Repurposing alpelisib, an anti‐cancer drug, for the treatment of severe TIE2‐mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data

Remy, Amandine; Tran, Thai Hoa; Dubois, Josée; Gavra, Paul; Lapointe, Catherine; Winikoff, Rochelle; Garcia‐Bournissen, Facundo; Théôret, Yves; Kleiber, Niina

doi:10.1002/pbc.29897

Cited by 10 publications

(7 citation statements)

References 25 publications

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“…Similar efficacy was reported by other authors describing their experience in a cohort of 19 patients and two case reports of patients with PIK3CA -related overgrowth syndrome (PROS) 11 – 13 . In our study, we also report the efficacy of alpelisib on VMs in patients without germline mutations but with somatic mutations, and moreover, this report describes alpelisib efficacy in the largest cohort of patients with somatic mutations in the TEK gene so far, thus following up on work of Remy et al 15 .…”

Section: Discussionmentioning

confidence: 59%

“…In addition to patients with activating PIK3CA mutations, alpelisib treatment might also be beneficial for patients with activating TEK alterations, as the PI3K/AKT pathway is considered to be a central part of signaling through the TIE2 receptor encoded by this gene 14 . This was recently demonstrated in work published by Remy et al, in which the authors described the efficacy and pharmacokinetics of alpelisib in 3 patients with VMs harboring TEK mutation 15 .…”

Section: Introductionmentioning

confidence: 75%

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Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity

Sterba,

Pokorna,

Faberova

et al. 2023

Sci Rep

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This was a prospective cohort study of eighteen patients with large and debilitating vascular malformations with one or more major systemic complications. In all patients, we discovered activating alterations in either TEK or PIK3CA. Based on these findings, targeted treatment using the PI3K inhibitor alpelisib was started with regular check-ups, therapy duration varied from 6 to 31 months. In all patients, marked improvement in quality of life was observed. We observed radiological improvement in fourteen patients (two of them being on combination with either propranolol or sirolimus), stable disease in 2 patients. For 2 patients, an MRI scan was not available as they were shortly on treatment, however, a clinically visible response in size reduction or structure regression, together with pain relief was observed. In patients with elevated D-dimer levels before alpelisib administration, a major improvement was noted, suggesting its biomarker role. We observed overall very good tolerance of the treatment, documenting a single patient with grade 3 hyperglycemia. Patients with size reduction were offered local therapies wherever possible. Our report presents a promising approach for the treatment of VMs harboring different targetable TEK and PIK3CA gene mutations with a low toxicity profile and high efficacy.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 75%

Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity

Sterba,

Pokorna,

Faberova

et al. 2023

Sci Rep

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“…For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients 41 Avapritinib [ 70 ] Mucosal melanoma and thymic carcinoma 1 + 3 + 5 Symptoms improved Case 1: grade 2 vasculitis and grade 2 uveitis occurred, in the absence of predisposing factors. Case 2: grade 2 haematologic toxicity occurred, including anaemia and thrombocytopaenia 42 Lumasiran [ 71 ] Primary Hyperoxaluria Type 1 1 Cure No serious AEs 43 Alpelisib [ 72 ] Extensive venous malformations 1 + 3 + 4 Cure No serious AEs 44 Avacopan [ 73 ] Antineutrophil Cytoplasmic Antibody–Associated Vasculitis 1 Symptoms improved No AEs during treatment 45 Bulevirtide [ 74 ] HDV-related cirrhosis 1 + 3 Symptoms improved No AEs during treatment 46 Asfotase Alfa [ 75 ] Childhood Hypophosphatasia 3 Symptoms improved No side effects were observed except for mild injection site reactions (erythema, pain, lipohypotrophy, and lipohypertrophy) a (1) The clinical trial support, or the patient participated in the clinical trial with good treatment effect and applied for CU program after the trial; (2) Case report or small series of research literature support; (3) Pharmacological action (such as target) support; (4) Preclinical study support; (5) Similar indications support. b IV: Intravenous injection c AEs: adverse events d CMV: cytomegalovirus e GO: Gemtuzumab Ozogamicin f rhAT: Human recombinant antithrombin g Ph (−): Classical Philadelphia chromosome-negative h GVHD: graft-versus-hos...…”

Section: Resultsmentioning

confidence: 99%

Efficacy and safety of compassionate use for rare diseases: a scoping review from 1991 to 2022

Wu,

Yang,

et al. 2023

Orphanet J Rare Dis

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Background Compassionate use is a system that provides patients with expedited access to drugs which has not yet been approved, but currently in clinical trials. The investigational drugs have been authorized for compassionate use in cases involving patients suffered from life-threatening diseases and with no alternative treatments. For instance, patients afflicted with highly heterogeneous rare diseases are eligible for treatment assistance through the compassionate use program. This study aims to investigate the characteristics of compassionate use in the context of rare diseases, evaluate the efficacy and safety of compassionate use for rare diseases, and analyze the marketing approval of investigational drugs. Methods The case reports/case series of compassionate use were collected by conducting searches on Embase, PubMed, Web of Science, CNKI and SinoMed, spanning from January 1991 to December 2022. Subsequently, two independent reviewers evaluated these reports. Case reports/case series that met the inclusion criteria and exclusion criteria were enrolled. Information extracted from these reports and series included patients' basic information, the investigational drug's name, its indication, adverse events, treatment outcomes, and other relevant data. Results A total of forty-six studies were included, encompassing 2079 patients with an average age of 38.1 years. Thirty-nine different drugs were involved in 46 studies. Furthermore, neoplasms emerged as the most common therapeutic area for compassionate use in rare disease management (23/46, 50.0%). Regarding the treatment efficacy, four studies reported successful disease resolution, while 35 studies observed symptom improvement among patients. Conversely, four studies documented no significant effects on patients' diseases. Moreover, one study reported worsened results following compassionate use, while the efficacy was not described in 2 studies. Adverse events were reported in 31 studies (67.4%) because of the compassionate use, while no adverse events occurred in 13 studies (28.3%). In other 2 studies, there was no description about whether treatment-emergent adverse events (TEAEs) were happened. 136 patients (6.5%) had Grade 5 adverse events (death), of which 19 deaths (0.9%) were considered to be related to compassionate use. Furthermore, the investigational drugs in 33 studies (33/46, 71.7%) received new drug approval at the end of January 31, 2023.The time lag from the start of the compassionate use to the formal approval of the investigational drug was 790.5 (IQR 359–2199.3) days. We found that in 11 studies, encompassing 9 different drugs, some compassionate use indications had not received regulatory authorities at the end of January 31, 2023. Conclusion The current status of compassionate use for rare diseases was clarified systematically in this study. Compassionate use of investigational drug is a significant treatment option for rare disease. In general, compassionate use appears to demonstrate favorable efficacy in the context of rare diseases, with a significant proportion of compassionate use drugs subsequently receiving marketing approval. However, the safety of drugs for compassionate use cannot be fully evaluated due to the safety data were not covered in some enrolled studies. Therefore, the establishment of an adverse event reporting system specific to compassionate use is warranted.

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“…Currently, alpelisib-a selective PI3Kα inhibitor-is being investigated and used in an experimental setting for patients with a PIK3CA or TEK mutation [83,84]. Another example is trametinib, which is a MEK inhibitor, and promising results have been reported in patients with complex lymphatic anomalies associated with mutations in the RASpathway [85].…”

Section: Medical Therapymentioning

confidence: 99%

Congenital Vascular Malformations in Children: From Historical Perspective to a Multidisciplinary Approach in the Modern Era—A Comprehensive Review

Bouwman,

Verhoeven,

Klein

et al. 2024

Children

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Congenital vascular malformations (CVMs) are the result of an aberrant development during embryogenesis. Although these lesions are present at birth, they are not always visible yet. Once symptomatic, patients suffer from pain, bleeding, ulcers, infections or lymphatic leakage, depending on the subtype of vessels involved. Treatment includes conservative management, surgery, sclerotherapy, embolization and pharmacological therapy. The clinical presentation varies widely and treatment can be challenging due to the rarity of the disease and potential difficulties of treatment. This review gives an overview of the historical developments in diagnosis and classification and exposes the key elements of innovations in the past decades on the identification of genetic mutations and personalized treatment. These advances in the field and a multidisciplinary approach are highly valuable in the optimization of clinical care aimed at both curing or stabilizing the CVM and pursuing physical and psychosocial wellbeing.

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Repurposing alpelisib, an anti‐cancer drug, for the treatment of severe TIE2‐mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data

Cited by 10 publications

References 25 publications

Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity

Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity

Efficacy and safety of compassionate use for rare diseases: a scoping review from 1991 to 2022

Congenital Vascular Malformations in Children: From Historical Perspective to a Multidisciplinary Approach in the Modern Era—A Comprehensive Review

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