The Business Of CNS with Acumen's Jim Doherty, Ph.D.

We've interviewed hundreds of biotech builders founders , mds , phds , executives , ceos on this podcast , and it is very uncommon , if not close to unheard of , to have the opportunity to interview someone who has been as singularly focused in an area of science or research space as you have for so many years .

You earned your PhD in the early 1990s and you've been in neuroscience R&D ever since . So I want to start there . I want to gain an understanding of why you are so steadfastly committed to addressing brain health .

I think there's a couple of different reasons why I worked in this space for so long and more or less exclusively , but I think probably the place to start would be that there's just so much need for new therapeutics , cns disorders and of course , we'll talk today mostly about neurology and things like neurodegenerative diseases and Alzheimer's disease , but there's also

quite a diversity of patient groups that need help in CNS disorders . So I also think , when you're talking about neurology , about things like seizure disorders , when you think about psychiatry mood disorders like major depression or postpartum depression , schizophrenia and even , in neurodevelopment , autism spectrum disorders .

So there's a tremendous breadth of work that's going on to treat CNS disorders , and that's certainly kept my interest and attention throughout my career . I mean , what we do takes a lot of time , a lot of efforts , and it really , at least for me , is pretty motivating to think about the patients that you can potentially help .

I'm just curious is that breadth of modalities that's available to address some of these disorders part of your lifelong interest there , or have you sort of found yourself married to some specific approaches ?

cell-based therapies the pace at which new learning is happening and that learning is being applied to potential treatments is pretty amazing .

I think we're early days in a lot of spaces if you're thinking beyond large molecules and small molecules , but I think there will be exciting things to come in the years and decades in front of us that will allow us to address things that just wouldn't have been possible to address with approaches that were available even 20 , 30 years ago .

Or vice versa , do you , you know , discover a drug and then you know , see where it might , you know , be applicable and determine which you know therapeutic area or which indication is the right fit ?

I mean , there are mechanisms and targets that people are aware of that we know have meaningful clinical benefits , and so you know being able to optimize , interacting with that target is a pathway you know you want to be able to go after .

But there are also times when you take the approach of saying you know these are the patients I'm trying to help and you know how can we ? How can we get there ? How can we really find the right way to go ?

And I think for a lot of large molecule approaches there was a time when you just couldn't do some of these things with small molecule approaches , and so being able to now access targets that you couldn't access before has been a huge thing .

That's happened with large molecules in CNS , and so it really does depend on the approach you want to take , and in my experience both can be viable either starting with the target or starting with a disorder and trying to figure out which of the things are going to be most beneficial for those patients .

Is a is a clearly an unmet need , you know , needed a therapy .

But , to your point , there was also some parallel work going on showing that the particular way we are interacting with these receptors an endogenous pathway that's already in the brain and was implicated in postpartum depression , and so we really came at it from the perspective of we know that we want to go after this mechanism , but there are a number of different

patient populations and indications that you'd see benefit and we had some clinical evidence that postpartum depression could be one of those .

And I will always remember the results of our first blinded clinical trial where we actually saw , indeed , that you could have a rapid beneficial effect in postpartum depression with psoriasis or this medication that targets GABA A receptors .

So , yeah , it's a great example of taking that target-based approach but aligning it with clinical information and identifying patient populations . That hadn't been tried before .

You know , over the course of your time in the space , there's been a real dearth of progress for many , many years , prior to the approval of licanumab , now dananumab and aducanumab . What kept you motivated during so many years of the industry's clinical failure ?

But as I've been re-engaging with the space through Acumen , I'm sitting and talking and listening to a number of investigators who have spent literal decades going after how to treat this disorder and it's an amazing story .

And it's amazing to be able to see the perseverance paying off , because it's been to your point , decades where a lot of effort has been put into treatments for AD .

And of course you draw on the distinction right , there have been a number of therapies that treat the symptoms of Alzheimer's disease and , yeah , there's been some success there limited success , but some success . But being able to interfere with the progression of disease and actually slow down the progress of the symptoms for someone just wasn't feasible .

And over a number of years a large number of companies made an effort using biologics , antibodies , to target some of these key systems that we know are going wrong in Alzheimer's disease , and early attempts didn't work .

And it's a space where you're talking about showing improvement over time , which means for clinical trials running relatively long clinical trials to show that people have not declined as much .

It's a progressive disorder and so there are people that are at different stages of progression at any given time , and there are plenty of stories about companies and sponsors running trials where , in the end , the trial itself didn't work , which is devastating to all the people involved certainly the patients involved , but also all of the investigators .

But people learned and I think the part that's amazing is that people have applied that learning sequentially and stayed with it , and that's part of the reason why the recent approvals of lacadumab and denatumab , and starting with aducanumab , were so amazing and such a change for the field .

I mean , like with aducanumab , there was some , I guess , criticism post-approval around efficacy , data around you know the finite number of patients that were seeing benefit and a lot of that . I don't want to dredge all the backup .

I mean it played out over the course of , you know , a couple , a year or so , a couple of years ago , the course of a year or so , a couple of years ago , but I'm interested in your perspective on it , given that you're now working on the development of an antibody in the Alzheimer's space . What's your take ?

What do you make of that criticism and sort of the detractors ?

And without going into the whole thing , I'm sure you know the story some trial data positive , some trial data not positive .

That's not that uncommon , especially in your early attempts to treat a population , and so fundamentally that's my take on it is that we're now seeing some therapies being approved that have been demonstrated to have a meaningful effect on the rate at which people are declining . Now , is that a cure ?

No , of course not , and I think the people involved with those programs know it's not a cure . But it's that first step that really can show that these processes and these approaches that we're taking can have meaningful effects for patients , and that's the way I think about it .

There's plenty of room to improve from here , but being able to take that first step is , I think , sometimes underappreciated for just how hard it is .

But I'm just curious about your take on like why maybe that kerfuffle , if you will , was seemingly more magnified than it would have been maybe in another indication , right , Like another indication where drugs approved on maybe limited or even questionable efficacy data that doesn't get such splashy headlines and get so much noise around the controversy .

It seemed like it was a sort of a bigger mainstream story with that approval . Is it because we're talking about an indication that is so one widespread , touches everyone sensitive ? I mean , do you think that that's what contributed to the noise around that ?

And you know , look , part of the reason I got into neuroscience is because I have my own family members who have challenges associated with various types of disease and CNS , not specifically Alzheimer's disease . But I have spoken with many , many people friends , family , people that I've interacted with since coming to Acumen and the stories are heartbreaking .

People that I've interacted with since coming to Acumen and the stories are heartbreaking . It really is . It's a terrible thing to happen to both the person but also to the family , and that generates a huge amount of interest in being able to treat this disorder and I think you know that probably contributes to the salience of it .

We know for sure that amyloid , you know , is a primary player in the progression of Alzheimer's disease . That seemed to be in question almost , you know , around the approval of Adjuhelm .

Or is it just the approach that you're taking or the particular drug you're working with ?

And when you're in the middle of it you don't know the answer to that , and so , of course , after a number of lack of successes , you start to question well , maybe this target is not as important or isn't important in the ways that we think it's important , but I think the more recent data does give pretty compelling evidence that amyloid is involved in the

pathophysiology of Alzheimer's disease . I think it's also clear it's not the only thing involved , and that's part of this shift in going to the future that , ok , now we have some firm ground , and the question is how do you expand out from this firm ground into understanding what's really going on in the brain for folks who are dealing with this disorder ?

And so when you have that , couple that with and we can talk about biomarkers you mentioned them just a minute ago . I think it's a really important thing to mention .

There's a lot of new information that makes this more tractable , and I think when people are looking at developing new therapies , one of the things you're looking at is okay , is this something that we can provide some benefit to ?

And having those initial successes allows people to say , okay , here's the path , but we can do better than this , and so this is what we can do to differentiate from what's already been done .

It sounds like a relatively straightforward thing , and maybe it is , but the reality is that the investment in producing a new therapeutic in any patient population is substantial , and you really want to have that firm ground to build from . So that's where I think we are and I think the field in general . As I re-engage with people .

It's an exciting time in that people are now looking at the progress that's been made and saying , okay , I see what we want to do next . How about we look at this ? How about we look at this combination ?

How about we understand this biomarker population as a population that made you better on the treatment than others might do , and so you start to ask all those kinds of questions , which is really about trying to match the right patient to the right treatment , and until you get an active treatment , you really can't even start that process .

You're educated there but your depth of knowledge in the therapeutic approach in the space is also sort of an uncommon thing in a biotech landscape . That I don't want to say it's dominated , but it certainly features , you know , vc turned biotech CEO types which I've spent plenty of time .

Nothing against it , like there's some great ones out there , but when I look at a potential guest for the business of biotech , as I mentioned , from the outside , I look for things that are unique and different to me , and your unrelenting commitment to this space was one .

Another was your title your president and chief development officer at Acumen , and that's not a title combination . I would say that we see , sure , we have MD PhDs who are founders and CEOs and presidents of the companies we talk to , but maybe not you know , as specifically as chief development officers .

So I'm just hoping you can unpack a little bit about what that means . It appears to me correct me if I'm wrong you're like the president who's got a foot in the C-suite and a foot maybe in the lab , foot in the C-suite and a foot maybe in the lab .

You have to string all those pieces together and I see my role and the benefit that I have of being able to have gone through that process from the very beginning . So you mentioned Sage Therapeutics .

When I joined Sage , we had there were about 10 of us and we were just getting started we had some really , as it turned out , good ideas , but not much else . And building a company to be able to take a couple of different therapies all the way from the lab through the clinic into the marketplace amazing experience .

And then one thing you learn is a small group of people that are motivated and all pulling in the same direction could do some pretty cool things .

But you also learn that nobody can do it by themselves and the real , the value of a team and I think you know that's what I see with going to Acumen is bringing some of that thinking and to take a what we think is a really exciting potential therapy for Alzheimer's disease , building off of all of that initial work that we were talking about just a minute

ago but then showing how you can match that to the right patients and maybe take the next step .

And I think that's the perspective that I bring , because that's what I've learned from stepping through a process from the beginning of the lab through the end of the clinic and that's what I'm open to bring and I hope I am bringing to Acumen as we move forward with our treatment for Alzheimer's disease .

Like that rolls up to you in neuroscience , your time in pharma , your time at SAGE . What would you kind of point to as the inflection points that enabled you or empowered you to wrap your mind around more than the development of science but the development of a business ? You know raising funds , managing people , and I know that's inviting a big conversation .

But if we could identify just a couple of inflection points , you know we have a lot of listeners who are perhaps aspirational scientists , scientists who aspire right to go into business , either to run their own companies or to just move into the business side of the companies they work for now . What does it take ? What did it take for you ?

What were some of those inflection points ?

It's a substantial process , both in terms of science but , as you say , also in terms of having a clear vision that you can articulate to potential investors , being able to make the case for why a particular approach is going to benefit patients , and to be able to continue to deliver those results as the story grows and as the asset gets farther and farther along

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It's not straightforward , and the scientific training that a lot of us get fantastic , but it doesn't teach you that , and so I think that is part of running any company , but certainly running a small , growing biotech company is being able to marry those two things together Make the right choices , do the right thing from the scientific and the medical perspective ,

but also be able to do it in a way that will allow you to gain and maintain support for your program .

Were there , were there any sort of key , key moments or points or resources like that for you along the way ?

You know , I think I didn't take the pathway of going for an MBA or something like that , and then , as you say , people do that and I'm sure you get benefit from that as well , but for me it was finding those mentors and those folks who make you think about things a different way , take the knowledge that you have and learn to apply it in a slightly

different way , and you know again , that's the kind of thing that , uh , that's where the growth comes in and , honestly , that's where it's most exciting , too , is where you can take what you've already learned and think about it in a new way .

So we've named , I think , the ones that have been approved .

I think one of the things that's a challenge in the field is that amyloid can assume lots of different shapes and sizes , and that's a very long conversation .

But there are different forms of amyloid that are interacting with various parts of brain circuitry and brain function , and so one of the questions in the space is okay , amyloid clearly a bad actor in Alzheimer's disease , but is it the large plaques that are visible post-mortem and actually was part of the original diagnosis of Alzheimer's disease by Aldous Alzheimer ,

or is it these smaller fragments that are different shape , sizes and do different things ? So I'm paraphrasing a larger body of work , but what we have targeted at Acumen is something called sibiloligamers . These are relatively small forms of amyloid protein , but ones that are .

There's plenty of evidence that preclinically showing that they cause toxicity and you know , not surprisingly , that's for us something that is a highly relevant point . So you can show impairment of synapses , you can show impairment of cognition with these small soluble oligomeric forms of A-beta .

They're not primarily a target for a number of other approaches , but suburnatug is specifically targeted and raised against these soluble A-beta oligomers , and so that's the piece that we think is going to be a key differentiation point for suburnatug moving forward .

As with most large molecule therapeutics , it's hard to do in oral routes , it doesn't survive the transit through the gut and it's hard to absorb into the bloodstream for the most part , and so you go to more systemic routes of administration , starting with IV administration with IV administration .

So our current clinical trials are with an IV administration of Subirnatuck , as is the case for the approved drugs at this point as well .

But we and others are looking at how to broaden the reach of these therapies to different patients and if you think about it , although yes , one can go and have an IV infusion and people do it every day , there are some barriers that come with that and there are some inconveniences that come with that .

So being able to produce a subcutaneous formulation where you could use an auto injector or some other subdermal delivery system would make a lot of sense for a lot of patients , but certainly make a lot of sense for Alzheimer's patients . So we are very interested in being able to produce a subcutaneous form of Subirnatug as well . So we're kind of developing .

Both Our lead program and our altitude AD phase two study is using an IV formulation and we would anticipate going to market with the IV formulation . And we would anticipate going to market with the IV formulation . But part of the vision is fairly quickly to be able to have subcutaneous option versus burn target as well .

So that's one way to differentiate and I think the other ways that you generally think about are from the efficacy point of view . We talked about that a little bit and then the last way is from the safety tolerability point of view .

There are , for the benefits of these approaches , there are also some target specific challenges that come in , and this is the Alzheimer's related imaging abnormalities , or ARIA . That seems to be a challenge for a number of different potential therapeutics .

It's a challenge for the approved therapeutics and you know we think the challenge will be there as well for subornatog , given that this is related to the target .

But we do think that the approach that we're taking with these small soluble oligomers , the hypothesis is that there will be less risk for these ARIA-related events , and so we see a couple of different ways that we could differentiate , and I think it's back to this concept we were talking about at the beginning .

Once you've got some firm ground under your feet , then you can think about okay , this is the way to take the next step . It could be from an efficacy point of view or from the safety point of view , or potentially both .

So that's about 7 million people in the US that fall under this early Alzheimer's designation . I think one of the things that's very exciting about the field that we haven't talked about yet is , you know , as we mentioned , the trials and how much learning has accumulated over the past couple of decades .

One of the things that has been accumulating rapidly is knowledge about biomarkers fluid-based biochemical biomarkers , and what people have learned is that , although the signs , the clinical signs of Alzheimer's disease , the memory challenges and things like that are occurring relatively late in life , typically the changes in the brain are occurring years to , in some cases ,

decades , before those clinical symptoms show up , and so it really does open up the possibility to say okay , can you use these biomarkers to identify the patients who are going to be best suited for this therapy or that combination of therapies , to be best suited for this therapy or that combination of therapies and can you identify patients who are going to respond

well and perhaps have better tolerability . So there's a tremendous amount of work going on in parallel to the therapeutic development in biomarker developments that is going to help with diagnostics .

So both identification of patients earlier in their personal journey , but also hopefully being able to link patients to the therapies that are going to be best suited for them .

You think about and I know you know that space oncology I mean that's been a huge effort over this sort of similar period of time and oncology is to take all these new therapies and identify which are the best patients to respond . I think something like that will be coming for the treatment of Alzheimer's disease .

I think , to be humble about it , it's going to be . We're at the very early stages of that , but I do think that that's a realistic thing to think that panels of plasma blood-based biomarkers are going to be useful to be able to help guide patients and match patients' treatments .

Are they sort of neck and neck ? What do you see on the development side in those biomarkers in Alzheimer's or in CNS broadly ?

I think it's hard to compare directly between oncology and CNS , but I would say I don't think it's much of a stretch to say the process of matching therapies and biomarkers is much further along in oncology than it is in CNS or in Alzheimer's disease . But I do think it's coming for neurodegenerative disorders like Alzheimer's .

Now you're in a phase two clinical trial , correct ? That is correct .

You know , it's not uncommon to have a conversation with someone who's you know in the mRNA space or the ATMP , like cell and gene therapy space or whatever the space du jour is , who it doesn't really matter what they're doing . They can't help but to run into money , right ?

This space has a unique context in that there has been some recent progress , there have been some recent antibody-based approvals and that's got to have some sort of a dynamic effect on the fundraising community , the capital that's available , and I'm just curious about it . I don't know what that dynamic effect is . That's what I'll ask you .

What that dynamic effect is , that's what I'll ask you . So yeah , sort of a two-part question how has Acumen specifically prepared itself to sustain the rigors of clinical trials from a financial perspective and what's that been like in the current ?

I think it is the process of understanding what it is that you need to do and being very rigorous and careful about prioritizing the right things to focus on , because you know , drug development is a sequential process and you've got so many steps to take over time .

You've got to take the right steps in the right order and in order to do that , you need the resources , but you need to manage those resources very , very carefully .

So we , like a lot of companies , spend a lot of time in making sure that we've got the right sequence of activities at the right time and that we're investing in the pieces that you need to invest in .

And I think this is one of the benefits of working in a previous biotech company that grew from a small company to a commercial stage company , because you see that sequence in action and you can do the right things in the wrong order and not succeed .

And so it's not just doing the right things , it's being very careful with your capital and being able to sort of carefully manage things , and you know , for Acumen end of September we're at about $259 million , and so we've got the resources that we need to be able to progress our programs .

But nobody has endless resources and if you're not careful you can get yourself out of sequence and into trouble . So that's . We spend a lot of time being sure that we've got the right path and that we're staying on that path . And then I think the second question around funding environment . It's interesting for CNS . It's a challenging time for biotech .

We all know that and you know that's a macro economic thing . It's a challenging time right now and it has been for a little while . I think it's a little bit of a lagging indicator . My hope is that we start to see people looking towards healthcare and towards CNS therapeutics as opportunity for the future .

There's no question in CNS there's a tremendous amount of unmet medical need to try to bring treatments for , and it's my hope that some of these exciting changes that we're talking about some of this progress in the biomarkers and really being able to maybe use oncology as a model and link the right patients to the right treatments we haven't been able to do that

too much to date , and so it's my hope that that becomes attractive to investors to be able to see that those tools are developing and couple that with some of the recent successes that we've seen in the treatment of Alzheimer's . The future is bright and the opportunity is there . So it's back to , as you mentioned earlier , the business of managing a company .

You have to have the right ideas , you have to have the right approaches , but you also have to be able to articulate a vision and have the right funding environment to be able to raise the resources .

This is going to be another sort of fuzzy , open-ended , vague question , because I know that's not prescriptive . Like I can't ask Jim Dougherty to spell it out for our aspirational listeners . Well , here's the order of things you do . The order of things right Like this is just such a tough question to ask . I know it's not all gut and intuition .

There's got to be some advice you can offer there around . Like you know , it helps if you pay attention to X , we'll talk to . You know , talk to so-and-so .

And what I mean by that is to see the entire R&D process , and what I mean by that is , you know , developing a new medicine . You start with an idea . You have a lot of work to do to show that your particular molecule fits the bill . You've got to be able to convince the regulators to allow you to start clinical trials .

You've got to go through clinical trials . You've got safety and manufacturing issues , and that could go on for a while . The statistics say it's a 8 to 10 to 12 to 15-year process to be able to go from the beginning to a marketed drug , and we won't even talk about the success rates because they're not hot .

So that sounds pretty daunting and it can be , but one of the things that I think is most valuable is to be able to see beyond the horizon , because this idea of doing the right things in the right order , it's not so much that you couldn't figure it out , but if you don't know the question you're going to be addressing two years from now .

You might address three questions today because it feels like these are important questions , and I'll spend my resources answering these three questions when the reality is two years from now you're going to be answering a new question that you don't even have to worry about today , but it will guide your decision making and the way you think about staging your resources

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It's one of the hardest things to do , because we're all trained in a particular part of the process , and it's one of the things that I'm most grateful for is , in my career I've been able to sort of see it from the beginning of R to the end of D , and that also , by the way , applies to the commercial side of things or to the regulatory side of things .

Being able to be able to see beyond that horizon is really important . And , yeah , you can't intuit that . You've got to talk to people . You've got to make some connections with people who have been there or are used to thinking about a different part of the process than you are and kind of grow that awareness .

That's probably the thing that's the most helpful in addressing these things when they come up . Obviously , every individual program it's a different story and there are different challenges , but in almost every case that I can think of , it's being able to know where you're going and to know what questions you're going to be addressing two years from now .

That is the most helpful in setting the path .

improvement in the rate of cognitive decline in Alzheimer's patients . So the study is a relatively large global study 540 subjects across three different arms and the goal is to demonstrate the efficacy and safety and tolerability of Suburban Suck . It will be a very critical study for the company and , we hope you know , a next step forward for the treatment in AD .

But it would be for the first time to be able to take the biomarker data that we gathered in phase one and match it to what we hope to be robust efficacy data in the phase two study .

And so , given that it's an 18-month primary endpoint after that , so 18 months from when we could complete enrollment in the first half of 25 is the rough timeframe .

As I said earlier , it's going to be happening sequentially , so we'll be following along with our sub-Q approach . The exact timing is one of these sequencing questions that we were just talking about . So , as always , it's going to be data-driven .

We'll see you next week and thanks for listening .