What are the challenges with Project Optimus?

The Food and Drug Administration (FDA) launched Project Optimus, an initiative to establish a dose-optimisation paradigm for cancer therapies. The goal is to collaborate with medicine developers, academia and patients to develop oncology therapies with dosing regimens that improve safety while maintaining efficacy.

While the goals of Project Optimus have been widely welcomed, its implementation has also raised important questions for medicine developers, regulators and other stakeholders.

This blog explores the potential limitations and practical challenges associated with the initiative, including the impact on development timelines, clinical trial complexity, resource requirements, manufacturing considerations and the implications for smaller biotechnology companies. It also examines the challenges of applying dose-optimisation principles to paediatric and rare cancers and discusses ongoing debate surrounding the FDA's approach to orphan drug development.

Using pirtobrutinib as a case study, the blog considers concerns regarding regulatory consistency and whether Project Optimus principles are being applied uniformly across oncology programmes.

What does Project Optimus propose?

The FDA’s dosage optimisation recommendations emphasise a shift toward a data-driven, patient-centric approach to drug development. The overarching goal is to identify an optimised dosage that maximises the benefit–risk profile by providing the desired therapeutic effect while minimising toxicity, rather than simply finding the MTD.¹ The FDA also outlines that review through an expedited programme, i.e. breakthrough therapy designation, does not justify avoiding the need to conduct dosage optimisation before or at the same time as establishing a drug’s safety and efficacy.¹ Taking advantage of early FDA engagement is recommended, as oncology development programmes can vary tremendously.

Download our full whitepaper to explore how oncology developers can adapt their clinical development strategies to meet evolving regulatory expectations and maximise the probability of long-term success.

Potential limitations of Project Optimus

As with any new initiative proposing significant changes, questions are circulating regarding how this will impact drug development. Subbiah (2024)² and Murphy et al. (2023)³ outlined the potential challenges medicine developers may perceive when implementing Project Optimus’ dose-optimisation initiatives.

• Longer development timelines

Aiming for more comprehensive dose finding could lengthen clinical development timelines, particularly if this calls for additional phase 2 trials. Increasing the development timeline inevitably delays bringing new medicines to market. However, this must be balanced against the potential for increased discontinuation rates due to toxicity in patients receiving unnecessarily high doses and reduced PMRs to evaluate lower doses.²

• Increased trial complexity

The proposed shift from trial designs such as the 3+3 MTD early phase dose finding trials may significantly increase clinical trial complexity. For instance, it may be necessary to increase intervals between dose cohorts to capture PD and longer-term effects and integrate data on broad tolerability into dose-finding models, alongside PD and activity measures.³ Project Optimus proposes several dose-selection strategies at different stages of development, which require implementing sophisticated and adaptive trial designs.

• Increased resources

Dose selection under Project Optimus may also be resource-intensive. The guidance recommends robust PK sampling and detailed analysis plans, which may strain sponsor resources and increase the operational burden of early-phase trials. There is also the concern of increased cost of clinical development, which may pose a greater challenge to smaller biotechnology companies and academic institutions.²

• Manufacturing

Manufacturing considerations represent another potential hurdle. Project Optimus emphasises evaluating multiple dose strengths during development, which may pose challenges for companies that must produce and supply several dosing options simultaneously. For some sponsors, the perceived difficulty of manufacturing multiple strengths could affect the feasibility of conducting dose comparisons in early-stage clinical trials.²

• Paediatric and rare cancers

Sponsors may be hesitant to invest in paediatric and rare cancers in part due to financial return, and also due to small enrolment numbers as a function of these types of cancers. Subbiah (2024)² outlined industry’s potential concerns that hesitancy to develop medicines for paediatric cancers under the Project Optimus initiative could lead to delays or discontinuation in paediatric cancer development altogether. Critics argue the initiative, designed primarily for adults, may not suit paediatric needs, and highlight the importance of flexibility and collaboration with the FDA to tailor policies for rare and paediatric populations.²

• The effect on small biotechnology companies

Smaller biotechnology companies have expressed concerns about unexpected regulatory expectations associated with Project Optimus. Some sponsors report that expanded phase 1 trials and additional dose-optimisation cohorts may require more funding than originally anticipated. This can create financial pressure, particularly when additional trial arms or extended studies are needed.²

• Heterogeneity and endpoints

For molecularly targeted agents, the minimal biological dose may not be consistent across different patient populations, tumour types, disease stage and specific mutations.³ Additionally, comparing doses may be more difficult in situations where response rates are lower or combination products are used. Although PD endpoints can provide further evidence, PD data may depend on the mode of action and could result in increased tumour biopsies, which increases patient burden.³

Is the FDA waiving dose optimisation for orphan drugs?

Alongside implementation concerns from the industry, the FDA’s consistency in practising its new dose optimisation guidance through Project Optimus has also been called into question, particularly in the case of orphan drugs for rare diseases.

A 2023 paper used the FDA approval of pirtobrutinib (JAYPIRCA®) as a case study to highlight potential inconsistencies in regulatory oversight.⁴

Pirtobrutinib was approved in 2023 for mantle cell lymphoma at 200 mg QD. However, the authors argue this is not clearly the "optimal" dose because only 5% of patients in the clinical trial received lower doses, leaving minimal evidence to support 200 mg over lower, potentially safer levels.⁴

Additionally, serious adverse reactions occurred in 38% of patients at the approved dose, often leading to treatment interruptions or discontinuations.⁴ The authors suggest that PK in these patients might be confounded by cachexia and high protein binding.⁴

While some argue that dose optimisation is difficult in rare diseases due to small patient populations, the authors point to drugs like mitapivat, pacritinib, and mavacamten as proof that preapproval dose-finding is feasible for orphan indications.⁴

Much like the sotorasib dosing contention, the authors also point to a significant pharmacoeconomic burden associated with higher doses. They reported that pirtobrutinib costs approximately $25,200 per month at the 200 mg dose, whereas the minimally effective dose of 50 mg dose would cost $8,400.⁴ Optimising to a lower effective dose could drastically reduce "financial toxic effects" for patients and payers but reflects a lower reimbursement effect for the sponsor.⁴

Concern was expressed that ongoing phase 3 trials for pirtobrutinib in chronic lymphocytic leukaemia are using only a single dose level, which contradicts the central teachings of Project Optimus. They urge the FDA to mandate dose-ranging studies to ensure that patients with rare cancers are not receiving unnecessarily toxic or expensive treatments.⁴

Summary

Project Optimus seeks to reform oncology dose selection by promoting comprehensive dose optimisation strategies that prioritise efficacy, safety and long-term tolerability rather than relying solely on the maximum tolerated dose. While the initiative has been widely recognised as an important step forward in oncology drug development, its implementation presents several practical challenges for sponsors.

Potential limitations include longer development timelines, increased clinical trial complexity, greater resource requirements, manufacturing challenges associated with multiple dose strengths, and difficulties applying dose-optimisation principles in paediatric and rare cancer populations. Smaller biotechnology companies may face particular challenges due to the additional financial and operational demands associated with expanded dose-finding programmes. Furthermore, the heterogeneity of targeted therapies and patient populations can complicate the identification of a single optimal dose.

The application of Project Optimus to orphan drug development has also generated discussion within the industry. As Project Optimus continues to influence oncology drug development, balancing robust dose optimisation with practical development considerations will remain an important challenge for sponsors and regulators.

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