RGRN-305 / Debiopharm, Curis, BeBetter Med, Regranion, MC2 Therap - LARVOL DELTA

Association of inflammatory skin biomarkers with clinical response in RGRN-305-treated patients with hidradenitis suppurativa. (PubMed, J Eur Acad Dermatol Venereol) - No abstract available

Biomarker • Journal • Dermatology • Hidradenitis Suppurativa • Immunology

Effects of heat shock protein 90 inhibition with RGRN-305/MC2-32 on skin biomarkers in patients with hidradenitis suppurativa (EADV 2024) - P1b | "HSP90 inhibition with oral RGRN-305/MC2-32 was associated with the downregulation of multiple key inflammatory genes and reduced infiltration of immune cells in the skin of hidradenitis suppurativa patients. These findings support that HSP90 inhibition exerts a broad immunomodulation of multiple inflammatory pathways, supporting its potential as a therapeutic strategy for hidradenitis suppurativa."

Biomarker • Clinical • Dermatology • Hidradenitis Suppurativa • Immunology • CDC37 • CXCL5 • CXCL8 • HSP90AA1 • IL17A • IL1B • IL6 • ITGAX • MMP10 • MPO

The heat shock protein 90 inhibitor RGRN-305 attenuates SARS-CoV-2 spike protein-induced inflammation in vitro but lacks effectiveness as COVID-19 treatment in mice. (PubMed, PLoS One) - "This data shows that while RGRN-305 may be helpful in a 'cytokine storm', it has no beneficial impact on viral replication or survival in animals as a monotherapy. Further animal studies with HSP90 inhibitors in combination with an anti-viral drug may provide additional insights into its utility in viral infections and whether HSP90 inhibition may continue to be a potential treatment strategy for COVID-19 disease."

Journal • Preclinical • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • CDC37 • IL1B • IL6

A new TGF-β risk score predicts clinical and immune landscape in colorectal cancer patients. (PubMed, Ann Gastroenterol Surg) - "The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV-939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC-305 and by-product of CUDC-305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven. A CRC risk prognostic signature was developed on basis of TGF-β-related genes, which provides a reference for risk and further therapeutic selection of CRC patients."

IO biomarker • Journal • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RBL1 • TGFB1 • TGFB2 • TMB

Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line. (PubMed, Med Oncol) - "The results revealed that XL-888 and Debio0932 had a role in regulating many cancer-related pathways such as migration, invasion, metastasis, angiogenesis, and apoptosis in SH-SY5Y cells. In conclusion, it shows that HSP90 inhibitors can be considered as a promising candidate in the treatment of neuroblastoma and resistance to chemotherapy."

Journal • Preclinical • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • CDC37

Combination of navitoclax (Bcl-2 and Bcl-xL inhibitor) and Debio-0932 (Hsp90 inhibitor) suppresses the viability of prostate cancer cells via induction of apoptotic signaling pathway. (PubMed, Med Oncol) - "The results revealed that Navitoclax-Debio-0932 combination potently induced intrinsic apoptotic pathway in PC3 cells rather than using drugs alone. The combined treatment of Navitoclax and Debio-0932 displayed synergistic cytotoxic and apoptotic effects on prostate cancer cells, presenting a promising approach for combination therapy in prostate cancer."

IO biomarker • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • APAF1 • BAX • BCL2 • BCL2L1 • CASP3 • CASP7 • CASP9 • CDC37 • HSP90AA1

Heat shock protein 90 inhibition attenuates inflammation in models of atopic dermatitis: a novel mechanism of action. (PubMed, Front Immunol) - "Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNγ or TNF/IL-4) and a mouse model established by MC903 applications. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model. HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • CCL2 • CCL22 • IFNG • IL13 • IL1B • IL4 • IL6 • STAT3 • STAT6 • TSLP

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial. (PubMed, JAMA Dermatol) - P1b | "The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. ClinicalTrials.gov Identifier: NCT05286567."

Clinical • Journal • Dermatology • Hidradenitis Suppurativa • Immunology • Pain

MC2 Therapeutics Announces Positive Phase 2a Results of Novel HSP90 Inhibitor for Hidradenitis Suppurativa Presented at EADV (BioSpace) - '"Inhibiting HSP-90 leads to the inhibition of multiple inflammatory pathways related to HS not just IL-17, while the exceptional pharmacological properties provide a remarkably favorable safety profile. We believe that MC2-32's broad spectrum approach combined with oral delivery will propel the product to best in class status in the HS field,' said Professor Lars Iversen..."

Media quote

MC2 Therapeutics Announces Positive Phase 2a Results of Novel HSP90 Inhibitor for Hidradenitis Suppurativa Presented at EADV (GlobeNewswire) - P=2a | N=NA | "MC2 Therapeutics...announced presentation of highly positive Phase 2a data from MC2-32 (previously RGRN-305), its recently acquired novel HSP90 inhibitor for the treatment of hidradenitis suppurativa (HS), in a late-breaking news session at EADV....The primary endpoint, HiSCR50 at week 16 was achieved by 6 out of 10 patients in the MC2-32 group versus 1 out of 5 patients in the placebo group. The harder-to-reach HiSCR75 and HiSCR90 were achieved by 5 and 3 patients out of 10 in the MC2-32 treated group, respectively whereas none in the placebo group achieved HiSCR75 and HiSCR90 responses."

Late-breaking abstract • P2a data • Hidradenitis Suppurativa • Immunology

MC2 Therapeutics Acquires Option to Phase 2 Oral Drug Candidate for Hidradenitis Suppurativa and Other Indications (MC2 Therapeutics Press Release) - "MC2 Therapeutics announced today that it has acquired option rights from Regranion, LLC to exclusively license Regranion’s RGRN-305 for the treatment of all human diseases, incl, oral treatment of HS globally, excluding the greater China region. RGRN-305 is an orally administered new chemical entity in preparation for clinical phase 2b. Under the agreement, Regranion will receive an upfront option payment with additional development and sales milestones as well as royalties, once MC2 Therapeutics exercises its option."

Licensing / partnership • Hidradenitis Suppurativa • Immunology

MC2 Therapeutics Acquires Option to Phase 2 Oral Drug Candidate for Hidradenitis Suppurativa and Other Indications - '"During my time as Chair Professor of Dermatology at Aarhus University Hospital I had the chance to work with RGRN-305 and I was encouraged by the positive biological effects that RGRN-305 demonstrated both in cell cultures and in clinical trials in humans. The project is a perfect match to the MC2 pipeline, and I am very pleased to be able to further explore the major potential of this compound.' said Lars Iversen, CMO of MC2 Therapeutics."

Media quote

A double-blind, placebo-controlled, randomised trial evaluating the efficacy and safety of a HSP90 inhibitor (RGRN-305) in hidradenitis suppurativa: a novel mechanism of action (EADV 2023) - P1b | "RGRN-305 treatment resulted in a clinically meaningful improvement in hidradenitis suppurativa with a favourable safety profile. Thus, our proof-of-concept study demonstrates HSP90 inhibition may be a novel mechanism of action in treating hidradenitis suppurativa, presenting a potential treatment, which warrants further clinical investigation."

Clinical • Late-breaking abstract • Dermatology • Hidradenitis Suppurativa • Immunology • Inflammation • Pain

Heat shock protein 90 inhibitor RGRN-305 potently attenuates skin inflammation. (PubMed, Front Immunol) - "In summary, HSP90 inhibition robustly suppressed TPA-induced inflammation by targeting key proinflammatory cytokines and signaling pathways. Our findings suggest that HSP90 inhibition may be a novel mechanism of action for treating immune-mediated skin disease beyond psoriasis, and it may be a topical treatment option."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • CXCL8 • IL17A • IL1B • IL6 • JUN • NF-κβ

A Double-blind Placebo-controlled Randomized Trial Evaluating the Efficacy and Safety of a Novel HSP90 Inhibitor (RGRN-305) in the Treatment of Moderate to Severe Hidradenitis Supppurativa. (clinicaltrials.gov) - P1b | N=15 | Completed | Sponsor: Aarhus University Hospital | Recruiting ➔ Completed

Trial completion • Dermatology • Hidradenitis Suppurativa

Heat Shock Protein 90 Inhibitor Attenuates Inflammation Induced by 12-O-tetradecanoylphorbol-13-acetate in Primary Human Keratinocytes and Mice (ESDR 2022) - "Also, the inhibitory effect of RGRN-305 was associated with reduced expression of proinflammatory cytokines (TNFα, IL-1β, IL-6, IL-17A) in the ear tissue. In summary, inhibition of HSP90 mediates a robust antiinflammatory effect, providing a potential therapeutic strategy for the management of autoimmune skin diseases."

Preclinical • Dermatitis • Dermatology • Immunology • Inflammation • CXCL8 • IL17A • IL1B • IL6 • JUN • TNFA

[VIRTUAL] METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy (EANO 2021) - "DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery... Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere."

Clinical • Brain Cancer • Oncology • Solid Tumor

[VIRTUAL] METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy (EACR 2021) - "DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery...Conclusion Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere."

Clinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

[VIRTUAL] METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy (EACR 2021) - "DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery...Conclusion Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere."

Clinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

[VIRTUAL] METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy (EACR 2021) - "DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery...Conclusion Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere."

Clinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

[VIRTUAL] METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy (EACR 2021) - "DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery...Conclusion Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere."

Clinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

Debio-0932, a second generation oral Hsp90 inhibitor, induces apoptosis in MCF-7 and MDA-MB-231 cell lines. (PubMed, Mol Biol Rep) - "Debio-0932 decreased the migration of HUVEC cells as compared to the control group. These results indicate that Debio-0932 is a promising compound to treat triple-negative breast cancer and hormone receptor-positive breast cancer, and their metastases."

IO biomarker • Journal • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BAX • BCL2 • CASP9

Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90 inhibitor Debio0932. (PubMed, Acta Crystallogr D Struct Biol) - "Additionally, Debio0932 suppressed cell proliferation (IC values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HSP90AA1

A phase I-II evaluation of the safety and efficacy of the oral HSP90 inhibitor Debio 0932 in combination with SOC in first- and second-line therapy of Stage IIIb or IV NSCLC - the HALO study (HSP90 inhibition And Lung cancer Outcomes) (ELCC 2012) - Presentation time: Thursday, April 19, 2012; 8:00 AM - 7:30 PM; P1/2, N=138; Debio 0932-101; This international multi-center study will investigate the role of Debio 0932 in the first- and second line treatment of advanced NSCLC; Study results are expected in 2014

Anticipated P1/2 data • Clinical trial design • Non Small Cell Lung Cancer • Oncology

The Safety and Efficacy of a Novel HSP90 Inhibitor (CUDC-305) in the Treatment of Moderate to Severe Psoriasis. (clinicaltrials.gov) - P1b; N=16; Recruiting; Sponsor: Aarhus University Hospital; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open