Amnolake (tamibarotene) / Nippon Shinyaku, Zeria Pharma, RaQualia, Ohara Pharma, Rege Nephro - LARVOL DELTA

Durability of complete response outperforms complete response rates as a surrogate endpoint for advancing to phase III trials in high-risk myelodysplastic syndromes (ASH 2025) - "The HMA plus venetoclax cohort (n=59) had a CRrate of 11.9% (7/59) with 8.5% (5/59) durable CR, equating to 71% (5/7) of CRs durable. Clinical trial pts(n=41) receiving HMA plus novel agents (magrolimab, eprenetapopt, or tamibarotene) had a higher CRrate of 29.3% (12/41) with 24.4% (10/41) durable CR, translating into 83% (10/12) of CRs being durable.In subgroup analysis of pts with TP53-mutated MDS treated with HMA alone (n=242), achieving a durableCR was associated with a 38% reduction in risk of death (HR 0.62; 95% CI 0.39–0.97; p=0.037). Only durable CR translates into a survival benefit in HR-MDS. CR >6 months is a practical, clinicallymeaningful surrogate endpoint and may improve assessment of treatment efficacy and accelerate drugdevelopment in HR-MDS."

Clinical • P3 data • Hematological Malignancies • Myelodysplastic Syndrome • TP53

The conundrum of drug development in higher-risk MDS: Lessons learned from recently failed phase 3 clinical trials. (PubMed, Blood) - "Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials."

Journal • P3 data • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Polyethyleneimine-Assisted Fabrication of Poly(Lactic-Co-Glycolic Acid) Nanoparticles Loaded with Tamibarotene (Am80) for Meflin Expression Upregulation. (PubMed, J Funct Biomater) - "The nanoparticles upregulated Meflin expression in human fibroblasts (fHDF/TERT166 cells). These results suggest the potential of Am80-PLGA nanoparticles as a new intravenous anti-tumor drug that can improve the tumor microenvironment, thereby enhancing the efficacy of chemotherapy and immunotherapy."

IO biomarker • Journal • Oncology

Progress in Higher-Risk Myelodysplastic Syndromes (SOHO 2025) - P3 | "15 Nonetheless, the current treatment landscape for HR-MDS is limited to HMA monotherapy, either parenteral (azacitidine or decitabine) or a more recently available oral option (decitabine/cedazuridine), followed by allogeneic hematopoietic stem cell transplant when feasible, based on patient fitness and donor availability...Eprenetapopt 18,19 (P53-refolding agent), pevonedistat 20 (NEDD8 inhibitor), sabatolimab, 21 magrolimab 22 (anti-CD47 monoclonal antibody promoting macrophage-induced phagocytosis), and most recently, tamibarotene (a retinoid) (DeZern et al accepted Blood Advances 2025) were all once drugs many hematologists hoped could alter the course of disease beyond the current limited armamentarium available in HR-MDS...Conclusions Given an increased understanding of disease biology, improved efforts at predicting outcomes based on baseline genetic alterations, the development of more pragmatic response criteria, and the investigation of novel..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

Tamibarotene promotes differentiation of neuroblastoma SH-SY5Y cells into neurons, which is associated with activation of the PI3K/AKT signaling pathway. (PubMed, BMC Neurosci) - "Tamibarotene, a synthetic retinoid used in the treatment of acute promyelocytic leukemia, has been reported to induce differentiation in the SH-SY5Y cell line into neurons. Inhibition of the PI3K/Akt signaling pathway using LY294002 resulted in a decreased efficacy of AM80-induced differentiation in SH-SY5Y cells, along with downregulation of neuronal marker expression. These findings suggest that Am80 can effectively promote the differentiation of SH-SY5Y cells into neurons and reduce the proliferation of neuroblastoma cells, which is related to the PI3K/AKT pathway, providing a good model for the study of nervous system diseases."

Journal • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Solid Tumor • CNR1 • CXCR4 • NTRK2

RIG-I-Inducing Small Molecules Potently Inhibit HMA-Resistant AML Through Igniting the Overloaded dsRNA Arsenal. (PubMed, Adv Sci (Weinh)) - "A library of potential RIG-I-inducing compounds is rationally constructed and screened, in which the approved M3 AML treatment drug tamibarotene (TAM) exhibits strikingly 28036-fold selectivity and 779 pm IC50 in killing HMA-resistant AML cells. ATRA and TAM do not selectively inhibit p53-mutant cancer cells. Together, this study uncovers a common resistance mechanism in HMA-treated AML patients and, in addition, provides highly potent and selective agents that can overcome resistance through re-triggering IFN anticancer immune response."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

SINGLE-CELL PROFILING IDENTIFIES LEUKEMIC STEM CELL SUBTYPES LINKED TO ATRA SENSITIVITY IN RAS MUTANT ACUTE MYELOID LEUKEMIA (EHA 2025) - "Although their prognostic significance remains unclear, RASmut has emerged as a mechanism of resistance to venetoclax (VEN)...Functionally, overexpression of NRAS G12D (RASOE) in HEL cells (RASwt) conferred VEN resistance while significantly increasing sensitivity to NAMPT inhibitors, ATRA, and tamibarotene... In conclusion, we demonstrate that the LSPC profile of RASmut AML is linked to distinct mutational landscapes that dictate sensitivity to ATRA. These findings provide insight into the potential therapeutic use of ATRA in VEN-resistant AMLs."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • BCL2 • BCL2A1 • BCOR • BCORL1 • CD14 • CD34 • CEBPA • FLT3 • ITGAM • KIT • KRAS • MCL1 • NAMPT • NPM1 • NRAS • PTPRC • RAS • STAG2 • TP53

POTENTIATION OF RETINOID-INDUCED DIFFERENTIATION IN ACUTE MYELOID LEUKEMIA CELLS VIA NRF2 ACTIVATION (EHA 2025) - "ATRA-based differentiation therapy has revolutionized the outcome of acute promyelocytic leukemia (APL), and the RARα-selective retinoid tamibarotene (TMB) showed similar effects...We have demonstrated that the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor by electrophilic agents, e.g., carnosic acid (CA) or monomethyl fumarate (MMF; Bafiertam)], synergistically enhances non-APL AML cell differentiation induced by vitamin D derivatives... Further mechanistic and translational studies are expected to support the therapeutic potential of the above combinations in AML, particularly for patients with increased Nrf2 expression or activity, who often show poor responses to chemotherapy."

Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ITGAX • NFE2L2 • NQO1 • RARA

Little to show for much effort and investment: An industry perspective on MDS drug development (MDS 2025) - "Randomized studies incorporated lenalidomide, vorinostat, entinostat (MS-275), durvalumab, valproic acid, idarubicin, eltrombopag, pevonedistat (MLN4924), eprenetapopt (APR-246), sabatolimab (MBG453), magrolimab (Hu5F9-G4), or tamibarotene (SY-1425)...While the approval of luspatercept and imetelstat for lower-risk patients provides a glimmer of hope, this track record of failure in higher-risk MDS is enough to make a prudent investor or senior pharmaceutical executive think twice before committing further resources to development in this difficult group of diseases...Nor is it because the existing therapies are so good that they're hard to beat, although the practice of giving a few cycles of azacitidine or decitabine in local clinics before referring a patient to a trial center has been an unfortunate barrier to accrual...In this session I will discuss some potential fixes for a few of these problems. But solutions to other barriers are less clear, and will require..."

Acute Myelogenous Leukemia • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • FLT3 • TP53

Tamibarotene-Loaded Nanoemulsion Incorporating Toll-like Receptor 2/6 Agonist as an Intramuscular Adjuvant System Enhances Gastrointestinal Mucosal Immunity. (PubMed, ACS Nano) - "Immunization with recombinant intimin using TB/P2C-NE as the adjuvant resulted in a robust protective effect against the EHEC O157:H7 challenge. In summary, TB/P2C-NE offers an adjuvant strategy potentially accelerating the development of vaccines targeting gastrointestinal infections."

IO biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • IL6 • TLR2

Pivotal Results of SELECT-MDS-1 Phase 3 Study of Tamibarotene with Azacitidine in Newly Diagnosed Higher-Risk MDS. (PubMed, Blood Adv) - P3 | "The use of tamibarotene-based therapy to target RARα as a novel approach in HR-MDS pts with RARA gene overexpression is not a paradigm which can augment response rates beyond HMA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted."

Journal • P3 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • RARA

Rege Nephro Acquires Tamibarotene-Related Assets from Syros Pharmaceuticals for U.S. Clinical Trials (PRNewswire) - "Rege Nephro Co., Ltd....has announced that it has successfully acquired Tamibarotene-related clinical and non-clinical assets from Syros Pharmaceuticals, Inc...through a mutual agreement. The acquisition was completed on February 26, 2025...Tamibarotene (RN-014) is a retinoic acid receptor agonist for which Rege Nephro is currently conducting a Phase 2 clinical trial in Japan in autosomal dominant polycystic kidney disease (ADPKD). Rege Nephro expects to initiate clinical trials in the United States, after confirming the efficacy and safety in Japan. Syros Pharmaceuticals has previously carried out a Phase 3 clinical trial of Tamibarotene for indications including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)."

Commercial • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • Polycystic Kidney Disease

SELECT MDS-1: Tamibarotene Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P3 | N=246 | Terminated | Sponsor: Syros Pharmaceuticals | N=550 ➔ 246 | Trial completion date: Feb 2029 ➔ Nov 2024 | Recruiting ➔ Terminated; As per Sponsor decision, the study was terminated.

Enrollment change • Trial completion date • Trial termination • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Caenorhabditis Intervention Testing Program: all-trans retinoic acid-related compounds tamibarotene and bakuchiol do not extend lifespan in Caenorhabditis nematodes. (PubMed, MicroPubl Biol) - "Additionally, bakuchiol was broadly toxic at higher doses. These findings highlight the specificity of atRA's longevity effects and suggest that compounds related to atRA may not universally promote lifespan extension."

Journal

SELECT-AML-1: Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P2 | N=66 | Terminated | Sponsor: Syros Pharmaceuticals | N=95 ➔ 66 | Trial completion date: Apr 2028 ➔ Aug 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2028 ➔ Aug 2024; As per sponsor decision, the study was terminated.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Study of Tamibarotene in Patients With ADPKD (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Rege Nephro Co., Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Drug repositioning based on mutual information for the treatment of Alzheimer's disease patients. (PubMed, Med Biol Eng Comput) - "The results also highlight the diagnostic role of the 25 genes since we obtained good classification performances using a neural network model. We also suggest 12 repurposable drugs (like KU-60019, AM-630, CP55940, enflurane, ginkgolide B, linopirdine, apremilast, ibudilast, pentoxifylline, roflumilast, acitretin, and tamibarotene) interacting with 6 genes (ATM, CNR1, GLRB, KCNQ2, PDE4B, and RARA), that we linked to retrograde endocannabinoid signaling, synaptic vesicle cycle, morphine addiction, and homologous recombination."

Journal • Alzheimer's Disease • CNS Disorders • Psychiatry • ATM

Tamibarotene directly targets the NACHT domain of NLRP3 to alleviate acute myocardial infarction. (PubMed, Biochem Pharmacol) - "In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • Myocardial Infarction • NLRC5 • NLRP3

Abundance of Relapse-Predictive Cells Can be Estimated at Diagnosis and Is Strongly Associated with Outcome in Pediatric AML (ASH 2024) - "Patient-derived xenograft (PDX) models were treated with cytarabine (50 mg/kg/dose) or saline on days 1-4...The RARA/RXRA complex represses transcription in the absence of retinoic acid; transcription can be activated by the agonist tamibarotene (tami)...We validated the association of these cell types with chemoresistance in PDX models. We identified retinoic acid receptor agonism as a potential strategy to deplete one of these cell types."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Pediatrics • CDK6 • FLT3 • KMT2A

Population Pharmacokinetics of Tamibarotene in Pediatric and Young Adult Patients with Recurrent or Refractory Solid Tumors. (PubMed, Curr Oncol) - "In the final model, the body surface area was included as a covariate for apparent total body clearance, the central compartment volume of distribution, and the peripheral compartment volume of distribution. Visual prediction checks and bootstrap analysis confirmed the validity and predictive accuracy of the final model as satisfactory."

Journal • PK/PD data • Oncology • Pediatrics • Solid Tumor

Syros Announces Topline Data from SELECT-MDS-1 Phase 3 Trial of Tamibarotene in Higher-Risk Myelodysplastic Syndrome with RARA Gene Overexpression (Businesswire) - P3 | N=550 | SELECT MDS-1 (NCT04797780) | Sponsor: Syros Pharmaceuticals | "In the first 190 enrolled patients, the CR rate by intent-to-treat (ITT) in the tamibarotene/azacitidine treatment arm was 23.8% (n=126; 95% CI: 16.7%-32.2%) compared to a CR rate of 18.8% (n=64; 95% CI: 10.1%-30.5%) in the placebo/azacitidine control arm and was not statistically significant (p-value = 0.2084). In the safety analysis of all enrolled patients (n=245), tamibarotene in combination with azacitidine (n=160) appeared to be generally well-tolerated, with an adverse event profile that was similar to that seen in earlier Syros-sponsored studies.....SELECT-MDS-1 did not meet its primary endpoint. Company to discontinue study, review full data set, and evaluate next steps."

P3 data • Trial termination • Myelodysplastic Syndrome

Syros Reports Third Quarter 2024 Financial Results and Provides a Business Update (Businesswire) - "'We expect to announce topline results from the pivotal SELECT-MDS-1 Phase 3 trial in mid-November, and if successful, we plan to file our first New Drug Application (NDA) and to launch tamibarotene in the U.S.,'..."

P3 data: top line • Myelodysplastic Syndrome

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene. (PubMed, Angew Chem Int Ed Engl) - "Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N-benzylfuranamide by 1.2-fold, and F33L gave a 4-fold increase in conversion to tamibarotene."

Journal • Hematological Malignancies • Leukemia • Oncology

Synergistic Effects of the RARalpha Agonist Tamibarotene and the Menin Inhibitor Revumenib in Acute Myeloid Leukemia with KMT2A Rearrangement or NPM1 Mutation (DGHO 2024) - "The effect of the menin inhibitor revumenib in KMT2Ar or NPM1c AML cells is significantly improved by the combination with tamibarotene. Both pronounced induction of differentiation or rapid induction of apoptosis by revumenib and tamibarotene represent promising strategies for patients with molecularly defined relapsed or refractory AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK6 • CEBPA • KMT2A • NPM1 • RARA

SELECT-AML-1: Phase 2 Randomized Trial of Tamibarotene in Combination With Venetoclax and Azacitidine in Adult Patients With Previously Untreated AML With RARA Overexpression, Who Are Ineligible for Standard Induction Therapy (SOHO 2024) - P2 | "Tami-ven-aza demonstrated high CR/CRi rate and rapid onset of response in AML with RARA overexpression as a biomarker target. The combination was well tolerated with no new safety signals or increased myelosuppression compared with ven-aza. Data from a future prespecified interim analysis including at least 50% enrollment will be presented."

Clinical • Combination therapy • P2 data • Acute Myelogenous Leukemia • Oncology