<br /><h3>PURPOSE</h3>Primary analysis of the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788) showed clinically meaningful antitumor activity in von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other neoplasms with belzutifan treatment. We describe results of belzutifan treatment for VHL disease-associated pancreatic lesions (pancreatic neuroendocrine tumors [pNETs] and serous cystadenomas).<br /><h3>PATIENTS AND METHODS</h3>Adults with VHL diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, no renal tumor >3 cm or other VHL neoplasm requiring immediate surgery, Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior systemic anticancer treatment received belzutifan 120 mg once daily. End points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and linear growth rate (LGR) in all pancreatic lesions and pNETs per Response Evaluation Criteria in Solid Tumors version 1.1 by independent review committee, and safety.<br /><h3>RESULTS</h3>All 61 enrolled patients (100%) had ≥1 pancreatic lesion and 22 (36%) had ≥1 pNET measurable at baseline. Median follow-up was 37.8 months (range, 36.1-46.1). ORR was 84% (51/61; 17 complete responses) in pancreatic lesions and 91% (20/22; 7 complete responses) in pNETs. Median DOR and median PFS were not reached in pancreatic lesions or pNETs. After starting treatment, median LGR for pNETs was -4.2 mm per year (range, -7.9 to -0.8). Eleven patients (18%) had ≥1 grade 3 treatment-related adverse event (AE). No grade 4 or 5 treatment-related AEs occurred.<br /><h3>CONCLUSIONS</h3>Belzutifan continued to show robust activity and manageable safety in VHL disease-associated pNETs.
38 Results Found
<p>A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced a precious metal catalyst with a ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds of enzyme evolution that improved enzyme stability in the presence of acetonitrile and methanol. To maintain development progress and satisfy program timelines, process development around the reaction, workup, and isolation operations was performed in parallel with the enzyme evolution and required ongoing modification, as new variants were made available. Additionally, opportunities for improvements to product quality and process robustness were identified by resolving issues observed in piloting experiments. </p>
<p>An improved synthesis has been developed for belzutifan, a novel HIF-2 alpha inhibitor for the treatment of Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency of previous supply and commercial routes was encumbered by a lengthy 5-step sequence, needed to install a chiral benzylic alcohol by traditional methods. Identification and directed evolution of FoPip4H, an iron/alpha-ketoglutarate dependent hydroxylase, enabled a direct enantioselective C-H hydroxylation of a simple indanone starting material. While this enabling transformation set the stage for a greatly improved synthesis, several other key innovations were made including the development of a base-metal-catalyzed sulfonylation, a KRED-catalyzed dynamic kinetic resolution, and a facile SNAr reaction in water. Together, these improvements resulted in a significantly shorter synthesis (9 steps) versus the supply route (16 steps) and a 75% reduction in process mass intensity (PMI), while also removing the reliance on third-row transition metals and toxic solvents. </p>
<p>A convergent nucleophilic aromatic substitution (SNAr) was developed as the final step in an improved manufacturing process to belzutifan. The reaction was performed in water to enable a reactive crystallization and direct isolation of the drug substance toward a green and sustainable process. Due to reaction sensitivity to the vapor phase composition, engineering controls around the headspace pressure and sweep rate were tuned to balance reactivity and selectivity to maximize product yield and purity. Ultimately, our investigation resulted in a robust process, which was successfully demonstrated at pilot plant scale. </p>
<p>Belzutifan (MK-6482) is an FDA-approved hypoxia inducible factor 2 alpha inhibitor for the treatment of Von Hippel-Lindau disease-associated renal cell carcinoma. One of the key synthetic steps is an enzymatic benzylic hydroxylation of an indanone. Prior to optimization, hydroxylation reactions required dilute conditions (100 volumes of water) and high enzyme loading (50 wt %) to achieve the target conversion, which was unsuitable for a long-term manufacturing process. Reduction of reaction volumes introduced additional complexity for large-scale operations due to the low solubility of the reaction components. In addition to reaction development, it was also necessary to find an optimal method of protein residue removal from the reaction mixture to isolate a high-quality product. We present here our efforts to overcome these challenges and ultimately successfully developed, optimized, and demonstrated at a multikilogram scale a process with improved process mass intensity using only a 7.5 wt % enzyme, 25 volumes of water, and 1-octanol as a unique additive. </p>
<p>Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a commercial synthetic process has been established to make belzutifan, a further optimized process with fewer steps, improved cost-effectiveness, and a smaller environmental footprint is always in demand. In the new commercial synthetic route, a single-step biocatalytic hydroxylation reaction was used to replace the five chemical steps required in the previous route. In developing this new biocatalytic reaction, multiple process analytical technologies (PATs), such as Fourier transform infrared spectroscopy (FTIR), in situ imaging, dissolved oxygen monitoring, etc., were used to track important reaction parameters under complex reaction conditions (e.g., multiphases and dense slurry). With quantitative modeling, the product concentration and yield can be tracked in real time based on FTIR. This is particularly important for dense slurry reactions, for which offline sampling becomes challenging due to the sample inhomogeneity. In-depth mechanistic insights were also obtained using PATs revealing reaction kinetics controlled by different mass transfer limited processes, as well as the unique role of 1-octanol. These PAT-enabled capabilities for reaction tracking and understanding facilitated process development from the laboratory to the pilot scale and ensured a robust process for the hydroxylation reaction. </p>
<p>A nickel-catalyzed sulfonylation reaction was discovered and developed into a robust process for the manufacturing of belzutifan, an FDA-approved treatment for Von Hippel-Lindau disease-associated renal cell carcinoma. The reaction proceeds via a nickel-catalyzed reductive sulfinylation reaction utilizing two insoluble salts (potassium metabisulfite and potassium formate), followed by methylation with a nontoxic methylating reagent (trimethylphosphate). The doubly heterogeneous nature of the reaction proved difficult to scale due to mixing and particle size issues. Controlled addition of a solution of potassium formate in ethylene glycol was found to mitigate all scaling issues, and mechanistic studies revealed this to be due to control of the catalyst speciation. The reaction was demonstrated on a multikilogram scale with robust kinetics between scales. Reaction discovery, process development, multikilogram-scale demonstration, and mechanistic insights are detailed within. </p>
Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.© 2024 Wiley-VCH GmbH.
First and only hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor approved for these adult patients with advanced RCC This approval of WELIREG marks the first time a new treatment has been approved in a novel therapeutic class in advanced RCC since 2015 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved WELIREG, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). The approval is based on statistically significant and clinically meaningful results from LITESPARK-005, which is the only trial in advanced RCC to specifically evaluate patients who have progressed following a PD-1 or PD-L1 inhibitor and a VEGF-TKI. In the trial, WELIREG
<br /><h3>BACKGROUND</h3>Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented.<br /><h3>METHODS</h3>LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety.<br /><h3>RESULTS</h3>Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred.<br /><h3>CONCLUSION</h3>After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety.<br /><h3>CLINICALTRIALS</h3>gov. NCT02974738.Copyright © 2023. Published by Elsevier Ltd.