Collaboration key to delivering targeted medicines

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REVOLUTIONIZING HEALTHCARE

Targeted medicine typically refers to a product that binds to a defined target to treat a specific subset of patients (1).
A targeted therapy can selectively target abnormal signaling pathways or biological processes underlying a given disease, offering treatment tailored to a patient’s genetic mutations or protein expression profiles (2).
They have proved particularly effective in the field of oncology, where targeted therapies such as Imatinib (Glivec) and trastuzumab (Herceptin) are improving the survival rate of patients with certain types of cancer (3, 4).
Precision medicine can span myriad drug classes, including small molecules, monoclonal antibodies, antibody-drug conjugates, radioligand therapeutic agents and immunotherapies, as well as cell and gene therapies (5).
Connecting the right treatment with the right patient is enabled by biomarkers and companion diagnostics (CDx), while artificial intelligence has proved invaluable in target identification.

 

MAKING THE RIGHT CONNECTIONS

Given how interlinked therapeutics and diagnostics are, a collaborative approach to the development of targeted therapies is imperative. Indeed, therapeutics companies often rely on their diagnostics partners to support the process.
The therapeutics developer must understand how a drug works to determine the biomarkers are relevant for efficacy. This helps guide the development of the companion diagnostic to identify who the therapy would most benefit. This is not only important after approval but also for enrollment in clinical trials.
Biomarkers help detect or confirm the presence of a disease. With targeted medicine, predictive biomarkers help identify patients most likely to benefit from a treatment, as well as prevent the delivery of inappropriate treatment, avoiding unnecessary associated risks (6).
Healthcare providers and researchers use them to match the right medication to the right patient according to an individual’s biological characteristics; to monitor response to treatment; and to predict treatment resistance by monitoring biomarker profiles over time (7).
Thousands of biomarkers have been identified and studied, including genomic biomarkers, protein-based, lipids, imaging and other molecular signatures associated with treatment response.
A companion diagnostic (CDx) is a test to detect a predictive biomarker, showing which patients are suitable candidates for specific therapies (8). A CDx can also help determine those patients at greater risk of serious side effects from a treatment, controlling the safe and effective use of a therapy (9).
These tests, which must provide adequate precision, sensitivity and specificity, are often co-developed with the targeted therapy, though they go through a different regulatory pathway. The US Food and Drug Administration (FDA) approved 62 CDx products between 1997 and December 2023, most of which were for oncology drugs. Among the success stories is the advanced treatment of certain cancers, with CDx enabling the identification of specific biomarkers associated with tumor types (10).

ENGAGING EARLY WITH REGULATORS

A personalized approach to drug dosing and administration requires rigorous scientific evidence to support a drug’s efficacy and safety. As such, developers of targeted therapies face additional regulatory hurdles, making it critical to take advantage of any early guidance offered.
Regulators may demand extensive data on biomarker validation, patient selection criteria, and long-term follow-up to support approval decisions. Pharmaceutical companies are also increasingly being asked to justify dosing regimens based on comprehensive pharmacokinetic and pharmacodynamic data (11).
While the path to approval is difficult, regulators recognize the urgent needs of many patients. Accordingly, they will carefully balance safety and efficacy concerns with this cohort’s higher acceptance of risk, where there are no effective standard treatments, or the efficacy of existing treatments is limited. Several regulatory mechanisms, including conditional marketing authorization in the European Union and accelerated approval in the United States, have been put in place to address the benefit-risk balance.
Regulatory authorities also offer scientific advice early to guide the development of precision medicines. Through the Office of Therapeutic Products, the FDA encourages developers to engage in formal and informal meetings during the development process (12).
The European Medicines Agency (EMA) and national competent authorities (NCAs) offer direction to companies at any stage of development . For EMA, the Committee for Medicinal Products for Human Use (CHMP) provides scientific advice and protocol assistance on the recommendation of the Scientific Advice Working Party (SAWP) (13).
Different regulatory frameworks for manufacturing around the world present another challenge. With targeted medicines, it is difficult to balance customization – developing a highly individualized treatment – with standardization, which can further complicate manufacturing processes. The FDA maintains the need for “more mechanistic understanding, improved manufacturing capabilities and additional tools” if pharmaceutical companies are to deliver on the promise of precision medicine (14).

 

THE ROAD AHEAD

Targeted medicines are revolutionizing healthcare. With the effective implementation of biomarkers and CDx, they have helped personalize treatment plans, improve patient outcomes, and prevent ineffective or potentially
harmful approaches.
Computer-aided drug design, which is helping to enhance drug discovery, and the use of machine learning and AI promise further advances in targeted medicine (15, 16).
While oncology patients have been the primary beneficiaries of these scientific and technological advances, targeted medicines have also been developed in other fields, including immunology and genetic disorders.
But the science behind these products is highly sophisticated, making them complex to develop and creating more hurdles to approval. A truly collaborative approach at all stages of development, involving sponsors, researchers and regulatory authorities, will provide a clearer path to those desperately awaiting more targeted therapies.

Disclaimer:
This information provided in this article does not constitute legal advice. PharmaLex GmbH and its parent, Cencora, Inc., strongly encourage readers to review available information related to the topics discussed herein and to rely on their own experience and expertise in making decisions related thereto.

 

REFERENCES AND NOTES

1. Considerations for Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease, Clin Pharmacol Ther., 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347014/
2. Amplifying gene expression with RNA-targeted therapeutics, Nature, May 2023. https://www.nature.com/articles/s41573-023-00704-7
3. Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/imatinib
4. How Herceptin is Thought to Work. https://www.herceptin.com/patient/metastatic-breast-cancer/about-herceptin/how-it-works.html#:~:text=Herceptin%20%E2%80%9Ctargets%E2%80%9D%20HER2%20receptors%20to,to%20destroy%20that%20cancer%20cell.
5. List of Targeted Therapy Drugs Approved for Specific Types of Cancer, National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/approved-drug-list
6. Biomarkers: Promising and valuable tools towards diagnosis, prognosis and treatment of Covid-19 and other diseases, Heliyon, Feb 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884646/
7. Circulating Biomarkers for Therapeutic Monitoring of Anti-cancer Agents, Oncologist, May 2022.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074993/
8. Predictive Biomarkers and Companion Diagnostics. The Future of Immunohistochemistry – ‘in situ proteomics’, or just a ‘stain’? Appl Immunohistochem Mol Morphol., 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215952/
9. Companion diagnostics, FDA. https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics
10. A Companion Diagnostic With Significant Clinical Impact in Treatment of Breast and Gastric Cancer, Front Oncol, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343532/
11. A framework to guide dose & regimen strategy for clinical drug development, CPT Pharmacometrics Syst Pharmacol., 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592517/
12. Interactions with Office of Therapeutic Products, FDA. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/interactions-office-therapeutic-products
13. Scientific advice and protocol assistance, EMA. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-advice-protocol-assistance
14. Focus Area: Individualized Therapeutics and Precision Medicine, FDA. https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-individualized-therapeutics-and-precision-medicine
15. Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance, Bioengineering, Aug 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332125/
16. Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance, Bioengineering, Aug 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332125/