Case Nos: CA-2024-002655/002675/002676 - [2025] EWCA Civ 936

Common general knowledge

The judge set out the common general knowledge of the skilled team at [29]-[145]. Rather than setting it out all over again, I shall largely take this as read. In order to make this judgment intelligible, however, it is necessary to explain a few key points that would be known respectively to the cancer biologist and the medicinal chemist (with some overlap between them).

The cancer biologist

The prostate is an androgen-dependent gland and requires androgens for normal function. Androgens are steroid hormones. The predominant and most active androgens in men are testosterone and its metabolite 5α-dihydrotestosterone (“DHT”). Androgens bind to a protein called the androgen receptor (“AR”). The AR is a steroid hormone receptor and is found in many of the body’s tissues. The AR functions as a ligand-inducible transcription factor, which means that, upon binding of a ligand (such as testosterone or DHT), the AR modulates the expression of certain genes. When testosterone or DHT bind to the AR, they agonise (i.e. activate) the receptor and thereby initiate a cascade of processes that contribute to the survival, growth, and proliferation of normal and cancerous prostate cells.

Prostate-specific antigen (“PSA”) is a protein that is made predominantly in the luminal epithelial cells of the prostate gland, and is a well-known prostate tumour marker used in clinical practice for prostate cancer detection and the monitoring of treatment. 

For treatment purposes, prostate cancer can be broadly categorised as clinically localised or metastatic, and as hormone-sensitive (i.e. androgen dependent) or hormone-resistant (i.e. cancer that has progressed despite initial androgen deprivation therapy (“ADT”)).

ADT is intended to reduce the quantity of androgens available to bind to the AR, or antagonise the action of androgens in the body, slowing the spread of the disease. One approach to ADT is to use molecules that compete with androgens for binding with the AR and thus inhibit activation of the AR. Instead of agonising the AR, the molecules would prevent binding of the circulating androgen to the AR, thereby preventing its activation. This is referred to as AR antagonism. These types of molecules are known as antiandrogens or AR antagonists. By 2006 this class included the non-steroidal antiandrogens flutamide, bicalutamide and nilutamide. Bicalutamide was commonly regarded as the “standard of care” treatment.

The available anti-androgenic therapies were widely used and clinically useful agents, but they did not prevent prostate cancer progressing from the hormone sensitive to the hormone refractory state. Moreover, they were ineffective in treating HRPC as the drugs lost their anti-androgenic activity and could become agonists, stimulating further progression of the disease rather than inducing its regression.

At the outset of a drug discovery project, the skilled team would typically have in mind an intended approach to treating the disease of interest. This would usually be led by the cancer biologist, who would provide the concept of how the disease would be targeted i.e. what biological pathway would be sought to be targeted, and which proteins or receptors or other biological features need to be modulated in order to achieve that biological effect.

With the intended biological target in mind, the skilled team would identify a target product profile (“TPP”) for their prospective therapeutic compound. This is a description of the properties of the compound which the skilled team would be seeking to identify. These would typically include physicochemical properties (e.g. appropriate molecular weight and lipophilicity), biological properties (e.g. activity against the target and minimal off-target effects), pharmacokinetic and pharmacodynamic properties (e.g. appropriate half-life), and drug-like qualities (e.g. not toxic at therapeutic doses). The TPP would typically be framed in a discussion between the cancer biologist and the medicinal chemist.

Compounds synthesised by the medicinal chemist would be tested for biological activity by the cancer biologist. A number of in vitro and in vivo assays were used to assess a compound for its potential effect on prostate cancer. With each assay, it is common to compare the test compound against a drug with a known behaviour, for example bicalutamide. In vitro assays include assays using cell lines (cells of a certain type which are maintained in culture).

A commonly used cell line in prostate cancer research in 2006 was LNCaP (Lymph Node Carcinoma of the Prostate). LNCaP cells express an endogenous level of functional AR and are androgen sensitive (so they can be stimulated by the presence of androgen or alternatively their function can be inhibited by an anti-androgenic agent). LNCaP cells also express PSA. Owing to those properties the cell line was used commonly in laboratory testing as a model of hormone sensitive prostate cancer. The effect of a putative antagonist or agonist in this hormone sensitive model could be assessed, for example, by measuring the PSA level produced by the cell line with the test compound present versus the PSA level produced by the cell line against a suitable control (for example, without the test compound being present or in the presence of an anti-androgen such as bicalutamide).

Half maximal inhibitory concentration (“IC₅₀”) is a measure of potency, and is a quantitative measure that indicates how much of a particular inhibitory substance is needed to inhibit the activity of the target in a given biological process by 50%. IC₅₀ values are typically expressed as molar concentrations. The IC₅₀ of a drug can be determined by constructing a dose-response curve and examining the effect of different concentrations of an antagonist on inhibiting activity. IC50 values are used to compare the potency of two or more antagonists in development, or against an approved drug. A numerically lower IC50 value indicates a higher potency.

The medicinal chemist

With the TPP in mind, the medicinal chemist would seek to identify a compound or collection of compounds, which are a starting point for improvement. Once a suitable starting point is identified, the medicinal chemist would most likely adopt an iterative approach to modify the starting molecular structure to try to improve its activity, selectivity and/or physicochemical properties, bearing in mind the TPP. Iterative modification of a compound is done by developing a molecule that has a structure partially similar to the starting compound but with some different chemical substituents or modifications (i.e. a structural analogue). In order to progress the drug design process, the medicinal chemist often builds up a structure-activity relationship (“SAR”) library of such compounds and their test data.

To do this, the medicinal chemist would ordinarily make a series of chemical modifications to the starting compound, resulting in a number of different structural analogues. The medicinal chemist is trained in methods of adding functional groups to compounds, converting functional groups, and carrying out coupling reactions. These analogues would be tested to determine how each of the modifications affects their properties, including activity against the target, selectivity (by measuring activity against non-targets), solubility, permeability, etc. Through this process, the medicinal chemist would build up an idea of which parts of the compounds and what types of substituent modifications impact the relevant properties (such as binding, efficacy, physicochemical properties, metabolism, etc.), and the size and nature of the effects.

The physicochemical properties of a compound include its solubility, permeability and lipophilicity (how hydrophobic it is). A measure of lipophilicity is log P, the logarithm of the partition coefficient between water and a lipophilic solvent. ADME is a framework of concepts commonly used to help guide drug optimisation. The components of ADME are Absorption, Distribution, Metabolism and Excretion. Pharmacokinetics (“PK”) refers to how the body affects a specific substance after administration. PK is important in the development of drugs as part of understanding whether they will be safe at the appropriate dose and maintain efficacy for the desired amount of time.