there was really nothingthat was mechanism-based and
highly effective really untilthe GLP-1 drugs came along or
set melanotide and MC4 agonist.
Most people won't have heard ofthat because it's used for rare
syndromic obesity, but I wantto describe that because it gets
(13:27):
to the broader role that basicresearch has had.
So what's happened, which is aclassic example of how
biomedical research powersprogress, is that by discovery
of the mechanisms and themolecules that regulate satiety,
hunger, food intake, discoveryof the gut peptides like GLP-1,
(13:51):
discovery of the hypothalamiccircuits involving leptin and
the melanocortin circuit system,ultimately the pharmaceutical
industry was able to develop nowtwo highly effective, different
mechanism-based therapeuticsfor obesity.
On the one end, we have setmelanotide from Rhythm
(14:11):
Pharmaceuticals, which is a MC4agonist.
The trade name is Imcivree.
It's an MC4 agonist that'shighly effective in treating
syndromic obesity where thesyndromes have a defect in the
primary melanocortin system, somaking the agonist for MSH.
(14:34):
Those patients lose 20-25% bodyweight.
They're effectively normalizedbecause the drug replaces the
endogenous activator of the MC4receptor that's defective in
certain types of syndromicobesity, such as palm seed
deficiency or hypothalamicobesity, as it's called, which
(14:57):
results from a tumor calledcraniopharyngioma.
Anyway, so on the one end wehave mechanism-based therapies
that have dramatic positivemechanism-based effects,
reducing obesity and raresyndromic obesity early onset
syndromic obesity and then,through the evolution of
(15:17):
understanding of the biology ofthe GLP-1s and spectacular work
in both academia and thepharmaceutical industry, we have
the development of theGLP-1-based drugs, like Wegovy
and Mounjaro, which are justanalogs of the native GLP-1
peptide.
The remarkable story there isthat GLP-1 is a peptide made by
(15:43):
the gut but it's incredibly weakand has a very modest effect on
hunger and food intake,primarily because your native
GLP-1, made by the gut whenyou're full, only has a
half-life of about a minute, andso it has an incretin effect
working on the pancreas toimprove glucose-mediated insulin
(16:07):
release to help you take up theglucose that you obtain from
eating a meal.
But it really doesn't get intothe brain very well and do very
much in terms of making you feelfull.
It has a little effect.
What academia and ultimately thepharmaceutical industry did was
they started playing with GLPto make it better.
(16:28):
They asked well, what if wemade it more stable and long
acting?
Could it do a better job atreducing food intake?
And if you look at theevolution of the GLP-1 analogs,
from liraglutide to semaglutideto terzepatide, we've gone from,
you know, 5% to 7% weight losswith liraglutide to 10% to 15%
with 10% weight loss, let's say,with Wagovi, and all the way up
(16:52):
to 15% to 20% weight loss insome studies with terzepatide.
And it's simply by tweaking themolecule and making it more
stable and making some othermodest changes to the GLP-1
hormone that the pharmaceuticalindustry has been able to make
these very successful and safedrugs.
They're basically simplyanalogs of your own hormones but
(17:12):
do a little better job ofmaking you feel full and
reducing food intake.
Ben Comer (17:18):
And that weight loss benefit has a lot to do with
extending the half-life, Ibelieve, which I think was a
pretty big hurdle for academicsand the pharmaceutical companies
to get over.
I mean, I just I know that withexenatide, which was originally
marketed as Byetta, very shorthalf-life, potentially very
(17:39):
effective in larger doses, butyou start getting into
toxicities and you know thepatent expired before it was
ever really optimized for aweight loss indication.
It was only ever approved fordiabetes.
So that's a really interestingdevelopment that you know those
drugs were the originalsliraglutide, exenatide.
It's been quite some time sincethose original approvals.
(18:02):
I wanted to add withsetmelanotide, that was only
approved in the last few years.
Is that right?
Do you know what year that wasfirst approved?
Roger Cone, Ph.D. (18:11):
Yeah, 2020.
Ben Comer (18:13):
2020.
Wow yeah.
Roger Cone, Ph.D. (18:14):
Okay, it gets to the fact that drug
development is very, verycomplicated and takes a long
time.
The clinical trials take a longtime.
The development of themolecules to make them safe and
effective takes a long time.
The success rate is small.
So yeah, we cloned themelanocortin receptors.
We published the first cloningin 1992.
(18:34):
The first drug based on the MC4didn't get approved by the FDA
until 2020.
Ben Comer (18:40):
Right, yes, well, I can hear our audience for the
business of biotech noddingtheir head and agreeing along
with you on those comments aboutthe challenges and length of
time that it takes to do drugdelivery or drug development.
Excuse me, I want to talk alittle bit about Courage
Therapeutics.
(19:00):
This is the third biotechcompany that you founded and
before actually we get into whatCourage is up to, I wonder if
you could tell us a little bitabout the two previous companies
that you founded and maybe whatthose experiences were like.
Roger Cone, Ph.D. (19:15):
Sure.
So because I'm in the GPCRfield, it's been very
interesting and there's beenvarious points in the
development of the cloning andcharacterization of GPCRs where
I had some interesting entreesinto biotech, um Northwest
neurologic.
So when I was at um, when I wasat the volume Institute, that
(19:45):
the GPCRs were being cloned forthe first time and in many of
the GPCR families that wascritically important because it
made it much easier to developreceptors, subtype specific
compounds, um, when you once youhad the cloned receptor
subtypes.
So in the melanocortin familythere's five subtypes.
(20:06):
The serotonin family has a verylarge number of subtypes and so
in addition to cloningreceptors at the Volum Institute
, some of the dopamine receptorswere first cloned there.
The neurotransmittertransporters were first cloned
at the Volum Institute.
Some of the dopamine receptorswere first cloned there.
The neurotransmittertransporters were first cloned
at the Volum Institute by SusanAmara and so we had a bunch of
(20:28):
investigators there identifyingthe genes for receptor and
channel subtypes for the firsttime.
We thought we could use thistechnology to improve drug
development and drug discovery.
So we formed NorthwestNeurologic and we actually had a
number of pharma contracts tohelp pharma companies develop
(20:51):
better drugs.
We helped provide some of thedata that was used in the FDA
approval for venlafaxine, forexample.
And then quickly, we got abuyout offer early on and so our
exit was that our company andtechnology was picked up by
Neurocrine Biosciences of SanDiego.
So that was my first companyexperience.
(21:13):
I was a young assistantprofessor.
I was in Oregon, where it'squite a bit harder to raise
venture capital, et cetera, etcetera.
So, you know, rather than growthe company, uh, we, we uh sold
it off to Neurocrine Biosciencesreally early in our development
.
But it was a lot of fun and wefelt we did some good, you know,
working with with Wyeth onvenlafaxine and, um, uh, I.
(21:36):
I went on to serve Neurocrine ontheir SAB for I don't know,
five years perhaps after theypurchased the company, they made
an effort to developmelanocortin drugs.
The molecule they developed,the small molecule they
developed, had toxicity and sothat killed the program and, as
I mentioned, ultimately Rhythmwas successful in developing the
(21:59):
first FDA-approved MC4 agonist.
But it was a great experience,got to know fabulous scientists
like Wylie Vale, who was one ofthe scientific founders of
Neurocrine, and it also providedlots of tools and funding for
my basic research lab as well.
That's one thing I would pointout to investigators who are
(22:20):
considering getting involved incompany formation in biotech,
particularly if you're in afield where you can benefit from
having really state of the artpharmaceutical tools for your
research.
My work with companies over theyears has given me access to
(22:42):
really state-of-the-art toolsfor basic research as well.
Ben Comer (22:46):
Yeah, yeah.
So you got a taste for companyformation.
Then with the second company,was that a similar network of
people that you were workingwith, or was that something
completely different?
Roger Cone, Ph.D. (23:02):
completely different.
Yeah, the second company was azebrafish company designed to
try to leverage the zebrafish asa genetic model for gene
discovery, for drug targetdiscovery based on conservation
of multiple physiologicalprocesses from zebrafish, from a
very simple vertebrate tohumans.
So you know, many basicresearchers use the roundworm C
(23:26):
elegans or the fruit fly tostudy basic physiologic
mechanisms, but really you needto get into a vertebrate to get
after many of the criticallyconserved vertebrate
physiological mechanisms.
And so as the technology wasdeveloping and this was of
course and so as the technologywas developing and this was of
course long before the genomewas available and before it was
(23:46):
possible to simply go online andfind genes of interest, it was
very useful to have a geneticmodel system where we could
interrogate all the genes at onetime.
So that company, Xenomics,created a library of mutations
in every gene in the zebrafishand the basic model was to
(24:07):
provide that as a tool fordiscovering new drug targets.
And the company was developingvery nicely and we had raised
significant funding and had someexciting research projects
identifying drug targets incollaboration with other
academics and with industry.
(24:29):
And then the fall of 2008 camearound.
The market collapsed at acritical time for the company
where we needed to do the nextraise and we ended up having to
liquidate the company.
Next raise and we ended uphaving to liquidate the company.
Probably the best outcome inthe sense that, of course,
genome technology quickly tookover the world and the value of
(24:50):
having a library of mutations inevery gene in the zebrafish is
not now what it was then.
Ben Comer (24:58):
Before we move on to Courage.
I'm curious.
You know, as an academicscientist, uh founding, uh a
biotech company for the firsttime, how did you um, I guess
learn about the?
You know the, the businessaspects of financial aspects.
Maybe you you already knewabout that, knew what was going
to be expected, knew what youhad to do to raise funds.
(25:20):
I mean, you had a successfulexit.
So clearly you know you guysknew what you were doing.
But was that a challenge foryou?
And I'm thinking of you knowothers who might be listening to
this episode, who are workingin academia, who have a great
idea for a biotech company butare perhaps, you know, concerned
about the.
You know the whole picture ofcompany formation and the.
You know concerned about the.
(25:40):
You know the whole picture ofcompany formation and the.
You know the necessary to putit, to state it lightly,
requirement for funding, whatyou know.
How did you manage that?
How did?
Did you kind of learn as youwent?
Or did you have someone thatyou worked with?
How'd you go about doing that?
Roger Cone, Ph.D. (25:58):
Absolutely the latter.
Having experts to work with, Iwould never get involved with
company formation on my own.
A I don't have any expertise inthe business end of things, and
B I just love science and wantto do science.
And so, in the case of my firsttwo companies, I had a business
partner, a fellow named RichardSessions, who was an MBA and
(26:23):
was very keen to beentrepreneurial and start
companies, and he actuallygathered scientists together at
the Vollum Institute.
He was the managing director ofthe Institute at that time and
said I think there's enoughtechnology here for a great
company.
Do you all want to participate?
I'll do all the business, allthe business work.
And he did, and he did, and sothat was a great relationship, a
(26:45):
wonderful guy I had.
I did not intend to start acompany.
Rhythm obviously had done wellbringing setme lanotide to
market.
A entrepreneur from Bostoncontacted me and said you know,
I think I think we can do better.
I think we can generatenext-gen melanocortin compounds
(27:05):
and I think there's multipleother clinical applications
using both the MC3 and the MC4receptor.
So if I do all the businesswork and raise the money, would
you be interested in being thescientific founder?
And so I've always been atinstitutions that have allowed
me to do this and been verysupportive of company formation,
(27:27):
and then I've been veryfortunate to have great business
partners who've done theincorporation, legal,
fundraising, all those thingsthat need to be done.
Ben Comer (27:37):
And I think you're talking about Dan Hausman, who
is Courageous CEO, correct?
Roger Cone, Ph.D. (27:42):
Correct, he was the fellow at Boston.
Ben Comer (27:44):
Yeah Well, can you and again I'm thinking of our
listeners here can you give me asense of that relationship, you
know, just kind of on aday-to-day basis, like how you
guys work together to you knowprogress assets move the company
forward.
Roger Cone, Ph.D. (27:58):
So you know again, I just consider myself
incredibly lucky having bumpedinto Dan.
Dan had sold a prior company ofhis in the software space and
said I'll devote 100% of my timeand not take any pay to create
(28:19):
this company.
He was personally motivated andhe talks about this publicly.
His daughter suffered terriblyfrom anorexia nervosa and the
company was focused aroundoriginally focused around seeing
if we could use theMelanocortin system to develop
the first treatments ever foranorexia nervosa, and that's a
critical piece of the company.
(28:40):
Now we ended up making fasterprogress on new compounds for
various types of obesity, but wealso have a program focused on
developing therapeutics foranorexia nervosa as well.
So he was personally motivated.
He had the time and energy todevote a hundred percent effort
to growing the company.
(29:02):
We brought on other boardmembers, including leaders in
the field, like Steve O'Rahilly,a leading human obesity
endocrinologist and geneticist,and Fred Mermelstein, a drug
development expert.
So we brought on reallytalented people as advisors and
board members and we scheduledweekly one-hour board meetings.
(29:24):
We began developing the ideasfor our approach.
I then wrote STTR grants tofund the company.
Dan raised some angel funds.
I wrote a bunch of STTRs and wefunded the company for four
years on a very small initialangel round plus three different
STTRs that we've funded.
Ben Comer (29:45):
That's fantastic.
I appreciate that background.
I wanted to ask about theprocess of spinning out the
company from the University ofMichigan and you know.
I wonder what you could sayabout that, just in terms of
securing the IP and what thatprocess was like.
Roger Cone, Ph.D. (30:04):
So initially I had some patents before Dan
came along, one in particularthat was relevant to the company
and continued to generate IP.
Working with the company, theSTTRs provided subcontracts to
my lab at the University ofMichigan and so right away Dan
(30:25):
began a negotiation for anoption agreement with the
University of Michigan from thepre-existing and the
forward-looking IP in awell-defined space based on this
initial option agreement.
So he succeeded in negotiatingan option agreement with the
university that gave the companyrights to narrowly defined IP
(30:49):
coming out of my lab andsubsequently, with the STTR
funding, the IP ends up beingjointly owned between the
company and the university, asdefined by the option agreement,
owned between the company andthe university as defined by the
option agreement.
With this round of funding thatwe've just completed, the
company is now finalizing a fulllicense agreement with the
(31:12):
university for all of the IPthat we've generated in the last
four years.
Ben Comer (31:18):
Yeah, that was a correct me if I'm wrong.
$7.8 million seed investmentfrom Arsenal Bridge Ventures
that came in in May, is thatcorrect?
Roger Cone, Ph.D. (31:28):
So about half of that has come in and they're
raising the final amount now,but the target is $7.8.
And they're still so.
We had a first early close sothat we could start funding some
additional research right away,and now they're finishing up
the rest of the round.
Ben Comer (31:43):
So does Dan get you out of the lab to come talk to
those investors, go to some ofthose meetings and answer
questions, or are you completelyyou know walled off from that
kind of activity?
Roger Cone, Ph.D. (31:54):
No, I'm still the science guy and you know a
lot of the work is done withoutme, but when investors want more
detail on some of the science,I'll hop on a Zoom, Got it.
Yeah, got it Answer questions?
Yeah.
Ben Comer (32:07):
Yeah, okay, I wanted to add just because I don't even
need to say this, but a numberof successful companies have
begun as spin-outs fromuniversities, as spin outs from
universities, and I'm curiouswhat you would say about the
kinds of support, outside offinancial support, that the
University of Michigan provides.
(32:29):
Are they working with you oncourage therapeutics?
Roger Cone, Ph.D. (32:34):
So absolutely so where to begin?
So most universities allowfaculty one day a week or 20% of
their time roughly that sort ofaverage to consult, to consult
for drug companies or or otherinstitutions, to be on the board
(32:55):
of other research institutionsor departments or what have you
and?
And so Michigan, like otheruniversities, allows me 20% of
my time to do other things thatare relevant to my research but
not directly under the umbrellaof the University of Michigan,
and so my company work fallsunder that time that allows me
(33:19):
to do those types of things.
I also serve on the HHMIscientific review board and you
know I serve on some other, yeah.
Ben Comer (33:27):
You have a lot, a number of roles.
I was going to ask you aboutthat at the University of
Michigan.
Roger Cone, Ph.D. (33:31):
Yeah, so you know, as I was saying, I mean, I
I probably don't spend morethan you know, a couple hours a
week directly working for thecompany.
You know, giving scientificpresentations to investors or
putting together documents orwhat have you for the company.
Um, and then I get to do a lotof really great research in my
(33:52):
lab that I get to publish.
So you know a couple of things.
One is universities allow youthe time to do this.
Secondly is Michigan and otheruniversities will manage your
conflicts of interest for you.
So you just need to betransparent and tell them what
you're doing, and they'llprovide a conflict of interest
(34:15):
management plan to avoid anyconflict of interest between
your university duties and yourrole in a company you might be
involved in.
And so that involves disclosingmy activities with the company,
which I do on a regular basis,involves disclosing my
activities with the company,which I do on a regular basis.
And you know, when I submitgrants, they ask questions about
(34:36):
it, this and that.
And then there's various otherregulations that ensure that the
university's rights are held.
So the IP ownership iswell-defined in advance, et
cetera.
And so the university has beenincredibly supportive.
They've provided me with aconflict of interest management
(34:56):
plan.
They regularly address anyconflict of interest issues that
might come up.
They have taken an interest inthe company, so part of the
license agreement they get apercent of the company.
This is fairly standard at mostuniversities and additionally
(35:17):
they've connected me with someinvestment from here at the
university.
So we have a Michigan BiomedicalVentures Fund, which is a
venture philanthropy fund fundedby Michigan alums that helps
with startups, and so part ofour angel fund was resulted from
(35:40):
investment from the MichiganBiomedical Ventures Fund, or
MBVF.
Many universities have similarfunds, either venture
philanthropy or true venturefunds, so a small piece of
investment from that helped thecompany out.
Of course, tech Transfer hasbeen very active in helping us
file patents as well, soMichigan has been very
(36:05):
supportive.
They want to see theirinvestigators not only teach and
do research and do all thethings that professors normally
do.
They also want to see the workof the university have societal
impact and in the case ofbiomedical research that
involves either licensing yourtechnology to other companies or
forming your own companies tomove them forward.
Ben Comer (36:26):
I would imagine it's also a draw for you know
potential incoming students.
You know who may be interestedin working in this field.
Roger Cone, Ph.D. (36:35):
So my institute, the Life Sciences
Institute, provides most of thecore drug discovery technology
for the entire University ofMichigan.
We have all the chemicallibraries here.
We do high-throughput screeninghere x-ray crystallography,
cryo-em, structural biology,natural products, chemistry All
(36:57):
of these are provided as coreresources to the entire
university.
People take their NIH grants.
They come here and they say,okay, I want to do a screen at
this target and they can pay forthat at cost, using standard
recharge rates to get work done.
And then if they discoversomething particularly
(37:19):
interesting, they can talk tothe university about licensing
it out to a company or creatinga company, but taking
potentially useful technologyand seeing it do societal good.
So the university is highlysupportive of drug discovery.
We have a very robust drugdiscovery environment here at
University of Michigan and righttwo floors below me is the High
(37:42):
Throughput Screening Centerwith the same tools that are
found in industry.
We have state-of-the-artequipment for high-throughput
screening and chemical librariesand such, and our screening
center is run by a fellow thatwe recruited from Bristol Myers
who ran their high-throughputscreening for eight years.
So we bring in industry levelexpertise to do the work.
(38:04):
So, yeah, many universitiesprovide these types of resources
for their investigators.
Ben Comer (38:11):
Well, that is a solid pitch for the University of
Michigan that you just gave.
Let's talk about some of thedevelopment work that you're
doing at Courage Therapeutics.
I mentioned at the top thatyou're in the preclinical stages
, but could you describe whereyou are at the know, where you
are at the company?
You know what you're focused onat this moment and then maybe
(38:35):
you know the potential for aproduct that is synergenistic
with a GLP-1 product.
Roger Cone, Ph.D. (38:41):
Right, right, great question.
So so here's where we're at.
We've spent four years doingSAR to try to develop
best-in-class MC3 and MC4agonists for anorexia nervosa
and various forms of obesityrespectively.
Cite that the issues with thecurrent drug on the market,
(39:11):
setmelanotide, are that thecompound lacks adequate potency
to treat many of the obesitysyndromes and to treat dietary
obesity.
For example, it lacks adequatepotency to treat MC4
haploinsufficiency, the mostcommon genetic cause of human
syndromic obesity.
Furthermore, that compound,that that drug, lacks receptor
subtype specificity, meaning itacts at multiple melanocortin
(39:35):
receptors and so it causeshyperpigmentation through
activation of the msh, or mc1receptor, as we call it.
So best in class for us meantto develop mc4 compounds with
better potency and betterspecificity to be able to treat
some of the syndromes that setmelanotide can't treat without
(39:58):
the side effects.
So we've developed thosecompounds and basically what's
in between us and the clinic issafety and talk.
So we're doing safety talks andefficacy studies now to
nominate compounds to go intothe clinic and so we could be
(40:20):
six to 18 months away from beingready for clinical studies in
obesity.
We're still at the researchphase with our MC3 agonists.
We've got some really gooddrug-like molecules and we're
doing the preclinical researchon them now, and so then what
(40:41):
happened was we discovered thisunique phenomenon that we're
calling melanocortinhypersensitization, and we've
published on this in a recent2024 paper in the Journal of
Clinical Investigation.
What we found is that and thisis my brilliant postdoc, Naima
Dahir, who's soon going to betaking a faculty position at UT
(41:05):
Southwestern what we discoveredthrough her work was that even
when we give sub-threshold dosesof MC4 agonists, we can
hypersensitize animals to theweight loss effects of any of
the GLP-1 drugs.
We can effectively dose shiftthem about five-fold to the left
(41:29):
, and that's all published inthis Journal of Clinical
Investigation paper.
So what we think is happening isthe following the MC4 compounds
largely act in the hypothalamus.
The GLP-1 compounds are knownto act primarily first in the
area postrema of the brainstem,but the melanocortin and the
(41:53):
hypothalamic circuits areessential for inhibition of food
intake, ultimately by the GLP-1compounds.
And we know this from the workof Kevin Williams and others,
where they've demonstrated thatif you disrupt the melanocortin
circuits, you can block theinhibition of food intake by the
GLP-1 drugs.
So what we think is happeningis we're sensitizing the
(42:13):
hypothalamic circuits to theultimate end site of action of
the GLP-1 drugs.
Even though they come in andstart acting in the brainstem,
they need these hypothalamiccircuits.
If we sensitize thehypothalamic circuits, we can
improve the activity of theGLP-1 drugs in inhibition of
food intake without increasingtheir side effect profile, which
(42:35):
results from the brainstemaction.
By the way, that's well knowntoo, the main side effect being
nausea resulting from the actionof GLP-1 in the centers that
generate nausea in the brainstem.
Ben Comer (42:48):
So you would yeah, sorry, go ahead.
Roger Cone, Ph.D. (42:50):
Yeah.
So anyway, we think there'salso application of some of our
best in class compounds for umfor action as adjuvants for any
of the GLP-1 drugs.
Ben Comer (43:02):
So would that potentially lead to a lower dose
needed to achieve the sameamount of weight loss with a
GLP-1, or is that not how itwould work?
Roger Cone, Ph.D. (43:12):
We've been able to.
We have evidence that we canachieve either that we can get
the same weight loss with alower dose of the GLP-1 drug, or
we can get more weight lossthan the GLP-1 drug allows.
Now, this is all in mice.
Obviously, we need to translatethis and we're gearing up to go
(43:32):
and test this in non-humanprimates next, and then,
ultimately, clinical trials.
Ben Comer (43:41):
So forgive my ignorance on this, but with
anorexia nervosa, would thetreatment essentially provoke
hunger?
Is that what the ultimate goalis for a treatment for that
disorder, or describe that to me?
Roger Cone, Ph.D. (43:57):
So there's a couple of interesting bits of
data there, and so first of all,let me mention that, as you
alluded to, the melanocortincircuits are bidirectional.
When you activate them, youinhibit food intake.
When you alluded to, themelanocortin circuits are
bi-directional.
When you activate them, youinhibit food intake.
When you inhibit them, you canpotently stimulate food intake
even in fully sated animals, andthere's a preliminary clinical
(44:21):
study from Pfizer it's beenpublished, and rat studies from
Pfizer that have been publishedthat show that MC4 agonists can
stimulate food intake potentlyand they have a small molecule
compound that they're workingwith a small molecule MC4
(44:45):
antagonist.
So anyway, the melanocortincircuits are bidirectional, you
can inhibit or stimulate foodintake.
So certainly in any of theeating disorders one can imagine
simply turning on food intakein disordered eating where
there's inadequate drive to eat,now it turns out in classic
(45:07):
restricting type anorexianervosa.
Most of the thinking suggeststhat there is still a strong
drive to eat but thatindividuals are suppressing that
homeostatic drive, and so it'snot clear that making people
hungrier in classic restrictingtype anorexia is necessarily
advantageous.
(45:28):
However, there is evidence thatthe leptin-melanocortin
circuits and this is frompublished work of a fellow in
Germany there is evidence thatchronic maintenance of
substandard weight has a numberof other impacts, including
(45:52):
neuropsychiatric impacts, thatlead to the severity of anorexia
nervosa.
What he's found is that severehospitalized patients with
anorexia nervosa can exhibitsignificantly reduced depression
and anxiety following treatmentwith leptin.
(46:15):
Leptin activates melanocortincircuits.
It's very likely those sameeffects can be achieved with
melanocortins.
So anyway, in addition to insome eating disorders, in
addition to in some eatingdisorders, simply increasing
appetite will be highlyefficacious.
(46:37):
And it's also likely andthere's evidence suggesting some
of the neuropsychiatric aspectsof anorexia nervosa that
prevent people from regainingand prevent people from
developing more ordered eatingmay be treatable with molecules
along the leptin-melanic cordpathway as well.
(46:58):
So it's complicated, but let megive you an example where it's
less complicated than anorexianervosa, a very complicated
neuropsychiatric disorder that'snot well understood.
Let's look at the anorexia ofaging.
So it's a very commonexperience that as people age
they lose their appetite, andthis becomes really problematic
(47:20):
in the elderly, in nursing homesand in people with chronic
diseases.
They lose their appetite andthey start losing lean mass and
you know they have a hipfracture or what have you, due
to, you know, significant lossof muscle mass and bone mass,
and then you know there's a veryhigh morbidity and immortality
rate.
What if you could improveappetite and restore lean mass
(47:43):
and bone mass in the elderly?
So I think that's an examplewhere we don't have the
neuropsychiatric complicationsof anorexia, but yet a very
significant need for maintaininghealthy body weight.
That could be ameliorated witha melanocortin compound to
(48:06):
stimulate appetite.
Ben Comer (48:08):
That's really interesting.
I want to go back to obesitybecause I was curious, you know,
given the enormous success ofthe GLP-1 so far and kind of
cascading number of indicationsthat are being added in terms of
cardiovascular outcomes, kidneyfunction, even substance use
(48:29):
disorders that they couldpotentially help with, what are
the remaining key unmet needs inobesity that are not adequately
being met by the GLP-1therapies and potentially next
generation GLP-1 therapies?
Roger Cone, Ph.D. (48:46):
So great question, and you've hit on a
couple of these issues already.
I mean one is simply that thesedrugs are so effective and safe
, apparently, that you want tomake them available to people
that need them.
Some people can't tolerate them.
(49:07):
A significant percentage ofpeople can't tolerate them due
to the nausea.
Then there's the issue that,while we talk about the
fantastic success of these drugs, if you actually look at the
weight loss that individualsexperience on these drugs, it's
a big, broad bell curve andthere's a significant percentage
of people who only lose 5% or10% body weight after a year on
(49:31):
the current state-of-the-artGLP-1 compounds.
So improving weight loss fromthese compounds is still very
important.
Allowing people to successfullygo on the drugs is still an
unmet need.
People that suffer from theside effects too significantly.
(49:52):
And then, of course, there'sthe application of these drugs
to all of the differentconsequences of obesity.
Thus far, it appears that a lotof the health benefits of these
drugs come from losing weight,and we know that from decades of
studies of obesity and theincreased prevalence of heart
disease, diabetes, hypertension,orthopedic diseases, even
(50:14):
cancer risk that comes fromobesity.
So all of these things will beimproved by achieving healthy
body weight through the use ofthese drugs.
So so, theoretically, simplymaking these drugs better,
(50:38):
increasing the amount of weightloss that can be achieved for
them, will also haveapplications to reducing risk
from cardiovascular disease,diabetes, et cetera, et cetera.
Ben Comer (50:46):
Yeah, yeah.
So what about the, the kind oflean muscle mass that you hear
about?
Roger Cone, Ph.D. (50:51):
I know I forgot to touch on that, so it's
still.
It's still being investigated.
Um, when you lose body weight,you lose fat mass, but you also
lose lean mass.
Similarly, when you gain weight, you not only gain adipose mass
but you gain lean mass as well,simply from gaining weight.
(51:12):
Some people refer to that asthe gravitas stat that you know,
simply weighing more willproduce more lean mass, and the
exact mechanisms by which thathappen aren't known.
But when you lose weightthrough any process diet and
exercise, drug B you will losethe lean mass as well.
Losing lean mass is at somepoint not good, as we discussed.
(51:34):
Better muscle mass obviouslyreduces orthopedic problems and
injuries and helps preventdiabetes and multiple reasons
why you want to have adequatelean mass.
There are some studiessuggesting that the GLP-1 drugs
(51:58):
may produce more lean mass lossthan diet and exercise does.
The jury's not totally in onthat.
There's controversy in theliterature.
Let's say about that.
Nonetheless, whether the leanmass is due to the GLP-1,
whether there's enhanced loss oflean mass due to the GLP-1
drugs or not, preventing theloss of lean mass from weight
(52:19):
loss is important and there aremultiple companies pursuing that
.
We'll certainly look at thatwith our combination therapies
with our dual use ofmelanocortins and GLP-1 to see
if we can ameliorate the weightloss seen with the GLP-1s.
We are able to reproduce thatin the rodent.
It may or may not be relevantto the human, but we can see
(52:41):
greater loss of lean mass withthe GLP-1 drugs in rodents than
we do from the melanocortincompounds in rodents, than we do
from the melanocortin compound.
So you know, we may be able tostudy that in our rodent models
and it may or may not berelevant in the human, but it's
something that needs to belooked at.
Ben Comer (52:58):
Interesting.
Well, I'm coming up at the endof my time with you here, Roger,
but maybe we could end withjust your kind of top priorities
for the rest of 2025 and anykind of final thoughts that
you'd like to mention before wewrap up here.
Roger Cone, Ph.D. (53:15):
So at Courage , you know, our priority is to
finish the preclinical studiesand nominate compounds for
safety and toxicity studies andwith the goal of, you know,
being ready for the clinicpossibly, you know, in six to 18
(53:36):
months.
So that's, those are the goalsfor the company over the next,
over 2025 and first part of 2026.
Ben Comer (53:41):
Well, thanks so much for being on the show.
I really appreciate it.
We've been speaking with DrRoger Cohn, founder and chair of
the scientific advisory boardat Courage Therapeutics.
I'm Ben Comer and you've justlistened to the.
We've been speaking with DrRoger Cohn, founder and chair of
the Scientific Advisory Boardat Courage Therapeutics.
I'm Ben Comer, and you've justlistened to the Business of
Biotech.
Find us and subscribe anywhereyou listen to podcasts and be
sure to check out new weeklyvideocasts of these
(54:02):
conversations every Monday underthe Business of Biotech tab at
Life Science Leader.
We'll see you next week andthanks for listening.
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(00:44):
Welcome back to the Business ofBiotech.
I'm your host, Ben Comer, chiefeditor at life science leader,
and today I'm speaking with Dr.
Roger Cone, founder and chairof the scientific advisory board
at Courage Therapeutics, apre-clinical company focused on
obesity and eating disorders.
Courage Therapeutics'intellectual property is based
(01:05):
on Rogers' discoveries anddecades of research into the
melanocortin system, a pathwaycrucial to eating behaviors and
energy homeostasis.
Rogers is a professor at theUniversity of Michigan and has a
number of other roles andresponsibilities at UM's Life
Sciences Institute andBiosciences Initiative.
Courage Therapeutics is aUniversity of Michigan spinout
(01:29):
and the third company Roger hasfounded, so we'll find out what
he's learned from thoseexperiences, what role Courage
Therapeutics might play in thewhite-hot obesity space and how
he approaches company leadershipas a founding scientist.
Thanks so much for being here,Roger.
Roger Cone, Ph.D. (01:46):
Thank you, Ben.
Ben Comer (01:48):
I want to start with a little bit of your background
and experience and I guess,first of all I'm curious about
how you set out on the path ofresearching how the body
regulates hunger, caloric intakeand energy expenditure and
other related eating disorders.
Roger Cone, Ph.D. (02:10):
Well, great question, and, like so many
other things in science, therewas a bit of serendipity
involved.
Many, many years ago, I wasengaged in cloning G-protein
coupled receptors, just whencloning cloning began, actually,
and and?
that was the what mid eighties,early eighties late eighties,
(02:31):
late eighties, late eighties Iwas cloning receptors, GPCRs,
and they had just the technologyfor identifying and cloning
GPCRs had just been developed.
And we cloned the MSH receptor,the receptor in your
melanocytes that regulatespigment production.
We cloned the ACTH receptor,the receptor in your adrenal
(02:56):
gland that regulates the stresshormone, the glucocorticoids
that your body produces.
And then we found that therewere three other receptors in
that same family.
Those first two receptors werehighly related.
We found three more highlyrelated receptors in the family.
We had no idea.
Nobody knew what they did,They'd never been seen before
(03:18):
and they were orphans in thatregard, and so we just gave them
numbers MC3, MC4, and MC5.
And so we just gave themnumbers MC3, MC4, and MC5.
We proceeded to delete themfrom mice and we proceeded to
develop agonists and antagoniststo find what the orphans did.
And MC3 and MC4 were in thebrain and we ultimately
discovered that MC3 and MC4 werecritical to feeding behavior
(03:41):
and the regulation of bodyweight.
And I've studied thosereceptors ever since.
Yeah, could you give me a senseof just what that was like when
you made that discovery of theorphans and, you know, started
working on the, you know, theknockout mouse models?
I mean, as someone who won'thave a chance to make a
discovery like that, I'm justcurious about you know how you
(04:02):
might describe what it felt liketo actually first make the
discovery and then go and start,you know, exploring those
receptors and what they couldpotentially do.
Yeah, it was a fantastic time inmy career.
At that time there was not asingle human obesity gene known,
(04:22):
or not a single obesity geneknown, and what happened was
that, and the way that wediscovered that the MC4 was
involved in energy homeostasiswas that there were five
monogenic obesity models in themouse at Jackson Labs, the lab
that produces all the mousestrains that most people work
(04:44):
with, and over the years theyhad found five super obese mice,
that in which the obesitysyndrome was monogenic.
They knew from genetic studies.
It was passed on by a singlegene, and the five obesity
strains were called OBDB forobesity and diabetes, called
(05:10):
OB-DB for obesity and diabetes,ob-db, fatty tubby and agouti.
And we had some clues that theagouti animal might have
something to do with themelanocortin peptides, because
this mutation not only made theanimals morbidly obese, it also
converted their coat color fromblack to yellow, and so we knew
(05:31):
that there was a gene that wasimpacting both body weight,
which is controlled by the brain, and pigmentation, which is
controlled by the melanocytes,and here we had a receptor
family with, you know, onemember critically important in
pigment production and anothermember in the brain with unknown
activity, and so we tested thehypothesis that maybe this
defect was affecting both themelanocortin-1 and 4 receptors,
(05:51):
the MSH receptor and the orphan,and indeed we were able to
prove that the Agouti mutationis a mutation which blocks both
the MSH receptor and the MC4receptor in the brain at the
same time.
Well, within a year of ourdiscovery of that which we
published in one of the topjournals, Nature, within a year
(06:15):
of the discovery of that, humangeneticists working with early
obese kids had discovered thatthe most common cause of
monogenic obesity in kids wasdue to mutations in the MC4
receptor, Philippe Froguel inFrance and Stephen O'Rahilly in
England published thosediscoveries.
(06:36):
So not only was it incrediblyexciting to find one of the
first obesity genes, butliterally within a year or so,
human geneticists discoveredthat what was true in the mouse
was true in people as well.
Ben Comer (06:51):
And when you say monogenic obesity, you're
talking about obesity that canbe directly attributed to a
single gene mutation.
Is that correct, correct?
What percentage I guess, ifpercentage I guess of, of, if
you had to kind of ballpark it,of overall obesity, would you
say is, uh, is monogeneic.
Roger Cone, Ph.D. (07:12):
Uh well, I don't have to ballpark it.
There's been a lot of researchon that from geneticists like
Steve O'Reilly and uh he'sdemonstrated that the prevalence
of obesity due to mutations inthe MC4 receptor is very common.
It's as high as one in athousand individuals has early
(07:32):
onset obesity due to mutationsin the MC4 receptor.
Ben Comer (07:37):
And this is something that you can discover through
genotyping a patient, I assumewhether they have that mutation
or not.
Roger Cone, Ph.D. (07:43):
It's not uncommon now if children present
with early onset severe obesity, it's not uncommon for
endocrinologists to request someDNA sequencing to find out if
they have a leptin mutation oran MC4 mutation corresponding to
those mouse models I talkedabout, because there's different
treatments available dependingon the genetic background for
(08:06):
this severe syndromic obesity.
Ben Comer (08:09):
So these discoveries and this research was started
off in the late 80s with youknow, at your lab.
And where were actually?
Where were you based at thattime?
I don't think you were at theUniversity of Michigan yet,
right?
Roger Cone, Ph.D. (08:24):
Correct, I was at the Vollum Institute at
Oregon Health SciencesUniversity.
Ben Comer (08:28):
Okay, all right, and you have been continuing this
research ever since then and I'mcurious about you, know what
you might say has kept youinterested and kept you focused
on this area, you know, forupwards of 30 years.
Roger Cone, Ph.D. (08:45):
Well, I got fascinated by the mechanisms
underlying energy homeostasis.
Energy homeostasis most peopledon't think about that.
You know, when we think abouthomeostatic systems, we think
about things like bodytemperature.
You know, we're all basicallyat 98.6 unless we get a fever.
We think about blood oxygen,things like that, sleep-wake
(09:10):
cycles.
You know, we think about thingslike that when we think about
physiological homeostasis.
Many people don't understandthat your long-term fat stores
are also controlledhomeostatically by the brain and
critically, involving thecentral melanocortin circuits
and hormones such as the fathormone leptin, which tells the
(09:30):
brain how much long-term energyyou have on board.
So three basic forms of energythat we use every day glucose in
our bloodstreams, glycogen inour liver and fat in the fat
cells.
Typically, your blood glucoseis good for a few hours.
(09:52):
Then you start tapping intoliver glycogen, start burning
liver glycogen if you skip a fewmeals and then, within a few
days, you start burning fat.
So fat is our long-term energystore and, evolutionarily, in
(10:13):
all vertebrates andinvertebrates for that matter
those energy stores areconserved and the brain has
developed very sophisticatedmechanics for conserving the
amount of fat that you have.
Now you would ask then well, whydo people become obese if those
fat levels are stored?
They are conservedhomeostatically, like the
(10:35):
temperature in the room, and Ihave two answers to that.
First of all, if you actuallylook at how people become obese,
it's incredibly tinyincremental gains in fat mass
that occur over a long period oftime.
In fact, if over 20 years,typically you get out of school
(10:56):
and 20 years later you're 20pounds overweight or whatnot,
that's only a pound per yearthat you're putting on on
average, or basically 3,500kcals in a year, 10 kcals in a
day.
That's the equivalent ofstoring one potato chip worth of
energy more per day than you'reburning the.
(11:27):
You know 40% of Americans beingoverweight or obese.
Even in the light of that, thebrain is still doing a really,
really good job of conservingyour long-term fat stores.
So that process is incrediblycomplex and 30 years later I'm
still trying to solve criticalissues to understand how the
brain regulates body weight.
Ben Comer (11:43):
So the freshman 15 that you hear about probably
takes a full year it's the fullfreshman year to get you to that
15-pound increase.
Roger Cone, Ph.D. (11:54):
Oh yeah, at least.
Ben Comer (11:56):
All right, I wanted to ask you a question.
Obviously, there is a lot ofdiscussion, a lot of interest, a
lot of excitement about theGLP-1 therapies and their
ability to help people loseweight and a number of other
things as well.
I wonder what you might say assomeone who's worked, you know,
(12:18):
kind of broadly, not in the GLPspace specifically, but more
broadly in this larger metabolicspace, I guess I'll call it.
What would you say about howthe obesity research field has
changed or evolved since youknow you started working in it,
maybe like before the discoveryand promotion of GLP-1s, and now
(12:41):
kind of where it stands today?
Roger Cone, Ph.D. (12:44):
So it's been a really remarkable period of
time in the history of scienceto see the field go.
When I started out from a placewhere we didn't have a single
obesity gene and there were noobesity therapeutics that really
worked.
You know, phentermine andfen-phen was used molecules that
(13:05):
block fat uptake for the gutbut had terrible side effects.
So there was really nothingthat was mechanism-based and
highly effective really untilthe GLP-1 drugs came along or
set melanotide and MC4 agonist.
Most people won't have heard ofthat because it's used for rare
syndromic obesity, but I wantto describe that because it gets
(13:27):
to the broader role that basicresearch has had.
So what's happened, which is aclassic example of how
biomedical research powersprogress, is that by discovery
of the mechanisms and themolecules that regulate satiety,
hunger, food intake, discoveryof the gut peptides like GLP-1,
(13:51):
discovery of the hypothalamiccircuits involving leptin and
the melanocortin circuit system,ultimately the pharmaceutical
industry was able to develop nowtwo highly effective, different
mechanism-based therapeuticsfor obesity.
On the one end, we have setmelanotide from Rhythm
(14:11):
Pharmaceuticals, which is a MC4agonist.
The trade name is Imcivree.
It's an MC4 agonist that'shighly effective in treating
syndromic obesity where thesyndromes have a defect in the
primary melanocortin system, somaking the agonist for MSH.
(14:34):
Those patients lose 20-25% bodyweight.
They're effectively normalizedbecause the drug replaces the
endogenous activator of the MC4receptor that's defective in
certain types of syndromicobesity, such as palm seed
deficiency or hypothalamicobesity, as it's called, which
(14:57):
results from a tumor calledcraniopharyngioma.
Anyway, so on the one end wehave mechanism-based therapies
that have dramatic positivemechanism-based effects,
reducing obesity and raresyndromic obesity early onset
syndromic obesity and then,through the evolution of
(15:17):
understanding of the biology ofthe GLP-1s and spectacular work
in both academia and thepharmaceutical industry, we have
the development of theGLP-1-based drugs, like Wegovy
and Mounjaro, which are justanalogs of the native GLP-1
peptide.
The remarkable story there isthat GLP-1 is a peptide made by
(15:43):
the gut but it's incredibly weakand has a very modest effect on
hunger and food intake,primarily because your native
GLP-1, made by the gut whenyou're full, only has a
half-life of about a minute, andso it has an incretin effect
working on the pancreas toimprove glucose-mediated insulin
(16:07):
release to help you take up theglucose that you obtain from
eating a meal.
But it really doesn't get intothe brain very well and do very
much in terms of making you feelfull.
It has a little effect.
What academia and ultimately thepharmaceutical industry did was
they started playing with GLPto make it better.
(16:28):
They asked well, what if wemade it more stable and long
acting?
Could it do a better job atreducing food intake?
And if you look at theevolution of the GLP-1 analogs,
from liraglutide to semaglutideto terzepatide, we've gone from,
you know, 5% to 7% weight losswith liraglutide to 10% to 15%
with 10% weight loss, let's say,with Wagovi, and all the way up
(16:52):
to 15% to 20% weight loss insome studies with terzepatide.
And it's simply by tweaking themolecule and making it more
stable and making some othermodest changes to the GLP-1
hormone that the pharmaceuticalindustry has been able to make
these very successful and safedrugs.
They're basically simplyanalogs of your own hormones but
(17:12):
do a little better job ofmaking you feel full and
reducing food intake.
Ben Comer (17:18):
And that weight loss benefit has a lot to do with
extending the half-life, Ibelieve, which I think was a
pretty big hurdle for academicsand the pharmaceutical companies
to get over.
I mean, I just I know that withexenatide, which was originally
marketed as Byetta, very shorthalf-life, potentially very
(17:39):
effective in larger doses, butyou start getting into
toxicities and you know thepatent expired before it was
ever really optimized for aweight loss indication.
It was only ever approved fordiabetes.
So that's a really interestingdevelopment that you know those
drugs were the originalsliraglutide, exenatide.
It's been quite some time sincethose original approvals.
(18:02):
I wanted to add withsetmelanotide, that was only
approved in the last few years.
Is that right?
Do you know what year that wasfirst approved?
Roger Cone, Ph.D. (18:11):
Yeah, 2020.
Ben Comer (18:13):
2020.
Wow yeah.
Roger Cone, Ph.D. (18:14):
Okay, it gets to the fact that drug
development is very, verycomplicated and takes a long
time.
The clinical trials take a longtime.
The development of themolecules to make them safe and
effective takes a long time.
The success rate is small.
So yeah, we cloned themelanocortin receptors.
We published the first cloningin 1992.
(18:34):
The first drug based on the MC4didn't get approved by the FDA
until 2020.
Ben Comer (18:40):
Right, yes, well, I can hear our audience for the
business of biotech noddingtheir head and agreeing along
with you on those comments aboutthe challenges and length of
time that it takes to do drugdelivery or drug development.
Excuse me, I want to talk alittle bit about Courage
Therapeutics.
(19:00):
This is the third biotechcompany that you founded and
before actually we get into whatCourage is up to, I wonder if
you could tell us a little bitabout the two previous companies
that you founded and maybe whatthose experiences were like.
Roger Cone, Ph.D. (19:15):
Sure.
So because I'm in the GPCRfield, it's been very
interesting and there's beenvarious points in the
development of the cloning andcharacterization of GPCRs where
I had some interesting entreesinto biotech, um Northwest
neurologic.
So when I was at um, when I wasat the volume Institute, that
(19:45):
the GPCRs were being cloned forthe first time and in many of
the GPCR families that wascritically important because it
made it much easier to developreceptors, subtype specific
compounds, um, when you once youhad the cloned receptor
subtypes.
So in the melanocortin familythere's five subtypes.
(20:06):
The serotonin family has a verylarge number of subtypes and so
in addition to cloningreceptors at the Volum Institute
, some of the dopamine receptorswere first cloned there.
The neurotransmittertransporters were first cloned
at the Volum Institute.
Some of the dopamine receptorswere first cloned there.
The neurotransmittertransporters were first cloned
at the Volum Institute by SusanAmara and so we had a bunch of
(20:28):
investigators there identifyingthe genes for receptor and
channel subtypes for the firsttime.
We thought we could use thistechnology to improve drug
development and drug discovery.
So we formed NorthwestNeurologic and we actually had a
number of pharma contracts tohelp pharma companies develop
(20:51):
better drugs.
We helped provide some of thedata that was used in the FDA
approval for venlafaxine, forexample.
And then quickly, we got abuyout offer early on and so our
exit was that our company andtechnology was picked up by
Neurocrine Biosciences of SanDiego.
So that was my first companyexperience.
(21:13):
I was a young assistantprofessor.
I was in Oregon, where it'squite a bit harder to raise
venture capital, et cetera, etcetera.
So, you know, rather than growthe company, uh, we, we uh sold
it off to Neurocrine Biosciencesreally early in our development
.
But it was a lot of fun and wefelt we did some good, you know,
working with with Wyeth onvenlafaxine and, um, uh, I.
(21:36):
I went on to serve Neurocrine ontheir SAB for I don't know,
five years perhaps after theypurchased the company, they made
an effort to developmelanocortin drugs.
The molecule they developed,the small molecule they
developed, had toxicity and sothat killed the program and, as
I mentioned, ultimately Rhythmwas successful in developing the
(21:59):
first FDA-approved MC4 agonist.
But it was a great experience,got to know fabulous scientists
like Wylie Vale, who was one ofthe scientific founders of
Neurocrine, and it also providedlots of tools and funding for
my basic research lab as well.
That's one thing I would pointout to investigators who are
(22:20):
considering getting involved incompany formation in biotech,
particularly if you're in afield where you can benefit from
having really state of the artpharmaceutical tools for your
research.
My work with companies over theyears has given me access to
(22:42):
really state-of-the-art toolsfor basic research as well.
Ben Comer (22:46):
Yeah, yeah.
So you got a taste for companyformation.
Then with the second company,was that a similar network of
people that you were workingwith, or was that something
completely different?
Roger Cone, Ph.D. (23:02):
completely different.
Yeah, the second company was azebrafish company designed to
try to leverage the zebrafish asa genetic model for gene
discovery, for drug targetdiscovery based on conservation
of multiple physiologicalprocesses from zebrafish, from a
very simple vertebrate tohumans.
So you know, many basicresearchers use the roundworm C
(23:26):
elegans or the fruit fly tostudy basic physiologic
mechanisms, but really you needto get into a vertebrate to get
after many of the criticallyconserved vertebrate
physiological mechanisms.
And so as the technology wasdeveloping and this was of
course and so as the technologywas developing and this was of
course long before the genomewas available and before it was
(23:46):
possible to simply go online andfind genes of interest, it was
very useful to have a geneticmodel system where we could
interrogate all the genes at onetime.
So that company, Xenomics,created a library of mutations
in every gene in the zebrafishand the basic model was to
(24:07):
provide that as a tool fordiscovering new drug targets.
And the company was developingvery nicely and we had raised
significant funding and had someexciting research projects
identifying drug targets incollaboration with other
academics and with industry.
(24:29):
And then the fall of 2008 camearound.
The market collapsed at acritical time for the company
where we needed to do the nextraise and we ended up having to
liquidate the company.
Next raise and we ended uphaving to liquidate the company.
Probably the best outcome inthe sense that, of course,
genome technology quickly tookover the world and the value of
(24:50):
having a library of mutations inevery gene in the zebrafish is
not now what it was then.
Ben Comer (24:58):
Before we move on to Courage.
I'm curious.
You know, as an academicscientist, uh founding, uh a
biotech company for the firsttime, how did you um, I guess
learn about the?
You know the, the businessaspects of financial aspects.
Maybe you you already knewabout that, knew what was going
to be expected, knew what youhad to do to raise funds.
(25:20):
I mean, you had a successfulexit.
So clearly you know you guysknew what you were doing.
But was that a challenge foryou?
And I'm thinking of you knowothers who might be listening to
this episode, who are workingin academia, who have a great
idea for a biotech company butare perhaps, you know, concerned
about the.
You know the whole picture ofcompany formation and the.
You know concerned about the.
(25:40):
You know the whole picture ofcompany formation and the.
You know the necessary to putit, to state it lightly,
requirement for funding, whatyou know.
How did you manage that?
How did?
Did you kind of learn as youwent?
Or did you have someone thatyou worked with?
How'd you go about doing that?
Roger Cone, Ph.D. (25:58):
Absolutely the latter.
Having experts to work with, Iwould never get involved with
company formation on my own.
A I don't have any expertise inthe business end of things, and
B I just love science and wantto do science.
And so, in the case of my firsttwo companies, I had a business
partner, a fellow named RichardSessions, who was an MBA and
(26:23):
was very keen to beentrepreneurial and start
companies, and he actuallygathered scientists together at
the Vollum Institute.
He was the managing director ofthe Institute at that time and
said I think there's enoughtechnology here for a great
company.
Do you all want to participate?
I'll do all the business, allthe business work.
And he did, and he did, and sothat was a great relationship, a
(26:45):
wonderful guy I had.
I did not intend to start acompany.
Rhythm obviously had done wellbringing setme lanotide to
market.
A entrepreneur from Bostoncontacted me and said you know,
I think I think we can do better.
I think we can generatenext-gen melanocortin compounds
(27:05):
and I think there's multipleother clinical applications
using both the MC3 and the MC4receptor.
So if I do all the businesswork and raise the money, would
you be interested in being thescientific founder?
And so I've always been atinstitutions that have allowed
me to do this and been verysupportive of company formation,
(27:27):
and then I've been veryfortunate to have great business
partners who've done theincorporation, legal,
fundraising, all those thingsthat need to be done.
Ben Comer (27:37):
And I think you're talking about Dan Hausman, who
is Courageous CEO, correct?
Roger Cone, Ph.D. (27:42):
Correct, he was the fellow at Boston.
Ben Comer (27:44):
Yeah Well, can you and again I'm thinking of our
listeners here can you give me asense of that relationship, you
know, just kind of on aday-to-day basis, like how you
guys work together to you knowprogress assets move the company
forward.
Roger Cone, Ph.D. (27:58):
So you know again, I just consider myself
incredibly lucky having bumpedinto Dan.
Dan had sold a prior company ofhis in the software space and
said I'll devote 100% of my timeand not take any pay to create
(28:19):
this company.
He was personally motivated andhe talks about this publicly.
His daughter suffered terriblyfrom anorexia nervosa and the
company was focused aroundoriginally focused around seeing
if we could use theMelanocortin system to develop
the first treatments ever foranorexia nervosa, and that's a
critical piece of the company.
(28:40):
Now we ended up making fasterprogress on new compounds for
various types of obesity, but wealso have a program focused on
developing therapeutics foranorexia nervosa as well.
So he was personally motivated.
He had the time and energy todevote a hundred percent effort
to growing the company.
(29:02):
We brought on other boardmembers, including leaders in
the field, like Steve O'Rahilly,a leading human obesity
endocrinologist and geneticist,and Fred Mermelstein, a drug
development expert.
So we brought on reallytalented people as advisors and
board members and we scheduledweekly one-hour board meetings.
(29:24):
We began developing the ideasfor our approach.
I then wrote STTR grants tofund the company.
Dan raised some angel funds.
I wrote a bunch of STTRs and wefunded the company for four
years on a very small initialangel round plus three different
STTRs that we've funded.
Ben Comer (29:45):
That's fantastic.
I appreciate that background.
I wanted to ask about theprocess of spinning out the
company from the University ofMichigan and you know.
I wonder what you could sayabout that, just in terms of
securing the IP and what thatprocess was like.
Roger Cone, Ph.D. (30:04):
So initially I had some patents before Dan
came along, one in particularthat was relevant to the company
and continued to generate IP.
Working with the company, theSTTRs provided subcontracts to
my lab at the University ofMichigan and so right away Dan
(30:25):
began a negotiation for anoption agreement with the
University of Michigan from thepre-existing and the
forward-looking IP in awell-defined space based on this
initial option agreement.
So he succeeded in negotiatingan option agreement with the
university that gave the companyrights to narrowly defined IP
(30:49):
coming out of my lab andsubsequently, with the STTR
funding, the IP ends up beingjointly owned between the
company and the university, asdefined by the option agreement,
owned between the company andthe university as defined by the
option agreement.
With this round of funding thatwe've just completed, the
company is now finalizing a fulllicense agreement with the
(31:12):
university for all of the IPthat we've generated in the last
four years.
Ben Comer (31:18):
Yeah, that was a correct me if I'm wrong.
$7.8 million seed investmentfrom Arsenal Bridge Ventures
that came in in May, is thatcorrect?
Roger Cone, Ph.D. (31:28):
So about half of that has come in and they're
raising the final amount now,but the target is $7.8.
And they're still so.
We had a first early close sothat we could start funding some
additional research right away,and now they're finishing up
the rest of the round.
Ben Comer (31:43):
So does Dan get you out of the lab to come talk to
those investors, go to some ofthose meetings and answer
questions, or are you completelyyou know walled off from that
kind of activity?
Roger Cone, Ph.D. (31:54):
No, I'm still the science guy and you know a
lot of the work is done withoutme, but when investors want more
detail on some of the science,I'll hop on a Zoom, Got it.
Yeah, got it Answer questions?
Yeah.
Ben Comer (32:07):
Yeah, okay, I wanted to add just because I don't even
need to say this, but a numberof successful companies have
begun as spin-outs fromuniversities, as spin outs from
universities, and I'm curiouswhat you would say about the
kinds of support, outside offinancial support, that the
University of Michigan provides.
(32:29):
Are they working with you oncourage therapeutics?
Roger Cone, Ph.D. (32:34):
So absolutely so where to begin?
So most universities allowfaculty one day a week or 20% of
their time roughly that sort ofaverage to consult, to consult
for drug companies or or otherinstitutions, to be on the board
(32:55):
of other research institutionsor departments or what have you
and?
And so Michigan, like otheruniversities, allows me 20% of
my time to do other things thatare relevant to my research but
not directly under the umbrellaof the University of Michigan,
and so my company work fallsunder that time that allows me
(33:19):
to do those types of things.
I also serve on the HHMIscientific review board and you
know I serve on some other, yeah.
Ben Comer (33:27):
You have a lot, a number of roles.
I was going to ask you aboutthat at the University of
Michigan.
Roger Cone, Ph.D. (33:31):
Yeah, so you know, as I was saying, I mean, I
I probably don't spend morethan you know, a couple hours a
week directly working for thecompany.
You know, giving scientificpresentations to investors or
putting together documents orwhat have you for the company.
Um, and then I get to do a lotof really great research in my
(33:52):
lab that I get to publish.
So you know a couple of things.
One is universities allow youthe time to do this.
Secondly is Michigan and otheruniversities will manage your
conflicts of interest for you.
So you just need to betransparent and tell them what
you're doing, and they'llprovide a conflict of interest
(34:15):
management plan to avoid anyconflict of interest between
your university duties and yourrole in a company you might be
involved in.
And so that involves disclosingmy activities with the company,
which I do on a regular basis,involves disclosing my
activities with the company,which I do on a regular basis.
And you know, when I submitgrants, they ask questions about
(34:36):
it, this and that.
And then there's various otherregulations that ensure that the
university's rights are held.
So the IP ownership iswell-defined in advance, et
cetera.
And so the university has beenincredibly supportive.
They've provided me with aconflict of interest management
(34:56):
plan.
They regularly address anyconflict of interest issues that
might come up.
They have taken an interest inthe company, so part of the
license agreement they get apercent of the company.
This is fairly standard at mostuniversities and additionally
(35:17):
they've connected me with someinvestment from here at the
university.
So we have a Michigan BiomedicalVentures Fund, which is a
venture philanthropy fund fundedby Michigan alums that helps
with startups, and so part ofour angel fund was resulted from
(35:40):
investment from the MichiganBiomedical Ventures Fund, or
MBVF.
Many universities have similarfunds, either venture
philanthropy or true venturefunds, so a small piece of
investment from that helped thecompany out.
Of course, tech Transfer hasbeen very active in helping us
file patents as well, soMichigan has been very
(36:05):
supportive.
They want to see theirinvestigators not only teach and
do research and do all thethings that professors normally
do.
They also want to see the workof the university have societal
impact and in the case ofbiomedical research that
involves either licensing yourtechnology to other companies or
forming your own companies tomove them forward.
Ben Comer (36:26):
I would imagine it's also a draw for you know
potential incoming students.
You know who may be interestedin working in this field.
Roger Cone, Ph.D. (36:35):
So my institute, the Life Sciences
Institute, provides most of thecore drug discovery technology
for the entire University ofMichigan.
We have all the chemicallibraries here.
We do high-throughput screeninghere x-ray crystallography,
cryo-em, structural biology,natural products, chemistry All
(36:57):
of these are provided as coreresources to the entire
university.
People take their NIH grants.
They come here and they say,okay, I want to do a screen at
this target and they can pay forthat at cost, using standard
recharge rates to get work done.
And then if they discoversomething particularly
(37:19):
interesting, they can talk tothe university about licensing
it out to a company or creatinga company, but taking
potentially useful technologyand seeing it do societal good.
So the university is highlysupportive of drug discovery.
We have a very robust drugdiscovery environment here at
University of Michigan and righttwo floors below me is the High
(37:42):
Throughput Screening Centerwith the same tools that are
found in industry.
We have state-of-the-artequipment for high-throughput
screening and chemical librariesand such, and our screening
center is run by a fellow thatwe recruited from Bristol Myers
who ran their high-throughputscreening for eight years.
So we bring in industry levelexpertise to do the work.
(38:04):
So, yeah, many universitiesprovide these types of resources
for their investigators.
Ben Comer (38:11):
Well, that is a solid pitch for the University of
Michigan that you just gave.
Let's talk about some of thedevelopment work that you're
doing at Courage Therapeutics.
I mentioned at the top thatyou're in the preclinical stages
, but could you describe whereyou are at the know, where you
are at the company?
You know what you're focused onat this moment and then maybe
(38:35):
you know the potential for aproduct that is synergenistic
with a GLP-1 product.
Roger Cone, Ph.D. (38:41):
Right, right, great question.
So so here's where we're at.
We've spent four years doingSAR to try to develop
best-in-class MC3 and MC4agonists for anorexia nervosa
and various forms of obesityrespectively.
Cite that the issues with thecurrent drug on the market,
(39:11):
setmelanotide, are that thecompound lacks adequate potency
to treat many of the obesitysyndromes and to treat dietary
obesity.
For example, it lacks adequatepotency to treat MC4
haploinsufficiency, the mostcommon genetic cause of human
syndromic obesity.
Furthermore, that compound,that that drug, lacks receptor
subtype specificity, meaning itacts at multiple melanocortin
(39:35):
receptors and so it causeshyperpigmentation through
activation of the msh, or mc1receptor, as we call it.
So best in class for us meantto develop mc4 compounds with
better potency and betterspecificity to be able to treat
some of the syndromes that setmelanotide can't treat without
(39:58):
the side effects.
So we've developed thosecompounds and basically what's
in between us and the clinic issafety and talk.
So we're doing safety talks andefficacy studies now to
nominate compounds to go intothe clinic and so we could be
(40:20):
six to 18 months away from beingready for clinical studies in
obesity.
We're still at the researchphase with our MC3 agonists.
We've got some really gooddrug-like molecules and we're
doing the preclinical researchon them now, and so then what
(40:41):
happened was we discovered thisunique phenomenon that we're
calling melanocortinhypersensitization, and we've
published on this in a recent2024 paper in the Journal of
Clinical Investigation.
What we found is that and thisis my brilliant postdoc, Naima
Dahir, who's soon going to betaking a faculty position at UT
(41:05):
Southwestern what we discoveredthrough her work was that even
when we give sub-threshold dosesof MC4 agonists, we can
hypersensitize animals to theweight loss effects of any of
the GLP-1 drugs.
We can effectively dose shiftthem about five-fold to the left
(41:29):
, and that's all published inthis Journal of Clinical
Investigation paper.
So what we think is happening isthe following the MC4 compounds
largely act in the hypothalamus.
The GLP-1 compounds are knownto act primarily first in the
area postrema of the brainstem,but the melanocortin and the
(41:53):
hypothalamic circuits areessential for inhibition of food
intake, ultimately by the GLP-1compounds.
And we know this from the workof Kevin Williams and others,
where they've demonstrated thatif you disrupt the melanocortin
circuits, you can block theinhibition of food intake by the
GLP-1 drugs.
So what we think is happeningis we're sensitizing the
(42:13):
hypothalamic circuits to theultimate end site of action of
the GLP-1 drugs.
Even though they come in andstart acting in the brainstem,
they need these hypothalamiccircuits.
If we sensitize thehypothalamic circuits, we can
improve the activity of theGLP-1 drugs in inhibition of
food intake without increasingtheir side effect profile, which
(42:35):
results from the brainstemaction.
By the way, that's well knowntoo, the main side effect being
nausea resulting from the actionof GLP-1 in the centers that
generate nausea in the brainstem.
Ben Comer (42:48):
So you would yeah, sorry, go ahead.
Roger Cone, Ph.D. (42:50):
Yeah.
So anyway, we think there'salso application of some of our
best in class compounds for umfor action as adjuvants for any
of the GLP-1 drugs.
Ben Comer (43:02):
So would that potentially lead to a lower dose
needed to achieve the sameamount of weight loss with a
GLP-1, or is that not how itwould work?
Roger Cone, Ph.D. (43:12):
We've been able to.
We have evidence that we canachieve either that we can get
the same weight loss with alower dose of the GLP-1 drug, or
we can get more weight lossthan the GLP-1 drug allows.
Now, this is all in mice.
Obviously, we need to translatethis and we're gearing up to go
(43:32):
and test this in non-humanprimates next, and then,
ultimately, clinical trials.
Ben Comer (43:41):
So forgive my ignorance on this, but with
anorexia nervosa, would thetreatment essentially provoke
hunger?
Is that what the ultimate goalis for a treatment for that
disorder, or describe that to me?
Roger Cone, Ph.D. (43:57):
So there's a couple of interesting bits of
data there, and so first of all,let me mention that, as you
alluded to, the melanocortincircuits are bidirectional.
When you activate them, youinhibit food intake.
When you alluded to, themelanocortin circuits are
bi-directional.
When you activate them, youinhibit food intake.
When you inhibit them, you canpotently stimulate food intake
even in fully sated animals, andthere's a preliminary clinical
(44:21):
study from Pfizer it's beenpublished, and rat studies from
Pfizer that have been publishedthat show that MC4 agonists can
stimulate food intake potentlyand they have a small molecule
compound that they're workingwith a small molecule MC4
(44:45):
antagonist.
So anyway, the melanocortincircuits are bidirectional, you
can inhibit or stimulate foodintake.
So certainly in any of theeating disorders one can imagine
simply turning on food intakein disordered eating where
there's inadequate drive to eat,now it turns out in classic
(45:07):
restricting type anorexianervosa.
Most of the thinking suggeststhat there is still a strong
drive to eat but thatindividuals are suppressing that
homeostatic drive, and so it'snot clear that making people
hungrier in classic restrictingtype anorexia is necessarily
advantageous.
(45:28):
However, there is evidence thatthe leptin-melanocortin
circuits and this is frompublished work of a fellow in
Germany there is evidence thatchronic maintenance of
substandard weight has a numberof other impacts, including
(45:52):
neuropsychiatric impacts, thatlead to the severity of anorexia
nervosa.
What he's found is that severehospitalized patients with
anorexia nervosa can exhibitsignificantly reduced depression
and anxiety following treatmentwith leptin.
(46:15):
Leptin activates melanocortincircuits.
It's very likely those sameeffects can be achieved with
melanocortins.
So anyway, in addition to insome eating disorders, in
addition to in some eatingdisorders, simply increasing
appetite will be highlyefficacious.
(46:37):
And it's also likely andthere's evidence suggesting some
of the neuropsychiatric aspectsof anorexia nervosa that
prevent people from regainingand prevent people from
developing more ordered eatingmay be treatable with molecules
along the leptin-melanic cordpathway as well.
(46:58):
So it's complicated, but let megive you an example where it's
less complicated than anorexianervosa, a very complicated
neuropsychiatric disorder that'snot well understood.
Let's look at the anorexia ofaging.
So it's a very commonexperience that as people age
they lose their appetite, andthis becomes really problematic
(47:20):
in the elderly, in nursing homesand in people with chronic
diseases.
They lose their appetite andthey start losing lean mass and
you know they have a hipfracture or what have you, due
to, you know, significant lossof muscle mass and bone mass,
and then you know there's a veryhigh morbidity and immortality
rate.
What if you could improveappetite and restore lean mass
(47:43):
and bone mass in the elderly?
So I think that's an examplewhere we don't have the
neuropsychiatric complicationsof anorexia, but yet a very
significant need for maintaininghealthy body weight.
That could be ameliorated witha melanocortin compound to
(48:06):
stimulate appetite.
Ben Comer (48:08):
That's really interesting.
I want to go back to obesitybecause I was curious, you know,
given the enormous success ofthe GLP-1 so far and kind of
cascading number of indicationsthat are being added in terms of
cardiovascular outcomes, kidneyfunction, even substance use
(48:29):
disorders that they couldpotentially help with, what are
the remaining key unmet needs inobesity that are not adequately
being met by the GLP-1therapies and potentially next
generation GLP-1 therapies?
Roger Cone, Ph.D. (48:46):
So great question, and you've hit on a
couple of these issues already.
I mean one is simply that thesedrugs are so effective and safe
, apparently, that you want tomake them available to people
that need them.
Some people can't tolerate them.
(49:07):
A significant percentage ofpeople can't tolerate them due
to the nausea.
Then there's the issue that,while we talk about the
fantastic success of these drugs, if you actually look at the
weight loss that individualsexperience on these drugs, it's
a big, broad bell curve andthere's a significant percentage
of people who only lose 5% or10% body weight after a year on
(49:31):
the current state-of-the-artGLP-1 compounds.
So improving weight loss fromthese compounds is still very
important.
Allowing people to successfullygo on the drugs is still an
unmet need.
People that suffer from theside effects too significantly.
(49:52):
And then, of course, there'sthe application of these drugs
to all of the differentconsequences of obesity.
Thus far, it appears that a lotof the health benefits of these
drugs come from losing weight,and we know that from decades of
studies of obesity and theincreased prevalence of heart
disease, diabetes, hypertension,orthopedic diseases, even
(50:14):
cancer risk that comes fromobesity.
So all of these things will beimproved by achieving healthy
body weight through the use ofthese drugs.
So so, theoretically, simplymaking these drugs better,
(50:38):
increasing the amount of weightloss that can be achieved for
them, will also haveapplications to reducing risk
from cardiovascular disease,diabetes, et cetera, et cetera.
Ben Comer (50:46):
Yeah, yeah.
So what about the, the kind oflean muscle mass that you hear
about?
Roger Cone, Ph.D. (50:51):
I know I forgot to touch on that, so it's
still.
It's still being investigated.
Um, when you lose body weight,you lose fat mass, but you also
lose lean mass.
Similarly, when you gain weight, you not only gain adipose mass
but you gain lean mass as well,simply from gaining weight.
(51:12):
Some people refer to that asthe gravitas stat that you know,
simply weighing more willproduce more lean mass, and the
exact mechanisms by which thathappen aren't known.
But when you lose weightthrough any process diet and
exercise, drug B you will losethe lean mass as well.
Losing lean mass is at somepoint not good, as we discussed.
(51:34):
Better muscle mass obviouslyreduces orthopedic problems and
injuries and helps preventdiabetes and multiple reasons
why you want to have adequatelean mass.
There are some studiessuggesting that the GLP-1 drugs
(51:58):
may produce more lean mass lossthan diet and exercise does.
The jury's not totally in onthat.
There's controversy in theliterature.
Let's say about that.
Nonetheless, whether the leanmass is due to the GLP-1,
whether there's enhanced loss oflean mass due to the GLP-1
drugs or not, preventing theloss of lean mass from weight
(52:19):
loss is important and there aremultiple companies pursuing that
.
We'll certainly look at thatwith our combination therapies
with our dual use ofmelanocortins and GLP-1 to see
if we can ameliorate the weightloss seen with the GLP-1s.
We are able to reproduce thatin the rodent.
It may or may not be relevantto the human, but we can see
(52:41):
greater loss of lean mass withthe GLP-1 drugs in rodents than
we do from the melanocortincompounds in rodents, than we do
from the melanocortin compound.
So you know, we may be able tostudy that in our rodent models
and it may or may not berelevant in the human, but it's
something that needs to belooked at.
Ben Comer (52:58):
Interesting.
Well, I'm coming up at the endof my time with you here, Roger,
but maybe we could end withjust your kind of top priorities
for the rest of 2025 and anykind of final thoughts that
you'd like to mention before wewrap up here.
Roger Cone, Ph.D. (53:15):
So at Courage , you know, our priority is to
finish the preclinical studiesand nominate compounds for
safety and toxicity studies andwith the goal of, you know,
being ready for the clinicpossibly, you know, in six to 18
(53:36):
months.
So that's, those are the goalsfor the company over the next,
over 2025 and first part of 2026.
Ben Comer (53:41):
Well, thanks so much for being on the show.
I really appreciate it.
We've been speaking with DrRoger Cohn, founder and chair of
the scientific advisory boardat Courage Therapeutics.
I'm Ben Comer and you've justlistened to the.
We've been speaking with DrRoger Cohn, founder and chair of
the Scientific Advisory Boardat Courage Therapeutics.
I'm Ben Comer, and you've justlistened to the Business of
Biotech.
Find us and subscribe anywhereyou listen to podcasts and be
sure to check out new weeklyvideocasts of these
(54:02):
conversations every Monday underthe Business of Biotech tab at
Life Science Leader.
We'll see you next week andthanks for listening.
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