Kinome

Kinome

Bright future for next generation kinase inhibitors

The human kinome, consisting out of more than 500 individual kinases, represents one of the most druggable protein families in the human genome. Kinases are involved in most physiological processes and their deregulation has been linked to over 400 disease indications.

Since the first approval of a small molecule kinase inhibitor (imatinib, Gleevec in 2001 for CML targeting Bcr-Abl), the industry has heavily focused on this class of agents with over 50 kinase inhibitors on the market and many more under regulatory review today.

It took over a decade before a first kinase inhibitor was approved for a non-oncology indication (tofacitinib, Xeljanz in 2012 for RA targeting JAK3).  Nevertheless, Oncology indications remain, by far, the main areas of interest for these types of molecules. Kinase inhibitor therapeutics face a number of inherent challenges that are gradually being resolved as next generation molecules start to emerge.

During early stages of development, potency and specificity represent a formidable hurdle in the search of new agents: high potency (in the low nanomolar or even picomolar range) is essential for inhibitors that compete with high levels of ATP in cells. Specificity within the human kinome is required to avoid severe side effects. While addressing both of these challenges, molecules need to retain good drug-like properties in order to advance towards therapeutic application. In the clinical setting, low predictability of the pharmacokinetic behavior of these molecules and unexpected toxicity can be issues, effects on long term usage are still rather unknown, and acquired resistance against these targeted agents in oncology are areas to address further.

Despite these challenges, the market expectations for these type of agents are bright, since next generation kinase inhibitors, in combination with an enhanced understanding of the biology of kinases and their role in pathophysiology, mitigate many of these weaknesses for the future benefit of patients in many therapeutic indications. Using Globaldata as a source of information, we undertook an analysis of available data to better understand the ongoing development and market impact of small molecule kinase inhibitors over the next 6 years.

Kinase Inhibitors Market | 2019-2026

In 2019, 44 licensing and acquisition deals of small molecules targeting kinases were registered, at all stages of development from discovery to pre-registration, with a deal average of 600 million USD including upfront and milestone payments. Interestingly, 38 different kinase targets were involved in those deals, showing the multitude interest of biotech and pharmaceutical companies for this class of targets. Oncology remains the main therapeutic area for kinase inhibitors with 60% of deals, but other therapeutic areas such as the central nervous system, infectious and immunology diseases gather growing interest from pharmaceutical companies and investors. The following analysis focuses on kinase inhibitors market, in order to exemplify how deals concluded in the pre-registration phases translate into sustainable sales once they reach the market.

Sustained market growth of kinase inhibitors in 2019-2026.

The kinase market represented 38.2 billion USD in 2019 worldwide. It should grow and reach 98.4 billion USD in 2026, with a 14.5% growth rate over the period for all indications, excluding generic drugs. The US remains the main market for kinase inhibitors: 58% in 2019, 65% in 2026, while a 9-fold increase is expected on the Japanese market.

*Market growth of kinase inhibitors in 2019 2026

Who are the main actors?

Most of big pharmaceutical companies are present on the kinase inhibitors market, along with mid-size pharmaceutical companies and small companies such as Verastem and Puma. Sanofi and Merck, with molecules still in development (e.g. Sanofi BTK inhibitor SAR442168 for the treatment of multiple sclerosis), are the only missing actors from the Top 10 pharmas.

Novartis is currently leading the market with 9.7 billion USD sales in 2019, which corresponds to a 23% market share. With already seven molecules on the market, including five blockbusters (Tasigna, Afinitor/Votubia, Gleevec/Glivec, Mekinist+Tafinlar, Jakavi), Novartis is expected to bring  five new kinase inhibitors to the market by 2026. Those new kinase inhibitors should lower the impact of 3 patent expiries by 2026 on Novartis sales. Consequently, Pfizer is expected to take the lead with 15.7 billion USD sales in 2026, or 15.7% of market shares thanks to the CDK4/6 inhibitor Palbociclib.

*Top 10 of kinase inhibitors

A diversification of kinase inhibitor origin before 2026

Currently, the Top 10 actors represent 91% of total sales for kinase inhibitors. In 2026, it should represent 70% of total sales due to the emergence of 58 new actors with one or more molecules on the market (versus 19 in 2019). 19 companies should generate more that 1 billion USD sales in 2026 (versus 10 companies in 2019).

New potential actors are listed in the table below. They are mainly small US biotech companies that should conclude deals / acquisitions with / by bigger actors. Asian companies will also play a more important role by 2026, in particular Chinese companies such as BeiGene with its BTK inhibitor Brukinsa for the treatment of lymphomas and leukemias. Beigene is expected to enter the Top 10 sales in 2026 thanks to its Brukinsa drug, but it should represent the only entry in the top 10 company.

*
List of expected actors in 2026

The Top 3 sales emerging over the 2019-2026 period will be Brukinsa (Beigene, BTK inhibitor in Oncology), Calquence (Astrazeneca, BTK inhibitor in Oncology), and Verzenio (Eli Lilly, CDK4/6 inhibitor in Oncology). Their sales will, however, remain significantly lower as compared to Imbruvica (Abbvie/J&J, BTK inhibitor in Oncology), Ibrance (Pfizer, CDK4/6 inhibitor in Oncology) and Tagrisso (AstraZeneca, EGFR inhibitor in Oncology).

*evolution top 10 kinase inhibitors

Market evolution in line with Nanocyclix® development

Oncodesign’s Nanocyclix® platform delivers macrocyclic kinase inhibitors that are small, highly potent and specific across the kinome, based on a 3D shape complementarity paradigm. Following their synthesis, they are extensively profiled against the human kinome in biochemical or cell-based assays. Results allow the identification of probes, characterized by high potency, selectivity and drug-like potency against specific kinases. Newly identified pairs of probes and targets are then qualified, based on literature and IP research and analysis of competitors, for a therapeutic indication with high unmet medical needs. Having early probes in hand that readily cross cell membranes, these hypotheses can be quickly validated during a short subsequent orientation phase.

This chemocentric approach starting from the Nanocyclix® collection has allowed the construction of extensive portfolio of early projects, with a tremendous potential to generate First-in-Class assets on unexplored and intractable kinases distributed across the human kinome tree.

Oncodesign advanced, alone or in partnership, a number of these probes to the drug candidate stage, as demonstrated by our activated EGFR-PET tracer Florepizol in NSCLC (successful in Phase 1) and our RIPK2 inhibitor ODS-101 in inflammatory diseases (1 in 2021). Many additional probes have been identified on attractive kinase targets that are available for partnering.

The bright future of small molecule kinase inhibitors in multiple indications represents a great opportunity to establish win-win partnerships around next generation inhibitor platforms. Capitalizing on our Nanocyclix® platform and know-how to co-develop therapeutics - either from existing programs or by identifying probes on novel kinases – will strengthen the pipeline of first-in-class inhibitors in a broader range of therapeutic indications, paving the way for new treatments for patients in medical needs.

*Methodology : the primary source of data were from Globaldata. Analyses per deal type, therapeutic type, indication type and company type were performed for pre-registration and sales analysis.

We open up a path to new kinases of therapeutic interest