Hello, everyone, and welcome to the Life Science Report, a podcast from Back Bay Life Science Advisors. My name is Pete Bach and I'm a managing director here at Back Bay in Boston. Welcome to our second podcast installment of 2026. And today, I'm lucky to be joined by not just one, but two of my esteemed colleagues, the newly minted director, Mavrin Assir, and our indefatigable consultant, Trent Gordon. Mavrin, Trent, welcome.

I don't know if Trent can even say the word indefatig I can't say it.

Regardless, it means always there and reliable, which I think is a perfect description of of both of you. So Great. Nevertheless Miss

Lauren will be here, Pete. Thank you very much.

An honor to have you, Trent. So as we're moving through our podcast topics this year, we thought we would do a little bit of a different tack, and instead of covering, you know, some broad issues with respect to a certain type of technology class, or a certain thematic regulatory or business development issue, we dive in and talk a little bit about a certain disease area. So today we're going to discuss a specific area of oncology we've been tracking quite closely lately and that is ovarian cancer. So we'll sort of take you through a tour of where the field has been and where we think it's going. So before we get into specifics, Mavra, maybe you can tell us a little bit about patient population, current treatment approaches, and sort of set the stage for our discussion today?

Yeah. Happy to, Pete. Before we get into specifics, and as you said, so everybody's on the same page. So ovarian cancer, as a lot of our listeners may know, it is one of the leading causes of death worldwide when it comes to gynecological cancers. Just in the around the world, around two hundred thousand women died ambly off of ovarian cancer.

In The US alone, it still is one of the top killers. Looking at just some of the statistics out there, it's the fifth. It ranks fifth when it comes to cancer deaths just among females. Even though female cancer when you look at female cancer diagnosis, it only accounts for three percent of female cancer diagnosis. According to the American Cancer Society, roughly twenty one thousand women will be diagnosed in 2026.

And if you just look at the mortality rates, more than half are expected to die from ovarian cancer. So just to kind of compare it to breast cancer, for example, which is much more prevalent, but if you look at the five year survival rates for breast cancer, given all the innovation that has happened and hopefully continues to happen, For breast cancer, the five year survival rates across all tumor types are around ninety percent in in most countries most developed countries, I should say. But if you look at ovarian cancer, that's still fifty percent in The US. Just to kinda make the point that there is a pretty high unmet need when it comes to improving survival rates for this type of cancer among women as well. In terms of how when women are diagnosed, not surprisingly typical to most kind of niche cancers, most women are diagnosed at an advanced stage.

And this is primarily because early symptoms can be nonspecific, so they'll have some bloating, pelvic pain, and it's not very specific for ovarian cancer diagnosis. And also because there is no screening modality similar to breast cancer, they just haven't been specific enough to garner approval and and and be adopted, like, as in breast cancer. So by the time women do get diagnosed with ovarian cancer, they're all they are in an advanced stage. If you again look at statistics and even talking to some of the specialists that we interact with on a regular basis, I would say ten to fifteen percent of women with ovarian cancer are diagnosed at that localized or early stage where the cancer is just restricted to your ovaries. It's not gone to surrounding tissues, certainly not gone beyond surrounding tissue.

That's stage one. Versus majority, so, you know, your remainder, anywhere from eighty five percent to ninety percent, have advanced disease or metastatic disease anywhere from stage two all the way to stage four. And just, you know, I'll talk about treatment quickly. So with regard to treatment options, and it's one of the reasons we're here today. So the backbone remains similar to some of the other solid tumors and as well as hematological tumors that we look at.

The backbone is still anchored on surgery if it can be resected, plus chemotherapy in ovarian cancer case. It's platinum based chemotherapy with targeted and maintenance therapies that have been approved and layered on in the last couple of years. So why are we talking about this today? So if I was Trent and I well, mostly Trent. I'm just putting my name there.

He's done a lot of this work. But if you look at how innovation has happened in this space in the last you know, two to three decades, there's really been three kind of turning points, I would say. So 2014 is the year we saw bevacizumab as well as PARP inhibitors got approved. And then there was nothing for almost a decade or so. And then 2022 is when we got our first target therapy approval, and it wasn't for a p d one or some other monoclonal antibody.

It was for an ADC. Bolide receptor alpha targeting ADC. AbbVie got it to the finish line in 2024, two years later. So they got the accelerated approval and then full approval in 2024. And it has really shifted the treatment paradigm for women who are able to get it, and we'll talk about it.

Like, it's not for broadly all women. It's a very niche population. And then just as we were preparing for this podcast two weeks ago, Keytruda got to the finish line on top of chemotherapy. So they finally have an finally, yes, have an approval. But, you know, it's on top of chemotherapy with or without bevacizumab, and it it's in patients who've already had at least one or two lines of chemotherapy and then advanced to this setting as well as they need to have high PD L1 expression.

So it's with a companion diagnostic. I do need to give a shout out to twenty twenty five. There was an approval for a very targeted population. So both it was a MEK RAF MEK inhibitor and FAC inhibitor that got approved in the KRAS mutated setting. It's a very niche population, but still, you know, another another another therapy option for these patients who have these very specific mutations in that setting.

The pipeline is really interesting. And by interesting, I mean, you know, typically for solid tumors, you see and especially those that haven't had a lot of approvals, if you look at you know, go look at lung cancer, breast cancer, you see this kind of plethora of, like, anywhere from, like, small molecules to mAbs, and then you see the ADCs and bispecifics kinda emerging over the years. For ovarian cancer, because the landmark approval happened for an ADC, If you look at the pipeline right now, around 64 assets in development, anywhere from phase one to phase three, and a third of them roughly. I'm exaggerating a bit. It's 26%, but a third are ADCs, which is why I wanted to talk about it today.

Yeah. Okay. Yeah. And certainly, we'll talk a little bit about the activity in the in the ADC space and how people are gravitating to ovarian cancer given the success of of Ellie here thus far. So so Trent, maybe with with that as a background, you could sort of tell us, you know, in the near term, maybe talk about therapeutic development in in the platinum resistant setting, and what are we watching, and what do we think is most likely to matter clinically over the next two to three years?

Yeah, and I think that's the big question right now, is there is so much activity in the space that really the question is, how is the standard of care gonna change not just in two years, but potentially in five or six or seven? So I think what we should see is a shift in the next one to two years, that largely being from CORCEPs, they filed an NDA for relacorilant, this is a small molecule, and we should see some uptick with this in the PROC patient population. But I think what's really exciting is some of the ADC readouts that we should see in a few years. So what we saw in 2024 was Rina s, which was an asset in development from Profound Bio, was acquired by Gemmab, and this is a folate receptor alpha ADC. This is now in in phase three development after they showed roughly a 50% ORR in a phase one two study.

And so I think what we're poised to see in 2027 is is that asset's gonna have its readout, and Endaiichi has a phase two three study ongoing with their CDH six targeting drug. This has shown an OR of roughly 50.5 as well too, and this is again gonna read out in 2027. So I think 2027 is gonna be be a big year for the PROC setting. It's also gonna be a big year for oncology in general. Their HARMONI I seven study from Summit, This is the big one with their p d one VEGF against Keytruda.

So I think this is gonna be one that we'll have to do a whole another Back Bay podcast series on.

We can't I think you're required by law, Trent, to mention p d one VEGF bispecifics in any discussion about oncology. So I'm not surprised that popped up here in an on in a ovarian cancer podcast.

I'll just I'll just quickly add. When we say PROC, we mean platinum resistant ovarian cancer. We'll say that a bit in the next couple of minutes. And then just to level set, as Fred mentioned, you know, some of the next gen ADCs like the Renas from Genmab, they're demonstrating around ORs in the fifties. So just to just so you know, like, Ilhaer, which is the approved folate receptor alpha ADC, that demonstrated, like, that was around 42%.

So already kind of moving the needle along with some of these next in class approaches that are coming down the pipeline.

Yeah. Yeah. It was interesting if if you hear, you know, some of the folks at Genmab talk, of what they saw in that early Rinnez data was they felt it was really intriguing enough where in the context of the transaction, they viewed it as a phase three ready asset, given the totality of data and how impressive some of the early results were. And I think that's why they sort of aggressively went after ProFound in that in that context. So given all the activity, I mean, how are people thinking about segmenting these patients?

Is this an area where we're gonna see more biomarker brace stratification in these patients to guide treatment?

You know, Pete, I think that's exactly what we're gonna see. I think what we're seeing is that this patient population is likely gonna become very much like the breast cancer patient population, where it's very much driven by the biomarker status that the patient has. So what we're seeing is in this space, it's not just one or two kind of biomarkers in development, we're seeing a plethora. So we have obviously the folate receptor alpha ADCs in development, but we also have ADCs targeting b seven h three, b seven h four, we have ADCs targeting new targets such as NAPP two b, this is from Tubulus, is a well funded German biotech company. So I think what we're eventually gonna see is that we're gonna have a number of different target assets that are approved, and then I think what we can see is ADC stacking in the patient populations, where once there is potentially some target exhaustion with let's say a folate receptor alpha ADC, then a physician might switch that patient over to NAPI two b ADC for example.

Yeah. Yeah. And I think that's sort of a broader question in the ADC field, is sort of how do you sequence based on payload and and target in an indication and space where you have a couple of options at play. So but that's a topic for another day. So if we're if we're just focusing on, you know, maybe what's approved in in L here, and what's coming down the pipeline in that space, you know, how do we view these programs trying to differentiate from one another from an efficacy tox, you know, eligibility issues with respect to payload differentiation and the like, Mavra?

Yeah. So I think the Ella here, well, case study or that that kind of asset class is really interesting right now. So Elohir, this is a folate receptor alpha ADC. It has a DM four microtubule inhibitor payload. The reason I mentioned that well, I'll be clear in a second.

But basically, if you look at just the data it was approved upon, so two trials, one accelerated approval, one confirmatory full approval, and demonstrated an ORR of forty two percent, also demonstrated overall survival benefit. The reason I'm saying that it's is important is because, to some extent, the other ADCs have to keep that benefit in mind as they're demonstrating kind of the trades trade offs between the risk benefit profile, which brings me to the risks. So if you talk to physicians today and certainly what was seen in the trials as well, the main issue that physicians and patients have to grapple with is ocular toxicity. So roughly right now, focusing on, I guess, the trial data, if you are getting Ella hair, if you're eligible for it, which, like I mentioned earlier, it is your platinum resistant population that has failed at least two to three lines of prior chemotherapy and has high expression of folate receptor alpha, which is determined using, again, a companion diagnostic. That population right now is around thirty percent of patients that are platinum resistant, so you're you're kinda really talk talking about a niche population.

So in those patients, right now, the rates of ocular toxicity are around most patients have anywhere from forty to forty three percent have some sort of keratopathy, which is basically a disorder of cornea. You can have swelling, structural changes, blurred vision, they have dry eye. Basically, they have to be monitored for ocular toxicity when they're getting it, which is they need to do a baseline exam, then they need to come in for after every cycle for at least for the first eight cycles. They also are prescribed lubricating agents. And the reason I'm emphasizing this again and again is because the trial population, if you think about it, those are likely patients who are able go to trial settings, get these injections, and follow-up with monitoring.

In the real world setting, especially if you are working at the same time or even if you're not working, if you're geographically not close to a center, certainly an you know, an optometristian, this can have logistical issues. So just something to keep in mind. So let's look at what's coming down the pipeline and if any of the agents are able to address it. Trent mentioned Rina S. You know, that's that's the the most advanced and the most near term competitor in that class.

Lilly and AstraZeneca also have folate receptor alpha ADCs that are being developed. And I'll just touch briefly on Genmab's and Lilly's programs because they have some data that I think is interesting. I mean, I I would I would say that when it comes to the payloads or warheads, to me, they're somewhat the same. They're all microtubule inhibitors. AbbVie has I feel like people might come at me for this, but AbbVie has a DM four payload inhibitor with Elohair.

But Genmab and Lilly, they have a topo inhibitor payload, which can have some differences, but I'll just you know, they're kind of the same in my opinion. They're microtubule inhibitors.

Send all complaints to mnis here at bblsa dot com. Continue, Marla.

You know what? I should caveat it. The other payloads haven't shown the same level of ocular toxicity. So there there is a difference. But I'll I'll come back to why I said it was roughly the same because from a anyways.

So for Arena s, it's the most advanced, like I said, has demonstrated an ORR of 55% in the data that has been released today from phase two studies. And if that is regardless of folate receptor alpha expression, so that may be higher if you segment the population of where there's high expression, which in in Ella Harrier's case was, like, 75% of or more cells tumor cells need to express folic receptor alpha. And most importantly, no, you know, ocular toxicities. The main trade off was there was some hematologic and GI issues that were managed during the trial. Lilly's is, I think, even more interesting personally because same they were able to kind of have the same ORR, 55% as Genmab's.

But they also included a post Ella hair population. So now they're they're able according to them, they're able to show some signal in those that have either failed or stopped ELAHARE, which kind of brings me to the last point I wanna make here is the how do phys which ADC to give. Let's say all three are on market. How do physicians, you know, pick an ADC, communicate about it to the patients? And and I think if you talk to physicians right now, they're gonna bring this back.

Like, it's gonna come down to really which ADC is able to report efficacy in a resistant population, which, you know, I think Lily is is showing that with post ALAR data so far, or which is kinda able to go earlier in lines of therapy, which is a playbook we've seen across all other solid tumors. So AbbVie is already trying to do that with their ADC. They have not just in earlier lines of PROC, but also platinum sensitive patients who have phase two, three trials running. But I do think it's such an important point of, you know, how and and it maybe does come to the payload class when you think about risk benefit. We know from some studies like DM four has that ocular effect, which other payloads don't have.

So I don't want to discredit or make it seem like they're exactly the same. But to me, the the sequencing is going to be the differentiator when it comes to which ADC gets taken up.

Yeah. Yeah. Alright. We've talked a lot about ADCs. So maybe, you know, shifting to other types of modalities.

What non ADC readouts are we looking at that could reshape the treatment paradigm and practice in the near term?

Yeah, and I think what's interesting about PROC is it's likely gonna resemble what we're seeing across oncology broadly, in the sense that, in general, what we're seeing is really a shift towards combination therapies for more targeted patient populations. And I know Pete, you're gonna hate me for bringing this up again, but obviously the bispecifics are an incredibly hot topic in other tumor types, mainly NSCLC, but what we're seeing actually is there's a lot of enthusiasm for their ability potentially to turn what we historically thought of cold tumors, so tumors that really have not responded well to immunotherapy, HOT, so more of an immunogenic tumor type. And from doing some research in this space and talking to a few KOLs, we do see that there is potential excitement for p d one VEGF combinations to make the historically immunoresistant tumor types more amenable to immunotherapy. So I think what we've seen is a company like BioNTech sort of wanting to validate this approach, so they did a basket study where they looked at their p d one VEGF in combination with an ADC where they showed some, I think a high ORR of over sixty percent.

So I think what we could potentially see is some more combination based therapies with bispecifics, and then what that will really bring into question is then, can you think about moving these therapies ahead of platinum chemo? And I know that's sort of a long moonshot at where we are right now, but I think if you are able to potentially make these tumors more immutable to immunotherapy, then it's reasonable to think that chemotherapy could be utilized in later lines of therapy, where you have a less cytotoxic immunotherapy in the first line setting. So that's sort of a long shot, but what we are seeing now is AbbVie is looking at the improving the duration of response, so they are testing Ella here in a study called Chloriosa in patients who have responded to second line platinum based chemotherapy alongside Avastin, and seeing if they can use Eli here to extend the duration of response.

Interesting. Yeah. And I I think the question of how immunotherapy evolves in this space will be sort of an interesting case study to look back on, you know, when and if the dust ever settles. Because I think it's a space that, know, ever since some of the first approvals from Keytruda and Opdivo and other indications, it's been a space that people are looking at as sort of a Goldilocks. It's not necessarily an immune desert, but certainly an immune suppressed environment, and how do you think about, you know, complementary mechanisms to finally unlock the potential of the p d ones, but again, a topic for another day.

So, you know, I guess, given all this development, right, it kinda makes one think of, right, if you're an early stage company developing a drug, how do you think through and almost quote unquote future proof your development against a shifting standard of care against which you may be measured in the future where it may not necessarily be fully fleshed out at this point.

Yeah. And it's certainly a question we do have to help some of our partners manage and and think about ahead of time. So designing oncology trials in particular, when where there is, you know, a moving target, let's say, when it comes to standard of care or your comparator arm is is definitely complicated and can be challenging. You basically have to think about choosing the most ethical and relevant standard of care comparator arm while also generating actionable data because you don't want the by the time you get to the FDA, whether it certainly, when it's phase three, you don't want to be shut down by them because you have an obsolete standard of care arm. And if you're a big pharma, maybe you have the resources to do another trial.

But if you have limited resources, it's something you need to take into account now to bet to better just understand what some of the risks are. Our first advice would be definitely hire a biostatistician when planning your studies. But really, of the things we've seen and come across and heard from experts in this space, I'll kinda outline them. And, you know, we we're happy to discuss if you have additional questions to our listeners. I think, like, there's it's not something like that's you need to, like there's there's relevant tumor types and other settings where this has happened, you know, lung cancer, breast cancer, highly competitive markets.

They Multiple myeloma.

Yep. Yep. Multiple myeloma, where we've seen developers adopt certain protocols that help them basically prepare for a evolving pipeline and evolving side of care. One thing, you know, you'll you'll notice is starting with a release biomarker relevant or niche population where, you know, you can have a standard of care where it's specific to that population or you don't need to worry about, like, different different kinds of therapies that need to be given in that setting. We see that happen all the time in lung cancer still, later line, bio you know, really certain muted populations.

You can certainly think about that while designing a trial, especially at the phase two stage. Another thing we've seen in lung cancer is where they have these you know, this is where my knowledge also starts to get limiting, but these are like adaptive and master protocols that have been developed. Lung MAP is one great example where the protocol itself basically continuously screen patients as they get enrolled and then assigns them to different studies that are happening. And each study has its own control arm, But the adaptive part is as that standard of care gets obsolete, the control arms are updated. So by the time you're done with the study, you're able to focus on the data that is most relevant during that time.

Another approach that a lot of and this happened in ovarian cancer too. If you look at the trials, you'll see that developers allow the standard of care, the comparator arm, to be investigator's choice chemotherapy, which is another way, obviously, that's gonna add heterogeneity to your data. But it's more relevant to what's happening in real world. And all you need to be able to do at that time is if you're allowing that number of variables to enter your study, especially when the standard of care is still evolving and it's not set, you just have to have enough patients enrolled at the end of the day to compare the different But it will reflect real world practice at the end of the day. The other two options I'll say is that we've seen again is definitely have a contingency plan.

So, you know, you as a biotech in the space, you know if the pipeline is dense, it's something that might change. And certainly, if there are agents in later lines, they might get approved. So you need to be able to have certain prespecify, you know, certain amendment triggers that that might happen, and you might have to move around comparator arms around that, incorporate sensitivity analysis. And then the other piece I'll mention that has happened is if you're running something that's multicenter sorry, and multiple geographies as well, you might have regional approvals happen in one geography and not the other. So that's another one where what ends up happening is you you know, the f definitely talk to the FDA if that's the case.

That's that's happened. And you need to have a comparative discussion during your pre phase three meeting after your phase two data just to align on this is what we're gonna be doing. If things are gonna change, this is how we're gonna collect it. Do you agree or not? But in in that setting, a lot of times, the FDA has allowed post, you just keep on collecting the data even in those patient populations that may be now on a new standard of care, and that becomes part of your real world data collection post potential approval.

So you just need to be able to plan around it and understand that if you are developing a therapy that is in a highly competitive market with evolving standard of care, it's somewhat of a risk you need to think about and plan around.

Excellent. And certainly an issue that's relevant not just to ovarian cancer as well. Yeah. Trent?

Yeah. And maybe a few things I can add on top of what Mavra was saying. I just wanna echo the fact that in a highly dynamic space like proc, it is critical to have strong competitive intelligence capabilities to monitor which assets are reaching which milestones, and how that is shifting the benchmark for approval, and how that might then therefore affect the adoption of your drug in development. So I think not only just monitoring the clinical pipeline, but if drugs do get approved, it's critical to assess how they are or not being adopted into specific guidelines like NCCN or ESMO, and then really thinking about the reimbursement for those drugs. Are there any access challenges that these companies are facing?

And if so, is there a particular way that you can position your drug to circumvent that and make it easier or more beneficial for a broader subset of patients?

Yeah. Excellent. Excellent. A lot of food for thought there. So Well, thanks, Marvara.

And and thank you, Trent

Thank you.

For guiding us through this space. Really, really interesting. Hopefully, we can maybe do some more deep dives on certain indications and spaces that we we think are particularly notable with respect to the development and and pace of change. And we'll monitor this certainly and maybe have an update in the next year or two. So, like to thank you all for listening to the Life Science Report from Back Bay Life Science Advisors.

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