Alongside the multitude of guidance documents, recent years have seen the US Food and Drug Administration (FDA) ramp up workshops and project implementation efforts in a bid to drive innovation in drug development. Agency eyes have zeroed in on oncology, with the FDA Oncology Center of Excellence (OCE) introducing frameworks such as Project Optimus to reform the dose optimisation and dose selection paradigm in oncology drug development.

While the framework of Optimus is not new to drug development, it is relatively new to oncology. In non-deadly indications, researchers have been employing the framework for quite some time because the chances of patient survival are higher, making drug toxicity less acceptable in these indications compared to a high-morbidity indication such as cancer, says Dr Fouad Namouni, president of research & development at Blueprint Medicines.

The philosophy of oncology drug development—both academically and in pharma—is to save patient lives. However, development has historically prioritised drug efficacy and eliminating tumours and cancer at the expense of increased treatment toxicities. This can be seen across several therapies such as chemotherapy, small molecules, antibodies, and cell and gene therapies, most of which have a positive impact on efficacy and patient survival but come at the cost of toxicities.

“We are looking to get drugs to patients as quickly as possible. While this is a noble gesture, it has some challenges in terms of what we are able to show is an effective and safe dose,” said Dr R Donald Harvey, professor at Emory University School of Medicine.

“Efficacy is the bare minimum,” adds Namouni, who drives the argument that Project Optimus is a timely initiative with the potential to fine-tune drug development. Increased emphasis on optimal doses will allow patients to reap maximum benefits from treatment as they do not have to discontinue a given treatment due to toxicities. In addition, this is important because cancer can reemerge in the absence of treatment and lead to mortality, he explains.

Therefore, Project Optimus is a bid for balance: maintaining treatment efficacy at a therapeutic dose that does not generate toxicities that could otherwise be avoided with a different dose. What the FDA is asking pharma to do is implement cohorts and subsequent analyses, and fundamentally more observations of doses that are different from each other, experts agree.

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Project Optimus: apply with care

In the existing model, a handful of patients are evaluated at a dose that is adjusted according to response data, the adverse event rate, and clinical pharmacology. Given that a therapeutic’s tolerable side effects are different at initiation versus over a longer period of time, what the FDA is asking pharma to do is evaluate multiple, diverse doses that increase the knowledge surrounding a therapy, thereby maximising its potential benefits for patients.

The reform in the dose optimisation model is needed because many drugs—particularly the newer, orally administered drugs—have a relationship between side effects and efficacy that is not linear, explains Harvey. An increasing dose may correlate with an increasing side effect profile early on in the development lifecycle.

But at some point, efficacy plateaus despite dose escalation, while side effects continue to increase in frequency and severity. This is the trajectory for many cancer drugs because the field actively follows a model of drug development where dose escalation is continued until problematic side effects materialise, at which point escalation is ceased.

The key is to apply Project Optimus to the right projects, as it could potentially be a hindrance when developing drugs with other modes of administration, Harvey explains. The biggest culprits for subpar doses are oral formulations and orally dosed medications such as capsules and tablets. Subsequently, these oral medications provide the biggest opportunity for Project Optimus to create an impact.

“A key operational aspect of the Project is understanding the molecule more at the outset of human trials,” explains Harvey. At early clinical stages, the drug profile of an intravenous therapy will be more extensively characterised than the profile of an oral drug because there is more available knowledge about the former.

Oral formulations have more variability at the outset, and subsequently more knowledge gaps regarding drug absorption and drug interactions, he adds.

“If a new PARP inhibitor were to be developed today, there would be a lot more known about it, and there would probably be a much more predictable dose. However, in terms of risk, if you have a brand-new antibody that is a first-in-class target, we’re going to know a lot more about that than we will a first-in-class oral agent,” Harvey says.  

Furthermore, Harvey believes the project will be more applicable to drugs with mechanisms of action that have more data and proven history, as opposed to drugs with novel mechanisms that are first-in-class or innovators: “If you’re the third agent in a class, then we know a lot about what the on-target side effects of that agent are.”

However, Project Optimus is particularly applicable when it comes to efficiency in understanding a selected dose in a registrational package. Typically, the agency asks companies to evaluate the dose of a cancer therapy after it has been approved for the said dosage, which is “not an ideal scenario” because the non-optimal therapy is already on the market and being used to treat patients who could be at risk for certain toxicities, explains Fouad.

With the framework suggested by Optimus, a selected dose that has completed Phase III studies and is entering registration would be supported by a chronological progression of data, and subsequently, better understood in a fraction of the time.

Smaller companies will take bigger hits

Project Optimus will impact the cost of the trial, the timeline of execution, and the timeline of development.

“In small companies, it is always difficult because resources are constrained and the people investing and financing small companies more often want to see results as quickly as possible and confirm the hypothesis the company is built upon,” says Fouad.

Smaller companies may feel the brunt of the negative effects of this FDA initiative because they are often dependent on buying and selling parties that can allocate the necessary capital and resources. Fouad says the impacts of an initiative such as Project Optimus would have been more significantly felt by Blueprint ten years prior.

The more significant issue at hand for Fouad, however, is that when it comes to discussions held with the FDA on the work needed to substantiate treatment efficacy and safety in both acute and long-term settings, pharma is more involved while biotechs are less so. The effects of Optimus will be felt by pharma in the extended timelines and increased costs, but the effects will more acutely and presently be experienced by biotechs.

By pressuring and squeezing drug development (through regulation) in both the clinical research phase and the post-approval stage, the subsequent risk for R&D is to bias areas of research towards what is not being pressured.

“Will people working in the rare disease space continue to be incentivised to look at diseases that are rare? Will researchers continue to take huge risks in oncology or turn to disease areas that are less risky than oncology? What we need to be thinking about is making sure that the pressure in a given area does not disincentivise researchers from taking risks and going into areas where they can make a difference,” explains Fouad.

While Project Optimus will undoubtedly impact the companies developing small molecule and biologic therapies, Diakonos president and COO Jay Hartenbach finds that an initiative such as Project Optimus is less applicable to cell and gene therapies, an area on which clinical-stage biotech Diakonos focuses.

The existing model of drug development—that has established a working “equilibrium” amongst pharma, biotechs, and innovation—is a cycle where biotechs develop a product with reasonable hypotheses, de-risk it and mature it, at which point pharma acts on the product to scale and commercialise it, says Fouad.

“Clearly, all these projects will impact the equilibrium of when a biotech is ready to transact with pharma versus when pharma is interested in transacting with a biotech, but if we lose the model of biotech, feeding to pipelines of large pharma, then it’s going to be really a steep change in the industry, and I don’t know how or what kinds of other models are ready to replace that.”