A Q&A with Principal Scientific Advisor and research strategy expert Dr. Manu Kohli on critical pre-hit identification groundwork and decision-making

A challenging funding environment significantly increases pressure on drug developers to build best-in-class value propositions for early-phase research, backed by greater weights of evidence to support scientific and commercial viability. Risk is less attractive and investment confidence harder to come by. 'Striking gold' during hit identification is more important than ever.

We talked to Dr. Manu Kohli from the Charles River Scientific Advisory team about pre-hit identification groundwork and critical early-phase decision-making. "Striking gold," Manu says, "or acquiring hits that become advanceable leads and successful candidates is 95% about strategic hit campaign design and the groundwork you do at the target phase to inform that." In this interview we cover some common questions researchers ask before initiating hit campaigns and discuss some of the data required to build enough momentum to overcome downstream roadblocks.

How do I decide the best modality for my target, and do I need to know that before I begin hit identification?

MK: Everything begins with a thorough understanding and validation of the target before engaging in hit identification. For example, is the target druggable based upon structure/topology/distribution? What is the desired mechanism of action? Is the target surface exposed? If so, an antibody, antibody-drug conjugate (ADC), bispecific, or cell therapy approach may be reasonable. If the target has biochemical activity with accessible pockets, then a small molecule approach might make sense, but if the target is a scaffolding protein, then a proteolysis targeting chimera approach could be reasonable.

In addition, business factors are important as well, such as intellectual property, size of the market, market positioning, go-to-market strategy, etc. For example, perhaps an antibody approach has been effective, but the market is saturated, and there may be equal or better clinical benefit by developing a cell therapy approach.

Thus, the choice of modality is dependent on a multifactorial decision tree that is not necessarily straightforward. Since the modality will determine the design of a hit identification campaign (for example, should a high-throughput small molecule screening campaign be initiated, or should phage display identify binders), the modality in most cases needs to be selected prior to initiating hit identification.

How much do I need to know about my target before initiating hit finding?

Target validation is critical. Once the target has been identified and associated with a disease, evidence must be collected to support target rationale, including pathway and structural information. In addition, the target must be experimentally validated to demonstrate that modulation provides a clinical benefit. This information is essential before beginning a hit finding campaign, since the attrition rate in drug development is very high, and there is significant financial risk if a drug development campaign is begun before ensuring that target engagement will provide clinical benefit.

How do I determine which hit identification approaches will yield advanceable candidates aligned with my research goals?

There are numerous approaches for finding hits depending on the modality, such as biochemical and binding screens for small molecules, and display technologies for biologics. A thorough understanding of target structure and biology will help determine what hit finding approach will most likely yield an advanceable candidate. For example, if a target has demonstrated biochemical activity with a structurally druggable active site, then a biochemical screen demonstrating target activity inhibition may be a reasonable approach for a small molecule hit finding campaign.

However, if the target falls into a common class where the active site may not provide specificity, such as a kinase, then an allosteric inhibitor identified through biophysical approaches (fluorescence polarization, protein thermal shift) may work far better. Leveraging the experience of your screening/hit identification team will help guide the selection of the best approach to identify advanceable candidates.

Should I be looking for hits that support best in class, or first in class?

Both best-in-class as well as first-in-class drugs can yield significant benefits for patients as well as financial benefits for drug developers. The advantage of best-in-class drugs is that the patient population and disease target have been identified and validated, which can be exceedingly challenging when beginning a drug development program. However, when developing a best-in-class drug, there is the risk that the drug developer is entering a crowded space, and the challenge of developing a drug that is better than the standard of care in terms of efficacy and/or safety is significant.

With a first-in-class drug, effective hit identification depends on the quality of your target validation, since the patient population, disease indication, and target druggability have to all be thoroughly assessed before engaging in a drug development program. This carries significant risk in terms of the likelihood of developing a safe and effective drug, as well as the time to market. However, if a first-in-class drug can be developed, then the company is afforded first-mover advantage with considerable control of the market and significant brand recognition. Thus, the choice of best-in-class versus first-in-class begins with market analysis and a comprehensive evaluation of risk versus benefit.

How do I approach hit identification when the patient population is very small?

Regardless of the size of the patient population, hit identification is fundamentally the same since research and development will proceed according to the rigors of science. However, the important question to be asking is whether a small patient population is financially sustainable for a business. The short answer is yes.

Drugs for orphan indications (those with small patient populations) are afforded incentives by most governments, including market exclusivity, favorable pricing, tax breaks, and paths to accelerated approval. In addition, since the patient population is small, there is likely much less competition in the drug development space, further providing significant potential to control drug availability and pricing. These business advantages will go a long way to inspire companies to invest in drug development programs regardless of the size of the patient population.

How do I prove my hits can become commercially viable therapies?

Building weight of evidence to prove that hits, leads and candidates are worthy of advancement and investment begins long before you have your hits in-hand. When building a commercial venture in drug development, a foundational principle is the strength and quality of the science. If the drug demonstrates robust efficacy for the target disease indication with a favorable safety profile, then an important impediment to developing a commercially viable therapy has been overcome.

However, the strength of the science alone is insufficient for a commercial venture. The engine for growth and sustainability for a drug development company, as in most companies, is predicated on the fundamental principles of economics. Has the market space been evaluated? Have the right patients been identified for which the drug would provide clinical benefit? Is there competition in this space, and does the drug under development provide significant value as compared to the competitive landscape? What is the go-to-market strategy? Will the drug provide significant return on investment?

Thus, the first, and most critical, step in advancing a drug development program begins with extensive market analysis to ensure that the economics of drug development are sound. This analysis must be based upon actual data to provide clarity on (and evidence to support) the path forward. Once this analysis has demonstrated that there is an unmet need that can be addressed, and that this is a financially sustainable venture, then you have a firm foundation on which to begin identifying hits for your program.

Recommended content suggestions:

• Podcast: Confessions of a Hit Man: Matching Target Strategies to the Need
• Webinar: Novel In Vitro Strategies to De-Risk Small Molecule Candidate Selection
• eGuide: Compound Screening Libraries

Bringing more than 20 years of biotechnology and pharmaceutical experience to the Scientific Advisory team, with expertise in target identification, validation, drug discovery and development, Manu Kohli has led senior scientific research teams in the biotech/pharma sector to advance drugs for a variety of disease indications, heading research programs in small molecules, immunotherapies, biologics, and cell therapies, and developing research strategies using diverse modalities. Manu has a PhD in biochemistry/molecular biology from Georgetown University with post-doctoral training from Johns Hopkins University, holds numerous patents, and has published many research articles in top-tier scientific journals.

Liz Hudson is Senior Marketing Manager at Charles River Laboratories focusing on Small Molecule and Platform Technologies in early-phase drug discovery.

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