PharmaShots Interview: Ikena Oncology’ Mark Manfredi Shares Insight on IK-930 for the Treatment of Solid Tumors

In an interview with PharmaShots, Mark Manfredi, President, and CEO at Ikena Oncology shared his views on the US FDA’s IND clearance of IK-930 for the treatment of solid tumors that harbors genetic alterations in the hippo pathway

Shots:

The US FDA has accepted its IND application to initiate the P-I study of IK-930 for solid tumors harboring genetic alterations in the hippo pathway. The trial is expected to initiate in early 2022
The preclinical studies including data presented at the AACR-NCI-EORTC reported that the therapy can be effective both as monothx. & in combination with multiple targeted agents for cancers
The company plans to identify the combinations of IK-930 with other targeted agents for solid tumors including EGFR-mutant NSCLC & KRAS-mutant solid tumors. IK-930 is designed to bind TEAD & disrupt TEAD-dependent transcription of key genes in cancer progression, metastases & therapeutic resistance

Tuba: Can you briefly describe some of the key details and specialties about IK-930, including its MOA?

Mark Manfredi: IK-930 is designed to bind and inhibit TEAD, a downstream transcription factor in the Hippo pathway. As a key driver of cancer pathogenesis, the Hippo pathway regulates cell fate, proliferation, and survival. The pathway is genetically altered in approximately 10% of all human cancers. The Hippo pathway is also implicated in therapeutic resistance, as it can provide compensatory growth and survival signals in tumors when patients are treated with other therapies. Inhibiting TEAD could prevent the transcription of multiple genes that drive cancer progression.

Tuba: Can we have a glance at the pre-clinical research results of IK-930?

Mark Manfredi: Our comprehensive set of preclinical experiments includes multiple elements to ensure a well-rounded and thorough data package. First, we have shown that IK-930 can be both selective and potent in inhibiting the transcriptional output of the pathway. Next are two important pillars: exploring IK-930 in genetically defined tumor models and diving into the biology to identify the indications IK-930 has the best possible chance of helping patients. We have demonstrated efficacy and safety in multiple tumor models and robust bioinformatics and proprietary immunohistochemical analyses to identify clinical opportunities with the most potential for impact. The efficacy studies have shown great results for IK-930 as monotherapy in cell models and animal models of Hippo dysregulated tumors, including NF2 and LATS1/2 deficient mesothelioma as well as other genetic alterations. Furthermore, we saw promising results when IK-930 was combined with EGFR and MEK inhibitors in EGFR and KRAS mutated cancers, including those in lung and colon cancer. We integrated genomic, transcriptional, tissue-based, and pharmacological profiling to identify our clinical development plans which include NF2-deficient mesothelioma and a subset of soft tissue sarcoma for our TEAD inhibitor, IK-930, as a monotherapy. We also identified EGFRm non-small cell lung cancer (NSCLC) for IK-930 as a combination therapy.

Tuba: When can we expect the initiation of the P-I clinical trial for IK-930 in solid tumors that harbor genetic alterations across the Hippo pathway?

Mark Manfredi: The Phase I clinical trial for IK-930 is on track to enroll patients by early 2022, with its IND approved in late October 2021. We will focus on patients with tumor types that have a high frequency of Hippo pathway alterations, including but not limited to NF2-deficient malignant mesothelioma and solid tumors with YAP/TAZ genetic fusions, including Epithelioid Hemangioendothelioma (EHE), a rare form of soft tissue sarcoma in which 100% of tumors have Hippo dysregulation. We also plan to explore combinations of IK-930 with other targeted agents including but not limited to MEK inhibitors and EGFR inhibitors for the treatment of solid tumors in indications that have shown promise in our preclinical studies.

Tuba: Discuss the clinical development strategy in genetically defined cancers for patients with high unmet needs.

Mark Manfredi: At the core of our strategy is our desire to understand each patient’s cancer and the pathways that drive it. We ask what pathways are most involved in tumor growth, how we can best identify those mutations, and what molecules we can use to target them. This gives us the ability to develop precision oncology treatment candidates driven by a comprehensive understanding of each target’s profile, which we hope will increase the probability of clinical benefit.

Additionally, we carefully design our clinical trials so that more patients can benefit early on in the trial either through dose escalation or cohort expansion. Our robust biomarker approach allows us to both understand our clinical data and pre-select patients. The IK-930 trial includes a wide range of markers, important for the emerging excitement in the Hippo pathway which has several nodes involved in multiple cancers. In another one of our programs, we recently expanded our trial of IK-175, an Aryl Hydrocarbon Receptor (AHR) antagonist, in urothelial carcinoma (bladder cancer), creating new opportunities for patients with this indication.

Tuba: Can we have an insight into Ikena’s other pipeline programs and their target indications?

Mark Manfredi: We are investigating multiple potential candidates in targeted oncology, including therapies that target the tumor microenvironment (TME). Our targeted oncology programs focus on non-traditional biomarkers for difficult-to-treat cancer types. Our diversity of translational approaches allows us to be unconstrained by any single platform or method.

Ultimately, all our programs – past, present, and future – center on the patient. We are continually expanding our pipeline based on a deep understanding of the biology underlying cancer in each patient population, which leads us to select a lead candidate and begin clinical development.

Tuba: What makes you work on precision medicine for patients suffering from cancer?

Mark Manfredi: We envision a world in which every cancer patient has a cure. Advancing precision medicines for cancer expands the toolbox we have to fight each individual’s cancer. We believe the future of cancer treatment is targeted oncology treatments that are tailored to the biology and needs of individual patients, which could be one single targeted therapy or a combinations strategy targeting multiple markers in a patient’s tumor. We expect that combination therapy strategies will play an increasingly vital role in targeted oncology treatment plans geared toward addressing and preventing therapeutic resistance. The addition of targeted therapies to the oncology landscape provides patients with options and the hope that their treatment can be as specific as possible to their tumor.

Our team is united in our desire to see, know, and understand what drives every patient's cancer, and we all have something important to contribute to this goal. We encourage our team to take risks and follow the data they generate. When you don’t know what’s around the corner and you may be one experiment away from possible disaster, you’re also consistently on the edge of breakthrough discoveries. It’s an exciting approach that has allowed us to carve out unique programs and keeps our scientists passionate and excited about their work.

Tuba: Can we also talk about the epidemiology and the prevalence of some of the lead indications being targeted by IK-930?

Mark Manfredi: IK-930 could have a life-changing impact across many cancers with high unmet needs given the prevalence of the Hippo pathway in cancer and the emerging growth of information about therapeutic resistance to other targeted therapies. Approximately 10% of solid tumors had Hippo pathway genetic alterations, frequently presenting as an NF2 deficiency and/or YAP1 or TAZ fusion genes. Based on the prevalence of the Hippo pathway in different solid tumors our lead indications are NF2 deficient malignant pleural mesothelioma (MPM), which corresponds to 40% of all MPM and a soft tissue sarcoma (STS) called Epithelioid HemagioEndothelioma (or EHE). This is a very rare solid tumor type associated with the presence of a TAZ fusion gene (called CAMTA1) in more than 90% of the cases and with a YAP1 fusion gene in the other 10% of the cases.

We are initially focusing our efforts on NF2 deficient mesothelioma. According to the American Cancer Society, around 3,000 people in the U.S. are diagnosed with mesothelioma each year, and this disease, which most commonly occurs from exposure to asbestos, led to more than 45,000 deaths between 1999-and 2015 according to the CDC. In the last 17 years, only two new systemic treatments have been approved by the regulatory agency for first-line treatment of MPM and no treatment has been approved until now for the subset of NF2 deficient MPMs.

Our second lead indication as mentioned is EHE, a rare STS where 100% of patients have Hippo pathway dysregulation, with significant unmet medical need; no systemic treatment has been specifically approved for these patients with metastatic disease. We look forward to exploring how IK-930 may make a difference for these patients as well as other patient populations with cancers caused by Hippo pathway mutations.

Source: Children's Healthcare of Atlanta

About Author:

Mark Manfredi, President, and CEO at Ikena Oncology. He has over two decades of experience in cancer drug discovery and translational research. Mark is currently an advisor at Atlas Venture & earned his BS from the University of Rhode Island and his Ph.D. in Biology from Boston College.