Romidepsin

Innate will now progress its CTCL asset, lacutamab, to a confirmatory Phase III trial in the condition. Credit: Dermatology11 / Shutterstock.com. The Swedish Orphan Biovitrum, or Sobi, has inked a licensing deal worth up to $580m with Innate Pharma for its cutaneous T-cell lymphoma (CTCL) hopeful, lacutamab, amid an accelerated approval submission. Under the terms of the deal, Sobi will hand $75m upfront to help Innate begin the confirmatory Phase III TELLOMAK-3 study in CTCL, which the latter hopes will back lacutamab’s potential full approval in two CTCL subtypes: Sézary syndrome and mycosis fungoides. In exchange, Innate will offer Sobi the exclusive global rights to commercialise lacutamab provided it secures accelerated approval, as well as the worldwide development rights to the drug if Phase III results are positive. On top of the upfront sum, Sobi has also committed to hand over $40m in potential near-term development milestones associated with lacutamab’s Sézary programme, as well as up to $465m if the company chooses to secure the full development rights to the drug alongside future regulatory and commercial milestones. Sobi will offer Innate double-digit royalties on any resulting lacutamab sales if the drug makes it to market. This comes as Innate eyes an accelerated approval for lacutamab in Sézary syndrome, a rare and aggressive variant of CTCL, based on a win from the Phase II TELLOMAK study (NCT03902184). In the trial, lacutamab prompted durable responses and favourable safety in a heavily pre-treated patient population. Lacutamab, a first-in-class medicine, acts as an anti-killer-cell immunoglobulin-like receptor 3DL2 (KIR3DL2), which helps to control immune cell activity and is often overexpressed in patients with CTCL. The therapy has already received Fast Track and PRIME designations from US and European regulators, respectively. According to Innate’s CEO, Jonathan Dickinson, the advancement of lacutamab into a Phase III study marks a “pivotal moment” for the company as it looks to secure a place on the oncology market. However, the company is not just pinning its hopes on lacutamab, Dickinson notes, as it is also expecting key milestones for its Nectin-4-targeting antibody-drug conjugate (ADC), IPH4502, and its immune checkpoint inhibitor, monalizumab, which he says represent “important developments” for Innate in 2026. Treating CTCL CTCL is a rare form of non-Hodgkin lymphoma caused by the accumulation of abnormal T-cells in the skin – leaving patients with itchy skin afflictions that often look like rashes, psoriasis or eczema. In recent years, there have been multiple advancements in the treatment of CTCL, with the approval of drugs like Pfizer-owned Seagen and Takeda’s Adcetris (brentuximab vedotin), as well as Amneal Pharmaceuticals’ romidepsin injection solution in 2024 and June 2026, respectively. However, several drugs have failed to cross the line to regulatory approval in CTCL, with a dedicated Phase II trial for Karyopharm Therapeutics’ selinexor being put on ice due to challenges around enrolment. Meanwhile, 4SC also failed to secure the European Medicines Agency’s (EMA) blessing despite its drug, Kinselby (resminostat), meeting its primary endpoint in the Phase II RESMAIN study (NCT02953301), due to the drug’s perceived lack of benefit to warrant approval. Most recently, Soligenix opted to terminate its development programme for topical CTCL therapy, HyBryte, after a data monitoring committee deemed it unlikely the drug would meet its primary goals in a pivotal Phase III trial. Currently, researchers estimate that the global incidence of primary cutaneous lymphomas (PCL), a category which includes CTCL, is one in 100,000.

Researchers have cracked the code behind bacteria's ability to naturally manufacture multiple versions of powerful anti-cancer drugs. The discovery could make it much easier to engineer new cancer treatments inspired by nature, including improved versions of existing medicines.Scientists have uncovered how bacteria naturally manufacture multiple versions of powerful cancer drugs, solving a mystery that has puzzled researchers for decades. The discovery could help speed the development of new treatments for cancers that are still difficult to treat. For years, scientists have hoped to harness bacterial enzymes to create new drug variants through a process known as combinatorial biosynthesis. However, progress has been limited because researchers did not fully understand how the enzymes coordinate their work. Published in Nature Communications, the new study reveals how bacterial enzymes communicate with one another to assemble a family of closely related anti-cancer compounds. That family includes Romidepsin (Istodax), an FDA-approved treatment for certain blood cancers. By uncovering this natural "mix and match" system and reproducing its underlying principles in the laboratory, the researchers have established a new strategy for designing future cancer therapies. "For decades, we've known that bacteria can naturally produce multiple versions of powerful anti-cancer drugs, yet we had no idea how they achieved this," said first author Dr. Munro Passmore, Research Fellow, Department of Chemistry, University of Warwick. "This work finally cracks that code. We've identified how the different enzymes communicate and cooperate to produce these drug variants, something that has eluded researchers because the system is so elegantly economical. It's the breakthrough we needed to actually engineer these drugs ourselves." Tiny Molecular Connectors Reveal Nature's Drug-Making Strategy The researchers discovered that small molecular regions known as 'docking domains' serve as connectors between the core drug-building machinery and the enzymes responsible for adding different components. These docking domains share a conserved connection point that allows them to interact with multiple enzyme partners. This flexible design explains how bacteria can create a variety of related drug molecules while still maintaining the precision needed for the compounds to remain effective. The study also sheds light on how these natural drug-producing systems evolved. According to the researchers, the newly identified compound most likely developed from a related drug-producing pathway through gene duplication and recombination over time. Prof. Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry, University of Warwick and Monash University concludes: "This research gives us a blueprint to do what nature does, but better and faster. By reverse-engineering nature's evolutionary logic, we can now design synthetic pathways that generate new anti-cancer drug candidates with properties optimized for clinical use, such as superior potency, improved selectivity, fewer side effects. Our immediate goal is to build an expanded library of candidates for various cancers where new treatments are urgently needed. This discovery is moving us from understanding how the systems work to building new ones." How the Discovery Could Improve Cancer Drug Development The work focuses on a class of anti-cancer medicines known as HDAC inhibitors. These drugs block histone deacetylases, enzymes that help regulate which genes are switched on or off inside cells. Romidepsin (Istodax) is an FDA-approved HDAC inhibitor used to treat T-cell lymphomas. A chemically related compound called FR-901375 has been known for decades, but scientists had never identified the biological pathway bacteria use to produce it. This study finally fills in that missing piece. Like other HDAC inhibitors in its family, FR-901375 belongs to a group of complex cyclic molecules called depsipeptides. These compounds are assembled from amino acid building blocks along with a conserved hydroxy acid pharmacophore, all connected through a combination of peptide and ester bonds. Inside bacteria, these molecules are built by massive protein complexes called PKS-NRPS hybrids, which combine the activities of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS). The new research shows that the key to this assembly process is the docking domains, which act like molecular connectors that allow one part of the production line to recognize and pass its product to the next. This mechanism is what enables combinatorial biosynthesis and allows bacteria to naturally generate multiple drug variants. How the Researchers Solved the Mystery To uncover how this system works, the team combined structural biology, biochemistry, genetics, and computational modeling. Their work included: