Project Optimus Series | Navigating the Realities of Project Optimus

Launched in 2021 by the FDA's Oncology Center of Excellence, Project Optimus seeks to reshape traditional oncology trial designs and dosing paradigms, shifting from maximum tolerated doses to precision dosing strategies. While the FDA's hope was that the added time and cost of collecting comprehensive dose and exposure response data would benefit both patients and sponsors, there is also concern and debate in the biotech community that, if the Optimus formula is closely followed, the additional time, cost, and patient needs may, in fact, be crippling to cash-strapped emerging companies. 

So what is the reality around Project Optimus? And how best can it be implemented and navigated?

Kicking off a new special series on Project Optimus, in this episode Nick Kenny, Chief Scientific Officer at Syneos Health, is joined by Dr. Wael Harb, Vice President on the Syneos Health Medical Oncology Team, to explore this transformative initiative, diving into the implications for biotech companies and discussing the balance between upfront investment and long-term benefits, the operational challenges of implementation, and the critical role of early planning.

Stay tuned for upcoming episodes in this series, which will dive deeper into the regulatory, statistical, clinical, and operational implications of this evolving regulatory framework.

The views expressed in this podcast belong solely to the speakers and do not represent those of their organization.

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Transcript

SPEAKER_01 0:00

In 2021, FDA's Oncology's Center of Excellence launched Project Optimus with the bold, perhaps overdue, intent to transform oncology study designs and dosing assumptions that had dominated decades of drug development based on a cytotoxics paradigm. The FDA's hope was that the added time and cost of collecting comprehensive dose and exposure response data would benefit both patients and sponsors by defining the benefit risk profile of new cancer products more precisely sooner, thereby de-risking later-phase studies. However, there is also concern and debate in the biotech community that if the Optimus formula is closely followed, the additional time, cost, and patient needs may in fact be crippling to cash-strapped emerging companies. So, what is the reality around Project Optimus and how best can it be implemented and navigated? I am Nick Kenny, the CSO at Synos Health, and today I'm joined by Dr. Weilhab, Vice President in the Synos Health medical Oncology team, to unpack just what Project Optimus means and how best biotechs can implement and benefit from this approach. Each episode will provide a deep dive into some critical aspects of Project Optimus, looking to balance regulatory, statistical, clinical, and operational perspectives. The realities of Project Optimus next on the Senior's Health Podcast.

SPEAKER_00 1:25

Way, welcome. Thank you, Nick. It's a pleasure to join you on this important topic.

SPEAKER_01 1:30

So, Will, I know Optimus began life in 2021 and there have been updated draft guidances in the past couple of years. But just for our listeners, can you set the stage for really why this is important and what you're seeing in the real world of drug development as people try to navigate what this all means?

SPEAKER_00 1:47

Of course, Project Optimus was launched by the FDA's Oncology Center of Excellence in 2021. And the goal is to reshape how dose selection is approaching oncology. As we all know, historically, dose selection in cancer trials has relied on finding the maximum tolerated dose or MTD. This approach worked well for traditional chemotherapies, where higher doses often correlated with better outcomes. But for modern therapies, especially biological therapies like tyrosine kinase inhibitors, antibody drug conjugates, immunotherapies, MTD is no longer an ideal metric because these drugs have a flatter dose response curve and can cause cumulative toxicity even at lower doses. So with the project Optimus is promoting precision dosing, the idea of identifying a dose that provides maximum efficacy with fewer side effects. So the initiative's primary goal is to shift focus from how much can the patient tolerate to what dose offers the best balance of efficacy and safety.

SPEAKER_01 2:55

That's a very clear explanation, Well, because I think we've all seen examples of where dosing has been pursued too far with a biologic way beyond biological activity. And as you say, you can run into a cumulative toxicity situation. So really I think this approach to get a more precise biological activity sooner has got to be better. What are the downsides to Optimus? Why have we seen all this debate in this biotech community about added cost and time burden? What's driving that?

SPEAKER_00 3:23

From a biotech company perspective, they are trying to reach proof of concept. This is drug work. And should we invest more in further development? And as we all know, the drug development is a very expensive process. The biotech is driven by making that decision of go no go. And they try to avoid doing additional patient that would required for this optimization. The FDA argument is that if you don't select the right dose early on, actually this will harm the drug development process because you might select a dose as too toxic or might not be efficacious. So in the long run, you would save more money, but also it will improve the chance you're going to find the right dose that be able to proceed forward. So that's really the balance is that when to do the dose optimization and before exposing a large number of patients to a dose that might be incorrect as far as the balance between safety and efficacy.

SPEAKER_01 4:27

I think that's great. Because I think we've all seen examples of products that have made it into phase two development and then run into major problems or often failure because the dose wasn't correctly selected, correct?

SPEAKER_00 4:39

Absolutely. That has been one of the major reasons why the FDA launched the product optimus because we have seen those in multiple drugs that were already approved in the market, but after post-marketing, we found that the dose is not tolerable and causing significant cumulative toxicities that required dose reduction or even stimulation.

SPEAKER_01 5:01

Yeah, and in fact, I think in some ways it's actually taken what potentially were really good drugs and sort of hampered their adoption because they were poorly developed. I think with lower doses and perhaps lower time exposures, we could have used these drugs somewhat better in the clinical community. I think we've all seen examples of that. So then, Will, maybe just to switch gears a little bit. Is the agency operating in a vacuum? And what are other regulatory bodies around the world doing? Are they adopting this same sort of approach?

SPEAKER_00 5:28

We're seeing some interest from the EMA and from Japan and other regulatory agencies. We all know FDA is pioneering this project, but this isn't really driven because of the change in the landscape of drug development and the biological therapies. And although the European and other countries might be slow to adapt, we're seeing adoption moving forward. We would predict that this is going to be the default way of doing clinical trials globally.

SPEAKER_01 5:57

Yeah, that makes sense. And well, I think one term we've all heard bandied around, and maybe you can just sort of demystify it for our listeners. So what is model-informed drug development MIDD, and how does that weave into the whole optimus approach?

SPEAKER_00 6:11

Model-informed drug development or MIDD is take into account the totality of data. Traditionally, with those escalation studies, we're primarily looking at adverse events and safety in determining and selecting the dose that we move forward in those expansion phase two and beyond. The FDA is encouraging us to look into the pharmacokinetics, pharmacodynamics, and do modeling in addition to the safety and efficacy of data. So that's what is required, basically, with the MIDD, is we are integrating all of this data in finding the optimal dose.

SPEAKER_01 6:54

Well, it really is taking a more of a total approach to the information around a drug than simply just blasting through and trying to find out an MTD and then trying to figure things out after that. It's a really a much more upfront informed approach. So then with that in mind, Whale, it seems to me that with Project Optimus for the development of precision oncology therapies, that pre-IND meeting is going to become more critical to sit down with the agents and define exactly what your plans are beyond just I can show what this drug looks like in preclinical. And here's my, if you like, very standard approach to dose finding. Is that what you're seeing when you're consulting with a lot of the biotech companies that you work with through us?

SPEAKER_00 7:35

We absolutely recommend to have this pre-I and D meeting for early phase oncology trials, the first new human trials, to discuss the unique features of the drug, the mechanism of action, and how does Project Optimist apply to it? Adding the project optimist or dose optimization in the design can be complex. Do you do a backfill? Do you randomize to more than one dose levels? Do you do that in a certain tumor type? So there's a lot of questions that need to be addressed. And if we delay that, often what happens when the IND is submitted to the FDA, the FDA comes back with these questions, which we force the biotip to going back to redesigning the trial, which takes even more time and lose really critical time from drug development. So it's really important to have that meeting early on and discuss this element and get the feedback from the FDA and implement these features into the design of the trial.

SPEAKER_01 8:35

So a lot more early, deliberate planning, if you like, rather than just a race to get into patients and then take it from there when you see some evidence of benefit or perhaps you see safety signals and kill it. So it's a much more considered approach. So switching gears a bit from an operational delivery standpoint, what have you seen when you've been working with customers in terms of the operational challenges they face when trying to align to this new guidance and perhaps the dialogue we've had in the agency? Are there immediate impacts to the standard way of pick three sites, do cohorts, all of this stuff? Is it requiring a re-engineering of early development?

SPEAKER_00 9:10

It does require several things. One, it's what site to go to, but also depends on the tumor types the drug is being intended to. If you we go back one step, those escalation studies traditionally done three plus three design, we're looking at toxicity, those limiting toxicities, and determining the maximum tolerated dose. Since we are now looking at the optimal dose, we're not only looking at safety, but we're also looking at efficacy. We all know efficacy is very difficult to determine based on heterogeneous patient population. That means we have to expand into a specific tumor type and more selected line of therapy so we are able to compare different dose levels. With that approach, we would have to think about first how can we dose escalate efficiently. So we encourage going into adaptive designs such as Bowen or MTPI2 or others, and we're going away from 3 plus 3 design, but we also have some other elements during the dose escalation, such as backfills, looking into expanding a certain dose level. Ultimately, we would like to select a dose range, which will help us select which dose to move forward with the dose optimization and randomization.

SPEAKER_01 10:33

Right. So it really is around the fine-tuning of the planning part then and making sure that everybody involved is fully aware of what we're trying to look at. So I think it's a mindset shift for both delivery of the trial as well as working closely with investigators to look at how that all flows through a trial. It's not business as usual, if you like. I think we alluded to earlier examples of where drugs have not done as well as they might have done because early dosing strategies led to post-marketing, those adjustments. Can you give us a couple of examples of those and maybe contrast those challenged examples to examples of people who've adopted Optimus and really done very well?

SPEAKER_00 11:10

Absolutely. So we have seen, especially when tarising kinase inhibitors came out, that doses have been approved. And these doses, when post-marketing, we realized that the drugs were not tolerable and required multiple dose reductions and required some discontinuation, which pushed us back to looking into really did we select the right dose? That's really the impetus for, you know, we should not wait until we expose a lot of patients to toxic drug. I would say TKI was the first one we have seen issues with it. But now we have realized this is a true problem in the majority of biological drugs that we have. Because of that flatter dose response curve, you really don't need to dose a higher dose to get to uh more efficacy and actually it will add more toxicity. Because of that, it is important to implement the dose optimization in early phase oncology trial before we're exposing a large number of patients to toxic dose.

SPEAKER_01 12:14

And if I sort of pull that thread a little bit more, Wail, it seems to me that if you launch, and you and I have talked about a couple of examples of this, but if you launch a product and then face those toxicities and dose reductions, it seems to me that you've got a couple of major issues now. So one, from a physician perspective, you're sort of eroding trust in that drug, and it opens up the door for another drug to maybe come along and replace that or poor adoption of your drug. And then secondly, it would seem to me like you can have a significant impact on your commercial planning and go-to-market approach. If you launch a product expecting it to be adopted in a certain way, and in fact the doses need to be reduced and it doesn't get adopted the way you thought, the commercial impact to your overall development plan is going to be impacted. Is that what you're seeing? Is that correct? That's an excellent point, Nick.

SPEAKER_00 13:03

The approval of the drug does not mean commercial success. We have seen for several reasons. We have competitive drugs, we have the physicians and patient ability to use the drug effectively. We've seen when the drugs have a lot of toxicity, there's a slow adoption of the new drug. And for all of these reasons, thinking with the endpoint in mind, we really have to do this work early on in the process. So by the drug becomes approved, we have selected the optimal dose that does not have cumulative toxicity. And this is what we would consider to be a patient-centric approach. Ultimately, all these drugs are developed to help patients live longer, live better, able to control the disease. So we need to also look into not only these parameters we talked about, but even implement patient-reported outcomes because ultimately, if patients are not taking the drug, they're not benefiting from it, and ultimately the biotech is not benefiting because they're not able to commercialize their drug.

SPEAKER_01 14:05

Right. And I think that's a great point, Well, that I want to elaborate on. We've talked earlier in other podcasts when we talked about circulating tumor DNA, for example, about designing more patient-friendly trials early on in oncology drug development. And this to me seems like a natural extension of that way you've described it. So if we can integrate, as you said, patient reported outcomes, so EPROS, into this, you're getting an added dimension to the overall safety and tolerability and acceptance of a drug that we hitherto, with traditional cytotoxic designs, have not seen. So you're sort of creating this perfect wheel of opportunity for both sponsors to have better design trials that have better long-term opportunity for success, both clinically, regulatory and with patients. And yet we're asking people to invest more money earlier. So it's almost as if Optimus is encouraging people to think more, do more slowly up front, invest more for the potential better outcomes. Are you seeing any of our biotech customers sort of push back on this, that they have minimal cash to expend up front and it's going to, if you like, cramp their ability to do early development? Or are people really warming up to this approach?

SPEAKER_00 15:12

I think overall, biotech companies have been struggling with the issue because a lot of them are looking at milestones early on in drug development where they can get more funding. And that's typically at the proof of concept go no go. So they're really not looking necessarily at the end game of getting the drug commercialized. Therefore, they would rather not do the dose optimization early on in the process. The return of investment on that is likely to be realized in the big picture. So, therefore, how to balance that in the early phase oncology trials? The FDA argument is that if you don't do dose optimization in the early phase oncology trial, if you start expanding to a larger number of patients by selecting the wrong dose, it might harm drug development because you've selected dose as too toxic and might result in stopping the trial and/or clinical hold. Therefore, they highly recommend that you really need to do the dose optimization before the dose expansion. One way is to think of this that we are no longer looking into traditional phase one, phase two. We're really looking at dose finding studies, looking at both safety and efficacy in seamless design, where we go quickly from a dose escalation to dose expansion. During that process, there's an interim step where we do the dose optimization. Getting that proof of concept in select tumor type, optimize the dose before we move further into the pivotal study.

SPEAKER_01 16:47

Right. So if I really sort of pull on this thread a little bit more, Will, it seems to me like Optimus is actually offering, well, if you like, mandating perhaps, a paradigm shift that doesn't just impact how we think about interactions of the agency and trial design. It's actually going to switch the paradigm of about how investors think about early phase oncology drug development. So no longer can they be thinking about, I'm just going to sprinkle a small amount of money in the front end of this and hope I get a dose that shows minimal safety concerns and some evidence of efficacy. And then I'll invest a bit more, but I might lose because I've picked the wrong dose. It's asking people to take more informed but bigger bets sooner because the downstream impact is going to be a lot better if they get it right. Is that a fair assessment? So take a bigger bet earlier with your cash to get more sophisticated data in the hope of a long-term better outcome. Is that what we're seeing?

SPEAKER_00 17:43

Yes, and partially it's true that this is what the FDA asking is you really more from a patient perspective before exposing more patients to those that's maybe toxic, you need to select the dose. From a biotech perspective, there's always that tension. They're more interested in having the proof of concept early on before they would do those optimizations. So that we see a lot of back and forth between biotech and FDA regarding this issue. But I agree with you that it is a paradigm shift and it is a bigger investment up front. But it is important from a biotech perspective and from investment perspective, is that if we find a good biomarker or PD marker that will give us insight into the efficacy, and we're seeing the efficacy signal early on in this design, it will help de-risk the trial later on by not adding a large number of patients when it's not effective. In a sense that is de-risking the trial later on, if that design is done well, it will help not only satisfy the FDA requirement, but it would help make a better informed decision whether to further develop the drug in the stumer type or not.

SPEAKER_01 18:57

My hope then, Will, really would be from a patient-centric standpoint, we'll develop the right drug at the right time and put a lot less patients through the traditional sort of cytotoxic 3 plus 3 where it wasn't that many people that could derive a benefit from those early phase trials. These more sophisticated approaches theoretically could benefit patients even in the phase one, two setting, I believe. So certainly it is an interesting paradigm shift. I know we've got more podcasts coming up where we can get into more of the details. Any sort of last closing thoughts for you before we close this one up and prepare for the next one?

SPEAKER_00 19:32

Yeah, I think that your comments earlier about paradigm shift resonate with me. I think this is not something that's happening short term. This is a process that will continue to affect drug development in oncology for the next decade. It's a work in progress because the FDA realized there's a lot for us to learn in how to model what is the best approach. So we encourage biotech companies to have a dialogue with trusted partners to consult on this. We encourage to talk to the FDA. I think it's a very interesting topic that will continue to evolve.

SPEAKER_01 20:06

Well, it is well. And thank you for your time and insights. And we'll look forward to the next podcast on this topic.

SPEAKER_00 20:11

Thank you very much, Nick.

SPEAKER_01 20:13

That's all for today's episode of the Senior's Health Podcast. I'm your host, Nick Kenny. If you have other topical issues you'd like to hear on this podcast, please do send us a message at podcast at Senioshealth.com. And for access to more future-focused, actionable life science insights, please visit the Senior's Health Insights Hub at insightshub.health.