Innovative approaches in developing T-cell-engaging molecules are shifting the idea of what’s possible in our medical landscape. To see these transformative immunotherapies change lives, developers must create, implement, and execute the right strategies to get these products to market, beginning with a non-clinical development strategy.
This article from KreaMedica outlines our processes for working with clients to build robust, effective, non-clinical development strategies for T-cell-engaging molecules. Read on as we explore the process and outline the best approach to tackle your strategy.
Finding the Right Strategic Partner
The first step in forming a non-clinical development strategy is identifying the right consulting firm to execute your project.
You and your consultant will work closely together throughout this phase of drug and product development; you must share a high level of trust, and your consultant must maintain a firm grasp of your molecule, its mode of action (MoA), and your organization’s unique needs, including:
- Understanding the molecule
- Defining your resource availability in terms of budget, time and staff
- Understanding lab logistics: in-person vs. virtual location
- Quantifying existing assets and goals
- Learning and meeting (realistic) desired timelines
Your consultant should conduct a gap analysis to assess the performance of your current and proposed projects. From there, they will help you take the next best steps to continue in the right direction.
After the analysis, your consultant will define the extent and scope of services your project requires, with a focus on biopharmaceuticals like monoclonal antibodies (mAbs), T-cell engagers (TCEs) and NK-cell engagers (NKCEs) in the nonclinical areas of toxicology, pharmacology, bioanalytics, biomarkers etc.
Standard Issues to Address
Every non-clinical development strategy for T-cell engaging molecules requires consultants and project teams to address specific elements of the project. Below are the standard issues you must address when developing your plan.
- Understand the Clinical Indication and Patient Population
Nonclinical programs are to some extent generic. But they profit a lot in terms of speed, resource allocation and efficiency if the goal of the clinical development is defined as early as possible. This comprises the target indication, the patient population, the Route of Administration, the length of treatment and the related readouts. The nonclinical program can be designed to meet the regulatory requirements to get approval for moving the project into clinical development in the intended clinical indication. A Target Product Profile (TPP) is a well-established tool to handle these parameters in a competitive landscape and communicate them to all stake holders.
- Carve Out a Non-Clinical Development Plan
Proper planning is key to successful pharmaceutical development. The overall development plan comprises several sub-plans like a CMC development plan, a bioanalytical development plan and a clinical development plan, but also a non-clinical development plan. This plan translates the science- and guideline-defined generic aspects of nonclinical development into a more specific framework for your strategy and project, including
- The status of your project
- Acquired data
- Future data required to complete non-clinical development
You must account for these factors before moving the project into clinical development and other phases and strategies. This is a costly, time-consuming exercise. Solidify your non-clinical development plan before pursuing further phases.
The overall development plan will then integrate the various more specific plans and define interfaces and deliverables like test item (clinical candidate, amount, quality), methods and study results.
- Justification of the Relevant Species
Once you have made sufficient progress with the basic planning exercise, your consultant must ensure you understand development guidelines, including a justification of the relevant species. Conducting studies in relevant species ensures the regulatory acceptance of the pivotal studies performed and allows you to define the overall targets of nonclinical development like (1) identification of potential target organs, (2), identification of safety parameters for clinical monitoring, and (3) identification of an initial safe dose and subsequent dose escalation schemes in patients.
- Maintain Compliance with ICH Guidelines
Most projects can be developed in a way that is compliant with ICH guidelines. More innovative approaches may deviate from these guidances and require a more science-based approach. Discussing your development strategy with the regulatory authorities (FDA, EMA, etc.) ensures that they understand the specific needs of your project. Should issues arise, you can then adapt accordingly without wasting time or resources.
Toxicological considerations are crucial to meeting ICH guidelines and continuing the momentum of your non-clinical development strategy. Below are the primary considerations to bring forward during these vital conversations:
- Organ toxicity
- Mortality
- Potential Off-target effects
- Pharmacokinetics
- Immunogenicity
- Cytokine Release Syndrome—Note that CRS is a side effect inherent to these molecules that cannot be avoided but can ––and must –– be managed.
- T-Cell and NK Cell Activation and Cytotoxicity
T-cells and NK-cells are highly active cells from the immune system that destroy cancer cells by releasing cytokine molecules. However, if too great a volume of these molecules are released, the patient can be harmed.
Part of your strategy is to ensure patient safety regarding this cell activation. Patient harm in this scenario is unnecessary and preventable. If you run into this problem, you have insufficient oversight, an issue that’s preventable with the right consulting partner.
- CRO Management for Toxicology Studies
At this point in strategy development, it’s about implementing the whole plan, requiring carefully selecting a contract research organization (CRO). Your CRO must fit your goals, budget, time availability and schedule, and animal species availability. Very often, these strategies require highly specific bioanalytical development and validation activities. Your consultant will help ensure the CRO you partner with has the expertise and bio-analytic resources to execute a meaningful study.
Selecting a relevant and specialized CRO is just one step in conducting your toxicology study. You’ll also need to execute the following:
- Study Audit
- Study Monitoring
- Study Support Preparation
- Support with Finalization of Toxicology Report
- Your study report is a critical component for regulatory submissions. As you interact with various regulatory authorities, this compilation puts all relevant data in one spot. The report acts as a proof of proposal, which you can then present and, with approval, begin executing the plan and moving to other phases. Your report outlines benefits, highlights possible risks, and determines a plan to mitigate and manage those risks.
- Address Regulatory Compliance and Needs
The final phase of creating a non-clinical development strategy for T-cell- and NK-cell engaging molecules addresses regulatory compliance issues.
Various regulatory documents are composed in this phase: science advice briefing books, safety assessments for formulation, excipients, impurities, etc.
This will also be your last chance in the non-clinical phase to interact with health authorities, receive feedback, and pivot your approach if necessary.
Lastly, you’ll need to finalize your risk assessment and management plan. All your studies have shown that the benefits are greater than the risks. You have a risk mitigation strategy. It’s time to implement a clinical development plan.
Building Non-clinical Development Strategies that Get Your Product to Market
The success of your non-clinical development strategy for T-cell- and NK-cell-engaging molecules relies heavily on your team and your consultant. The right partner will help you get each aspect of your plan right the first time. From selecting a study director to in-person study monitoring, testing, and development, your consultant is integral to moving your non-clinical strategy toward clinical development.
At KreaMedica, our team is equipped to guide you through your non-clinical development. We bring together years of experience and a network of expertise to deliver solutions that ensure long-term momentum for your projects.
Reach out to KreaMedica today to learn more about how our resources and expertise can support your development strategies and put you on the path toward clinical development.