scholarly journals Case Report: Five-Year Experience of AKT Inhibition with Miransertib (MK-7075) in an Individual with Proteus Syndrome

2021 ◽  
pp. mcs.a006134
Author(s):  
Christopher A Ours ◽  
Julie C Sapp ◽  
Mia B Hodges ◽  
Allison J de Moya ◽  
Leslie G Biesecker
Keyword(s):  
Case Report ◽  
Phase 1 ◽  
Cancer Therapeutics ◽  
Proteus Syndrome ◽  
Single Individual ◽  
Akt Inhibitor ◽  
Pharmacodynamic Study ◽  
The Individual ◽  
Favorable Safety

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the five-year follow up of an 18-year-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-week phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. He has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to five years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. While an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.

scholarly journals Clinical Experience with the AKT1 Inhibitor Miransertib in two Children with PIK3CA-related overgrowth syndrome

2020 ◽  
Author(s):  
Karina Forde ◽  
Nicoletta Resta ◽  
Carlotta Ranieri ◽  
David Rea ◽  
Olga Kubassova ◽  
...  
Keyword(s):  
Obstructive Uropathy ◽  
Phase 1 ◽  
Case Series ◽  
Proteus Syndrome ◽  
Akt Inhibitor ◽  
Respiratory Compromise ◽  
Open Label ◽  
Open Label Phase ◽  
Objective Clinical Response

Abstract Background PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. Results Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. Conclusions We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

scholarly journals Simultaneous arterial and venous thromboembolic events associated with COVID-19. A case report

2021 ◽  
Vol 17 (2) ◽  
Author(s):  
Ashley Reed ◽  
Caroline Howard ◽  
Mohamed Barakat ◽  
Ali Navi
Keyword(s):  
Case Report ◽  
Patent Foramen Ovale ◽  
Holistic Approach ◽  
Foramen Ovale ◽  
Artery Thrombosis ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
The Individual ◽  
Support Decision Making

Infections with COVID-19 can induce thrombophilia and increase the risk of thrombotic events. We describe a case of a 64- years-old male who presents with intermediate-risk pulmonary embolism and brachial artery thrombosis secondary to an undiagnosed patent foramen ovale and COVID-19 infection. The patient was successfully treated with thrombolysis and heparin infusions and was discharged home with long-term anticoagulation. Managing patients with multiple pathologies occurring concurrently requires effective inter-speciality working in order to take a holistic approach to managing the patient opposed to managing the conditions in isolation. This case report highlights how clinical guidelines can support decision making of the individual pathologies but working as a team will enable the best care.

Understanding the Results of CATIE in the Context of the Field

CNS Spectrums ◽  
2006 ◽  
Vol 11 (S7) ◽  
pp. 40-47 ◽  
Author(s):  
Ira D. Glick
Keyword(s):  
Side Effects ◽  
Treatment Adherence ◽  
Atypical Antipsychotics ◽  
Phase 1 ◽  
Metabolic Effects ◽  
Valid Assessment ◽  
The Individual ◽  
Meta Analyses ◽  
Term Management

AbstractThe Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was undertaken to provide a valid assessment of the differences between conventional and atypical antipsychotics and among the atypicals themselves in patients with schizophrenia. The CATIE investigators reported that while none of the study medications were ideal, olanzapine was the most effective in terms of treatment discontinuation, and there were no significant differences in effectiveness between the conventional antipsychotic perphenazine and the atypicals quetiapine, risperidone, and ziprasidone. Each drug differed slightly in rates of side effects, with more patients discontinuing perphenazine due to extrapyramidal side effects and more patients discontinuing olanzapine due to weight gain and metabolic effects. In order for data from phase 1 of the CATIE study to be interpreted within the appropriate context, physicians must understand how aspects of study design and statistical methods affect interpretation, and how this trial weighs against other data in the literature. This article enumerates the factors that complicate our understanding of the CATIE results and compares these findings with those from previously published meta-analyses. It is clear that therapeutic and side effects of antipsychotics vary from person to person. The goal of schizophrenia management is to maintain pharmacotherapeutic efficacy and tolerability over the long-term in order to maximize treatment adherence and benefits. What should emerge from CATIE is a renewed commitment to tailor schizophrenia treatment to the individual patient for long-term management.

scholarly journals Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Karina Forde ◽  
Nicoletta Resta ◽  
Carlotta Ranieri ◽  
David Rea ◽  
Olga Kubassova ◽  
...  
Keyword(s):  
Obstructive Uropathy ◽  
Phase 1 ◽  
Case Series ◽  
Proteus Syndrome ◽  
Akt Inhibitor ◽  
Respiratory Compromise ◽  
Open Label ◽  
Open Label Phase ◽  
Objective Clinical Response

Abstract Background PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. Results Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22–28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. Conclusion We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

Long-term side effects following pneumonectomy: A case report and review of the literature

2019 ◽  
Author(s):  
BA Högerle ◽  
EL Bulut ◽  
L Klotz ◽  
F Eichhorn ◽  
M Eichhorn ◽  
...  
Keyword(s):  
Case Report ◽  
Side Effects ◽  
Review Of The Literature

Long-term management of resistant, fistulazing Crohn's disease by ongoing 4-weekly infliximab therapy (a case report)

2005 ◽  
Vol 43 (05) ◽  
Author(s):  
R Schwab ◽  
P Lakatos ◽  
E Schäfer ◽  
J Weltner ◽  
A Sáfrány ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Case Report ◽  
Crohn's Disease ◽  
Infliximab Therapy ◽  
Term Management
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