Vijoice: First Targeted Treatment for PIK3CA-Related Overgrowth Spectrum (PROS)

Highlights

Vijoice (alpelisib) is a new drug indicated for the treatment of adults and pediatric patients (two years and older) with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy.

Vijoice is the first and only targeted drug against PROS.

Vijoice, developed by Novartis, is approved by the U.S. Food and Drug Administration (FDA) in early April 2022 on a conditional basis, meaning the drug has yet to have its therapeutic efficacy finally confirmed.

Alpelisib under the brand name Piqray made its commercial debut in late May 2019; the drug is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

For U.S. patients, a month of treatment with Vijoice would cost $32,500 (wholesale acquisition cost, WAC). In comparison, Piqray is priced at $19,700.

 

What Is PIK3CA-Related Overgrowth Spectrum

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term for very rare syndromes characterized by malformations (abnormalities) and excessive tissue growth caused by somatic mutations in the PIK3CA gene. In PROS diseases, malformations appear in a variety of tissues, such as skin, vascular system, bones, adipose tissue, and brain tissue, depending on the specific disease.

The prevalence of PROS is approximately 14 cases per one million people.

The PIK3CA gene encodes the p110α protein, which is the catalytic alpha-subunit of phosphatidylinositol 3-kinase (PI3K), a key regulator of important cellular functions such as proliferation, growth, and apoptosis. PIK3CA gain-of-function mutations cause excessive PI3K activity resulting in altered cell and tissue growth patterns. The different phenotypic manifestations of PROS diseases are explained by the post-zygotic mosaic acquisition of mutations at different time points and in different cell types during embryonic development.

Treatment of PROS diseases is varied and depends on the specific pathology. No curative therapy has yet been proposed; the existing methods are aimed at managing the symptoms. Overgrowth and malformations of solid tissue are treated surgically. Sclerotherapy is used to treat vascular malformations.

The PROS diseases classification was proposed in 2013; previously, these pathologies were considered separate clinical syndromes.

The clinical diagnostic criteria for the PIK3CA-related overgrowth spectrum are as follows:

• Presence of somatic PIK3CA mutation
• Congenital or early childhood onset
• Overgrowth is sporadic and mosaic (patchy, irregular)
• At least two spectrum features or one isolated feature:

• Spectrum features:

• Overgrowth: adipose, muscle, nerve, skeletal
• Vascular malformations: capillary, venous, arteriovenous, lymphatic
• Epidermal nevus

• Isolated features:

• Large isolated lymphatic malformation
• Isolated macrodactyly OR overgrown splayed feet/hands, overgrown limbs
• Truncal adipose overgrowth
• Hemimegalencephaly (bilateral)/dysplastic megalencephaly/focal cortical dysplasia type II
• Epidermal nevus
• Seborrheic keratoses
• Benign lichenoid keratoses

PIK3CA-related overgrowth spectrum disorders include, for example, the following pathologies:

Klippel–Trénaunay syndrome (KTS), also known as angioosteohypertrophy syndrome, hemangiectatic hypertrophy (hypertrophic hemangiectasia), osteohypertrophic variceal nevus, vascular-bone dysembryopathy, sixth phakomatosis, partial gigantism of the vascular system.

• Capillary, venous, and lymphatic malformation, varicosity of unusual distribution (particularly the lateral venous anomaly), and unilateral soft and skeletal hypertrophy (usually in the lower extremities).
• Disfiguring port-wine stains, lymphatic overgrowths combined with lymphedema, bleeding from the rectum, vagina, or bladder, localized and/or disseminated intravascular coagulopathy, enlarged limbs.

CLOVES syndrome. Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, skeletal or spinal anomalies.

• Soft fatty masses of variable size in the back, flanks, axilla, abdomen, and buttocks.
• Dilated veins in the chest, upper and lower extremities can cause thrombosis.
• Large lymph-filled spaces inside fatty masses, abdomen, chest, and extremities.
• Large wide digits, hands or feet, wide space between digits (sandal gap toe), uneven size of extremities.
• Scoliosis (curving of the spine), fatty masses and vessels pushing on the spinal cord, and tethered cord.
• Skin birthmarks include port-wine stains, prominent veins, lymphatic vesicles, moles, and epidermal nevus (slightly raised areas of skin with light brownish color).
• On the skin, port-wine stains, prominent veins, lymphatic vesicles, moles, epidermal nevi (slightly raised areas of skin light brownish color).
• Asymmetric kidney size with abnormal features and sometimes nephroblastoma (Wilms’ tumor).

CLAPO syndrome, also known as Lopez–Gutierrez syndrome. Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth involving one or more body segments.

Megalencephaly–capillary malformation–polymicrogyria syndrome (MCAP), also known as macrocephaly–capillary malformation (M-CM).

• Primary megalencephaly (abnormally large brain), prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies (syndactyly, postaxial polydactyly), connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria (excessive folded topography with the insufficient depth of sulci).
• Excessively large head and brain with abnormal enlargement of its ventricles containing cerebrospinal fluid (ventriculomegaly), which can lead to hydrocephalus. Enlargement and herniation of the cerebellar tonsils (Chiari malformation) lead to hydrocephalus and brainstem compression. Development of associated neurological abnormalities including developmental delay, neurocognitive impairment, seizures, and muscle tone abnormalities.
• Characteristic skin lesions in the form of nevus flammeus (salmon patch) on the midline face, generalized cutis marmorata (marbling of the skin), and infantile hemangiomas.
• Webbing of the digits (syndactyly), extra fingers and toes (polydactyly), loose (hyperelastic) skin, loose joints (joint laxity), prominent forehead (frontal bossing), facial and limb asymmetry.

Diffuse capillary malformation with overgrowth (DCMO). Multiple and/or extensive capillary malformations are associated with facial asymmetry, limb overgrowth, and hand or foot deformities.

• Capillary malformations forming a patchy network of spots may be present on the abdomen but never on the back.
• Excessive limb growth does not progress, and therefore there are no vascular complications.

Hemimegalencephaly (HME). One-half of the brain, or one side of the brain, is abnormally larger than the other, leading to epileptic seizures, often associated with cognitive and behavioral disabilities. If the affected side is surgically removed (anatomic hemispherectomy) or disconnected from other brain structures (functional hemispherectomy) at an early age, the remaining side of the brain may gradually take over the functions normally performed by the affected side.

Dysplastic megalencephaly (DMEG), or bilateral hemimegalencephaly. Overgrowth of both hemispheres of the brain leads to poorly pharmacologically treatable epileptic seizures, severe neurological impairment, abnormal muscle tone, developmental delays in motor, language, and cognitive skills, and heart failure.

Focal cortical dysplasia type II (FCORD2), also known as focal cortical dysplasia of Taylor (FCDT). Cerebral developmental malformation that results in a clinical phenotype of intractable epilepsy, requiring neurosurgical resection of affected brain tissue to ameliorate seizure frequency and severity.

Isolated lymphatic malformation (ILM). Masses consist of fluid-filled channels or spaces and affect any area of the body (except the brain), but most commonly affect the head and neck.

Hemihyperplasia–multiple lipomatosis syndrome (HHML). Non-progressive, moderate hemihyperplasia (asymmetrical growth of one or more parts of the body), frequently affecting the limbs, associated with slow-growing, painless, multiple, recurrent, subcutaneous lipomatous masses distributed throughout the entire body (in particular back, torso, extremities, fingers, axillae).

Facial infiltrating lipomatosis (FIL), also known as congenital infiltrating lipomatosis of the face (CILF) or facial infused lipomatosis (FIL). Hemifacial (on one side of the face) overgrowth of soft tissue and skeleton, precocious dental development, regional macrodontia (oversized teeth), hemimacroglossia (enlarged tongue on one side), mucosal neuromas.

Fibroadipose vascular anomaly (FAVA), also erroneously known as intramuscular hemangiomas. Phlebectasia (dilatation of veins) and fibro-fatty replacement of muscle (most commonly in the calf musculature, forearm, thigh). It manifests as pain syndrome, reduced mobility, swelling, or visible veins.

Fibroadipose hyperplasia (FAH), also known as fibroadipose overgrowth (FAO). Patchy and progressive overgrowth of a limb or body part due to an overgrowth of subcutaneous or visceral fatty tissue, fibrous tissue and/or blood vessels in a particular region of the body.

Macrodactyly. Local (localized) gigantism develops due to an abundance of infiltrating fibro-fatty tissue and most often affects the fingers and toes.

Muscular hemihyperplasia, also known as muscular hemihypertrophy. Overgrowth of muscle tissue on only one side of the body.

Lipomatosis of nerve (LON), also known as fibrolipoma of nerve, fibrolipomatosis of nerve, fibrolipomatous hamartoma of nerve, neural lipofibromatous hamartoma, fibrolipomatous hamartoma (FLH), lipofibromatous hamartoma (LFH), neurolipomatosis, macrodystrophia lipomatosa.

• Overgrowth of fibro-fatty tissue along the nerve trunk leads to nerve compression and entrapment. Occurs in the extremities, often affects the median nerve (can affect the ulnar, radial, perineal nerve, brachial plexus), grows very slowly, leads to pain and loss of motor function in the hand (or leg), often accompanied by macrodactyly, muscular hemihyperplasia, and carpal tunnel syndrome.

 

Vijoice: Mechanism of Action of Alpelisib

Alpelisib (BYL719) is an oral small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K) with inhibitory activity primarily against its alpha isoform (PI3Kα).

Functional mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) result in activation of PI3Kα and Akt signaling, cell transformation, and tumor formation in vitro and in vivo models.

Activating mutations in PIK3CA cause a range of overgrowths and malformations that constitute a broad group of clinically distinct disorders known as the PIK3CA-related overgrowth spectrum (PROS).

In an inducible mouse model of CLOVES syndrome (a combination of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, skeletal and spinal anomalies), inhibition of the PI3K signaling pathway by alpelisib resulted in prevention or improvement of organ anomalies associated with this disease, depending on the time of initiation of alpelisib treatment. After the withdrawal of alpelisib, beneficial therapeutic results were reversed.

 

Vijoice: Clinical Efficacy and Safety of Alpelisib Against PROS

The EPIK-P1 (NCT04285723) clinical trial, a retrospective non-interventional medical chart review of patients with PIK3CA-related overgrowth spectrum (PROS), studied treatment with alpelisib in a compassionate use program in five countries (Australia, France, Ireland, Spain, USA).

Patients (age 2 years and older) diagnosed with PROS and a mutation in the PIK3CA gene had to be characterized by clinical manifestations of the disease requiring systemic treatment because of severity or life-threatening.

Among the main features of the participants (n=37): mean age 14 years (2–38), 57% were female, 92% had the pathology congenital, and the remaining 8% had the disease manifested in early childhood. Patients were characterized by heterogeneous manifestations of PROS: CLOVES syndrome (in 81% of subjects), MCAP syndrome (8%), facial infiltrating lipomatosis (8%), Klippel–Trénaunay syndrome (2.7%), and other pathologies (5%). Concurrent manifestations of CLOVES and MCAP syndromes were observed in 5% of patients.

Subjects were administered once-daily oral Vijoice at doses ranging from 50 to 250 mg (depending on age).

The primary efficacy endpoint was the proportion of patients responding to treatment by week 24 (±4 weeks): at least a 20% reduction in the sum of the volumes of the target lesions (1–3 lesions), according to the radiological examination. Prerequisites were: none of the lesions increased by ≥ 20%, no progression of non-target lesions, no new lesions.

Among the secondary endpoints: duration of response to treatment — as time from first confirmed response to first confirmed disease progression or death from any cause.

At the end of PROS treatment with Vijoice, the response rate was 27% (95% CI: 14 to 44).

The median duration of response (DoR) at the time of data collection was not reached: NR (0.9+ to 42.9+). Response for 6 months or longer was seen in 70% of respondents, and 12 months or longer in 60%.

Nearly three-quarters of patients (74%) testified to definite reductions (at a median of 13.7%) in the volume of target lesions. None of the subjects experienced disease progression and no new lesions were recorded.

Use of Vijoice was associated with improvement of such symptoms and signs as pain syndrome (in 91% of subjects), vascular malformations (79%), fatigue (77%), limb asymmetry (69%), disseminated intravascular coagulation (55%).

Functional improvements related to daily activity, physical ability, and ability to care for oneself were registered in 30% of patients.

The most common adverse reactions to alpelisib administration included diarrhea (in 16% of patients), stomatitis (16%), hyperglycemia (12%), eczema (7%), dry skin (7%), alopecia (5%), headache (5%), cellulitis (5%).

Allpelisib usage was reflected by marked changes in laboratory values: decreased calcium (60%), decreased phosphate (59%), increased glucose (56%), increased creatinine (31%), increased bilirubin (29%), decreased leukocyte (22%), etc.

The prescribing information for Vijoice contains statements about the risks of severe cuutaneous adverse reactions [SCARs] (Stevens–Johnson syndrome [SJS], erythema multiforme [EM], toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms [DRESS]); hyperglycemia (may be associated with hyperglycemic hyperosmolar non-ketotic syndrome [HHNKS] or ketoacidosis); pneumonitis and interstitial lung disease; severe diarrhea, dehydration, and acute kidney injury; embryo-fetal toxicity.

 

Vijoice: Expert Comments

The emergence of Vijoice is without a doubt a great advance in pharmacological science. It cannot be said that Vijoice is the perfect rescue for all patients suffering from the PIK3CA-related overgrowth spectrum (PROS). Nevertheless, this drug is sure to help, even if not all patients will benefit as much as possible from its use.

The fact that the price tag of Vijoice is almost double that of Piqray (with the same active ingredient as alpelisib) is due to the very rare occurrence of PROS in the general population. Novartis could have charged even more, but apparently felt that using the drug on a permanent (lifelong) basis would pay for itself in the end.

A 5-year EPIK-P3 (NCT04980833) phase 2 clinical trial is being conducted among participants in the pivotal EPIK-P1 (NCT04285723) to determine the long-term efficacy and safety of Vijoice in the treatment of PROS.

In parallel, the EPIK-P2 (NCT04589650) phase 2 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) is being organized as a confirmatory study, which is necessary to obtain full regulatory approval of Vijoice.

The basis for a thorough study of alpelisib in the treatment of PROS was the very positive results of its clinical trial, conducted by French specialists, to whom Novartis provided the drug, still experimental at the time.

 

Extras

Vijoice (alpelisib). Prescribing information. U.S. [PDF]

LBA23 EPIK-P1: Retrospective chart review study of patients (pts) with PIK3CA-related Overgrowth Spectrum (PROS) who have received alpelisib (ALP) as part of a compassionate use programme. Ann Oncol. 2021 Sep. [source]

PIK3CA-related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015 Feb;167A(2):287-95. [source]

Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014 Jul;164A(7):1713-33. [source]

PIK3CA-related overgrowth spectrum. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2019. [source]

PIK3CA vascular overgrowth syndromes: an update. Curr Opin Pediatr. 2020 Aug;32(4):539-546. [source]

Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med. 2019 May;21(5):1189-1198. [source]

Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018 Jun 1; 558(7711): 540–546. [source]