Manfredi, Ikena Making Fresh Tracks With a Supportive Hive

08 Nov 2021
www.biospace.com
Small molecular drug
Ikena President and CEO Mark Manfredi, Ph.D/Courtesy Ikena Oncology Kindness. Respect. Innovation. Only one of those words typically features in biotech mission statements, but at Ikena Oncology, all three are important – and have been from day one. “We formed Ikena Oncology in 2016,” Mark Manfredi, Ph.D., president and CEO, began. “Our corporate culture was built around a lot of the things I learned throughout my time in the industry at small, medium and large companies.” Manfredi has spent more than 20 years in cancer therapeutics development and translational research. He has served as CSO at Raze Therapeutics, entrepreneur-in-residence at Atlas Ventures and VP of oncology at Takeda Pharmaceutical, where he contributed to Takeda’s global R&D strategy and helped advance eight mechanisms into the clinic. He had three goals for Ikena’s culture: 1. To create a vibrant, innovative environment for scientists. “At Millennium (acquired by Takeda in 2008), the mantra was ‘nothing is impossible.’ At Ikena Oncology, that mantra is ‘make fresh tracks,’” he said. Manfredi aims to encourage his team members to address the hard questions that have a big impact in science. “That means taking risks and working on the cutting edge. When you don’t know what’s around the corner and you may be one experiment away from possible disaster, you’re also on the edge of breakthrough discoveries. It’s exciting, but it also makes some people uncomfortable. That approach, however, has allowed us to carve out a unique program, and it makes our scientists very excited about their work.” 2. To embrace risks. Manfredi’s mandate is to develop good science that leads to good data – not merely the results the company hopes to see. This acceptance of risk, and the acknowledgment that some experiments lead in unanticipated directions, gives scientists and non-scientists alike the courage to stretch their limits. In so doing, they may achieve more than they thought possible. 3. To build a caring work environment. “Obviously, driving a R&D program into the clinic is a team sport,” he said. “Who you work with is as important as what you’re working on, so fostering a sense of caring for each other is important. This core value creates a unique environment,” and attracts impassioned people. Manfredi refers to Ikena’s nurturing professional environment as a “supporting hive.” In it, he said, “people share core values, so it’s easier for them to share their time and talent with those around them. People feel this (vibe) when they interview with us. In fact, new hires for the past 18 months have said that their number one reason for joining Ikena is our culture and our caring environment.” The corporate culture involves “everyone rowing in the same direction, and having the opportunity to interact,” Manfredi said. Now, 20 months since the first COVID-19 stay-at-home mandates, interaction is becoming easier. “We’re a hybrid office, with some people going into the office and some working remotely. When most of us (except those in the lab) were working from home, we interacted through Microsoft Teams and online functions. We had weekly ‘buzz’ meetings, where we got together and talked about our programs and corporate updates. We also instituted a social session, including games, online through Zoom.” The hour set aside for this often turned into two or more hours and helped maintain the company’s collegial culture even when everyone was apart. The ability to enhance the corporate culture despite the pandemic hints at both grit and resiliency – personal characteristics Manfredi hones as a runner. He’s run the Boston Marathon six times (his fastest time: 2 hours, 51 minutes). “There are a lot of biotech runners in Cambridge,” he said. “Running is analogous to how we think about ups and downs, and the resiliency you have to develop to succeed.” Therapeutically, Ikena develops patient-directed oncology therapies that target important signaling pathways and others that target the tumor microenvironment. They are based upon structural biology-guided chemistry and an understanding of deep cancer biology. Yet, Manfredi said Ikena’s most innovative program isn’t a program, but a mindset – specifically, the focus on the patient. “The ‘I’ in our name stands for ‘I, the patient,’ Manfredi explained. “‘Ken’ stands for the knowledge of science that the company brings to its programs.” The goal is to understand the biology of the program as it applies to a targeted patient population. “All of our programs have this patient selection approach, based on biomarkers related to the pathway,” Manfredi said. A lot of the stratification work starts early in the research stage. “In the early phases of new programs, for example, we ask what the pathway looks like in cancer patients and how much of that is activated in these patients.” Biomarkers are being applied for go/no decisions as well as for dose escalation and cohort expansion. They inform target oncology “where biomarkers are front and center to (therapeutics based upon) genetic alterations, and also to our immuno-oncology work in the tumor micro-environment, where biomarkers traditionally aren’t featured,” he said. The early use of biomarkers will, he hopes, help Ikena increase the probability of clinical benefit and avoid the failures that have beset more broad-based trials. “Next, we’re thinking about multiplexing biomarkers,” Manfredi said. This approach would use several biomarkers to address multiple areas of importance to a therapeutic, such as sensitivity to therapy, patient selection, therapeutic resistance or other factors. The company has robust clinical and research pipelines, with two programs in Phase Ib trials involving the tumor microenvironment. Its first and lead targeted oncology program just had its IND accepted. IK-930 is an oral, small molecule that inhibits the transcription factor known as TEAD in Hippo-mutated cancers. Ikena will initiate a Phase 1 clinical trial for IK-930 in early 2022. “It is looking at multiple alterations of the pathway, and also at secondary biomarkers related to therapeutic resistance,” he said. The Hippo pathway is associated with cancer pathogenesis and is genetically altered in about 10% of all cancers but in about 40% of all mesothelioma and all epithelioid hemangioendothelioma tumors. “Some of our programs that are earlier in development are looking at biomarkers that are known in the literature but that haven’t been developed as biomarkers,” he added. IK007, for example, is an oral, small molecule prostaglandin E2 receptor 4 (EP4) antagonist that has the potential to alter immunosuppression in the tumor microenvironment, resensitizing it to activity from checkpoint inhibitors. Ikena uses the higher levels of PGEM (a metabolite in the EP4 pathway) in the urine as a biomarker for this study. That Ikena is able to develop such innovative therapeutic approaches harkens back to its team. “Everything is about the team,” Manfredi said. “What I’m most proud of is the teams that I’ve built and worked with. When you have a good team that is executing and its people are passionate about what they do…their drive, their focus, are synergistic. It’s like magic.”
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