Developing a Novel Pipeline of Cancer Therapies

As we seek to improve the treatment of cancer, we are addressing a broad array of targets selected based on rigorous scientific and clinical evidence with the aim of developing a diverse pipeline with meaningful clinical potential. We are building discovery and development capabilities that allow us to advance multiple therapeutic modalities, including both small molecules and biologics, to pursue an optimal approach for each individual target.

Small Molecule Drug Discovery: Strong Legacy and Future Potential

Building on our legacy of small molecule oncology drug discovery, we have a diverse portfolio of programs in various stages of development. Cabozantinib has been successfully commercialized in multiple cancer indications and is the focus of a broad development program, including multiple ongoing pivotal phase 3 clinical trials designed to support additional label expansions. XL092, our next-generation oral tyrosine kinase inhibitor (TKI), is currently in phase 1b clinical testing and could enter pivotal studies before the end of 2021 or in early 2022. With a significant expansion underway, including additional laboratory space that opened in mid-2021, we anticipate a steady flow of internally discovered compounds advancing into preclinical development over the next few years.

We’ve supplemented our drug discovery efforts with collaborations that provide complementary expertise and approaches, including an agreement with Aurigene that has yielded XL102, our small molecule inhibitor of cyclin-dependent kinase 7 (CDK7), which entered clinical trials in January 2021. We are working with Aurigene on a number of earlier-stage programs for exciting targets and pathways. Separately, our collaboration with StemSynergy focuses on a novel approaches to inhibiting the beta catenin and Notch signaling pathways, two of the major undrugged pathways in human cancer. We also have a collaboration with STORM Therapeutics to discover and advance novel drug leads intended for the treatment of cancer. The collaboration will focus initially on ADAR1, advancing early work by STORM applying its proprietary RNA modifying enzyme platform, as well as explore an additional undisclosed target.

Biotherapeutics: A New Dimension of Our Pipeline

As our small molecule programs move forward, we’re broadening our pipeline to encompass biologics that cover a broad range of targets and therapeutic modalities. XB002, the tissue factor-targeting antibody-drug conjugate (ADC) program under our research collaboration with Iconic Therapeutics, is our first clinical-stage biologic therapy and the subject of an ongoing phase 1 trial that was initiated in the second quarter of 2021. In addition, a second custom ADC has been generated through the company’s collaboration network – XB010 – which was designated a development candidate in late 2021 and will enter preclinical development in 2022.

In building out our biologics capabilities, we’ve established a network of collaborations and partnerships that allow us to discover and advance novel therapies by gaining access to the building blocks necessary to assemble effective therapies for potential use in different tumor indications. Our agreements with Invenra, WuXi Biologics, and GamaMabs give us access to various novel antibodies and bispecifics. Collaboration and license agreements with Catalent and NBE-Therapeutics provide us with highly compelling ADC platforms. Through our work with Adagene, we can utilize a conditional antibody-masking technology with the potential for an improved therapeutic index through reduction of on-target toxicity.

For more information on the technologies that underpin our fast-moving biotherapeutics development efforts, visit our Collaborations page.

Please see our early compound pipeline chart, here. For additional information on our clinical trials, please visit www.clinicaltrials.gov.

Pipeline Overview

Cabozantinib

Exelixis’ flagship compound cabozantinib is a targeted agent that inhibits the activity of receptor tyrosine kinases including MET, AXL, VEGF receptors and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and resistance to multiple therapies, including immune checkpoint inhibitors (ICIs). Exelixis discovered cabozantinib internally and maintains exclusive rights to commercialize the product in the United States. Outside of the United States, Ipsen has exclusive commercialization and development rights for current and future cabozantinib indications, except in Japan, where Exelixis has granted exclusive rights to Takeda. Exelixis and its partners are collaborating on the global development plan for cabozantinib and Ipsen and Takeda are responsible for the cabozantinib development work specific to their respective regions.

For information on approved uses of cabozantinib, please visit Our Medicines page.

XL092

XL092 is a next-generation oral TKI that builds on our extensive experience with cabozantinib. XL092 also targets VEGF receptors, MET, TAM kinases and other kinases implicated in cancer’s growth and spread. In preclinical tumor models, XL092 showed excellent activity as a single agent and in combination with ICIs. XL092 also has an optimized pharmacokinetic profile aimed at facilitating adverse event management in the clinic. XL092 is the first new Exelixis-discovered compound to come out of the company’s reinitiated drug discovery activities, which entered phase 1 clinical development in 2019.

Throughout 2022, Exelixis expects to expand the ongoing phase 1b STELLAR-001 and STELLAR-002 studies, which are evaluating XL092 in combination with several immuno-oncology therapies, and may initiate additional studies in potential new tumor types and combination regimens (immuno-oncology and otherwise). Exelixis expects to present phase 1 clinical updates for XL092 at a medical conference in the second half of this year.

Exelixis is also on track to initiate STELLAR-303, a global phase 3 pivotal trial of XL092 in combination with atezolizumab as a third-line therapy in patients with microsatellite stable metastatic colorectal cancer in the second quarter of 2022. Multiple other phase 3 studies will follow.

XB002

XB002 is a next-generation ADC composed of a human monoclonal antibody against tissue factor that is conjugated to a cytotoxic agent. After binding to tissue factor on tumor cells, XB002 is internalized, and the cytotoxic agent is released, resulting in targeted tumor cell death. This rationally designed next-generation ADC leverages Zymeworks’ proprietary ZymeLink™ linker-payload.

Preclinical data demonstrated that XB002 binds to tissue factor without affecting the blood coagulation cascade, in contrast with prior therapies in this class. The data also demonstrated encouraging activity of XB002 in multiple solid tumor models and improved tolerability compared with other tissue factor-targeting ADCs. XB002 has shown significant tumor growth inhibition and, in some cases, complete regression.

In late 2020, Exelixis exercised its exclusive option for XB002 (formerly ICON-2) per its May 2019 agreement with Iconic Therapeutics. Exelixis has assumed responsibility for the future clinical development, manufacturing and commercialization of XB002.

In the first quarter of 2022, we also acquired broad rights to use the anti-tissue factor antibody incorporated into XB002, for any application, including conjugated to other payloads, as well as rights within oncology to a number of other anti-tissue factor antibodies developed by Iconic, including for use in ADCs and multi-specific biologics.

Our ongoing phase 1 clinical study (Jewel-101) is designed to evaluate XB002 as a monotherapy in multiple solid tumor indications. Exelixis expects to present phase 1 clinical updates for XB002 at a medical conference in the second half of this year.

XL102

XL102 is a potent, selective and orally bioavailable covalent inhibitor of CDK7, a key regulator of the cell cycle progression and transcription. CDK7 helps regulate cell cycle progression, with overexpression observed in multiple cancers, such as breast, prostate and ovarian cancers. In preclinical studies, XL102 revealed potent anti-proliferative activity, induced cell death in a large panel of cancer cell lines and caused tumor growth inhibition and regression in xenograft models, demonstrating its potential as a targeted antitumor agent.

In late 2020, Exelixis exercised its option to in-license XL102 (formerly AUR102) from Aurigene per the companies’ July 2019 collaboration, option and license agreement. Exelixis has assumed responsibility for the future clinical development, manufacturing and commercialization of XL102. Aurigene retains limited development and commercial rights for India and Russia. Our ongoing phase 1 trial (QUARTZ-101) is evaluating XL102 as a monotherapy, and in two combination regimens, in multiple solid tumors. Exelixis expects to present phase 1 clinical updates for XL102 at a medical conference in the second half of this year.

XB010

XB010 is the first custom ADC generated through the company’s collaboration network, which was designated a development candidate in late 2021 and will enter preclinical development in 2022. In designing XB010, Exelixis sourced antibodies from Invenra and worked with partners of Catalent to design a novel ADC with broad potential. XB010 targets the oncofetal antigen 5T4 which is overexpressed on a broad array of solid tumors including non-small cell cancer, head and neck squamous cell carcinomas, and gastric and breast carcinomas, and utilizes Catalent’s SMARTag® site specific conjugation platform to produce a homogeneous ADC with a defined drug-antibody ratio. XB010 also incorporates Catalent’s next-generation linker technology, which is designed to be significantly more stable than first-generation approaches.

XB014

XB014 is the first bispecific antibody generated through the company’s strategic collaboration with Invenra and is based on the emerging clinical profile of CD47 targeted agents. In designing XB014, Exelixis used Invenra’s B-Body platform to create a bispecific that targets PDL1 and CD47 with high fidelity. XB014 combines blockade of the PDL1/PD1 checkpoint, thereby activating T-cells and adaptive immunity, with blockade of the CD47/SIRPα checkpoint, resulting in innate immune cell engagement. Tight binding to CD47 has been known to result in anemia and thrombocytopenia due to the expression of CD47 on the surface of red blood cells (RBCs) and platelets. To minimize these side effects, Exelixis has tuned the affinity of individual arms of XB014, combining a tight binding PDL1 arm to a detuned CD47 arm, which enables tight binding to tumor cells while minimizing binding to RBCs. XB014 also incorporates a wildtype IgG1 Fc domain. Binding of Fc receptors along with CD47 on macrophages ultimately enhances the induction of phagocytosis. The compound was designated as a Development Candidate in 2022.

Forward-looking statements

This publication contains forward-looking statements, including, without limitation, statements related to: the clinical potential of Exelixis’ pipeline; Exelixis’ future clinical development plans for cabozantinib, XL092 and other product candidates; Exelixis’ expectation to advance internally discovered compounds and partnered programs into preclinical and/or clinical development within the next few years; Exelixis’ potential future financial and other obligations under its various collaboration agreements; and other statements relating to Exelixis’ goals, efforts and objectives. Any statements that refer to expectations, projections or other characterizations of future events or circumstance are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the level of costs associated with Exelixis’ research and development, in-licensing or acquisition of product candidates, and other activities; the potential failure of cabozantinib and other Exelixis product candidates, both alone and in combination with other therapies, to demonstrate safety and/or efficacy in clinical testing; uncertainties inherent in the drug discovery and product development process; Exelixis’ dependence on its relationships with its collaboration partners, including their adherence to their obligations under relevant collaboration agreements and the level of their investment in the resources necessary to complete clinical trials Exelixis’ continuing compliance with applicable legal and regulatory requirements; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating cabozantinib and other Exelixis products; Exelixis’ dependence on third party vendors for the development, manufacture and supply of its products and product candidates; Exelixis’ ability to protect its intellectual property rights; market competition; changes in economic and business conditions, including as a result of the COVID-19 pandemic; and other factors affecting Exelixis and its drug discovery and clinical development programs discussed under the caption “Risk Factors” in Exelixis’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 2, 2021, and in Exelixis’ future filings with the SEC. All forward-looking statements in this publication are based on information available to Exelixis as of November 2, 2021, the date of this publication, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.