Entospletinib Dimesylate

Lanraplenib is one of Kronos’ two clinical-stage assets. After a mid-stage flop, Kronos Bio is discontinuing a cancer trial for lanraplenib and seeking a partner to continue development of the SYK inhibitor—the second acute myeloid leukemia (AML) candidate to disappoint the biotech. The announcement, which was made last night after market close, sent the biotech’s stock spiraling 13%, from $1.47 per share yesterday to $1.27 as of 10:40 a.m. ET today. The pipeline update follows a review of phase 1b data from Kronos’ phase 1b/2 trial assessing lanraplenib in combo with Xospata among 24 patients with FLT3-mutated relapsed/refractory AML. The patients were split up across four groups, receiving 20 mg to 90 mg of lanraplenib in combination with 120 mg of Xospata. No complete responses (CRs) or CRs with partial hematologic recovery (CRh) were observed and several patients discontinued treatment early on, according to Kronos. The company has now chosen not to proceed with the phase 2 part of the trial but does want to continue development of lanraplenib with a partner. “Patients in our study were older, more heavily pre-treated, and frailer than the relapsed/refractory patients in earlier studies. Many patients experienced non-drug related infectious disease complications leading to discontinuation during the first two months of treatment without achieving the count recovery needed to achieve a CR or CRh,” Jorge DiMartino, M.D., Ph.D., chief medical officer and executive vice president of clinical development at Kronos, said in a Dec. 18 release. “Given the changes in the treatment landscape for relapsed/refractory FLT3-mutated AML, it would be challenging to demonstrate the clinical benefit of adding lanraplenib to gilteritinib in this population.” This summer, the FDA approved Daiichi Sankyo’s quizartinib (marketed as Vanflyta), the first FLT3 inhibitor approved across three phases of the common blood cancer. Lanraplenib is one of Kronos’ two clinical-stage assets. Attention will now turn to KB-0742, the company’s first internally discovered molecule. In November, the biotech shared positive preliminary phase 1/2 trial data for the solid tumor candidate and announced efforts to streamline operations that included a 19% workforce reduction.   Besides KB-0742, Kronos has a partnership with Roche’s Genentech for several undisclosed discovery programs. Inked in January, the Genentech partnership is crucial for Kronos, coming right after the biotech kicked a late-stage AML asset called entospletinib to the curb. The Roche unit jumped in to save the day for the struggling biotech with a $20 million upfront payment plus milestones that could top $177 million for the first program and $100 million for the first licensed product. Now, after another AML disappointment, Kronos has revealed a new development candidate, dubbed KB-9558. The preclinical asset is designed to modulate the IRF4 transcription regulatory network—a key driver in multiple myeloma. KB-9558 is Kronos’ second internally created product and is currently in IND-enabling studies, which are expected to be completed in the fourth quarter of next year. “Existing therapies for this disease, including CAR-T and bispecific antibody therapies, are not curative, and there is substantial need for new therapies,” said Norbert Bischofberger, Ph.D., Kronos Bio president and CEO. “Preclinical data indicate that treatment of multiple myeloma cells with KB-9558 leads to a rapid and potent down-regulation of IRF4, and we believe our product candidate has the potential to be an innovative treatment for patients with this incurable disease.”

The advent of immunotherapy has set a development foundation for modern cancer therapies, allowing emergence of novel modalities and targets shaping the future landscape for cancer treatment. A previously unidentified target, SYK is presenting as an interesting an attractive therapeutic target. Numerous studies are ongoing which have highlighted that SYK might be an important regulatory molecule involved in pathogenesis for several diseases. Therefore, the possibility of SYK inhibition is being actively explored as a therapeutic approach by the pharmaceutical industry. Download Report: Up until now, there is only one licensed SYK inhibitor drug available in the market, TAVALISSE that has produced clinical response in patients with immune thrombocytopenia (ITP) including those who are refractory to other treatments. Produced by Rigel Pharmaceuticals, the year 2022 observed growing sales for the drugs. During Q2 of 2022, TAVALISSE net product sales were US$18.6 Million, representing the highest net product sales since the launch an increase of 9% compared to the second quarter of 2021, as per Rigel’s quarterly report. For the third quarter of 2022, Rigel reported US$ 19.2 Million sales in TAVALISSE net product sales which increased by 20% compared to US$ 16.0 Million the third quarter of 2021, as per Rigel’s Quarterly Financial Report. Looking that commercial success of the only approved SYK inhibitor, the pharmaceutical industry aims to present more related treatment option for several other indications. This has encouraged numerous clinical research and development advancements to proceed in the area. Hutchmed Pharmaceuticals is testing their oral developed SYK inhibitor, Sovleplenib (HMPL-523). Currently, in its phase II/II clinical trials, the company is investigating the safety and preliminary efficacy of the drug in adult patients with warm antibody autoimmune hemolytic anemia. The phase III study aims to confirm the efficacy safety of HMPL-523, a novel, investigational, selective, small molecule inhibitor for oral administration targeting spleen tyrosine kinase (SYK). The pharmaceutical industry is always keeping up with the emerging and trending targets being identified by vigorous research and development all over the world. Therefore, it is surprising that the market is slowly shifting its focus on the emerging benefit of SYK inhibition. The topic has become attractive in the field and even though the underlying mechanism of SYK inhibitors has not been investigated in larger context. Kronos Bio Inc currently has two investigational spleen tyrosine kinase (SYK) inhibitors, Entospletinib and Lanraplenib in its clinical pipeline. The preclinical studies from both the drugs represent a promising future outcome and therefore, the company has started enrolling patients in the clinical study for each compound. Lanraplenib is being assessed in a Phase Ib/II study as a potential treatment for patients with relapsed/refractory acute myeloid leukemia in combination with Gilteritinib. Furthermore, Calithera Biosciences, a clinical stage precision oncology biopharmaceutical company is also investing a SYK inhibitor. The study has initiated patient enrollent in phase II trial evaluating Mivavotinib, a SYK inhibitoe in relapsed/refractory non-GCB diffuse large B-cell lymphoma (DLBCL). The data from the study is expected by the first quarter of 2023. The market landscape for SYK inhibitors looks flourishing with encouraging and robust clinical pipeline. The market however, still remains limited sixe as there is only one approved drug but with the positive promising results observed in clinical trials, it is not long that the market will see more approvals. With more drugs being in their advanced stages of development, the market for SYK inhibitors is expected to increase at a growing pace. There are several pharmaceuticals targeting this market segment; Alexion Pharmaceuticals, Aptose Biosciences, Archer Pharmaceuticals, Catithera Biosciences, Clevexel Pharma and many others.