Galunisertib (DB11911): A Comprehensive Oncological and Pharmacological Review from Preclinical Promise to Clinical Discontinuation

Executive Summary

This report provides an exhaustive analysis of Galunisertib (LY2157299), a first-in-class, orally bioavailable, small molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor I kinase (TGF-βRI/ALK5), developed by Eli Lilly and Company. Galunisertib emerged from a strong preclinical rationale, demonstrating potent, on-target inhibition of the canonical TGF-β/SMAD signaling pathway. This mechanism conferred broad anti-tumor, anti-fibrotic, and critically, immunomodulatory effects in a range of preclinical models, positioning it as a promising agent against cancers where TGF-β is a key driver of progression, such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. A significant early success of the development program was the proactive mitigation of a severe preclinical cardiac toxicity signal through the implementation of a sophisticated pharmacokinetic/pharmacodynamic (PK/PD)-driven intermittent dosing regimen (14 days on/14 days off). This strategy proved effective in clinical trials, rendering the drug safe and tolerable for human administration.

Despite this developmental success and a compelling scientific basis, the clinical translation of Galunisertib's preclinical promise was largely unsuccessful in the context of advanced solid tumors. Phase II clinical trials in both newly diagnosed and recurrent glioblastoma, as well as in refractory metastatic pancreatic cancer, failed to demonstrate a meaningful clinical benefit, with no improvement in primary survival endpoints. These disappointing outcomes stand in stark contrast to the more encouraging results observed in a Phase II study for very low- to intermediate-risk myelodysplastic syndromes (MDS), where Galunisertib monotherapy led to clinically significant rates of hematologic improvement and transfusion independence. This divergence underscores the highly context-dependent nature of TGF-β signaling, where inhibiting its myelosuppressive effects in a hematologic malignancy proved more tractable than reversing its complex, pro-tumorigenic role within the entrenched microenvironment of advanced solid tumors.

Ultimately, based on the totality of the clinical data, Eli Lilly discontinued the development of Galunisertib in January 2020 as part of a strategic portfolio prioritization. The story of Galunisertib serves as a critical case study in modern oncology, illustrating the profound challenges of targeting a pleiotropic pathway with a dual role in cancer. It highlights that even a well-designed drug with a validated mechanism and a successfully managed safety profile can fail if the biological context of the disease is not amenable to single-pathway inhibition. The program's legacy lies in the invaluable clinical data it generated, which has profoundly informed the ongoing development of next-generation TGF-β inhibitors and reinforced the strategic imperative for rational combination therapies and biomarker-driven patient selection in this complex therapeutic area.

Section 1: Molecular and Chemical Profile

1.1 Identification and Nomenclature

Galunisertib is a small molecule compound that has been identified and classified under several names and codes throughout its development and investigation.

• Primary Name: Galunisertib.[1]
• International Nonproprietary Name (INN): The officially recognized non-proprietary name is galunisertib.[2]
• Developmental Code Names: The compound was developed by Eli Lilly and Company under the code LY2157299. It is frequently specified in literature as LY2157299 monohydrate, reflecting the crystalline form used in clinical trials.[1]
• DrugBank ID: The compound is cataloged in the DrugBank database with the accession number DB11911.[8]
• CAS Registry Number: The unique Chemical Abstracts Service (CAS) number for the anhydrous form is 700874-72-2.[1]
• Chemical Class: Galunisertib belongs to the dihydropyrrolopyrazole class of heterocyclic compounds.[16] Based on its functional groups, it is further classified as a quinoline carboxamide.[17]

1.2 Physicochemical Properties

The physicochemical properties of Galunisertib define its behavior in biological systems and are critical for its formulation as an oral therapeutic.

• Type: Galunisertib is classified as a Small Molecule drug.[4]
• Molecular Formula: The chemical formula for the anhydrous compound is C22​H19​N5​O.[1]
• Molecular Weight: The average molecular weight of the anhydrous form is 369.43 Da. The batch-specific molecular weight can vary slightly due to the degree of hydration, which is an important consideration for preparing stock solutions for research and clinical use.[1]
• Chemical Name (IUPAC): The systematic IUPAC name for the molecule is 4-pyrazol-3-yl]-6-quinolinecarboxamide.[15]
• Physical Form: At room temperature, Galunisertib is a solid.[1]
• Purity: For research and clinical purposes, the compound is typically supplied at a high purity of ≥98%, as confirmed by methods such as Nuclear Magnetic Resonance (NMR) or High-Performance Liquid Chromatography (HPLC).[1]
• Solubility: Galunisertib exhibits poor aqueous solubility (0.0112 mg/mL), a common characteristic of orally administered small molecules that necessitates careful formulation strategies to ensure adequate bioavailability.[17] It is readily soluble in organic solvents like dimethyl sulfoxide (DMSO), with solubility reported up to 25 mg/mL.[1]

1.3 Synthesis and Solid-State Chemistry

The manufacturing process and solid-state characteristics of an active pharmaceutical ingredient are fundamental to its development, stability, and clinical performance.

• Chemical Synthesis: The synthesis of Galunisertib has been described, culminating in the formation of the desired monohydrate crystal form. The key final step involves the hydrolysis of the nitrile precursor, 4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carbonitrile. This reaction is carried out in N-methylpyrrolidinone (NMP) using aqueous sodium hydroxide at an elevated temperature range of 73–77 °C. Upon completion of the reaction, a controlled cooling and seeding process is initiated to induce crystallization. The final product, Galunisertib monohydrate, is isolated as an off-white solid with high HPLC purity (≥99.8%) and a yield of approximately 89%.[20]
• Solid-State Complexity (Polymorphism): Galunisertib presents a highly complex solid-form landscape, a factor that introduces significant risk and complexity into pharmaceutical development. It is characterized as a "prolific solvate former," with research identifying more than 50 distinct solvated crystal forms in addition to at least 10 neat (unsolvated) polymorphs.[21] Polymorphism, the ability of a compound to exist in multiple crystalline forms, is a critical concern because different polymorphs can possess different physicochemical properties, including stability, solubility, dissolution rate, and bioavailability. The unexpected appearance of a more stable, less soluble "late-appearing" polymorph during late-stage development or post-commercialization can have devastating consequences, potentially rendering a drug product ineffective or unsafe and invalidating years of research.

To mitigate this risk, an extensive solid-form screening was conducted for Galunisertib, employing state-of-the-art experimental techniques and computational crystal structure prediction (CSP).[21] This comprehensive investigation was not merely an academic exercise but a crucial strategic step to de-risk the program. Based on this work, the monohydrate form was selected for clinical development due to its favorable combination of thermodynamic stability, ease of crystallization, and suitable solid-state properties.[21] This decision reflects a pragmatic approach to managing the inherent risks associated with a molecule exhibiting such complex solid-state behavior.

Section 2: Pharmacological Profile: Targeting the TGF-β Signaling Axis

2.1 The TGF-β Pathway: A Dual-Edged Sword in Oncology

The Transforming Growth Factor-beta (TGF-β) signaling pathway is a central regulator of a vast array of fundamental biological processes, including cellular proliferation, differentiation, apoptosis, motility, and immune regulation.[4] Its role in cancer is profoundly paradoxical, embodying a "dual-edged sword" that complicates therapeutic intervention.

In normal tissues and during the early stages of tumorigenesis, the TGF-β pathway functions as a potent tumor suppressor. It achieves this primarily by inhibiting cell cycle progression, thereby acting as a crucial brake on uncontrolled cell proliferation.[23] However, as tumors evolve and progress to more advanced stages, cancer cells frequently acquire mutations or epigenetic alterations that render them resistant to these cytostatic effects. At this point, the pathway undergoes a functional switch, transforming into a powerful

tumor promoter. In this advanced context, elevated TGF-β signaling drives many of the hallmarks of cancer. It promotes tumor cell invasion and metastasis, largely by inducing a process known as epithelial-mesenchymal transition (EMT). Furthermore, it stimulates angiogenesis (the formation of new blood vessels to supply the tumor), induces fibrosis (the deposition of extracellular matrix that can form a physical barrier), and, critically, orchestrates a profoundly immunosuppressive tumor microenvironment (TME) that allows the cancer to evade destruction by the host immune system.[4] This complex, context-dependent duality is the central challenge for any therapeutic agent designed to target this pathway.

2.2 Mechanism of Action of Galunisertib

Galunisertib was designed to specifically and potently intercept the TGF-β signaling cascade at a key nodal point.

• Primary Target: Galunisertib is an orally bioavailable, small molecule inhibitor that is highly potent and selective for the kinase domain of the TGF-β receptor I (TGF-βRI), which is also known as Activin receptor-like kinase 5 (ALK5).[1]
• Molecular Mechanism: The drug functions as an ATP-mimetic inhibitor. It competitively binds to the ATP-binding pocket within the intracellular kinase domain of TGF-βRI/ALK5.[1] The canonical activation of the pathway begins when a TGF-β ligand binds to the TGF-β receptor II (TGF-βRII), which then recruits and phosphorylates TGF-βRI. By occupying the ATP-binding site, Galunisertib prevents this transphosphorylation and subsequent activation of the TGF-βRI kinase.[4]
• Downstream Effect: The primary consequence of TGF-βRI kinase inhibition is the blockade of downstream signaling through the canonical SMAD pathway. Activated TGF-βRI normally phosphorylates the receptor-regulated SMADs (R-SMADs), specifically SMAD2 and SMAD3. Galunisertib's action directly prevents this phosphorylation event. This, in turn, abrogates the formation of a heterotrimeric complex between phosphorylated SMAD2/3 and the common-mediator SMAD (co-SMAD), SMAD4. Without this complex formation, translocation into the nucleus and subsequent regulation of TGF-β target gene transcription are effectively halted.[4]
• Selectivity Profile: Galunisertib exhibits high selectivity for ALK5, with a reported half-maximal inhibitory concentration (IC50​) of approximately 56 nM in cell-free assays.[14] It also demonstrates inhibitory activity against the closely related ALK4 receptor ( IC50​ of 77.7 nM). At higher, submicromolar concentrations, it can also inhibit other kinases in the superfamily, including MINK, TGFβRII, ALK6, and ACVR2B, though its primary therapeutic effect is mediated through ALK5 inhibition.[19]

2.3 Preclinical Pharmacological Effects

The rationale for advancing Galunisertib into clinical trials was built upon a robust body of preclinical evidence demonstrating its multifaceted anti-cancer activities.

• Direct Anti-Tumor and Anti-Metastatic Effects: In numerous in vitro and in vivo models across a range of cancer types—including glioblastoma, hepatocellular carcinoma (HCC), breast, lung, and colon cancers—Galunisertib potently inhibited TGF-β-induced SMAD2 phosphorylation.[4] This on-target activity translated into significant functional consequences, as the drug was shown to prevent TGF-β-mediated EMT, a key process for metastasis, and to inhibit cancer cell migration and invasion.[16] In animal models, these effects contributed to delays in tumor growth.[4]
• Immunomodulatory Effects: A cornerstone of the therapeutic hypothesis for Galunisertib was its ability to counteract the profound immunosuppression orchestrated by TGF-β within the TME. Preclinical studies demonstrated that Galunisertib could reverse TGF-β-mediated suppression of T-cell proliferation.[19] It effectively restored the cytotoxic functions of key anti-tumor immune cells, including CD8+ T-cells and Natural Killer (NK) cells, by blocking the inhibitory signals from TGF-β.[16] Furthermore, it was shown to abrogate the suppressive activity of regulatory T-cells (Tregs), a major cellular mediator of immune tolerance in cancer.[31] These findings provided a strong scientific basis for combining Galunisertib with immunotherapies, such as immune checkpoint inhibitors, with the goal of synergistically unleashing an anti-tumor immune response.
• Anti-Fibrotic Effects: Beyond its direct effects on cancer and immune cells, Galunisertib also showed potential in modulating the tumor stroma. In preclinical models of dermal fibrosis, the drug successfully attenuated fibrotic phenotypes by normalizing the proliferation of TGF-β-activated fibroblasts.[28] This suggested that Galunisertib could potentially disrupt the dense, fibrotic matrix that characterizes many solid tumors (e.g., pancreatic cancer), which acts as a physical barrier to drug delivery and immune cell infiltration.

The compelling and consistent preclinical data painted a picture of a potent, multi-pronged anti-cancer agent. However, the subsequent clinical trials would reveal a significant disconnect between this preclinical promise and the realities of treating complex, advanced human cancers. The eventual failure of Galunisertib in most solid tumor settings, despite its confirmed on-target mechanism, strongly implies that merely blocking the canonical TGF-β/SMAD pathway is insufficient to overcome the deeply entrenched pro-tumorigenic state of these diseases. By the time patients with advanced cancer are treated, the TME has been so profoundly shaped by chronic TGF-β signaling—resulting in extensive fibrosis, stable mesenchymal cell phenotypes, and a deeply rooted network of immunosuppressive cells—that simply "turning off the switch" with a single agent like Galunisertib may be incapable of reversing the cancer's aggressive trajectory. This suggests that the timing of intervention and the need for combination strategies are paramount for successfully targeting this pathway.

Section 3: Clinical Pharmacokinetics and Pharmacodynamics (PK/PD)

3.1 Pharmacokinetic Profile

The clinical pharmacokinetic profile of Galunisertib characterized its absorption, distribution, metabolism, and elimination (ADME) properties in humans, confirming its suitability as an oral agent.

• Administration and Absorption: Galunisertib is an orally bioavailable compound.[5] Following oral administration, it is absorbed relatively quickly, with the time to reach maximum plasma concentration ( Tmax​) occurring approximately 2 hours post-dose.[32]
• Distribution: In human plasma, the fraction of Galunisertib that is unbound to plasma proteins (fu​) is 36%, indicating that a significant portion of the drug is free to distribute into tissues and interact with its target.[2]
• Metabolism and Elimination: The drug exhibits a predictable elimination profile, with a median plasma half-life (t1/2​) of approximately 8 to 9 hours.[2] This half-life supports a twice-daily (BID) dosing regimen to maintain therapeutic concentrations.
• Steady-State Parameters: At the recommended Phase II dose (RP2D) of 150 mg BID, steady-state pharmacokinetic parameters in cancer patients were established as follows:
• Maximum Plasma Concentration (Cmax​): Approximately 800 to 990 ng/mL.[2]
• Area Under the Curve (AUC): Approximately 2930 to 3730 ng·h/mL.[2]
• Drug-Drug Interactions: Clinical studies indicated a favorable drug-drug interaction profile. The pharmacokinetics of Galunisertib were not significantly altered by co-administration with the chemotherapy agent lomustine.[33] Furthermore, its PK profile remained consistent in patients taking concomitant medications known to affect drug metabolism, such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors, suggesting a low potential for clinically relevant metabolic interactions.[34]

3.2 Pharmacodynamics and Biomarker Strategy

A key component of Galunisertib's clinical development was the successful implementation of a pharmacodynamic (PD) biomarker to confirm target engagement and guide dosing.

• Target Engagement Biomarker: The level of phosphorylated SMAD2 (pSMAD2) was identified as the primary biomarker for assessing the biological activity of Galunisertib. Crucially, preclinical studies in rat models demonstrated a strong correlation between the inhibition of pSMAD2 in tumor tissues and the inhibition of pSMAD2 in peripheral blood mononuclear cells (PBMCs).[16] This finding was pivotal, as it validated the use of easily accessible PBMCs as a surrogate tissue for monitoring target engagement in patients, avoiding the need for repeated invasive tumor biopsies.[16]
• Dose-Response Relationship: Clinical studies confirmed that changes in pSMAD2 levels in patient PBMCs were directly associated with Galunisertib exposure, demonstrating on-target pharmacological activity in humans.[34] This allowed for the establishment of a clear concentration-effect relationship and the calculation of the total effective concentration required to inhibit 50% of pSMAD ( TEC50​), providing a quantitative measure of the drug's in vivo potency.[16]

3.3 Rationale for Intermittent Dosing: A PK/PD Success Story

The clinical development of Galunisertib provides a textbook example of how a proactive, model-based approach can successfully navigate a potentially program-ending toxicity signal identified in preclinical studies.

• Preclinical Safety Signal: A major impediment to the development of small molecule inhibitors of TGF-β signaling was a consistent class-wide signal of serious cardiovascular toxicity in animal models upon continuous, long-term exposure. For Galunisertib, these toxicities manifested as histopathologic changes at the heart valves and the development of aneurysms of the ascending aorta.[4] This presented a formidable challenge that had halted the development of previous inhibitors in this class and posed a significant threat to the viability of the Galunisertib program.
• PK/PD Modeling Solution: Rather than abandoning the molecule, the development team at Eli Lilly invested in building a sophisticated PK/PD model to dissect the relationship between drug exposure, target engagement (pSMAD2 inhibition), and the onset of toxicity.[4] The model was designed to identify a "therapeutic window"—a dosing strategy that could maintain plasma concentrations high enough for a sufficient duration to achieve the desired anti-tumor pharmacodynamic effect (i.e., sustained pSMAD2 inhibition) while allowing for a drug-free period to prevent the cumulative exposure believed to drive cardiotoxicity.[4]
• Translation to a Safe Clinical Dosing Regimen: The output of this PK/PD modeling directly informed the design of the clinical dosing schedule. The model predicted that an intermittent dosing regimen of 14 days on followed by 14 days off, administered in a 28-day cycle, would operate within this safe therapeutic window.[4] This strategy was adopted for all subsequent clinical trials of Galunisertib. The success of this approach was unequivocally demonstrated in the clinic; across trials involving over 300 patients, extensive cardiovascular monitoring—including echocardiography, Doppler imaging, and cardiac biomarkers—confirmed the absence of clinically significant Galunisertib-induced cardiac toxicities.[34] This successful de-risking of the compound represents a triumph of translational science, showcasing how a deep understanding of a drug's PK/PD relationship can be leveraged to design intelligent dosing strategies that overcome major safety hurdles.

Section 4: Clinical Efficacy and Development Program: A Multi-Indication Analysis

The clinical development program for Galunisertib was extensive, evaluating its efficacy and safety across a range of malignancies with high unmet need and a strong biological rationale for TGF-β inhibition. The outcomes, however, varied dramatically by indication, painting a complex picture of the drug's therapeutic potential.

Table 1: Summary of Key Clinical Trials for Galunisertib

Trial Identifier	Phase	Indication	Patient Population	Treatment Arms	Primary Endpoint(s)	Key Efficacy Results	Key Conclusion
NCT01220271	Ib/IIa	Newly Diagnosed Glioblastoma (GBM)	WHO Grade III/IV glioma	1. Galunisertib + TMZ/RTX 2. TMZ/RTX alone	Safety, Tolerability, PD Profile	Median OS: 18.2 vs 17.9 mos Median PFS: 7.6 vs 11.5 mos DCR: 80% vs 56%	No improvement in efficacy; addition of Galunisertib did not confer a survival benefit.37
NCT01582269	II	Recurrent Glioblastoma (GBM)	Recurrent GBM	1. Galunisertib + Lomustine 2. Galunisertib Monotherapy 3. Placebo + Lomustine	Overall Survival (OS)	Median OS: 6.7 mos (combo) vs 8.0 mos (mono) vs 7.5 mos (control) Median PFS: ~2 mos (all arms)	Failed to meet primary endpoint; no improvement in OS compared to control.33
NCT02734160	Ib	Metastatic Pancreatic Cancer	Recurrent/refractory, ≤2 prior lines	Galunisertib + Durvalumab (PD-L1i)	Safety, RP2D	ORR: 3.1% (1 PR) DCR: 25.0% Median OS: 5.72 mos Median PFS: 1.87 mos	Tolerable but with limited clinical activity in a heavily pre-treated population.41
NCT02008318	II	Myelodysplastic Syndromes (MDS)	Very low-, low-, intermediate-risk MDS with anemia	Galunisertib Monotherapy	Hematologic Improvement (HI) Rate	HI Rate (IWG 2006): 24.4% Erythroid Response (IWG 2000): 43.9% 32.1% of transfusion-dependent patients had HI	Met primary endpoint; demonstrated meaningful clinical activity and improved anemia.43
NCT01246986	II	Hepatocellular Carcinoma (HCC)	Advanced HCC	Galunisertib + Sorafenib	Efficacy, Safety	Median OS: 18.8 mos (150 mg cohort)	Combination showed prolonged OS compared to historical controls for sorafenib alone.29

4.1 Glioblastoma (GBM): A High Bar Unmet

Glioblastoma, the most aggressive primary brain tumor, is characterized by an immunosuppressive microenvironment enriched with TGF-β, making it a logical but exceptionally difficult therapeutic target.[37] The clinical evaluation of Galunisertib in this setting was comprehensive, spanning both newly diagnosed and recurrent disease, but ultimately yielded disappointing results.

• Phase Ib/IIa Trial (NCT01220271) in Newly Diagnosed GBM: This open-label study was designed to test the hypothesis that adding Galunisertib to the standard-of-care front-line therapy—radiotherapy with concomitant and maintenance temozolomide (TMZ/RTX)—would improve outcomes for patients with newly diagnosed malignant glioma.[37] The results, however, showed no evidence of clinical benefit. The primary efficacy endpoint of median Overall Survival (OS) was virtually identical between the two arms: 18.2 months for the Galunisertib combination versus 17.9 months for TMZ/RTX alone. More concerningly, median Progression-Free Survival (PFS) was numerically worse in the experimental arm (7.6 months) compared to the control arm (11.5 months). While the Disease Control Rate (DCR) was higher with the addition of Galunisertib (80% vs. 56%), this metric did not translate into a tangible survival advantage, leading to the conclusion that the combination was ineffective.[37]
• Phase II Randomized Trial (NCT01582269) in Recurrent GBM: This three-arm, randomized study evaluated Galunisertib in the more challenging setting of recurrent glioblastoma. Patients were randomized to receive either Galunisertib in combination with lomustine, Galunisertib as a monotherapy, or placebo plus lomustine.[33] The trial unequivocally failed to meet its primary endpoint of improving OS. There was no statistically significant difference in survival between the Galunisertib plus lomustine arm (median OS of 6.7 months) and the placebo plus lomustine control arm (median OS of 7.5 months). Galunisertib monotherapy yielded a median OS of 8.0 months, which was also not superior to the control. Furthermore, median PFS was poor across all three arms, at approximately 2 months, indicating a lack of meaningful tumor control.[33]

The consistent and unambiguous failure of Galunisertib in both the front-line and recurrent GBM settings, despite the strong biological rationale, serves as a powerful testament to the resilience of this disease. It suggests that by the time of diagnosis, the role of TGF-β in driving the aggressive phenotype of GBM is either too complex, supported by redundant signaling pathways, or has induced such profound and stable changes in the tumor microenvironment that it cannot be reversed by targeting the ALK5/SMAD2 axis alone.

4.2 Pancreatic Cancer: Limited Clinical Activity

Pancreatic ductal adenocarcinoma (PDAC) is another malignancy with a strong rationale for TGF-β inhibition, characterized by a dense, desmoplastic stroma that is heavily dependent on TGF-β signaling and creates a significant barrier to both drug delivery and immune attack.[45]

• Phase Ib/II Study (JBAJ) with Gemcitabine: An early study combining Galunisertib with gemcitabine in unresectable pancreatic cancer provided a hint of activity, showing a modest improvement in median OS compared to gemcitabine monotherapy (8.9 months vs. 7.1 months). However, the overall response rate (ORR) remained low, suggesting limited efficacy.[42]
• Phase Ib Study (NCT02734160) with Durvalumab: Building on the immunomodulatory rationale, this single-arm study evaluated the combination of Galunisertib with the anti-PD-L1 antibody durvalumab in patients with refractory metastatic pancreatic cancer.[41] The results were discouraging. In this heavily pre-treated population, the combination demonstrated very limited clinical activity. Among 32 evaluable patients, there was only one partial response (ORR of 3.1%). The DCR was 25.0%, with a median OS of just 5.72 months and a median PFS of 1.87 months. While the combination was deemed tolerable, its lack of efficacy led the investigators to conclude that future studies should focus on earlier lines of therapy or utilize predictive biomarkers to select patients more likely to respond.[41] The failure of this combination highlights the immense challenge of overcoming the profoundly immunosuppressive and fibrotic microenvironment of PDAC, suggesting that dual blockade of TGF-β and PD-L1 is insufficient to break immune tolerance in this disease.

4.3 Myelodysplastic Syndromes (MDS): A Glimmer of Hope

In sharp contrast to the results in solid tumors, the investigation of Galunisertib in Myelodysplastic Syndromes (MDS) yielded the most promising clinical data for the program. The rationale in MDS is distinct; it is a disease of bone marrow failure where TGF-β over-activation is a direct cause of the myelosuppression that leads to cytopenias, particularly anemia.[43] Therefore, inhibiting TGF-β is hypothesized to restore normal hematopoiesis by "releasing the brakes" on hematopoietic stem and progenitor cells.

• Phase II Study (NCT02008318) in Lower-Risk MDS: This single-arm monotherapy study enrolled patients with very low-, low-, or intermediate-risk MDS who were suffering from anemia.[43] The trial successfully met its primary objective, demonstrating a clinically meaningful rate of hematologic improvement (HI). According to the stringent International Working Group (IWG) 2006 criteria, 24.4% of evaluable patients achieved an erythroid response. By the less stringent IWG 2000 criteria, the response rate was 43.9%. Critically, among patients who were transfusion-dependent at baseline, 32.1% achieved a significant reduction in their transfusion requirement or became fully transfusion-independent. The drug was also well-tolerated in this population.[43]

This relative success in MDS is a crucial finding. It suggests that the therapeutic utility of TGF-β inhibition is highly dependent on the specific pathophysiology of the disease. In MDS, the pathology is more directly and linearly linked to the canonical, suppressive effects of TGF-β on a specific cell lineage. In this context, Galunisertib's direct mechanism of action was effective. This contrasts with advanced solid tumors, where the pathway's role is far more complex and integrated into a pro-tumorigenic network that may be irreversible with a single agent.

4.4 Hepatocellular Carcinoma (HCC): A Signal in Combination

Hepatocellular carcinoma (HCC) is another cancer type where TGF-β is known to be elevated and associated with disease progression.[46]

• Phase II Study with Sorafenib: A Phase II trial (NCT01246986) evaluated Galunisertib in combination with sorafenib, a multi-kinase inhibitor that was a standard of care for advanced HCC.[29] The results of this study were encouraging, suggesting potential synergy between the two agents. In the cohort receiving the 150 mg dose of Galunisertib, the combination demonstrated a prolonged median OS of 18.8 months. This was a notable improvement over the historical survival outcomes typically observed with sorafenib monotherapy.[45] While not a randomized comparison, this positive signal suggested that combination therapy was the most viable path forward for Galunisertib in solid tumors, potentially by simultaneously targeting angiogenesis (with sorafenib) and the tumor microenvironment (with Galunisertib).

Section 5: Comprehensive Safety and Tolerability Assessment

5.1 Overview of the Safety Profile

Across its extensive clinical development program, Galunisertib demonstrated an acceptable and manageable safety profile, a testament to the successful preclinical PK/PD modeling that guided its dosing strategy.[32] The intermittent dosing regimen (14 days on/14 days off) was well-tolerated whether the drug was administered as a monotherapy or in combination with standard treatments like temozolomide and radiotherapy (TMZ/RTX), with a safety profile comparable to the control arms in randomized studies.[37]

5.2 Common Treatment-Emergent Adverse Events (TEAEs)

The most frequently reported adverse events (AEs) possibly related to Galunisertib were predominantly low-grade (Grade 1 or 2) and manageable with supportive care. These common TEAEs included:

• Fatigue [35]
• Diarrhea [35]
• Pyrexia (fever) [43]
• Nausea and vomiting [43]
• Rash [32]

In the Phase II study in MDS, where Galunisertib was given as a monotherapy, the most common TEAEs of any grade were fatigue (20.5%), diarrhea (15.4%), pyrexia (10.3%), and vomiting (10.3%).[43]

5.3 Serious Adverse Events and Dose-Limiting Toxicities (DLTs)

• Cardiovascular Safety: The paramount safety concern entering clinical development was the potential for cardiotoxicity, based on severe findings in animal models exposed to continuous dosing.[4] However, the implementation of the PK/PD-guided intermittent dosing regimen proved to be a highly effective mitigation strategy. Across clinical trials involving extensive cardiac safety monitoring, no significant, drug-induced cardiovascular toxicities were observed.[34] This successful management of a major preclinical safety signal stands as a key achievement of the Galunisertib development program.
• Dose-Limiting Toxicities (DLTs): Galunisertib exhibited a favorable therapeutic window. In dose-escalation studies, DLTs were generally not observed at or below the recommended Phase II dose (RP2D) of 150 mg BID.[41] For instance, in the Phase Ib study combining Galunisertib with durvalumab, no DLTs were recorded during the dose-escalation phase. The maximum tested dose of 150 mg BID was therefore established as the RP2D, indicating that the maximum tolerated dose (MTD) was not reached within the planned dose levels.[41]
• Other Serious Adverse Events: While the overall profile was favorable, isolated serious adverse events (SAEs) were reported, particularly in studies involving heavily pre-treated patients or in combination with myelosuppressive chemotherapy. These included cases of thromboembolic events, severe thrombocytopenia, and infections.[35] However, in the context of advanced cancer and combination therapies (e.g., with lomustine), definitively attributing causality of these events to Galunisertib was often challenging, as they could be related to the underlying disease progression or the toxicity of the concomitant therapy.[35]

5.4 Contraindications and Exclusions

As a precautionary measure given the preclinical cardiotoxicity signal, patients with pre-existing moderate or severe cardiovascular disease were typically excluded from participation in Galunisertib clinical trials.[37]

Ultimately, the safety profile of Galunisertib did not appear to be the primary factor limiting its development. The successful management of the preclinical cardiac risk demonstrated high-quality, science-driven drug development. This makes the program's subsequent failure on efficacy grounds all the more significant. The story of Galunisertib is not one of a drug that was too toxic to administer, but rather one that, for most indications, was not effective enough to warrant further investment, even with a manageable safety profile.

Section 6: Regulatory Trajectory and Strategic Discontinuation

6.1 Orphan Drug Designations

In recognition of its potential to address high unmet medical needs in rare cancers, Galunisertib was granted orphan drug designation by major regulatory bodies early in its development. This status provides incentives, such as market exclusivity and fee reductions, to encourage the development of drugs for diseases with small patient populations.[49]

• U.S. Food and Drug Administration (FDA): The FDA granted Galunisertib orphan drug designation for two separate indications:
• Treatment of glioma (Designation #389412).[2]
• Treatment of hepatocellular carcinoma (Designation #378712).[2]
• European Medicines Agency (EMA): The EMA also granted orphan designations for similar indications:
• Treatment of glial tumor (granted April 26, 2013).[3]
• Treatment of adult hepatocellular carcinoma (granted March 12, 2013).[3]

Notably, the European designations were later listed as "withdrawn/expired".[3] The withdrawal of an orphan designation can occur for various reasons, including a sponsor's strategic decision to shift development focus or a failure to provide the required annual updates on the medicine's development status.

6.2 Development and Discontinuation by Eli Lilly

• Developer: Galunisertib was discovered and developed by Lilly Research Laboratories, a division of Eli Lilly and Company.[5]
• Clinical Program: Backed by a strong preclinical rationale, Eli Lilly invested significantly in a broad clinical program for Galunisertib. The drug was advanced into multiple Phase II and even Phase II/III studies across a wide spectrum of cancers, including glioblastoma, pancreatic cancer, HCC, and MDS, signaling a high level of initial confidence in the therapeutic potential of the TGF-βRI target.[2]
• Discontinuation: Despite the extensive effort, Eli Lilly officially announced the discontinuation of the Galunisertib development program in January 2020.[50]
• Reason for Discontinuation: The publicly stated reason for halting the program was a strategic portfolio decision to "focus its pipeline on 'higher conviction programs with the greatest potential for patients'".[50] This corporate language typically signifies a rational business decision based on a comprehensive review of the accumulated data. In the case of Galunisertib, the mixed and largely disappointing efficacy results from the key Phase II trials in solid tumors likely failed to meet the high internal bar required to justify the substantial financial investment and risk associated with proceeding to pivotal Phase III studies. The decision was therefore one of portfolio prioritization, reallocating resources away from an asset with a low probability of success toward other, more promising candidates in the company's pipeline.

6.3 Regulatory Status

As a consequence of its developmental discontinuation prior to the completion of pivotal trials, Galunisertib has not received marketing approval from the FDA, EMA, or any other major global regulatory agency.[45] It remains an investigational compound.

The regulatory trajectory of Galunisertib, from the early promise signified by multiple orphan drug designations to its ultimate discontinuation, starkly illustrates the "valley of death" in pharmaceutical R&D. Early regulatory support and incentives are valuable but cannot substitute for compelling clinical efficacy data. A drug must consistently clear progressively higher hurdles of evidence to justify the immense cost and risk of late-stage development. Galunisertib, despite its scientific elegance and well-managed safety, ultimately failed to clear the critical Phase II efficacy hurdle for its primary solid tumor indications, leading to a rational, data-driven decision to terminate the program.

Section 7: Concluding Analysis: The Legacy of Galunisertib and the Future of TGF-β Inhibition

7.1 Synthesizing the Disconnect: Why Did Preclinical Promise Not Translate?

The central question arising from the Galunisertib program is the stark disconnect between its robust preclinical efficacy and its largely negative clinical outcomes in advanced solid tumors. The synthesis of available evidence points to several interconnected factors that likely contributed to this translational failure.

The primary factor is the inherent biological complexity and context-dependent dual role of the TGF-β pathway. Preclinical models, such as cancer cell lines and immunodeficient xenografts, while essential for establishing mechanism of action, often fail to fully recapitulate the intricate and heterogeneous tumor microenvironment (TME) of advanced human cancers.[27] In these simplified systems, Galunisertib's ability to inhibit proliferation and migration was clearly demonstrated. However, in patients with established, treatment-refractory disease, the TME is a complex ecosystem shaped by years of evolution.

This leads to the critical issue of the timing of intervention. By the late stages of cancer, the pro-tumorigenic effects driven by chronic TGF-β signaling—such as extensive stromal fibrosis, entrenched immunosuppressive cellular networks, and stable EMT phenotypes—may become "locked in" or sustained by alternative signaling pathways. At this point, the disease may no longer be dependent on active TGF-βRI signaling, and simply inhibiting the pathway may be "too little, too late" to reverse the aggressive disease state.[27]

Finally, the clinical results strongly suggest that TGF-β inhibitors like Galunisertib are unlikely to be effective as monotherapies in most solid tumors. The modest positive signals observed in combination with sorafenib in HCC, and the strong scientific rationale for combining with immunotherapy, point toward a future where these agents are used not as standalone treatments, but as "TME modulators".[46] Their true value may lie in their ability to break down fibrotic barriers and reverse immunosuppression, thereby priming the tumor to be more susceptible to other therapeutic modalities like checkpoint inhibitors, chemotherapy, or anti-angiogenic agents.[25]

7.2 The Path Forward: Next-Generation Inhibitors and Novel Strategies

While the Galunisertib program did not result in an approved therapy, it was far from a failure in a scientific sense. It provided an invaluable trove of clinical data that has profoundly shaped the ongoing efforts to target the TGF-β pathway. The program successfully validated pSMAD2 in PBMCs as a viable clinical PD biomarker, established a safe intermittent dosing strategy to manage on-target cardiotoxicity, and generated a rich dataset on the clinical activity (or lack thereof) across multiple human cancers.

This knowledge provides a clear roadmap for the future, which is being pursued through the development of next-generation inhibitors and more sophisticated therapeutic strategies.

• Next-Generation Inhibitors (e.g., LY3200882): The development of new agents represents the next logical step. A successor molecule, LY3200882, is a novel, next-generation TGF-βRI inhibitor with a potentially improved pharmacological profile.[58] The first-in-human Phase I study of LY3200882 has already yielded intriguing preliminary results that stand in contrast to Galunisertib's outcomes. In this trial, LY3200882 monotherapy led to durable partial responses in patients with grade 4 glioma—an indication where Galunisertib failed. Furthermore, in combination with standard chemotherapy (gemcitabine and nab-paclitaxel) for treatment-naïve advanced pancreatic cancer, the LY3200882 regimen achieved a 75% disease control rate, including 6 partial responses out of 12 patients.[59] These early signals suggest that a more potent or pharmacologically optimized molecule may be able to achieve a level of efficacy that was unattainable with Galunisertib, rekindling hope for this therapeutic approach.
• Future Strategies: The future of TGF-β inhibition in oncology almost certainly lies in intelligent, rational combination therapies. This includes further exploration of combinations with immune checkpoint inhibitors, anti-angiogenic agents (like ramucirumab or bevacizumab), and standard chemotherapy regimens.[25] A critical element for the success of these future trials will be the development and validation of predictive biomarkers. Identifying which patients' tumors are most dependent on TGF-β signaling will be essential to enrich trial populations and move beyond the one-size-fits-all approach that may have contributed to Galunisertib's failures.[41]

7.3 Final Conclusion

Galunisertib represents a pivotal and informative chapter in the challenging endeavor of targeting the TGF-β pathway in cancer. It was a well-designed molecule that was expertly navigated through the perils of early clinical development, most notably by successfully translating a PK/PD model into a clinical strategy that mitigated a severe, on-target toxicity. Its ultimate failure to deliver compelling efficacy in major solid tumor indications was not a failure of drug design or development execution, but rather a humbling lesson in the profound biological complexity of its target. The legacy of Galunisertib is the wealth of high-quality clinical and translational data it produced. This knowledge has illuminated the immense challenges of targeting a pleiotropic pathway, clarified the critical importance of disease context, and provided a clear and rational roadmap for the future. The quest to effectively drug the TGF-β pathway for cancer therapy continues, now built upon the hard-won lessons from the Galunisertib program, with a renewed focus on next-generation molecules, rational combinations, and biomarker-selected patient populations.

Works cited

1. Galunisertib - BPS Bioscience, accessed September 3, 2025, https://bpsbioscience.com/galunisertib-82601
2. GALUNISERTIB - Inxight Drugs, accessed September 3, 2025, https://drugs.ncats.io/substance/3OKH1W5LZE
3. Galunisertib - Orphanet, accessed September 3, 2025, https://www.orpha.net/en/drug/substance/323215?name=&mode=pat®ion=&status=all
4. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway - PMC - PubMed Central, accessed September 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4539082/
5. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway - PubMed, accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/26309397/
6. LY2157299 CAS 700874-72-2 - United States Biological, accessed September 3, 2025, https://www.usbio.net/biochemicals/366899/LY2157299-LY-2157299-LY2157299-Galunisertib
7. CAS 700874-72-2 | Sigma-Aldrich, accessed September 3, 2025, https://www.sigmaaldrich.com/US/en/search/700874-72-2?focus=products&page=1&perpage=30&sort=relevance&term=700874-72-2&type=cas_number
8. Galunisertib | C22H19N5O | CID 10090485 - PubChem, accessed September 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/10090485?from=summary
9. Galunisertib Completed Phase 1 Trials for Pancreatic Metastatic Cancer Treatment, accessed September 3, 2025, https://go.drugbank.com/drugs/DB11911/clinical_trials?conditions=DBCOND0070216&phase=1&purpose=treatment&status=completed
10. GALUNISERTIB - precisionFDA, accessed September 3, 2025, https://precision.fda.gov/ginas/app/ui/substances/3OKH1W5LZE
11. Galunisertib 700874-72-2 | Tokyo Chemical Industry UK Ltd., accessed September 3, 2025, https://www.tcichemicals.com/GB/en/p/G0639
12. 700874-72-2|4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxamide - BLDpharm, accessed September 3, 2025, https://www.bldpharm.com/products/700874-72-2.html
13. LY2157299 (Galunisertib, CAS Number: 700874-72-2) | Cayman Chemical, accessed September 3, 2025, https://www.caymanchem.com/product/15312/ly2157299
14. Galunisertib (LY2157299) | TGFβRI Inhibitor - MedchemExpress.com, accessed September 3, 2025, https://www.medchemexpress.com/LY2157299.html
15. Galunisertib | C22H19N5O | CID 10090485 - PubChem, accessed September 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Galunisertib
16. Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor | Oncotarget, accessed September 3, 2025, https://www.oncotarget.com/article/23795/text/
17. Galunisertib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 3, 2025, https://go.drugbank.com/drugs/DB11911
18. Galunisertib | C22H19N5O | CID 10090485 - PubChem, accessed September 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/10090485
19. Galunisertib | TGF-β Receptors - Tocris Bioscience, accessed September 3, 2025, https://www.tocris.com/products/galunisertib_6956
20. CAS 700874-72-2 Galunisertib - BOC Sciences, accessed September 3, 2025, https://www.bocsci.com/galunisertib-cas-700874-72-2-item-286402.html
21. A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs | Journal of the American Chemical Society, accessed September 3, 2025, https://pubs.acs.org/doi/10.1021/jacs.9b06634
22. WO2018006870A1 - Galunisertib crystal form and preparation ..., accessed September 3, 2025, https://patents.google.com/patent/WO2018006870A1/en
23. Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor - PMC, accessed September 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5805504/
24. Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy, accessed September 3, 2025, https://www.biomolther.org/journal/view.html?uid=385&vmd=Full
25. Recent Advances in the Development of TGF-β Signaling Inhibitors for Anticancer Therapy, accessed September 3, 2025, https://www.jcpjournal.org/journal/view.html?doi=10.15430/JCP.2020.25.4.213
26. TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells - AACR Journals, accessed September 3, 2025, https://aacrjournals.org/clincancerres/article/23/3/804/80672/TGF-R1-Blockade-with-Galunisertib-LY2157299
27. On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges? - Frontiers, accessed September 3, 2025, https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00605/full
28. Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts - MDPI, accessed September 3, 2025, https://www.mdpi.com/1422-0067/23/12/6689
29. Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from... | Oncotarget, accessed September 3, 2025, https://www.oncotarget.com/article/4308/text/
30. www.tocris.com, accessed September 3, 2025, https://www.tocris.com/products/galunisertib_6956#:~:text=Biological%20Activity%20for%20Galunisertib&text=Inhibits%20TGF%CE%B2%2Dinduced%20SMAD%20phosphorylation,exhibits%20antitumor%20efficacy%20in%20vivo.
31. Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade, accessed September 3, 2025, https://jitc.bmj.com/content/6/1/47
32. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors - PubMed, accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/26526984/
33. A Phase II randomized study of galunisertib monotherapy or ..., accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/26902851/
34. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer - ResearchGate, accessed September 3, 2025, https://www.researchgate.net/publication/270001030_Pharmacokinetic_pharmacodynamic_and_biomarker_evaluation_of_transforming_growth_factor-b_receptor_I_kinase_inhibitor_galunisertib_in_phase_1_study_in_patients_with_advanced_cancer
35. Case Series of Cancer Patients Treated With Galunisertib, a Transforming Growth Factor-Beta Receptor I Kinase Inhibitor in a First-in-Human Dose Study, accessed September 3, 2025, https://www.journalmc.org/index.php/JMC/article/view/1966/html
36. Clinical development of galunisertib - Video abstract 86621 - YouTube, accessed September 3, 2025, https://www.youtube.com/watch?v=cN-vG9YO22I
37. (PDF) Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma - ResearchGate, accessed September 3, 2025, https://www.researchgate.net/publication/339733524_Phase_1b2a_study_of_galunisertib_a_small_molecule_inhibitor_of_transforming_growth_factor-beta_receptor_I_in_combination_with_standard_temozolomide-based_radiochemotherapy_in_patients_with_newly_diagn
38. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma - PubMed, accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/32140889/
39. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with, accessed September 3, 2025, https://d-nb.info/1210923696/34
40. Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma | Neuro-Oncology | Oxford Academic, accessed September 3, 2025, https://academic.oup.com/neuro-oncology/article/18/8/1146/1751761
41. Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer - PubMed, accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/33688022/
42. Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib ..., accessed September 3, 2025, https://jitc.bmj.com/content/9/3/e002068
43. Phase 2 Study of Monotherapy Galunisertib (LY2157299 Monohydrate) in Very Low-, Low-, and Intermediate-Risk Patients with Myelodysplastic Syndromes | Blood | American Society of Hematology, accessed September 3, 2025, https://ashpublications.org/blood/article/126/23/1669/134935/Phase-2-Study-of-Monotherapy-Galunisertib
44. Phase II Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low ..., accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/31481511/
45. New Players Join Quest for a Therapeutic Foothold Against TGFβ - OncLive, accessed September 3, 2025, https://www.onclive.com/view/new-players-join-quest-for-a-therapeutic-foothold-against-tgf-
46. Targeting TGF-β in Gastrointestinal Cancers: Is it a Viable Therapeutic Strategy?, accessed September 3, 2025, https://dailynews.ascopubs.org/do/targeting-tgf--x03b2-gastrointestinal-cancers-viable-therapeutic-strategy
47. Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine - MDPI, accessed September 3, 2025, https://www.mdpi.com/1422-0067/18/5/995
48. Phase 1b dose-escalation and cohort-expansion study of the safety, tolerability, and efficacy of a novel transforming growth factor-β receptor I kinase inhibitor (galunisertib [G]) administered in combination with the anti-PD-L1 antibody (durvalumab [D]) in recurrent or refractory metastatic pancreatic cancer. - ASCO Publications, accessed September 3, 2025, https://ascopubs.org/doi/10.1200/JCO.2017.35.4_suppl.TPS501
49. Orphan designation: Overview | European Medicines Agency (EMA), accessed September 3, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview
50. Galunisertib - Wikipedia, accessed September 3, 2025, https://en.wikipedia.org/wiki/Galunisertib
51. Galunisertib (LY2157299) | 99.99%(HPLC) | TGF-beta/Smad inhibitor - Selleck Chemicals, accessed September 3, 2025, https://www.selleckchem.com/products/ly2157299.html
52. Galunisertib | New Drug Approvals, accessed September 3, 2025, https://newdrugapprovals.org/2016/05/04/galunisertib/
53. Oncology (Cancer)/Hematologic Malignancies Approval Notifications - FDA, accessed September 3, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications
54. Truqap | European Medicines Agency (EMA), accessed September 3, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/truqap
55. Lynozyfic™ (linvoseltamab) Approved in the European Union for the Treatment of Relapsed/Refractory Multiple Myeloma | Regeneron Pharmaceuticals Inc., accessed September 3, 2025, https://newsroom.regeneron.com/news-releases/news-release-details/lynozyfictm-linvoseltamab-approved-european-union-treatment/
56. EMA Recommends Rare Blood Cancer Treatment and Seven Other Medicines, accessed September 3, 2025, https://www.biopharminternational.com/view/ema-recommends-rare-blood-cancer-treatment-and-seven-other-medicines
57. Selected EMA news - The European Hematology Association (EHA), accessed September 3, 2025, https://ehaweb.org/about-eha/european-affairs/regulatory-affairs-and-scientific-relations/selected-ema-news
58. First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer - AACR Journals, accessed September 3, 2025, https://aacrjournals.org/clincancerres/article/27/24/6666/675198/First-In-Human-Phase-I-Study-of-a-Next-Generation
59. First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer, accessed September 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9414273/
60. First-In-Human Phase I Study of a Next-Generation, Oral ..., accessed September 3, 2025, https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-21-1504/673955/am/First-In-Human-Phase-I-Study-of-a-Next-Generation