Expanding ADC Therapy: Jane Chung from Sutro Biopharma in an Engaging Conversation with PharmaShots

Shots:

Luvelta, an antibody-drug conjugate by Sutro Biopharma is designed to target FRα, expressed in ovarian cancer, developed and manufactured using the company’s proprietary cell-free technology, XpressCF

Today, at PharmaShots, we have Jane Chung, President and CEO at Sutro Biopharma, shedding on the ongoing REFRαME-O1 study evaluating luvelta

Sutro is now enrolling patients for the part 2 study to explore luvelta randomized against the investigator’s choice of chemotherapy

Saurabh: Could you walk us through how luvelta works on a molecular level to target platinum-resistant ovarian cancer? I'm curious about the specific mechanisms that make it effective against this challenging type of cancer. 

Jane: Luveltamab tazevibulin, or Luvelta, is an antibody drug conjugate (ADC) specifically designed to target folate receptor-alpha (FRα), a validated target that is highly expressed in ovarian cancer. Developed and manufactured using our proprietary cell free technology, XpressCF, Luvelta is a highly homogenous ADC that combines an antibody which specifically binds to FRα with a hemiasterlin payload. The result of this precise design is an ADC with the potential for a wider therapeutic window. When Luvelta is administered, it binds to FRα primarily found on cancer cells, becomes internalized, and the cytotoxic payload is released, killing the cancer cells. This targeted delivery directly to the cancer cells is what enhances Luvelta’s efficacy against platinum-resistant ovarian cancer, and we believe several other cancer types.

Saurabh: Could you elaborate on how luvelta brings hope to patients with low-medium FRα expression in platinum-resistant ovarian cancer? How does it cater to their specific needs, and why is targeting FRα expression so crucial in improving outcomes for ovarian cancer patients? 

Jane: Luvelta presents an exciting opportunity to broaden patient access to ADC therapy. There is a FRα-targeting ADC already approved today but for only 35% of platinum-resistant ovarian cancer patients who have very high expression of FRα on their cancer cells. Based on the clinical data we have generated to-date, we believe luvelta has the potential to effectively treat more patients with low and medium levels of FRα, which would expand this benefit to 80%, or 8 in 10 women, with platinum-resistant ovarian cancer. We believe Luvelta’s broader benefit is due to its highly homogenous structure and precise design for higher affinity and efficiency to engage FRα on the cancer cells, allowing it to address lower FRα expression levels. In addition, early clinical data suggests that combining luvelta with bevacizumab, an approved targeted cancer therapy, could further extend this benefit to nearly all women (i.e., 10 of 10), regardless of FRα expression, offering hope to a significantly larger patient population with this challenging condition.

Saurabh: Can you provide some insights into the design and objectives of the REFRαME-O1 trial, especially the randomized portion? How many patients are expected to participate in Part 2 and what endpoints will be assessed to evaluate the efficacy of luvelta compared to other chemotherapies? 

Jane: REFRaME-O1 is our pivotal clinical trial designed to reframe the opportunity so that more patients can benefit from a FRα-targeted medicine, by studying luvelta in women with platinum-resistant ovarian cancer with FRα expression levels of 25% or higher, which meets the threshold for low, medium and high expression levels, as discussed above. We completed the first phase of the trial with 50 enrolled patients in April, for which the data will confirm the optimal dose for luvelta. While we wait for outcomes from part 1 of the trial, we are currently enrolling patients in part 2 of the trial, which explores luvelta randomized against investigator’s choice chemotherapy, which is the current standard of care.

Once we have determined the optimized dose, the randomized portion will be adjusted to enroll only that luvelta dose level. Overall, we plan to enroll roughly 500 women in this pivotal phase, and the primary endpoints will be progression free survival (PFS) and overall survival (OS), with key secondary endpoints including overall response rate (ORR) and duration of response (DOR).

Saurabh: Could you shed some light on the significance of the interim analysis within the REFRαME-O1 trial and its potential impact on expediting the approval process for luvelta? What criteria will be used to determine the success of this interim analysis? 

Jane: The interim analysis could be significant for Luvelta’s approval, as we can file for accelerated approval after a certain number of patients have been randomized and treated with the optimized dose or chemotherapy. This is particularly important for women with low or medium expression levels of FRα, as there is currently no approved targeted therapy available for them and could enable us to get luvelta to patients on a faster timetable. The accelerated approval would be based on ORR and DOR results, with the opportunity to file for full approval based on PFS and OS results on the fully enrolled trial.

Saurabh: It's fascinating to hear about Luvelta's promising results across various tumor types. Can you provide more details on how these findings extend beyond ovarian cancer and their implications for reshaping cancer treatment strategies on a broader scale? 

Jane: Luvelta has demonstrated promising anti-tumor activity and tolerability in all four of the cancers that it has been studied – ovarian, endometrial, lung and CBFA2T3:GLIS2 (CBF/GLIS; RAM phenotype) acute myeloid leukemia (AML). This last indication – CBF/GLIS subtype AML – is our next most advanced opportunity and we plan to begin enrollment in a pivotal trial, REFRαME-P1, in the second half of 2024. CBF/GLIS subtype AML is a rare disease with a high need pediatric patient population. We have already shown a high rate of complete remission in dozens of infants and children through a compassionate use program. We view luvelta as a pipeline-in-a-drug and believe the clinical activity demonstrated to-date is just beginning to reveal its full potential to reshape treatment strategies across the wide spectrum of FRα-expressing tumors.

Saurabh: Beyond the ongoing trials like REFRαME-O1, I'm curious about Sutro Biopharma's future plans for exploring the potential applications of luvelta and other antibody-drug conjugates in different therapeutic areas. Are there any exciting initiatives on the horizon? 

Jane: We believe luvelta demonstrates strong proof-of-concept for the broad potential of our novel cell-free protein synthesis platform. We have shown with luvelta and our other pipeline and partnered programs that our platform is highly flexible, allowing for the modular design of complex biologics in a way no other company can. As we develop ADCs in different therapeutic areas, we can leverage our platform to mix and match different payloads, in different locations on the antibody and in different amounts, using non-natural amino acids – a feat that is impossible with traditional cell-bound methods. With our proprietary process that marries our cell-free manufacturing platform with cutting-edge biology and chemistry, we are pioneering next generation ADCs including a new class of ADCs called immunostimulatory ADCs (iADCs), which combine a cytotoxin and immune modulator in one medicine.

Saurabh: Given the rapid advancements in cancer treatment, how does Sutro Biopharma see luvelta and its other investigational products contributing to the evolution of precision medicine and personalized cancer care? I'd love to hear your insights on the company's vision for the future of cancer treatment. 

Jane: ADCs have proven to be groundbreaking treatments for people with cancer, but more is possible, and we believe Sutro is at the forefront of addressing the limitations of current therapies while leading future innovation. We have a bold strategy to transform how patients with cancer are treated – creating medicines that not only outsmart cancer but harness the immune system’s power to engage in the fight, enabling us to reach patients beyond the scope of current therapies. By revolutionizing ADC design and manufacture, we strive to offer better outcomes for more patients, with a more tolerable therapy. By creating medicines that precisely target the tumor, we offer patients more hope, more potency and more efficacy, but less toxicity, less inconvenience and less burden than chemotherapy.

Image Source: Canva

About the Author

Jane Chung

Jane Chung, RPh has over 20 years of pharmaceutical and biotechnology experience and has served as our President and Chief Operating Officer since December 2023 and previously our Chief Commercial Officer since August 2021. From 2015 to 2021, Ms.Chung served in several leadership roles at AstraZeneca, including as President and General Manager of AstraZeneca Canada, Vice President of Sales and Marketing of U.S. lmmuno-Oncology, and Senior Commercial Business Director. Prior to that, from 2013 to 2015, Ms. Chung served as a Regional Sales Director and Director of Sales Productivity and Effectiveness for Onyx Pharmaceuticals Inc. From 2003 to 2013, she served in various commercial roles for Genentech, Inc., including as Commercial Operations Manager, Division Manager and Senior Marketing Manager. Ms. Chung also serves on the Board of Directors of Viracta Therapeutics, Inc. and on non-profit boards in the science, education, and community development arenas. Ms. Chung received her B.A. from Columbia University, New York, and B.S. in Pharmacy from St. John’s University, New York.