Investigating multi-indication drug targets

Biotech companies are in a unique position to push forward new advances in drug development. In many cases, these organisations are on the leading edge of new and emerging modalities, spearheading the investigation of new directions for the treatment of a variety of indications.

In addition to new modalities, biotechs may be responsible for exploring additional applications for existing or developing therapies. One avenue for this is multi-indication drug targets, which have effects that can impact multiple disease states through the same mechanism of action. Being able to apply the same drug or therapy to address more than one indication can greatly increase its value.

For biotechs considering entering clinical trials with an investigational product that utilises a multi-indication target, there are unique factors to take into account. This blog will explore some of the multi-indication drug targets that have already been developed in multiple applications, as well as considerations for entering clinical trials, such as building evidence and trial design.

Multi-indication targets in practice

The expansion of a therapeutic’s applications through multi-indication drug targets spans a variety of modalities, from cell therapies and biologics to new chemical entities. The key is the identification of a shared mechanism of action that impacts disease pathology.

For example, CD20 is a surface glycoprotein expressed in mature B cells, which has been identified as an excellent target for treating B-cell lymphomas. Indeed, anti-CD20 monoclonal antibodies have been used for that purpose since the 1990s. However, because B cells play a major role in immune activity, researchers found that depleting their numbers also had a positive impact on the expression of autoimmune diseases. Therefore, by using monoclonal antibodies to target CD20, we can now also treat conditions such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and multiple sclerosis.

Other drug targets have undergone similar journeys in their development and usage. In a close parallel, some forms of CAR (chimeric antigen receptor) T-cell therapy targeting B cells, originally developed for use in oncology, are finding applications in SLE and lupus nephritis as well. On a different path, Janus kinase (JAK) inhibitors have been used in dermatology and autoimmune diseases, and are being investigated for applications in neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis. TYK2, an enzyme in the JAK family, has been targeted for its role in inflammation across a variety of indications, including psoriasis and inflammatory bowel disease.

Investigating additional indications

In many cases, the decision to expand the value of a drug by investigating additional indications occurs later in the development lifecycle, potentially even when it has already reached the market in one indication. Generally, pursuing an additional indication is most viable when there is good preexisting evidence of a common mechanistic target that the drug addresses.

If there is good reason to believe a drug candidate may have multiple applications, another option is to evaluate it early in the development process, by assessing shared pathological processes and determining the drug target’s potential for impact in additional indications. Doing so allows sponsors to design a drug development strategy that incorporates the potential value of the investigational product.

At minimum, a sponsor can gather evidence to support future research into a drug candidate’s utility in additional indications — a significant benefit, considering the importance of building a body of evidence to justify investigation past the lead indication. In early phase trials, exploratory endpoints can contribute to expanding one’s understanding of a drug candidate’s potential utility. Additionally, the human use data from early phase trials in the lead indication can inform pharmacokinetic and pharmacodynamic modelling for other indications. And, outside of clinical trials, in vitro and in vivo studies can help to provide the rationale for multi-indication research. However, given the complexity of such drugs, it is important not to make assumptions regarding the safety profile, and to gather safety data specific to the indication under investigation.

Multi-indication trial design

If it is clear from the outset that it is of interest to investigate multiple indications for a drug candidate, it may be worth considering specialised trial designs. Master protocols, for example, are specifically constructed to help evaluate multiple hypotheses. Although they are traditionally used more often in later-phase trials, master protocols can have utility in early phase, particularly proof-of-concept trials. As well as their capacity for multiple hypotheses, they also offer benefits, such as the use of a shared control arm, which reduces the number of participants who must be recruited and, as a result, reduces costs.

Basket trials, which utilise master protocols, are particularly relevant to multi-indication therapies. These are designed specifically to test a drug candidate across multiple indications, with separate cohorts, or “baskets,” for each indication being studied, all receiving the same investigational product. Frequently, basket trials are used in oncology to evaluate the effect of a treatment on different subtypes of cancer. However, they are not limited to oncological studies, and have been employed in a variety of other indications to determine a drug’s applicability.

Planning ahead

For biotechs entering clinical trials with an investigational product, there can be little room for error. This means that establishing goals — including multi-indication investigation — as early as possible is invaluable. And, though investigating multiple indications may add complexity and additional costs to clinical trials, it can also add significant value to the drug candidate, making it far more attractive and providing additional market options.

To learn more about considerations for biotechs entering early phase clinical trials, including novel modalities and multi-indication targets, read ICON’s whitepaper: Early phase challenges for biotechs.

Read the whitepaper

Multi-indication targets in practice

Investigating additional indications

Multi-indication trial design

Planning ahead

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