INI1

It’s a show-me year for many biotechs, which rode waves of layoffs throughout 2023 and cut programs in order to stay afloat amid an extremely challenging fundraising environment. The trees have been trimmed, branches pruned, underbrush cleared away. A thinner, leaner biotech forest arrived at the American Association for Cancer Research (AACR) conference in San Diego ready to showcase the budding data that have sprouted as a result of difficult decisions made during the sector’s so-called “nuclear winter.” It’s a show-me year for these companies, which rode waves of layoffs throughout 2023 and cut programs in order to stay afloat amid an extremely challenging fundraising environment. Many kept just the highest priority programs going. Reflecting on the tough times past, biotech executives told Fierce Biotech in interviews on the sidelines of the AACR conference that they are ready to show what all those gut-wrenching decisions were for. “It was devastating. It was really tough,” said Raquel Izumi, Ph.D., chief operations officer for Vincerx. The company cut 33% of staff in June 2022 and trimmed its pipeline to focus on just three cancer indications. Lead asset VIP152 (now known as enitociclib) took on an even bigger role, with trials continuing in three indications in lymphoma and leukemia. Click here for more AACR 2024 coverage from the Fierce Biotech team.  Mythic Therapeutics launched in December 2021 with a $103 million series A to develop new antibody-drug conjugates (ADCs). But the initial enthusiasm from the nine-figure raise quickly changed, and Mythic’s leadership had to revert back to its scrappy early days to survive. “We saw the hatches shut,” said Chief Scientific Officer Brian Fiske, Ph.D., on the funding environment in the past two years. And so the company battened down its own hatches, demonstrating the ability to stretch that cash as long as possible. But Fiske said it was still important to spend some money to ensure a stream of data would arrive to secure the next round. “You're looking at Mythic’s first investor,” he said with a laugh. “We rented six feet of lab space in basically a converted warehouse in a strip mall in order to start, so we had to be fuel efficient from the very beginning.” Meanwhile, Foghorn Therapeutics was sent into a spiral in 2022 when the FDA placed a clinical hold on blood cancer candidate FHD-286 after a patient death in a phase 1 trial. A second drug was partially halted by the FDA in April 2023 and then in June 2023, the company was forced to drop uveal melanoma as an indication for FHD-286. This all, of course, happened amid the larger market challenges for all biotechs. It’s been a whirlwind, but CEO Adrian Gottschalk says they’re on the other side now. “I think we've sort of weathered the valley of death, if you will, of biotech that everyone was going through for the last few years as best as one can,” Gottschalk said in an interview. “Obviously, when you're doing completely novel biology targets, some things are gonna work, some things aren't, and that's just the business we're in.”   Trimming the sails   The workforce reduction at Vincerx was personal for Izumi, who says she has long brought along colleagues from previous companies she had worked at to her next gig. “It was a difficult decision to make. But it was necessary because—as the term goes—we needed to trim sails to really focus,” she said. The drastic move was meant to extend Vincerx’s cash runway into late 2024. As of the biotech’s latest earnings report on March 29, the runway remains at the third quarter of 2024 with $12.8 million in cash and cash equivalents as of Dec. 31, 2023. This compares to $52.5 million a year prior. So the showing at AACR couldn’t be more important, Izumi said. “We have a great candidate in an enitociclib, and we're still developing it,” she said. What has changed is how the phase 1 study is funded. Instead of running it as a sponsored trial, Vincerx is now relying on the National Institutes of Health in an effort to reduce costs. That allowed the company to move two other candidates, VIP236 for advanced solid tumors and the ADC VIP943 in relapsed/refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and B-cell acute lymphoblastic leukemia. “Focusing our resources allowed us to get to where we are today with these two drugs with early phase 1 data,” Izumi said. Izumi could not speak to Vincerx’s fundraising needs, saying the company intends to present its case in the form of data and “take it from there.” “Last year, we call that one of the biotech nuclear winters, for sure. And there's a lot of companies in our position, but I don't know. I am an optimist. I'm seeing signs of change. And we think the future is bright,” Izumi said. At AACR, Vincerx presented early data for the two candidates behind enitociclib. Preliminary data for VIP236 as a monotherapy showed tumor reductions in patients with metastatic tumors who had tried all other standard options for treatment. The small, open-label dose escalation study has seen 15 patients receive the drug so far, every three weeks. VIP236 is a small-molecule drug conjugate, a modality that plays off of the ever-popular ADC that has been the apple of pharma’s eye the past few quarters. Just two doses into the cycle, seven patients achieved objective stable disease, including tumor reduction, Vincerx said. “Obviously, everybody in the industry does this, you're benchmarking against other drugs at this stage of development, and we're really happy because we're seeing results that we feel are on target and on track for this stage of development,” Izumi said. “We look at other drugs like [Gilead Sciences' breast cancer drug] Trodelvy and look at what they were like in their first-in-human trial, and we're seeing very similar results—and that's an approved drug. So we're really excited about what we're showing here.” The company said the every-three-week dosing schedule was well tolerated with no dose-limiting toxicities and no discontinuations due to adverse events. There were also no reports of life-threatening diarrhea, which is a common issue in this patient population, according to Izumi. “I'd like to remind people that phase 1 trials are 'Last Chance Saloon' for these patients. They've seen everything. They've failed everything. And this is the last thing for many of them. It's either that or hospice for many of them,” Izumi said. As for VIP943, a very early readout of seven patients across two cohorts provided some details on dose-limiting toxicities. Vincerx is lucky to be playing in an arena of great interest to Big Pharma with its ADC technology. The company has even funded its own efforts to showcase how the VersAptx bioconjugation platform can boost the efficacy of approved ADC like Gilead’s Trodelvy and AstraZeneca-Daiichi Sankyo’s Enhertu. While at AACR the biotech is showcasing its lead molecules, Izumi hopes the platform can attract some big-time partnerships.   Don’t be arrogant   While Vincerx’s CEO Ahmed Hamdy, M.D., blamed the markets for the workforce reduction, over at Foghorn Therapeutics, similar decisions were driven by data and regulatory hurdles. In the middle of 2023, Foghorn had about 165 people on staff and was running about three clinical trials. Then the melanoma indication for FHD-286 was dropped, and FHD-609 was paused in synovial sarcoma and SMARCB1-deleted tumors after the FDA’s partial hold in April 2023. “We knew at that point that we would need to reduce the footprint of our clinical organization,” Gottschalk said. The company conducted a round of layoffs initially, then a larger round in October 2023, while also taking a hard look at the pipeline. Ultimately about 35 to 40 people lost their jobs, while the total reduction was about 50 when resignations were accounted for. Gottschalk estimates the total head count is now around 115. “There's never a great way to do that stuff. We try to do it with as much dignity and grace and respect for all our colleagues,” the CEO said. After a tough year, Gottschalk and his Chief Scientific Officer Steve Bellon, Ph.D., are trying to take lessons from the clinical ups and downs. “What Steve and I talk a lot about is really learning from some of the challenges or the setbacks and then improving on the next generation of molecules we're bringing forward,” Gottschalk said. At AACR, Foghorn previewed preclinical data, including for BRM (SMARCA2) selective inhibitor FHD-909 in BRG1 mutated cancers, showing tumor growth inhibition and regression. The program is being developed with Eli Lilly’s Loxo Oncology unit, and the pharma plans to file for an investigational new drug application in BRG1-mutated non-small cell lung cancers this quarter. Bellon said the collaboration with Loxo has “clearly helped us drive to the sort of finish line in this challenging target. That collaboration is super important for helping us achieve this success.” Foghorn has emerged from the “valley of death” with a cash runway extending into 2026. Gottschalk said they entered the year with about $244 million and do not have any debt. “We're certainly not in an existential position or state. At the same time, biotech companies do spend a lot of money,” he cautioned. So Foghorn will likely look for fundraising opportunities or business development in the next six to 12 months, he said. While Foghorn survived, Gottschalk knows of many companies, made up of fellow biotech leaders and friends, who did not make it through. They have great scientists and physicians, and, through funding challenges or trial failures, they had to pack up and call it quits. “It comes back to, don't be arrogant in this business, because there's a lot of serendipity,” he said. “Everyone works really hard in this sector, I think. So it's not about the hard work. It's like, did you get the results? And sometimes that's a lot of luck. You try and be as smart as you can, but sometimes the science just doesn't work. So it was painful to see. It was painful to see people go through all of that. So, you know, hopefully we're in a brighter spot as a sector. It feels that way.”

Scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Scientists discovered that removing a second protein from cancer cells already experiencing tumor suppressor loss can reverse cancer cell identity. St. Jude Children's Research Hospital scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Findings showed that with the missing tumor suppressor, deleting or degrading the quality control protein DCAF5 reversed the cancer cell state. These results suggest a new approach to curing cancer -- returning cancerous cells to an earlier, more normal state rather than killing cancer cells with toxic therapies -- may be possible. The results were published today in Nature. "Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal," said senior author Charles W.M. Roberts, MD, PhD, Executive Vice President and St. Jude Comprehensive Cancer Center director. "This approach would be ideal, especially if this paradigm could also be applied to other cancers." "We found a dependency which actually reverses the cancer state," said first author Sandi Radko-Juettner, PhD, a former St. Jude Graduate School of Biomedical Sciences student, now a Research Program Manager for the Hematological Malignancies Program at St. Jude. "Standard cancer therapies work by causing toxicities that also damage healthy cells in the body. Here, it appears that we're instead fixing the problem caused by the loss of a tumor suppressor in this rhabdoid cancer." Drugging the un-targetable In many cancers, there is no easily druggable target. Often, these cancers are caused by a missing tumor suppressor protein, so there is nothing to target directly as the protein is missing. Loss of tumor suppressors is much more common than a protein gaining the ability to drive cancer. Consequently, finding a way to intervene therapeutically in these tumors is a high priority. The researchers were looking for a way to treat an aggressive set of cancers caused by the loss of the tumor suppressor protein SMARCB1 when they found a new approach to treatment. The St. Jude group found a little-studied protein, DCAF5, was essential to rhabdoid tumors missing SMARCB1. Initially, they identified DCAF5 as a target, using the Dependency Map (DepMap) portal, a database of cancer cell lines and the genes critical for their growth. DCAF5 was a top dependency in rhabdoid tumors. After the initial finding, the scientists genetically deleted or chemically degraded DCAF5. The cancer cells reverted to a non-cancerous state, persisting even in a long-term mouse model. "We saw a spectacular response," Roberts said. "The tumors melted away." Removing quality control to reverse cancer Normally, SMARCB1 is an essential component of a larger chromatin-regulating complex of proteins called the SWI/SNF complex. Unexpectedly, the study found that in the absence of SMARCB1, DCAF5 recognizes SWI/SNF as abnormal and destroys the complex. When DCAF5 degrades them, the researchers showed that SWI/SNF re-forms and maintains its ability to open chromatin and regulate gene expression. While the SWI/SNF activity level in the absence of SMARCB1 was to a lesser extent than usual, it was nonetheless sufficient to reverse the cancer state fully. "DCAF5 is doing a quality control check to ensure that these chromatin machines are built well," Roberts said. "Think of a factory assembling a machine. You need quality checks to examine and find faults and to pull it off the line if it doesn't meet standards. DCAF5 is doing such quality assessments for the assembly of SWI/SNF complexes, telling the cell to get rid of complexes if SMARCB1 is absent." "The mutation of SMARCB1 shuts off gene programs that prevent cancer. By targeting DCAF5, we're turning those gene programs back on," Radko-Juettner said. "We're reversing the cancer state because the cell is becoming more 'normal' when these complexes aren't targeted for destruction by DCAF5." Future therapeutic opportunities to reverse cancer "From a therapeutic perspective, our results are fascinating," Radko-Juettner said. "DCAF5 is part of a larger family of DCAF proteins that have been shown to be drug targetable. We showed that when DCAF5 is absent, mice had no discernable health effects, so we could potentially target DCAF5. This can kill the cancer cells but shouldn't affect healthy cells. Targeting DCAF5 thus has the potential to avoid the off-target toxicity of radiation or chemotherapy, making it a promising therapeutic avenue to pursue." Beyond DCAF5, the findings could have implications for other cancers driven by the loss of a tumor suppressor. "We have demonstrated a beautiful proof of principle," Roberts said. "Myriad types of cancers are caused by tumor suppressor loss. We hope we may have opened the door to thinking about new ways to approach targeting at least some of these by reversing, instead of killing, cancer."

A total of 45 positions will be impacted, with the changes likely to be completed by the end of the quarter. Two months after C4 Therapeutics discontinued one of its cancer assets, the small molecule medicines biotech has revealed that this narrowing of focus will come at the cost of a 30% reduction in headcount. C4 announced on Nov. 1 that it was halting work on an oral BRD9 degrader called CFT8634 in synovial sarcoma and SMARCB-1 null tumors after the high levels of BRD9 degradation identified in a phase 1/2 trial didn’t result in sufficient efficacy for heavily pre-treated patients receiving CFT8634 by itself. Instead, the Massachusetts-based biotech said at the time that it would prioritize its two other candidates in phase 1/2 trials. The company’s lead candidate, dubbed CFT7455, is an IKZF1/3 degrader being studied in combination with corticosteroid dexamethasone for patients with relapsed or refractory multiple myeloma (R/R MM), as well as a monotherapy for patients with advanced non-Hodgkin’s lymphoma.  The other asset being prioritized is CFT1946, a BRAF V600 degrader taking aim at solid tumors including non-small cell lung cancer (NSCLC), colorectal cancer and melanoma. The asset is currently being evaluated in a dose escalation phase 1/2 trial to treat solid tumors with BRAF V600 mutations. The company confirmed in a post-market release yesterday that it would also continue to support the phase 1 development of CFT8919—an oral degrader designed to treat EGFR L858R mutations present in patients with NSCLC—by its China-based partner Betta Pharmaceuticals, as well as “delivering on three discovery collaborations and progressing a streamlined internal discovery effort.” In the release, C4 explained that restructuring its operations in this way would result in around 30% of its employees being laid off. A total of 45 positions will be impacted, with the changes likely to be completed by the end of the quarter, it added in a related SEC filing. The biotech entered the new year with $330 million in cash and equivalents. This had been recently topped up by selling off $72 million in shares, as well as a $10 million upfront payment as part of a degrader-antibody conjugate collaboration with Merck & Co. in December and a $25 million equity investment from a subsidiary of Betta as part of the CFT8919 licensing deal. Combined with savings from the layoffs and restructured operations, C4 said it now expects its cash runway to extend into 2027. The decision to restructure the company “was not a decision we made lightly,” CEO Andrew Hirsch said in the Jan. 9 release. “Our sharpened focus on progressing CFT7455 and CFT1946 to critical clinical milestones, along with advancing targeted protein degradation research through our discovery collaborations with Roche, Biogen and Merck and our internal research efforts, will help C4T deliver breakthrough therapies for patients with cancer and other diseases,” Hirsch added. “Our strengthened balance sheet, coupled with cost savings from our restructuring, provide sufficient runway to execute through and beyond critical milestones across the portfolio.” Those milestones include updated data from the ongoing phase 1 dose escalation trial of CFT7455 in R/R MM, which is due in the second half of 2024 along with data from a trial in non-Hodgkin’s lymphomas. The second half of this year is also likely to see a readout from a phase 1 dose escalation trial of CFT1946 in melanoma, colorectal cancer, non-small cell lung cancer and other cancers with BRAF V600X mutations.