SIK3 x SIK2

Galapagos has cut anti-inflammatory drug candidate GLPG4399 following the completion of an early-stage healthy volunteer trial, according to its 2022 annual report released Thursday afternoon. GLPG4399 was a SIK3 inhibitor, one in a line of such salt-inducible kinase (SIK) inhibitors that Galapagos has been trying to develop for inflammatory diseases like rheumatoid arthritis and ulcerative colitis. Originally, the biotech had been planning to move the drug forward in a study with rheumatoid arthritis patients in the middle of this year, but now it’s halting the program and going back to search for new SIK inhibitors. “Medicinal chemistry activities to identify SIK inhibitors with improved pharmacology continues,” Galapagos noted briefly in its press release. GLPG4399 was the third SIK inhibitor Galapagos brought out of the clinic — all part of a franchise Galapagos dubbed Toledo. The first candidate, GLPG3312, similarly only made it through healthy volunteer studies before Galapagos scrapped it. The second, GLPG3970, disappointed in Phase II trials in ulcerative colitis and rheumatoid arthritis, and though it showed some signs of efficacy in psoriasis, Galapagos opted to toss that candidate as well. The small pipeline prune comes after Galapagos laid off 200 staffers and discontinued work on its fibrosis and kidney disease programs, cuts that followed a long string of setbacks at the biotech. In December, Galapagos also announced that its chief business officer André Hoekema and chief medical officer Walid Abi-Saab are retiring, though the latter is remaining with the company until the end of May. Galapagos shares $GLPG fell almost 8% after the markets opened Friday. The biotech did not immediately return request for comment.

FRISCO, Texas, June 24, 2022 /PRNewswire/ -- Green3Bio, a subsidiary of Greenfire Bio , today announced a publication in the Journal of Clinical Investigation1 led by researchers at The University of Texas MD Anderson Cancer Center demonstrating that SIK2 inhibitors, including GRN-300 sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. Zhen Lu, M.D., and Robert Bast, M.D., and colleagues demonstrated that a combination of PARPi and SIKi provides a novel therapeutic approach to enhance PARPi sensitivity in ovarian cancers that initially respond to PARPi and eventually develop drug resistance. The major findings from the preclinical research study include: GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300 GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC. These findings provide strong preclinical evidence supporting future clinical trials to determine whether the combination will benefit patients with ovarian and triple negative breast cancers. Animal studies, particularly those with olaparib and GRN-300, did not show significant toxicity based on weight loss. Pre-clinical toxicology studies in rodents and dogs showed no hematologic toxicity, which is particularly important for combination with PARPi. "Patients with ovarian and triple-negative breast cancers are in great need for more effective treatments due to the high prevalence of acquired resistance to standard therapies that involve PARP inhibition," said Steve Morris, MD (Chairperson, Scientific Advisory Board of Greenfire Bio). He added, "The GRN-300 preclinical data published in The Journal of Clinical Investigation shows the potential of GRN-300 and its unique mechanism of action through SIK2/3 inhibition to help change the combination treatment paradigm in gynecologic and breast cancers, irrespective of BRCA mutation status." Ajit Gill, CEO and founder of Greenfire Bio, commented that "This publication provides further support for the development of our clinical asset GRN-300. We believe this agent has the potential to improve treatment of ovarian and other cancers - both as a single agent and in combination with existing therapies such as the PARP inhibitor olaparib that is indicated for the treatment of ovarian and breast cancers under the tradename Lynparza." These data further support the preclinical proof-of-concept for SIK2 inhibitors as potential cancer therapeutics in combination with carboplatin for hard-to-treat ovarian cancer, recently published in Cancers, and they support the continued efforts in our first-in-human clinical trial ongoing at MD Anderson. About Ovarian Cancer According to the American Cancer Society2, ovarian cancer ranks fifth in cancer deaths among women. They estimate that in 2022 there will be about 19,880 new cases of ovarian cancer diagnosed in the United States and that about 12,810 will die of the disease. According to the World Cancer Research Fund International3, there were about 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early, more treatable stage; therefore, the current lack of salvage treatment for women, who experience a recurrence, results in a 5-year survival rate of less than 30%. About GRN-300 GRN-300 (previously ARN3261) is an orally bioavailable first-in-class novel, small molecule, dual inhibitor of the salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance based on its mechanism of action (MOA) and synergistic effects with standard of care including paclitaxel, carboplatin, PARP inhibitors, and immune checkpoint inhibitors (ICIs). SIK2 is overexpressed in 30% of ovarian cancer specimens suggesting a multifunctional role of SIK2/3 in tumorigenesis. SIK2 and SIK3 are known to play [an] oncogenic role in other tumor types, including prostate cancer, breast cancer, diffuse large B-cell lymphoma, and melanoma. Higher levels of expression of SIK2 have been shown to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth & inhibition in several preclinical xenograft ovarian cancer models as a single agent and in combination with paclitaxel. The clinical activity of GRN-300 as a single agent and in combination with paclitaxel is currently being evaluated in a Phase 1a/1b Clinical Study in subjects with Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers (ClinicalTrials.gov Identifier: NCT04711161). About Greenfire Bio Greenfire Bio, led by a team of experienced biopharma executives, is building a diversified portfolio of oncology products through in-licensing, acquisition, and partnering, and is advancing them through clinical proof of concept. About Green3Bio Green3Bio is a subsidiary of Greenfire Bio. Green3Bio is developing GRN300 through clinical trials with the expertise of Greenfire Bio team members. The currently ongoing clinical trial (ClinicalTrials.gov Identifier: NCT04711161) is sponsored by Green3Bio. 1 J Clin Invest. 2022;132(11):e146471 2 3 CONTACT: Ajit Gill, President and CEO of Greenfire Bio at [email protected]. Website: greenfirebio.com LinkedIn: Facebook: #GreenfireBio, #cancer, #ovariancancer SOURCE Green3Bio

FRISCO, Texas, May 31, 2022 /PRNewswire/ -- Greenfire Bio, LLC announced today that its subsidiary, Green3Bio, and its collaborators at MD Anderson Cancer Center will present an update on the ongoing first-in-human clinical trial of GRN-300 at the upcoming ASCO 2022 Annual Meeting. GRN-300 is a first-in-class, orally bioavailable novel small molecule inhibitor of the Salt Inducible Kinases 2 and 3 (SIK2/SIK3) that is highly expressed in ovarian cancer and has been identified to play a pivotal role in several other cancers. The transition of this emerging biologic pathway and a novel agent into the clinic marks a successful step in the progress of the GRN-300 program. The goal of the clinical study is to determine the recommended Phase 2 Dose (RP2D), safety/tolerability and the tumor response of GRN-300 as a monotherapy or in combination with paclitaxel in subjects with ovarian cancer. This study is registered at ClinicalTrials.gov Identifier: NCT04711161. Format: Poster Presentation Abstract number: TPS5616 Session: Poster Session/Gynecologic Cancer Time: Saturday, June 4, 2022, 1:15 PM-4:15 PM CDT Presenter: Siqing Fu, PhD, MD (Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center) Title: GRN300–001: Phase 1/1b evaluation of the safety, pharmacokinetics and efficacy of GRN-300, a salt-inducible kinase inhibitor, alone and in combination with paclitaxel, in recurrent ovarian, primary peritoneal, and fallopian tube cancers About Ovarian Cancer According to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women. They estimate that in 2022 there will be about 19,880 new cases of ovarian cancer diagnosed in the United States and that about 12,810 will die of the disease. According to the World Cancer Research Fund International, there were about 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early, more treatable stage; therefore, the current lack of salvage treatment for women, who experience a recurrence, results in a 5-year survival rate of less than 30%. About GRN-300 GRN-300 (previously ARN3261) is an orally bioavailable first-in-class novel, small molecule, dual inhibitor of the salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance based on its mechanism of action (MOA) and synergistic effects with standard of care including chemotherapy, PARP inhibitors, and immune checkpoint inhibitors (ICIs). SIK2 is overexpressed in 30% of ovarian cancer specimens suggesting a multifunctional role of SIK2/3 in tumorigenesis. SIK2 and SIK3 are known to play an oncogenic role in other tumor types, including prostate cancer, breast cancer, diffuse large B-cell lymphoma, and melanoma. Higher levels of expression of SIK2 have been shown to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth in several preclinical xenograft ovarian cancer models as a single agent and in combination with paclitaxel. The compound completed the first dose escalation groups without DLT, and preliminary PK analysis indicate dose proportionality. About Greenfire Bio Greenfire Bio, LLC is led by a team of experienced biopharma executives, building a diversified portfolio of oncology products through in-licensing, acquisition, partnering and advancing them through clinical proof of concept.