Translating early discovery into a product that can be put into humans and taken through clinical trials can be a bit like navigating a maze when it comes to targeted therapies.
The term targeted therapies typically refers to a product that binds to a defined target to treat a specific subset of patients[1]. Two well-known examples are Imatinib (Glivec) for the treatment of chronic myelogenous leukemia (CML)[2] and trastuzumab (Herceptin) for HER2 positive breast cancer[3]. These targeted therapies are the vanguard of personalized medicine, targeting a specific tumor in a specific patient.
Targeted therapies, or precision medicine, can span a number of drug classes, including small molecules, monoclonal antibodies, antibody-drug conjugates, radioligand therapeutic agents, immunotherapies, as well as cell and gene therapies[4]. The dominant field for targeted therapies is oncology, however these medicines have also been developed for other diseases such as in immunology and genetic disorders.
Our understanding of disease and therapies has evolved along with targeted therapies, and today disease is no longer defined purely by its pathology and anatomy, like breast cancer or melanoma, but by its molecular signature. By way of example, a patient would no longer be given a diagnosis of malignant melanoma; rather, that diagnosis would depend on the mutation – BRAF V600, MET, NRAS, ALK, ROS1, NTRK1, among others[5].
It is conceivable that in future each type of cancer will have hundreds or thousands of genetically defined subtypes.
These therapies require companion diagnostics (CDx) tests to ensure the right patient receives the right treatment[6]. The US Food and Drug Administration defines companion diagnostics as a medical device, often an in vitro companion diagnostic, that provides essential information for the safe and effective use of a corresponding therapeutic product[7]. These tests must provide adequate precision, sensitivity and specificity. Very often, these CDx products are codeveloped with the targeted therapy, though they need to go through a different regulatory pathway which can add to the development complexity[8].
The development process
While targeted therapies have changed the paradigm of medicine, the science behind these products is highly sophisticated, making them complex to develop.
Navigating non-clinical
Starting with non-clinical requirements, studies for targeted medicines will depend on relevance. Developers for any product must determine potential toxicity and pharmacological effects in humans, its proposed pharmacological effect and mechanism of action, and any unwanted pharmacodynamic effects. Toxicology testing with targeted therapies, however, can present a number of challenges. By way of example, genetically modified T cells that are directed to attack tumor cells, but since antigen recognition is highly species-specific, testing these in non-human animal models is questionable[9].
There are several possibilities with non-clinical toxicology testing. One is that testing the product in animals is not relevant since the T cells will only recognize the product in context with the corresponding human Major Histocompatibility Complex (MHC)-molecules[10]. A second possibility is to test in an MHC transgenic mouse model. This has limited relevance since the MHC expression may not have the same tissue distribution as in humans, and tissue cross reactivity will likely not be the same as in humans; however it has the potential to become a good model[11]. A third possibility is to test in a homologous model, where the T cells of an engineered mouse recognize mouse tumor antigens in a mouse MHC context; however, again, cross-reactivity is not sufficiently informative.
Drawing on our industry experience, there are various ways to solve for this, for example, through a literature and database searches to find antigen expression patterns or perhaps assessing similar products already available for tumor antigens or through the use of other models, for example, knockout mice – where one or more genes have been turned off — to investigate the effects of gene mutations[12].
Beginning the clinical journey
Once a product moves into the clinical phase, there are several important considerations. First, with targeted therapies the disease entity needs to be well defined by an appropriate CDx to ensure the right selection of patients for the trial. These should be patients who express the target and will likely benefit from the therapy. Equally, it’s important that patients not expressing the target are excluded, since they will not benefit from the therapy but are still at risk of adverse drug reactions.
Another dilemma concerns biopsies. Initially, the patient will have had their biopsy to diagnose the disease, but further biopsies are invasive procedures, and sometimes increase the risk of the tumor spreading. However, if this is a third- or fourth-line treatment for a disease such as melanoma, it is quite possible that the tumor may have mutated. If no new biopsy is taken, what would it mean if the targeted therapy does not work? Is it due to lack of efficacy – which would mean potentially discontinuing development — or lack of expression, which would not necessarily have to lead to discontinuation? Having a clearly defined strategy is key, potentially supported by a CDx.
Once the target is defined, the next step is to show it works in patients. It’s important to clearly define the primary clinical study endpoint, which might be time to progression or disease-free survival. It is possible that the biomarker will not only be useful for diagnosis but also for measuring recurrence. Prostate specific antigen (PSA) is a good biomarker example, since with prostate cancer, the prostate is removed and PSA production will drop to 0. If after a certain time, PSA goes up, it almost certainly means a recurrence of the tumor, and can also be useful during the course of treatment to measure recurrence.
Developers of targeted therapies also need to consider an appropriate comparator to demonstrate the therapy works in a relevant way. Often, that means comparing against the standard of care, for example, chemotherapy with one or more authorized targeted therapies. However, when carrying out multinational clinical trials, medical societies in various countries may have different recommendations of what the standard of care is or should be.
The way forward
Given the complexities, what needs to be done to progress a targeted therapy? Some key advice is to know your product and how it works as well as its limitations. Adopt a risk-based approach to non-clinical development (including risk due to lack of relevant knowledge due to inherent limitations), then assess and mitigate that risk. Learn from similar cases, where possible.
Most importantly, seek advice. The regulators are happy to offer scientific advice, even from the early stages. Consider which regulators to approach – for example, in Europe you might approach a national authority with specialized knowledge in certain areas. To determine where to get that advice, it helps to speak with clinical, regulatory or reimbursement experts who can recommend where to start. Be aware that there are regional differences, for example the European Medicines Agency and FDA do adopt a different approach to Orphan Drug Designation.
Finally, speak to key opinion leaders in the clinical domain, who can guide you on questions around standards of care, what’s changed or likely to change and whether a certain study makes sense.
Development of targeted therapies presents many challenges; however, these precision medicines have dramatically changed the treatment landscape for many patients. Where once a diagnosis of malignant melanoma was a death sentence for many patients with advanced disease, today, these patients have a much better prognosis, and some may even be considered to have a chronic but treatable disease. As the field grows and evolves, the mortality rate of patients with disease sub-types will continue to decrease, further transforming precision medicine.
About the author:
Dr. Christian K Schneider is a leading authority on advanced therapies and Head of Biopharma Excellence and Chief Medical Officer for Strategic Product Development Consulting at PharmaLex. He has broad global regulatory authority experience having served as chair of the European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT), and EMA’s Biosimilar Medicinal Products Working Party (BMWP), and was one of the key architects of the agency’s advanced therapies and biosimilars framework.
[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] Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/imatinib
[3] 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.
[4] 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
[5] The role of gene fusions in melanocytic neoplasms, Journal of Cutaneous Pathology
[6] A Review of Precision Medicine, Companion Diagnostics, and the Challenges Surrounding Targeted Therapy, ISPOR. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ispor.org/docs/default-source/publications/value-outcomes-spotlight/july-august-2019/feature—precision-medicine.pdf?sfvrsn=7ea533e5_0
[7] Companion diagnostics, FDA. https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics
[8] US FDA perspective on challenges in co-developing in vitro companion diagnostics and targeted cancer therapeutics, Bioanalysis, 2011. https://pubmed.ncbi.nlm.nih.gov/21338257/
[9] Nonclinical safety assessment of engineered T cell therapies, Regulatory Toxicology and Pharmacology, Dec 2021. https://www.sciencedirect.com/science/article/pii/S0273230021002051
[10] Immunobiology: The Immune System in Health and Disease. 5th edition, The major histocompatibility complex and its functions. https://www.ncbi.nlm.nih.gov/books/NBK27156/#:~:text=A%20T%20cell%20recognizes%20antigen%20as,cells%20is%20called%20MHC%20restriction.
[11] Improved Transgenic Mouse Model for Studying HLA Class I Antigen Presentation, Nature, 2016. https://www.nature.com/articles/srep33612
[12] The Knockout Mouse Project, Nature Genetics, 2004. https://www.nature.com/articles/ng0904-921
