Disharmonious overgrowth syndromes are rare genetic diseases associated with a mutation in the PIK3CA gene. Since 2016, a team made up of researchers from Inserm, AP-HP, University of Paris, the Institut Necker-Enfants malades (Overgrowth syndromes and vascular anomalies Unit) and the clinical services of Hospices civilians of Lyon has demonstrated the therapeutic efficacy of a molecule used against certain cancers, Alpelisib, to treat a group of children and adults with severe forms of these diseases. Dysharmonious overgrowth syndromes are rare genetic diseases associated with a mutation in the PIK3CA gene. Since 2016, a team made up of researchers from Inserm, AP-HP, University of Paris, the Institut Necker-Enfants Malades (Disharmonious Hypergrowth and Vascular Abnormalities Unit) and the clinical services of Hospices civilians of Lyon has demonstrated the therapeutic efficacy of a molecule used against certain cancers, Alpelisib, to treat a group of children and adults with severe forms of these diseases. In a new publication, the team reports this time a clinical, biological and imaging improvement of severe forms of two infants with disharmonious overgrowth syndromes treated with Alpelisib. These are the first data obtained concerning the treatment with this molecule of severe neonatal forms. The results of this one-year follow-up are published in the Journal of Experimental Medicine (JEM).
Disharmonious overgrowth syndromes are rare genetic diseases characterized by an increase in the size but also in the number of cells in the body. They are manifested by an asymmetry that can affect any part or tissue of the body (fat, vessels, muscles, bones, etc.), including the brain. In 95% of cases, the disease is linked to a mutation, during embryonic development, of the PIK3CA gene, which regulates cell proliferation and growth.
« When PIK3CA is over-activated, the parts of the body affected by the mutation undergo excessive growth giving rise to physical deformities, more or less disabling depending on the number of tissues affected. Surgery and other forms of supportive care can relieve some symptoms, but there is currently no approved medical therapy to treat the disease. »
In previous work, Alpelisib, a PIK3CA inhibitor drug recently approved to treat certain forms of breast cancer, showed promising results, first in animal models of overgrowth syndrome and then in a small number of adult and pediatric patients. The drug is currently in a series of larger clinical trials but, until now, there have been no data on its effectiveness in infants.
In this new study, a team of researchers from Inserm, AP-HP and University of Paris, coordinated by Professor Guillaume Canaud, reports the encouraging results of treatment with Alpelisib administered over a period of one year to two infants – an 8-month-old girl and a 9-month-old boy at the start of treatment – with a variety of severe symptoms caused by mutations in the PIK3CA gene. These symptoms included extreme malformations of blood vessels, anemia, asymmetrical overgrowth of limbs and fingers, and, in the boy’s case, overgrowth of one cerebral hemisphere (hemimegalencephaly) associated with epileptic seizures. . Before the start of treatment, the vital prognosis of the girl was engaged, and the boy presented a serious neurological prognosis, not responding to conventional antiepileptics.
Good tolerance to treatment
Daily oral doses of 25 mg Alpelisib induced rapid and significant clinical improvement of symptoms in both infants. Thus, 12 months of treatment made it possible to put an end to the epileptic spasms of the boy and to reduce the number of vascular malformations of the girl. The considerable reduction in the volume of her right leg allowed her to stand and to be able to walk with assistance. The anemia was corrected in both children following the introduction of treatment.
Both children presented with a break in their height-weight growth curves (when weight or height depart from the curve indicating the norm) which corrected after introduction of Alpelisib. Importantly, they did not develop any treatment-related adverse effects. Further analysis revealed that at a daily dose of 25 mg, the levels of Alpelisib accumulated in their blood were much lower than the levels safely tolerated by adults.
“The results of treatment with Alpelisib for these two infants are encouraging because they show an improvement in all the parameters, whether clinical, biological or even radiological. The high efficacy observed may be related to the early introduction of Alpelisib. Indeed, the two children were naïve to any surgery, yet we know that the changes induced by a surgical procedure can modify the good penetration of Alpelisib into the tissues. In addition, it is very likely that the plasticity of the tissues at this age allows better treatment efficiency, explains Professor Guillaume Canaud, coordinator of the study. However, these results must be interpreted with caution and will need to be confirmed over time and through new follow-ups,” he adds.
« This treatment with Alpelisib for overgrowth syndromes continues to be the subject of clinical trials among a population composed of adults but also children from the age of 6. These encouraging results make it possible to consider an extension of authorizations to clinically treat severe neonatal forms. »
The treatment of these infants with Alpelisib falls within the framework of a protocol for the compassionate use of a medicinal product, which is an exceptional authorization issued by the National Agency for the Safety of Medicines and Health Products allowing the treatment of patients suffering from diseases with a serious prognosis and without appropriate treatment, in a given therapeutic indication.
Source : Inserm (01.26.2022)