Introduction
Desmoid tumors (DT) are mesenchymal monoclonal lesions with a locally aggressive and recurrent nature [ 1 , 2 ]. Though the disease is non-metastasizing and with an annual incidence of only 2–4 per million individuals, it affects young patients and causes significant morbidity [ 1 , 3 ]. This morbidity arises due to the possibility of infiltration of vital organs and neurovascular structures which causes chronic pain, organ dysfunction, disability, and worsening quality of life [ 4 , 5 ]. The treatment options for DT include active surveillance, ablative therapies, and medical agents such as sorafenib and nirogacestat. Nirogacestat, a gamma secretase (GS) inhibitor, is the first and only drug to be approved by the Food and Drugs Administration (FDA) following results of the pivotal phase III DeFi trial [ 6 ]. This class of drugs was initially explored for the treatment of Alzheimer’s disease (AD) and certain malignancies such as pancreatic, ovarian, colorectal, and breast cancers [ 7 , 8 ]. They were eventually developed as a therapeutic option for DT based on unprecedented responses in early clinical trials, though initially their mechanism of action in DT was unclear. We hereby describe the understanding of the physiology of the GS enzyme system, its role in oncology, evolution of research into targeting it for the treatment of various disorders, and how GS inhibitors subsequently became the first-line treatment choice for DT.
The physiology of the gamma secretase enzyme
GS is an intramembrane enzyme complex which acts as an aspartyl protease involved in multiple physiological processes. GS belongs to the group of intramembrane cleaving proteases (i-CLIPs) which primarily functions by regulated intramembrane proteolysis [ 9 ]. A number of important type I membranous proteins such as amyloid precursor proteins (APP), Notch, E-cadherin, CD44, ErbB4 and tyrosinase are metabolized by this enzyme complex [ 10–15 ]. The human GS is a multi-unit complex consisting of the following components: Presenilin (Presenilin-1 and 2), Nicastrin (NCT), Anterior Pharynx Defective-1 (APH-1a and 1b) and Presenilin Enhancer 2 (PEN-2) [ 16 ]. The specific functions of the various components are described below and in Figure 1 :
Presenilin-1: This is the most critical and catalytic subunit, which depends on the maturity of the GS complex for its functioning. It exists in the form of N-terminal (NTF) and C-terminal (CTF) fragments that interact with presenilin enhancer-2 (PEN-2) and Anterior pharynx defective-1a (APH-1a)
PEN-2
APH-1a: This component helps in the assembly and stabilization of the GS complex, along with working in tandem with other subunits.
Nicastrin (NCT): This is a type-1 transmembrane glycoprotein that regulates the entry of the bulky substrates into the active site of the GS enzyme.
The physiological role of the GS enzyme commences upon cleavage of the substrate protein that leads to downstream translocation of the product into the nucleus and regulation of transcription. One of the most studied substrates metabolized by this pathway is the Notch and APP proteins. After cleavage, Notch protein is converted to the Notch intracellular domain (NICD) which thereby controls the processes of cell proliferation, cell survival, positioning, and differentiation ( Figure 1 ) [ 9 , 17 ]. Aberrations in this pathway have been found to cause defects in T-cell and B-cell differentiation, gastrointestinal toxicity, cutaneous defects, and neurological abnormalities [ 18–20 ]. Besides APP and Notch, multiple diverse pathways are initiated by cleavage of the type 1 transmembrane proteins with varied functions. This includes ion conductance regulation (by voltage-gated sodium channel), lipoprotein metabolism (by ApoER2), growth factor activity (by growth factor-dependent receptor tyrosine kinase ERBB4), cell fate determination (by Delta and Jagged) and cell-to-cell adhesions (by N-cadherin, E-cadherin, CD44 [ 21 ].
Exploring the role of GS inhibitors in Alzheimer’s disease
GS plays an important role in the onset and development of AD production because this enzyme is a part of the last processing step of the APP [ 22 ]. The normal metabolism of APP produces amyloid-beta 40 protein, while aberration in this pathway causes production of the toxic 42-amino acid amyloid-beta 42 that aggregates in the form of senile plaques. These insoluble aggregates in the brain are responsible for the development and gradual progression of the most common form of dementia, that is AD [ 22 ].
Considering this as the key pathogenic event in the onset and progression of AD, the pathway of APP metabolism has been a subject of therapeutic investigation [ 7 ]. It had been hypothesized that agents that inhibit the GS enzyme could reduce the formation of the offending aggregates [ 23 ]. Agents such as avagacestat and semagacestat were examined in phase 2 and 3 trials, respectively, with the findings precluding their further clinical use [ 24 , 25 ]. For instance, semagacestat tested the effects of short peaks of complete GS inhibition on a once-a-day dosing which could have contributed to the worsening cognition observed with this regimen [ 25 ]. Peripheral side effects such as skin toxicity, weight loss and vomiting were also noted. Both the central and peripheral side effects were thereby attributed to the strong concomitant inhibition of the Notch signaling pathway following inhibition of the GS enzyme. Similarly, avagacestat was also not found to have the notch-sparing APP-selective effect that it was thought to have in early pre-clinical studies [ 26 ]. These findings have now paved the way for investigation into GS “modulators” rather than “inhibitors” which would have better tolerance owing to potential sparing of impact on the Notch pathway [ 27 ].
Preclinical information on GS inhibition in oncology
There is currently evolving knowledge on the association of GS in oncology through proteins such as Notch, ErbB4, CD44, cadherins, VEGFR1, IGFR1 and MUC1 [ 8 ]. Notch signaling contributes to oncogenic pathways both via its own dysregulation as well as through crosstalk with other pathways such as Wnt, JAK/STAT, NF-kappa B, Hedgehog, HIF-1 alpha [ 28 , 29 ]. Both Notch and Wnt pathways are evolutionarily highly regulated by processes such as co-operative regulation of transcriptional targets, transcriptional targets of one affecting the other, and by a direct crosstalk at the molecular levels [ 30 ]. The impact of this Wnt-Notch signaling crosstalk has been observed in cases of colorectal cancers, as demonstrated in mouse models. In the APC min/+ mouse in-vitro model, beta-catenin (regulated by Wnt) increased the levels of the Hairy Enhancer of Split (HES) messenger RNA [ 31 ]. This finding provided evidence that dysregulation of the Wnt pathway directly upregulated the Notch signaling, an indicator of the link between the two systems. Moreover, the individual components of the GS complex per se also possess potential links to cancer. The examples of these include upregulation of presenilin-1 expression in head and neck squamous cell and esophageal carcinomas, PEN-2 in low-grade gliomas, and NCT in breast and hepatocellular carcinomas [ 32–36 ].
The role of GS and its accompanying pathways in the development of cancer became the subject of therapeutic interest for anti-cancer strategies. Pre-clinical evidence exhibited potential activity of GS inhibitors in cancers such as Kaposi’s sarcoma, multiple myeloma, glioblastoma, ovarian cancer, lung cancer and pancreatic cancer [ 37–42 ]. These findings could not be replicated in clinical studies in various malignancies across phase I/II trials. Patients with advanced malignancies of the lung, pancreas, ovary, central nervous system (glioma), breast, and colorectal systems were treated with GS inhibitors in early phase clinical studies [ 43–45 ]. However, the results obtained did not warrant further investigation due to their negative outcomes. There were certain studies wherein GS inhibitors were combined with previously used therapies such as using the GS inhibitor RO4929097 with exemestane in hormone-positive advanced breast cancer [ 46 ]. However, this phase Ib study yielded a clinical benefit rate of only 20% and progression-free survival (PFS) of 3.2 months.
Nirogacestat – the pharmacology of a GS inhibitor that forayed into treatment of desmoid tumors
An oral GS inhibitor, nirogacestat, was initially studied for the treatment of AD but did not advance from preclinical to clinical settings due to toxicities noted with other medicines of the same class [ 47 ]. It is currently available in the form of immediate-release, film-coated tablets with a strength of 100 and 150 milligrams (mg), primarily metabolized via the CYP3A4 pathway. Predominant drug interactions occur with CYP3A4 inhibitors and drugs such as proton pump inhibitors that raise the gastric pH. Clinically, important drug toxicities include diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, hepatotoxicity, hypophosphatemia, and hypokalemia [ 48 ].
Nirogacestat (then PF-03084014) was first investigated in a phase I study with 64 patients with various refractory solid malignancies including 14.1% patients with DT [ 49 ]. This 3 + 3 dose finding study followed by an expansion cohort established the maximum tolerated dose at 220 mg twice a day while the recommended phase 2 dose was 150 mg twice a day. The evaluable patients in the full cohort attained an overall response rate (ORR) of only 13%, but those with DT had an exceptional and durable response with ORR 71.4% and duration of response (DoR) up to 24 months. Long-term analysis showed a DoR maintained for 73.6 months, even among four patients who had discontinued treatment [ 50 ]. The impressive ORR observed in the patients with DT was better than that with tyrosine kinase inhibitors (TKI) such as imatinib [ 51 ]. It was thereby opined by the authors that the role of GS inhibitors deserved further studying in the field of DT.
This unexpected response produced with nirogacestat in patients with DT piqued interest in better understanding the biology of this phenomenon. The role of dysregulated Wnt signaling is implicated in DT pathogenesis both in germline and sporadic cases. Sporadic cases of DT occur due to mutation of the beta-catenin oncogene CTNNB1 gene leading to its constitutive activation, while germline cases occur in 5–10% due to mutation of the APC gene which itself is a regulator of beta-catenin degradation [ 52 , 53 ]. The APC gene act as a negative regulator of beta-catenin stability and its germline mutation in Familial Adenomatous Polyposis (FAP) leads to beta-catenin remaining in an activated state [ 54 ]. A stable, activated beta-catenin along with a dysregulated Wnt pathway, there is an over-expression of ADAM12, WISP1, SOX11, Fap-1 alpha, VEGF, and COX-2 genes [ 55 , 56 ]. These genes play pivotal roles in cell proliferation, fibrosis, angiogenesis, and activation of inflammatory pathways [ 57–60 ]. Moreover, the mesenchymal cells associated with CTNNB1 or APC mutations remain in a stem cell-like state in the form of myofibroblasts [ 61 ]. These are CD44 positive, which is an adhesion molecule upregulated by beta-catenin in colon cancer cell lines [ 62 , 63 ]. CD44 forms an adhesion complex along with alpha-catenin, beta-catenin, and fibroblast growth factor, which is cleaved by the GS enzyme. Upon cleavage by GS, the ectodomain component of this complex mediates cell migration [ 64 , 65 ]. Therefore, this epithelial–mesenchymal transition leads to loss of cell polarity, loosening of cell–cell adhesion properties and increase of migratory and invasive properties. All these pathways undergo a complex interplay and lead to the development of DT as described in Figure 1 .
GS inhibitors could thereby play a potential therapeutic role in DT because of the cross-links between Notch and Wnt signaling, and the involvement of GS in the Notch pathway [ 21 , 30 , 31 ]. With this background, Shang et al. analyzed the Notch pathway components in DT tissues and cell strains and assessed their response to the GS inhibitor PF-0308014 [ 66 ]. Compared with dermal scar tissue specimens, tissue microarray from DT specimens exhibited higher expression of nuclear HES1 (98.9% versus 44.4%, p < 0.001) which was already known to be a part of the Notch pathway system [ 31 ]. Evidence of Notch pathway activation was also shown by the high NICD expression in nuclear fractions in the DT cell strains. Additionally, PF-0308014 (nirogacestat) led to significant growth inhibition of the DT cells following 27 days of treatment. Besides cell division and cell cycle arrest, nirogacestat also demonstrated reduced DT cell migration and invasion. Thus, the authors provided evidence that the action of nirogacestat was present at Notch pathway inhibition and also potentially on other systems such as cell–cell adhesion mediated by CD44.
The encouraging outcomes in the phase I study warranted a phase II trial, however certain challenges were encountered in the course of this development. Research into rare diseases, such as DT with around 1000–1650 cases diagnosed annually, can suffer from issues such as reduced clinician awareness, misdiagnosis, less industry interest, and difficulties in recruitment [ 67 ]. Similar issues were encountered in the preparation for the phase II study on nirogacestat among patients with DT as well. Investigators at the National Cancer Institute (NCI) thereby engaged the Desmoid Tumor Research Foundation (DTRF) which has been a pivotal advocacy group for patients with DT. DTRF served as an able platform for bringing patients in touch with the involved researchers, so much so that the planned sample size for the study was attained much earlier than anticipated [ 68 ]. This phase II study recruited 17 patients with DT, assessing response in terms of Response Evaluation Criteria in Solid Tumors (RECIST) and patient-reported outcomes (PRO) by the psychometrically validated MD Anderson Symptom Inventory (MDASI) questionnaire. The study reported partial response (PR) in 29% and stable disease in 65% patients with 21-day cycles of nirogacestat dosed at 150 mg twice daily [ 69 ]. This improvement in patients’ symptom burden was also noted, reflected by continued ORR of 31.25% patients and no patients demonstrating disease progression at a median treatment period of 4 years [ 70 ]. There was a notable difference in the ORR obtained with nirogacestat between the phase I and II studies.
The success of this phase II study lays in the conduct of a single-center trial on a rare condition, which informed the need for a phase III trial in DT. The trial also emphasized the need for DT-specific PRO tools because ultimately the quality of life (QoL) was the more relevant metric as opposed to other endpoints such as RECIST-based ORR, progression-free survival (PFS) and overall survival (OS) in this chronic disease. The planning of a phase III trial was interrupted by the de-prioritization of nirogacestat development for DT. Following efforts by clinicians and researchers in academia, Pfizer’s out-licensing rights of nirogacestat, and engagement of investors, SpringWorks Therapeutics was founded [ 66 ]. SpringWorks Therapeutics is a company that focuses on development of newer treatments for underserved patient groups such as rare disease conditions [ 71 ]. One of the rare conditions that it concentrated research on in 2017 was DT, and multi-level efforts were commenced to arrange infrastructure and engage the FDA for negotiating the development of phase III trial of nirogacestat.
Conduct of the pivotal phase III trial and the ultimate FDA approval for nirogacestat in DT
Prior to the phase III study of nirogacestat, the only drug assessed in a randomized placebo-controlled setting for DT was sorafenib, the results of which were published in 2018 [ 72 ]. In advanced and refractory DT, the 2-year PFS with sorafenib was significantly better at 81% as compared to 36% with placebo, with an ORR of 33% with the former. It was emphasized by the authors here that RECIST-based parameters may not be the ideal metric in DT due to anatomical and mathematical discordances encountered in response assessments. The need for DT-specific PRO tools and Magnetic Resonance Imaging (MRI) for response assessment of patients was described. Although the study reported positive findings, it was ultimately not approved for a new drug indication for the treatment of DT by the FDA since it was not designed for regulatory approval. However, the completion of this phase III study in a rare condition such as DT paved the way for drug companies to follow a paradigm for a feasible trial design and drug development in this condition.
With Springworks’ efforts to secure adequate financing and collaboration with DTRF to ensure patient recruitment, the DeFi trial commenced recruitment in 2019 and was completed in 15 months [ 6 ]. DeFi trial was an international, double-blind, randomized placebo-controlled trial using nirogacestat 150 mg twice a day and a reduced dose of 100 mg if grade 3 clinical toxicity occurred. PFS was the primary endpoint, with the progression event consisting of clinical progression, radiological progression (using MRI scans) or death. At a median follow-up of 15.9 months, the median PFS was not reached (NR) with nirogacestat as opposed to 15.1 months in the placebo group. The risk of disease progression was reduced by a significant 71% with nirogacestat compared to placebo, and at 2 years the likelihood of being event-free was 76% versus 44%. Nirogacestat demonstrated an ORR of 41% including complete responses in 7% patients. Overall, 95% of adverse events with nirogacestat were grades 1 or 2 inclusive of the expected side effects of diarrhea, nausea, fatigue, hypophosphatemia, maculopapular rash, stomatitis, headache, cutaneous toxicity, and vomiting.
Ovarian toxicity was identified in 27 of 36 (75%) of the females of reproductive potential (FORP). The unique adverse event of ovarian toxicity was defined as amenorrhea, premature menopause, menopause, and ovarian failure in the DeFi study. As per preclinical data, nirogacestat produces ovarian dysfunction possibly due to the disruption of ovarian follicular cycling which is also mediated by Notch signaling. The development of normal ovarian follicles requires various components of the Notch pathway which is evident by their expression in the pre-antral follicles [ 73 ]. Due to the action of nirogacestat possibly on these receptors also, ovarian dysfunction can manifest with treatment in the form of clinical manifestations and laboratory aberrations such as increased follicular-stimulating and/or luteinizing hormones, reduction in estradiol and/or anti-Mullerian hormone [ 74 ]. Taking into account this important adverse event, the DeFi trial included amenorrhea as a safety signal and monitored reproductive profile hormones for the detection and characterization of possible ovarian dysfunction with nirogacestat. This was considered important more so because of the demographic profile of the included patients who belonged to the reproductive age group. A longer follow-up was conducted among the FORP who experienced ovarian toxicity with nirogacestat to better assess the adverse event and its reversibility [ 75 ]. The median duration of ovarian toxicity was 19.1 weeks with 15% patients requiring concomitant medications to manage the reproductive symptoms. Ovarian toxicity led to nirogacestat dose reduction in 7% and discontinuation in 15% of the FORP who experienced this side effect. Among the 27 women who developed ovarian toxicity, the dysfunction resolved in 11 (100%) who stopped nirogacestat and 10 (71%) who were on ongoing treatment. Of the 6 whose ovarian dysfunction was unresolved, 4 (29%) were still on nirogacestat therapy and follow-up information for the remaining 2 (7%) was not available. The mechanism of hypophosphatemia remains under exploration and has been hypothesized to be related to the class effect of the drug [ 76 ]. The proposed causes may be secondary to increased frequency of diarrhea, induction of phosphorus wasting by the sodium phosphate transporter-2a and altered levels of the phosphaturic hormones such as parathyroid hormone and fibroblast growth factor-23. It will be important to conduct mechanistic studies for better exploration into the cause of this dyselectrolemia for prevention and treatment of hypophosphatemia with nirogacestat.
PROs formed the secondary endpoints, measured using Brief Pain Inventory-Short Form (BPI-SF) average worst pain intensity score, GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS) Desmoid Tumor Symptom Scale (DTSS) and Impact Scale (DTIS) physical functioning domain score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 global health status – quality of life score, EORTC QLQ-C30 physical functioning score, and EORTC QLQ-C30 role functioning score. The GODDESS tool has been developed prospectively as a novel regulatory and clinical trial endpoint, also complementing the existing tools [ 77 ]. In the DeFi study, nirogacestat significantly improved the GODDESS DTSS total symptom and the GODDESS DTIS physical functioning domain scores along with the other scores of BPI-SF and EORTC QLQ-30 scores. In view of pain being a prime symptom of this condition, an assessment of pain scores also revealed that nirogacestat led to rapid, sustained, and consistent reductions per the GODDESS, BPI-SF, and EORTC QLQ-C30 pain scales [ 78 ].
Key considerations on the use of nirogacestat in DT
There was a difference noted in the response rates obtained with nirogacestat in the clinical trials conducted in DT across the years. The number of patients with DT in the phase I study was too small to make a concrete conclusion on the efficacy of the drug. In the phase II study, the ORR of 29% could be reflective of the refractoriness of disease because the included patients had received a median of 4 (1–9) lines of prior therapy, including cytotoxic therapy in 71%. In contrast, the DeFi trial included 26% treatment-naïve patients in the nirogacestat arm, with a median number of 2 lines of therapy in this cohort.
No direct comparisons are available between sorafenib and nirogacestat; only the latter is FDA approved. Sorafenib differs from nirogacestat due to its multikinase inhibition at the Ras/Raf/MEK/ERK signaling as well as the pro-angiogenic VEGF, PDGFR-beta, and c-KIT pathways [ 79 ]. This paradigm of action is also responsible for the difference in the adverse event profile of sorafenib inclusive of skin rash, fatigue, hypertension, and diarrhea [ 72 ]. The use of MRI-based response assessment and evaluation QoL using the GODDESS scale for nirogacestat offers unique insights as compared to the available data for sorafenib.
Data on the pharmaco-economic aspect of use of nirogacestat in DT remains lacking, and further studies are needed to determine the cost-effectiveness of the drug in this rare condition. It would be helpful to generate cost-effectiveness data on nirogacestat among different populations and healthcare settings to understand the hurdles in global access and affordability. Reimbursement options are available from insurance facilities in the Unites States. Nirogacestat has been approved in the United States and the European Union and has not yet obtained approval in India. Hence, there is a challenge in its accessibility in other countries. In these settings, clinicians may choose the treatment agents based on the local drug availability, affordability, and side effect profile in consideration. In India, sorafenib and imatinib are more in use for the treatment of DT, while the use of tamoxifen, non-steroidal anti-inflammatory agents, methotrexate, and vinblastine has reduced in recent years [ 80 ].
Regulatory affairs
Based on the outcomes of the phase I and II studies, the FDA had granted nirogacestat the Orphan Drug Designation and Fast Track Designation for the treatment of adult patients with progressive, unresectable, recurrent, or refractory DT in 2018 [ 81 ]. Further on, after the results of the phase I and II trials findings, the FDA in August 2019 granted Breakthrough Therapy Designation to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent, or refractory DT [ 82 ]. November 2023 finally saw the FDA approval for the treatment of adult patients with DT requiring systemic treatment, based on the positive findings of the DeFi trial [ 83 ].
Conclusions
The trajectory of development of nirogacestat demonstrates how a drug proceeded from evaluation for other diseases to various phases of progress in a rare disorder following early-phase unexpected results. The understanding of the pathophysiology vis-a-vis the functioning of the GS enzyme complex in DT enabled researchers to recognize this possibility. Currently, other GS inhibitors are under investigation for use in DT. AL-102 is currently being evaluated in the phase 3 RINGSIDE (AL-DES-01) trial, while the result from Part A or the phase 2 stage demonstrated its safety, tolerability, and dosage. At 1.2 mg once-daily dosing, the best response was PR in 50%, disease control rate was 100% and a deeper, rapid, and maintained result compared to other dose regimens [ 84 ]. Additionally, despite initial negative findings in the treatment of other malignancies, nirogacestat is being assessed as part of combination therapies to increase the efficacy of B-cell maturation antigen (BCMA)-directed myeloma treatments [ 85 ]. It will be interesting to see the further potential that GS inhibitors may exhibit in the field of cancer, with the work in the field of DT showing the path for further research and development.
Correction Statement
This article was originally published with errors, which have now been corrected in the online version. Please see Correction ( http://dx.doi.org/10.1080/14796694.2025.2560753 )
Funding Statement
Mrinal Gounder was supported by an institutional grant to MSKCC (P30 CA008748/CA/NCI NIH-HHS). Funding to permit Open Access for this article was provided by SpringWorks Therapueutics, however the funder had no role in the study design, data collection, data analysis, decision to publish, or preparation of manuscript.
Article highlights
Desmoid tumors are rare, locally aggressive, recurrent mesenchymal lesions causing chronic pain, decline in QoL, organ dysfunction, and disability in the young subset of population.
Desmoid tumors are driven by the Notch/Wnt cross-talking signaling pathway; Notch is a substrate of the gamma secretase enzyme.
Gamma secretase inhibitors were initially explored for treatment of Alzheimer’s disease because gamma secretase enzyme is involved in the amyloid precursor protein metabolism, but produced several off-target side effects.
Nirogacestat is a gamma secretase enzyme inhibitor, whose activity in phase I 3 + 3 dose-finding trial was found to be high with an overall response rate of 71%.
Conduct of a further phase II study faced difficulties in recruitment which were overcome with efforts from the patient advocacy group, Desmoid Tumor Research Foundation.
The response rates with nirogacestat 150 milligram twice daily dosage was 29%, with an improvement in the symptom burden of the recruited patients.
The pivotal phase III DeFi trial exhibited overall response rate of 41% and at 2 years the likelihood of being event-free was 76% versus 44% with nirogacestat and placebo respectively.
Significant side effects included diarrhea, nausea, fatigue, hypophosphatemia, maculopapular rash, stomatitis, headache, cutaneous toxicity, and reversible ovarian dysfunction.
The DeFi trial included assessment of patient-reported outcomes using a DT-specific GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS) Desmoid Tumor Symptom Scale (DTSS) and Impact Scale (DTIS).
Based on the findings of the phase I and II trials nirogacestat received breakthrough FDA approval for treatment of progressive, unresectable, recurrent/refractory DT in 2019.
Following the DeFi trial, nirogacestat received FDA approval for the treatment of progressive DT requiring systemic therapy.
Authors contributions
Ghazal Tansir contributed to the conception, execution, literature review, writing the manuscript
Sameer Rastogi contributed to the conception, revision, critical review of the manuscript
Mrinal Gounder contributed to the conception, execution, literature review, critical review, revision of manuscript
All authors have agreed on the journal to which the article is being submitted.
All authors have reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage.
All authors agree to take responsibility and be accountable for the contents of the article and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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