Our New York City Healthcare Conference. It's a pleasure to see you all. We have the Relay management team fresh from their flights from ASCO, as I am as well. They are filled with energy and really can talk for days. I'm very grateful to have the team here, especially as we're starting to see, I think, the HR-positive breast cancer space play out and understanding where there's different therapeutic opportunities. I'm actually quite excited to have this conversation with you. Sanjiv, why don't I hand it off to you to give some intro remarks. We'll get going.
Yes, excellent. Thanks, Akash, for the invitation, and thanks to Jefferies. We had a very productive year so far. We've shown three data sets in three large commercial opportunities. The first data set we showed was in second-line hormone receptor-positive, HER2-negative breast cancer, where zovegalisib, we showed in our pivotal trial dose of 400 mg BID, an 11-month PFS with an oral regimen, which we're going up against capivasertib with its five and a half months worth of PFS. We feel very confident as we run our pivotal trial that it will be a success and that will offer patients a paradigm shift in treatment. The second data set we shared was in looking at our frontline hormone receptor-positive, HER2-negative breast cancer trial that we'd like to run, where we announced that we will use a novel selective regimen with Zovega and atirmociclib, Pfizer's selective CDK4.
We showed what we believe to be a very clean safety profile with great efficacy in third-line patients, and we're excited to bring that into the frontline as rapidly as we possibly can. A couple of weeks ago at the ISSVA conference in Philadelphia, which is the largest conference for vascular anomalies, we showed what we believe to be paradigm-shifting data for these patients that are chronically underserved, where we showed a 60% volumetric rate of response in a field where the traditional characteristic has been somewhere between 11% and 20%. We're full speed ahead now to try and execute all three pivotal trials as rapidly as we can and get these medicines to patients.
Understood. I'm going to start with the breast cancer opportunity, though I want to acknowledge, I think the orphan story is just as interesting, and frankly, I think has had an even bigger impact in terms of your near-term stock performance. We're fresh from ASCO. I think we've got two really, really interesting data sets. We got finally the persevERA data, and then also we got data from Celcuity, which I think was really interesting. I wanted to start off a bit with Celcuity. Look, it does look like it was an impressive PFS benefit. No additive benefit on the triplet versus the doublet. Then 11 months, when we think about the absolute benefit on PFS, was in the range that your team had shown. I'd love to get your take in terms of how you look at the Celcuity data.
What did you learn about your own product and how it gets positioned post that data set?
Yeah. Obviously, as those of you who have been close to us, it has definitely been a question that we've been asking and trying to answer for the last year. It's great to actually have the data.
The experiment run in the public domain. For those of you who didn't follow it, what they showed with their triplet regimen, which is a weekly IV regimen of gedatolisib with palbociclib and endocrine therapy, an 11-month PFS, which is an impressive result, given the standard of care there on the control arm was five and a half months. We think it'll be a step forward for patients. I think as pertains to us, I think the question was: would it be a commercial headwind if we were to then launch into that market?
I think our belief is, having shown now two large cohorts of patients showing with our oral regimen an 11-month PFS, that it will not, and that we should be able to take share from that market that Celcuity will build very rapidly as patients are going to prefer an oral regimen. I think the concern was that they were going to show 15, 18 months, whatever the numbers that were being bandied around, which obviously would have been more challenging for us to compete against. I think in terms of just how we feel about the commercial opportunity, I think we feel very confident. In terms of their triplet versus doublet.
Yeah.
It was an interesting result to see that in the end, there was potentially perceived no benefit for adding a CDK4/6. We don't know if that's actually the conclusion. As you know, their doublet arm was there really only for a contribution of components. It was hard to statistically be accurate that they actually have no benefit. I think our belief is what we saw in the wild type arm is probably play out in the mutant arm in that there will probably be a little bit of benefit one to two months for having the CDK4/6 on board. Really now it does create some confusion for prescribers. Do they prescribe the triplet or the doublet given the data that has been seen there?
Understood. Look, this is a tricky question, and I'm struggling with this as well.
This one's definitely one for Peter then-
Forget patients. How about you? You have a partnership with Pfizer, with atirmociclib.
Yeah.
Really interesting early data, but early data.
Yep.
A potential to move this into a first-line setting. Has your confidence on the atirmociclib PI3K-alpha combo changed at all as a result of the Celcuity data? If not, why? Why does that data point not necessarily read across to the trials you're running?
Yeah, no, it really hasn't. As we're moving into a frontline setting, we have proof today from Roche's INAVO120 trial of inavolisib in an endocrine-resistant patient population, frontline treated, where we saw a doubling of PFS and an OS benefit for the triplet regimen of inavolisib with palbo and fulvestrant versus fulvestrant plus palbo. We know from that experiment that adding a PI3K inhibitor on top of a CDK4/6 inhibitor in frontline patients can have a very meaningful efficacy benefit. Now, one of the shortcomings of that trial was it was highly contrived, run in a heavily selected patient population to avoid some of the metabolic liabilities of inavolisib, and those data have therefore been challenging for prescribers to translate into real-world usage, and we've seen that as a headwind to uptake of inavolisib.
I think when we look at that, when we look at the fact that in endocrine-sensitive patients in frontline, patients with a PIK3CA mutation do not receive the full benefit of the CDK4/6 regimens and perform slightly poorer on PFS, about a year poorer than patients who are PI3K wild type, tell us that as you get into early-line breast cancer, being able to hit both the endocrine node, being able to hit the PI3K node, and then being able to complement that with CDK4 inhibition is really going to be optimal for maximizing outcomes for patients.
Understood. I do want to kind of stratify that a bit because if I remember correctly, Roche has run, I think, endocrine-resistant, that triplet frontline. The sensitive population is still coming out. Again, this will be a nice bridge to PERSEVERA and this topic of endocrine-sensitivity. How do you expect the benefit of a PIK3 triplet in a resistant versus sensitive population? It sounds like you also expect the Roche trial in the sensitive population, despite the safety liabilities, to still read out positively.
If patients can stay on inavolisib.
That's going to be the key question because the resistant, they only needed to stay 15 months. When you get into the sensitive population, the statistics of the INAVO123 trial are such that the assumption for performance of the control arm, the CDK4/6 doublet in that trial is 20 months.
They're looking for about 30 months in the triplet-treated arm. They'd have to keep patients on a fairly challenging regimen for about twice as long as they did in the INAVO120 endocrine-resistant population.
Okay. Understood.
I think part of your question was how do we have confidence that in the endocrine-sensitive patient population, that addiction to the pathway holds that we saw in the endocrine-resistant population.
That's probably best explained if you look at the MONALEESA-2 results of ribociclib plus AI in that study. We saw a good, robust subset in PIK3CA mutant versus PIK3CA wild type, and there's still a clear delta in performance there. The mutant population was about 19.5 months in that study, and the wild type population was closer to 30 months. Clearly articulating that there's addiction to the PI3K-alpha mutant pathway in that patient population.
That's a great point. Heading to the other data set, which was PERSEVERA. It's interesting. I think certainly on the pharma investor side, there's this idea that frontline adjuvant for SERDs is this kind of $20 billion to even $40 billion opportunity. I can tell you, I'm very much skeptical on that. I don't think we saw necessarily that same uptake with the CDK4/6s with the NATALEE trials. Major revenue contributor, but not to that level. When I look at the Roche monotherapy data, I say, "Okay, maybe these stage two, there's a subset of patients as a monotherapy. Okay, that's a group. That's not $20 billion, that's $3 billion-$5 billion." Substantial, but not what I think people talk about. To me, the uptake is really the combo. I'd love to get your take now that you've seen the PERSEVERA data.
Let's start with the first biological question. Do you feel like SERDs work, quote-unquote, "in first line" or do they work in a subset population?
There's no question they work. What the question is, do they work better than our existing drugs, aromatase inhibitors? If you go back, you mentioned the LEADER trial that was monotherapy, where clearly the SERD was superior to the available investigator's choice endocrine therapy in a monotherapy setting, where you're really just targeting the estrogen receptor node and where slightly better targeting, in that case, translated into a meaningful difference in terms of clinical outcomes. The challenge when you get into the combination setting is now you've got your CDK4/6 inhibitor on board, which we know from the registrational trials of the CDK4/6 inhibitors versus endocrine therapy monotherapy transformed the outcome for patients in terms of PFS.
That CDK4/6 inhibitor is driving a lot of the benefit. I think it's challenging in that setting to have slightly better endocrine inhibition and have that translate into a meaningful difference on PFS, which is what we've seen in persevERA. There's some suggestion when you look at the PFS curves that there may be some late separation of the curves that could be accounted for by suppressing the emergence of ESR1 mutations.
With the oral SERD as opposed to the aromatase inhibitor. Which would then place more into the SERENA-6 type approach, where you actually use the emergence of ESR1 mutation potentially as the trigger for identifying patients who would receive the more broadly potent SERD inhibitor or SERD.
Understood Don. That outcome did not go, let's say, to AstraZeneca's plan. Understood. When we think about the CDK4, because again, these are all external data sets, directly apply to your team. We're starting to see frontline data, new adjuvant data with the atirmociclib. There's also that even second-line data that they've only top-lined. To me, the question is really can we get separation faster? Obviously the safety benefit, could that late emergence tail occur as well? What have you seen so far with CDK4 that makes your team confident that this would have a benefit over, let's say, a CDK4-biased drug like VERZENIO? Again, because I know there's going to be extrapolation, what data sets are you seeing that's driving your confidence on this partnership?
Look, I think the main data is the data that we've generated. We know that in the frontline, tolerability is everything.
These patients are going to need to be on drug for multiple years. We know from the INAVO120 trial that the efficacy is there, of adding a PI3K inhibitor to a CDK4/6 backbone. The challenge is just adding a CDK4/6 backbone to a PI3K inhibitor leads to tolerability challenges, and patients just can't keep on drug and the dose intensity declines, and that is what's potentially going to lead to these trials not doing as well as they could. Our data in these late-line patients, third line on average, with both the selective profiles of a CDK4 selective and a PI3K selective, has shown a very tolerable, safe profile.
I think in these late-line patients, if we're seeing what we're seeing, I think we feel great that when we bring this to the frontline, you will see both the dose intensity and the longevity of these patients on treatment, which will then inevitably lead to the efficacy. I think that's what's given us confidence to put this in the frontline and run this trial.
It's really more about how many patients are still on drug right now, rather than just looking at the initial response rate.
Exactly.
Understood. There's a possibility, if you look at those curves, you're at 44. There's a few patients there which are pretty borderline.
Yep.
This is a discussion we've even had on your vascular malformations where you're like, "We haven't seen any patient not respond to this drug. They just may have not been on the drug long enough." When you think about how that early data set with the atirmociclib will evolve over time, is there a potential for responses to deepen? Is there any historical precedence we can maybe point to? In terms of data disclosure on Relay's side, when can we expect another update with the atirmociclib combo?
Maybe I'll take Don the first part and Peter the second part.
Yeah. With regard to responses deepening, I think there could be a possibility of responses deepening. The data we presented or that we disclosed in April was across all of the doses that we had tested for the triplet at or below our recommended phase II dose. A number of those patients were treated at dose levels below what we would ultimately take into phase III. Our experience in the fulvestrant doublet was that at some of the lower doses were active, but sometimes the responses came later.
I think in this patient population with the triplet, we'll just have to continue following the patients to see if some of those near responses on subsequent scans are able to deepen further.
On the disclosure, we've guided to showing additional triplet data in the first half of next year. I think what to expect with that update would be obviously more follow-up from the dose-finding portion of the study that we've already reported on. We've also since moved into dose expansions, as we've talked about in that disclosure, at the potential recommended phase III dose of 150 mg of Vega, 300 atirmo. We'll show, at that point in time, the data we have from some of those expansion cohorts also.
It'd be a good level of maturity from the dose-finding data and then early data from the expansion cohorts.
Understood. Could that update next year, could we start seeing signs on PFS, and is that still going to be mostly just focused on duration response, focused on ORR? Are we going to get enough maturity where you could start to see differentiation versus what you would expect in a first-line standard of care setting?
If we continue to just isolate the dose-finding portion of the study, that portion would have over a year of follow-up at that point in time, and so it's possible to potentially start to estimate a median PFS point estimate.
Okay.
With the caveat that we're in median third-line patients right now.
Right.
There'd have to be a correction.
Understood. Another tough question in terms of how to design these studies, but again, I selfishly ask because we're trying to figure it out. When you think about powering and your expectations on, let's just say, CDK4/6 plus AI in a frontline population, if we think about it in the broader population, okay, it can be about 25 months, but we've seen that PI3K-alpha mutated patients seem to have worse prognostic outcomes where PFS might actually be more like 18 months. What's the right assumption in terms of the comparator arm for your phase III design? How have you powered that?
Yeah. We have a few different data points to look at. The one I just cited recently was the MONALEESA-2 study.
they did good sub-characterization of the PIK3CA mutated population, and in that study you saw 19.5 months of median PFS. Additionally, in the INAVO123 study, they have posted their statistical plan on CTIS. They are assuming a 20-month performance in the control arm for that study. You would imagine they have pretty good real-world information in the fact that they own
Flatiron, Foundation Medicine. The most recent data set we could look at a little bit too is in the VIKTORIA-1 data that was just reported. They did give the median duration of treatment of the first-line metastatic therapy that those patients were just on, and you saw somewhere between 17 and 22 months of median PFS there too, or median duration of treatment. Not a perfect one, but again-
Get it right.
All things as you're saying, kind of triangulate back to about that 19, 20 months.
Okay. When you think about powering for a phase III to show a clinically meaningful effect, we're thinking PFS, are we thinking OS? What are we thinking on hazard ratios for both of those endpoints?
Yeah. I think we'll fall short of giving the precise hazard ratios, but I think the way to think about it is we've done some primary market research asking physicians what would be a clinically meaningful improvement against that 20 months in those patients, and generally the answer is about six months.
Wow.
I think obviously the primary endpoint in these studies is progression-free survival. We will certainly be conservative in how we power this to make sure we have enough powering for OS as a key secondary, and knowing that the threshold for clinically meaningful improvement is about six months, all these things will go into our statistical assumptions.
Understood. Bottom line, if in a frontline population that's not PI3K-alpha mutated, it's 25 months. You're saying, "Look, we're going to fix that problem, and then let's hope CDK4 can add something on beyond." Is that the right way to think about this?
Yeah. Our hypothesis is not at all based upon atirmo -
Yeah.
needing to add anything new or different on the efficacy side.
That's quite interesting.
It's simply that it needs to be safer, and I think the data we have to date is very supportive of that.
Let's go maybe on to the vascular malformation side, because I think, again, that's an incredibly important part of that story. Sanjiv, I want you to talk about this in terms of ROI, because I don't think that gets talked about enough. Help us understand how much additional capital will you really need to get this to the commercial stage onto the market? When we think about PROS versus the broader kind of population, what's the capital cost, what's the timelines as your base case right now?
I think, in contrast to breast cancer, which is a well-established market where we see capivasertib closing on $1 billion of sales, and the trials that we're running both in the second and the frontline, it's a very definite path to market. You kind of know what the trials are. There are 500 patients in the second line. You know the kinds of sales forces that are out there in the U.S. I think that world is relatively clear. This one is a little bit more opaque, but I think what we can tell you is the historical trials here have been relatively small. The Novartis retrospective chart review of 37 patients was what they got accelerated approval on, and their confirmatory trial was just over 100 patients.
Obviously we showed 32 patients' worth of data last week on the safety, 20 on the efficacy, and we're continuing to enroll at a rapid rate. To answer your question, it could be a very rapid pathway to an accelerated approval, and the confirmatory trials are in this zone of 100 patients at the upper end here. This could move both very rapidly and with relatively modest dollars. On the commercial build, it's relatively similar. There are only a small number of vascular anomaly centers in each large European country, and there's probably somewhere between 20- 30 in the U.S. You could probably build yourself a relatively modest commercial presence and footprint here to generate significant revenues. All in all, on one side it seems very attractive in that it's very small numbers of dollars here.
The unknown on this side, obviously, is how actually we build this market, because it's a nascent market. It's not a very well-developed market as we see on the breast cancer. The dynamics of both are attractive to us. One is well-trodden pathway, very clear, just produce the data, get share of voice, generate market share, and the other one is a huge potential for us with relatively modest dollars. It may take a little bit of time to develop that to fruition.
Understood. Just to put a finer point on that, would it be fair to say the amount of additional capital needed to run the clinical trials, we're talking about $50 million?
Yeah.
Okay.
I think that's a fair estimate. It's going to $50 million and $100 million worth of investment.
$50 million-$100 million in terms of running the clinical trials, and then in terms of sales force build, if we look at historical precedents, we're thinking about maybe something $100 million in terms of annualized run rate.
Yeah, probably less than that.
Even less than that?
Yeah.
Interesting. Now, you gave really encouraging early data. There's going to be more cohorts that enroll, there's going to be more subtypes, there's also an FDA discussion to really be had. Let's start with where are you in terms of your dialogue with the FDA? Have you had initial conversation after this top-line press release? Any updates there?
Yeah. We're currently guiding that we will have a regulatory interaction this year and come back to the Street later this year with the outcome or output from that interaction. The goal there is to have a conversation around what would be required if accelerated approval is available to us, which we think it is, and then what would be required to accomplish that.
The two key questions there are going to be around dose and the N required to support accelerated approval, and are going in assumption there will be that we would pool together both PROS and at least pool together PROS and lymphatic malformations. That's where we have a number of topics to try to get through with them, and we would come back and report the outcome of that later this year.
Understood. What I think would be very helpful is can you kind of prospectively lay out the outcomes? There seems to be three. One is, all right, we have data in PROS. That's what we're going to let you do the expansion in, which seems to be, I think, a bit restrictive. There's the one that I think your team hints is probably the most likely, which is we'll go after at least the two subtypes or the two biggest markets, and we'll say, "Hey, we show consistency of data in both of these malformations, and let us run a confirmatory trial there." Then in VM, we may have to run another separate study. Then there's the other outcome where, look, you can run a trial in all three. First of all, is that the right framework?
When you set investor expectations, what's the reasonable base case right now?
Yes. The one thing, a key point you mentioned there is consistency of data across these subtypes, which is something that the agency will look at. Today, we've reported on four patients in lymphatic malformations. Three out of the four patients responded. Two of our deepest responses are coming from the lymphatic malformation patients. I would say today we're seeing signs of consistency of data between the PROS and the LM patients. We're not seeing a difference in safety profile across those two patient populations. We need to now grow that end in lymphatic malformations, and that consistency has to continue to stay there. There's no drug-approved systemic therapy approved for lymphatic malformations, and we believe it to be a severe unmet medical need. Yes, our going-in hypothesis is a base case of keeping those two pooled together.
Now, if you landed in just an initial label in PROS and you had to separate out lymphatic malformations into a separate single-arm study for accelerated approval, perfectly fine outcome also.
Alpelisib with just a PROS label and all the shortcomings of that drug had probably treated on the neighborhood of about 5,000 patients or so since they've received accelerated approval. We know in this context, if you could have an agent that could really be used chronically, every 2,000- 3,000 patients would be about $1 billion in peak sales. If that's where we land for an initial label and we do sequential close-in sNDA for lymphatic malformations and venous malformations, that's a perfectly fine outcome also.
Understood. Now I know you had eight LM patients, four that were clinically evaluable. We may get more data on that subtype as well, and that might feed into the discussion of consistency. Can you remind us what dose those other four patients are going to be on, and really, what's the data cut we could get with that other subgroup by the end of the year?
Yeah. They're spread across the dose randomization doses, so 400 mg, 300 mg, and 100 mg. Those eight patients total from the dose randomization portion of the study, so 25% of the 32 patients fully enrolled. We've also started expansions. We started expansions a month or so ago at this point. We'll also have patients coming in on the expansion cohorts that could be included in an update later this year. We could have more than those eight lymphatic malformation patients.
Okay. Understood. It sounds like more updates to come there. Sanjiv, this is the question for you. You're in this unique perspective where, again, you talk about risk adjustment and spend then TAM. Both are very, very attractive markets, but the de-risking component on the breast cancer side is certainly going to take longer than maybe the orphan side. You're also, to a certain extent, capital constrained. How do you think about, we've seen external financing, royalty agreements, debt agreements. What other sources of capital do you think investors should be paying attention to when you counterbalance both of these opportunities? Number two, is there an appetite to maybe spin off one of these indications entirely because you feel like that could actually be a value unlock?
Okay, we'll take those slowly. As you know, we had ended the quarter with over $600 million of cash, and then we just did a $300 million financing. We have a pretty robust balance sheet that should take us through to having top-line data on both the breast cancer and the VAs pivotal trials. We don't imagine there'll be too much difference between the timing of those two approvals. In terms of the frontline trial, we have now money to prosecute that all the way out to the readouts from these two. In terms of just our ability in the near term to execute and generate meaningful value-creating data, we feel pretty confident. I think you're in a great situation because obviously you sit on two registrational data sets. You sit halfway through a frontline trial.
I think all of the tools that you just listed, debt, further equity, royalty financing, partnerships, all become available to us. I think we feel pretty confident now of our ability to get into the next decade and commercialize in all three indications.
Understood. I'm going to sneak in one more question. Post the ASCO data set, because again, there's multiple CDK4 players, there's multiple people looking at what to do in HR positive, do you feel like there's been this renewed interest externally of your drug in breast cancer specifically?
I think absolutely. If you go back 18, 24 months, there was a lot of unanswered questions.
Yeah.
PI3K inhibitors, were they going to be meaningful? What would happen to the oral SERDs? Would they dominate in the front line? What about CDK4/6 in PI3K alpha-mutated patients? CDK4/6 retreatment. All of these things I think are starting to resolve themselves, you come back to the simple basics of 40% of patients have a PI3K alpha mutation. In those patients, the best way to treat them in any line, early first line, metastatic second line, is to have a PI3K alpha inhibitor. I think that is becoming clearly understood by everyone in the field, providers, strategics, and biotech.
Understood. On that note, I really do appreciate it. Thanks so much