Summary Basis of Decision for Piqray

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Piqray is located below.

Recent Activity for Piqray

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Piqray

Date SBD issued: 2020-08-27

The following information relates to the new drug submission for Piqray.

Alpelisib

Drug Identification Number (DIN):

  • DIN 02497042 - 50 mg tablet, oral administration
  • DIN 02497069 - 150 mg tablet, oral administration
  • DIN 02497077 - 200 mg tablet, oral administration
  • DIN 02497085 - 50 mg and 200 mg tablets/kit, oral administration

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 226941

On March 11, 2020, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Piqray.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Piqray, in combination with fulvestrant, is favourable for the treatment of postmenopausal women, and men, with hormone receptor‑positive, HER2‑negative, PIK3CA‑mutated advanced or metastatic breast cancer after disease progression following an endocrine‑based regimen.

1 What was approved?

Piqray, an antineoplastic agent, in combination with fulvestrant, was authorized for the treatment of postmenopausal women, and men, with hormone receptor‑positive, HER2‑negative, PIK3CA‑mutated advanced or metastatic breast cancer after disease progression following an endocrine‑based regimen.

Piqray is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.

The safety and efficacy of Piqray in pediatrics (<18 years of age) have not been established. Piqray is therefore not authorised for use in pediatric patients.

No overall differences in the safety and efficacy were observed between geriatric patients (≥65 years of age) and younger patients. However, gastrointestinal toxicity (primarily diarrhea and nausea), hyperglycemia, weight decrease, hypokalemia and dyspnea were reported more frequently in older patients.

Piqray was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Piqray (50 mg, 150 mg, 200 mg, 50 mg and 200 mg tablets/kit alpelisib) is presented as a tablet. In addition to the medicinal ingredient alpelisib, the tablet contains hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, sodium starch glycolate, hypromellose, iron oxide black, iron oxide red, macrogol/polyethylene glycol (PEG), talc, and titanium dioxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Piqray Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Piqray approved?

Health Canada considers that the benefit‑risk profile of Piqray, in combination with fulvestrant, is favourable for the treatment of postmenopausal women, and men, with hormone receptor‑positive, HER2‑negative, PIK3CA‑mutated advanced or metastatic breast cancer after disease progression following an endocrine‑based regimen.

In Canada, breast cancer is the most common cancer diagnosed in women and the second leading cause of cancer‑related death in women. In 2017, approximately 26,000 newly diagnosed breast cancer cases were reported representing almost 25% of all new cancer cases in women. Approximately 5,000 women died from breast cancer, representing 13% of all cancer deaths in women. In men, breast cancer is rare, constituting less than 1% of all breast cancer diagnoses. In 2017, approximately 30 men were diagnosed with breast cancer and 60 men died from breast cancer.

Breast cancer can be categorized into different histopathologic subtypes based on the overexpression or gene amplification of the hormone receptor (HR; estrogen receptor and progesterone receptor), and human epidermal growth factor receptor 2 (HER2). Of the new cancers diagnosed worldwide each year, approximately 60% to 65% are HR‑positive, 20% to 25% are HER2‑positive (HR‑positive or negative), and 15% to 18% are triple negative.

Endocrine therapy is the treatment of choice for patients with HR‑positive advanced breast cancer. Endocrine therapies include selective estrogen receptor (ER) modulators (tamoxifen), ER antagonists (fulvestrant), and aromatase inhibitors (letrozole, anastrozole, and exemestane). Two classes of targeted agents (mammalian target of rapamycin [mTOR] inhibitors, and cyclin-dependent kinase 4/6 [CDK4/6] inhibitors) have demonstrated clinical efficacy when combined with endocrine therapy and obtained regulatory approvals in advanced HR-positive, HER2-negative breast cancer. No predictive biomarkers in relation to the mechanism of action of the drugs have been identified to select patients that would benefit the most from these therapies to date.

Progressive disease ultimately develops in all patients due to primary resistance (de novo resistance) or relapse/progression following an initial response (acquired resistance). Despite significant advances in treating patients with HR‑positive breast cancer, the development of endocrine resistance and hence disease progression remains a critical problem.

Constitutive activation of phosphatidylinositol 3‑kinase (PI3K) signaling is postulated to be a critical pathway that regulates cell proliferation, glucose metabolism, growth, survival, and apoptosis. Constitutive activation of this pathway has also been linked to resistance for a variety of therapeutic interventions. Mutations in PIK3CA, the gene coding for the catalytic subunit p110α of PI3K, are present in 34% of human breast cancers and are considered one of the key drivers in breast cancer. The majority of the PIK3CA mutations present as 'hotspot' mutations in exons 9 and 20 and, to a lesser extent, in exon 7. The high prevalence of PI3Kα mutations in breast tumours, and in particular in HR‑positive, HER2‑negative breast tumours, highlights the importance of testing for PIK3CA mutation status in guiding treatment decisions. Cross talk between the PI3K/AKT/mTOR and ER signaling pathways predestines HR‑positive, HER2‑negative breast cancer for dual inhibition treatment with a PI3K and an ER inhibitor. Targeted therapy with a PIK3CA inhibitor could therefore be considered a potentially valuable treatment option.

Alpelisib (the medicinal ingredient in Piqray) is an oral, PI3Kα inhibitor. Fulvestrant (Faslodex 50 mg/mL for injection), an ER antagonist, has been approved for the treatment of ER‑positive and HER2‑negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy or who have disease progression following prior anti-estrogen therapy.

The market authorization was based primarily on one pivotal Phase III, randomized, double‑blind, placebo‑controlled study (SOLAR-1; also known as C2301). In the study, Piqray in combination with fulvestrant was shown to be efficacious in postmenopausal women, and men, with hormone receptor‑positive, HER2‑negative, PIK3CA‑mutated advanced (metastatic or loco-regionally recurrent) breast cancer after disease progression following an endocrine‑based regimen. A total of 572 patients were enrolled into two cohorts based on PIK3CA mutation status: 341 patients in the PIK3CA mutated cohort and 231 patients in the PIK3CA non-mutated cohort. In both cohorts, patients were then randomized to receive either Piqray plus fulvestrant or a placebo plus fulvestrant treatment. The primary endpoint of the study was progression‑free survival (PFS), as assessed by investigators based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The study met its primary endpoint in patients with a PIK3CA mutation, with a clinically meaningful and statistically significant improvement in investigator-assessed PFS for Piqray plus fulvestrant compared to placebo plus fulvestrant. An estimated 35% risk reduction in disease progression or death was observed in favor of the Piqray plus fulvestrant treatment group, with an increase in the median PFS of 5.3 months (from 5.7 to 11.0 months). In addition, the PFS benefit was generally consistent across pre‑planned sensitivity, supportive, and subgroup analyses. Overall survival data, a secondary endpoint, were not mature but were not detrimental to patients treated with Piqray plus fulvestrant. Other secondary endpoints, including overall response rate and clinical benefit rate were supportive of the primary endpoint. The proof-of-concept criteria were not met in the PIK3CA non-mutated cohort, indicating a lack of clinical activity in this population. Therefore, Piqray is not recommended for use in patients with PIK3CA non‑mutated HR-positive, HER-2 negative breast cancer.

The safety assessment was primarily based on the safety data of 571 patients in the pivotal study. Almost all patients (99.3%) in the Piqray plus fulvestrant group experienced at least one adverse event. The most common adverse reactions were hyperglycemia, diarrhea, rash, nausea, fatigue and asthenia, decreased appetite, stomatitis, vomiting and weight decreased.

Serious adverse reactions reported in patients treated with Piqray plus fulvestrant which are included in the Serious Warnings and Precautions box of the Piqray Product Monograph are hypersensitivity (including anaphylactic reaction), severe cutaneous reactions (including Stevens-Johnson Syndrome), hyperglycemia (including diabetic ketoacidosis), and pneumonitis.

Piqray in combination with fulvestrant has a manageable safety profile for patients with HR‑positive, HER2‑negative advanced breast cancer. Reported adverse events are mainly associated with PI3K pathway inhibition, such as hyperglycemia, rash, and gastrointestinal toxicity. These adverse events are well characterized and manageable with dose modifications and/or intervention therapies.

A Risk Management Plan (RMP) for Piqray was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Piqray Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Piqray was accepted.

Overall, the therapeutic benefits of Piqray therapy seen in the pivotal study SOLAR‑1 (also known as C2301) are positive and are considered to outweigh the potential risks. Piqray has a manageable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Piqray Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Piqray?

Submission Milestones: Piqray

Submission MilestoneDate
Pre-submission meeting:2019-01-22
Submission filed:2019-04-17
Screening
Screening Acceptance Letter issued:2019-05-17
Review
Review of Risk Management Plan complete:2020-02-05
Biopharmaceutics Evaluation complete:2020-03-02
Quality Evaluation complete:2020-03-10
Clinical/Medical Evaluation complete:2020-03-11
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2020-03-11
Notice of Compliance issued by Director General, Therapeutic Products Directorate/Biologics and Genetic Therapies Directorate:2020-03-11

The Canadian regulatory decision on the clinical review of Piqray was based on a critical assessment of the data package submitted to Health Canada.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Piqray?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Piqray. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Alpelisib (the medicinal ingredient in Piqray) is an oral α‑specific class I phosphatidylinositol‑3‑kinase (PI3K) inhibitor belonging to the 2‑aminothiazole class of compounds. Alpelisib inhibits the signaling PI3K pathway by binding to certain phospholipids in the cell membrane. When inhibiting the transmission of signals, alpelisib stops the signaling of cell growth and cell reproduction. This inhibition in signaling pathway eventually causes cell death and stops tumour cells from spreading.

The pharmacokinetics of alpelisib have been studied in healthy subjects and adult patients with solid tumours. Steady‑state plasma concentrations (Cmax) were reached within 3 days following daily dosing. In adult solid tumour patients administered multiple doses of alpelisib 300 mg once daily, the mean steady‑state alpelisib Cmax was 2,480 ng/mL, the area under the plasma concentration‑time curve (AUCtau) based on a uniform dosing interval was 33,224 ng*h/mL, and the half‑life (t1/2) was observed to be approximately 9 hours. Alpelisib does not exhibit time‑dependent pharmacokinetics and accumulates in plasma up to 1.3- to 1.5‑fold following multiple dose administration. Plasma Cmax and AUC of alpelisib increase in a dose‑proportional manner over the range of 30 mg to 450 mg under fed conditions. The apparent steady‑state volume of distribution of alpelisib was 114 L with a plasma protein binding of 89%. Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form inactive metabolite BZG791 (40 to 45%), and cytochrome (CYP) 3A4‑mediated metabolites (12%) and glucuronides amounting to 15% of the dose. Approximately, 81% of the administered alpelisib dose was recovered in feces (36% alpelisib, 32% BZG791) and 14% (2% alpelisib, 7.1% BZG791) in urine as parent drug and metabolites.

The relationship between alpelisib exposure and clinical efficacy (progression free survival) demonstrated that time-normalized alpelisib Ctrough concentrations greater than or equal to the median value (373 ng/mL) and time-normalized alpelisib dose intensity greater than or equal to the median value (248 mg/day) was associated with a higher median PFS than for those with a value below the median. Exposure safety analysis showed that increased alpelisib exposure was associated with increased safety risk of hyperglycemia and rash that could be managed by dose interruptions and dose reductions.

No dose adjustment of alpelisib is necessary in patients with mild (estimated glomerular filtration rate [eGFR] 60 to <90 mL/min/1.73 m2) and moderate (eGFR 30 to <60 mL/min/1.73 m2) renal impairment. The effect of severe renal impairment (eGFR <30 mL/min/1.73 m2) on the pharmacokinetics of alpelisib has not been evaluated and is unknown.

No dose adjustment of alpelisib is necessary in patients with mild, moderate or severe hepatic impairment based on Child-Pugh classification.

Co‑administration of alpelisib with a strong CYP3A4 inducer (rifampin) may decrease alpelisib plasma concentration and must be avoided. Co‑administration of alpelisib with a sensitive CYP2C9 substrate (warfarin) may reduce the plasma concentration of CYP2C9 substrates and hence must be monitored. Co‑administration of alpelisib with breast cancer resistance protein (BCRP) inhibitor (cyclosporine) may increase alpelisib plasma concentration and the risk of adverse reactions, and should be avoided.

For further details, please refer to the Piqray Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Piqray, in combination with fulvestrant, was primarily based on one pivotal Phase III study (SOLAR‑1; also known as C2301). Supportive evidence was provided in a Phase I/II dose‑escalation and expansion study, X2101.

The pivotal Phase III SOLAR‑1 study was a randomized, multicentre, international, double‑blind, placebo‑controlled study which compared the efficacy and safety of Piqray plus fulvestrant in postmenopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had disease progression following endocrine based therapy. A total of 572 HR‑positive, HER2‑negative patients (including one male patient) were enrolled in the SOLAR‑1 study. Based on PIK3CA mutation tests using tumour tissue, patients were divided into two cohorts: the PIK3CA‑mutated cohort or the PIK3CA non‑mutated cohort.

Overall demographics and baseline disease characteristics, Eastern Cooperative Oncology Group (ECOG) performance status, tumour burden, and prior antineoplastic therapy were generally well balanced between the treatment groups. In the PIK3CA‑mutated cohort at baseline, 98% of patients had stage IV disease and 69% had <3 metastatic sites. The majority of patients had bone metastases with or without other metastases at baseline. Almost all patients received prior hormonal therapy as the last treatment either in metastatic or adjuvant setting, and 6% had previously been treated with a CDK4/6 inhibitor. Primary endocrine resistance was reported in 13% of patients and secondary endocrine resistance in 72% of patients.

In each cohort, patients were then randomly assigned in a 1:1 ratio to receive either Piqray plus fulvestrant, or placebo plus fulvestrant treatment. The dosing regimen consisted of administering Piqray 300 mg or matching placebo orally once daily on a continuous basis; while fulvestrant 500 mg was administered intramuscularly on Cycle 1 Day 1 and 15 and then at Day 1 of a 28‑day cycle (administration +/-3 days). Patients were not allowed to cross over from placebo to Piqray treatment group during the study or after disease progression. Patients received treatment until disease progression or if they experienced an unacceptable level of toxic effects. Overall, the median treatment duration was 8.2 months in the Piqray plus fulvestrant treatment group and 5.6 months in the placebo plus fulvestrant treatment group. The median study follow‑up in the PIK3CA mutation cohort was 20 months.

The primary endpoint of the study was progression‑free survival (PFS), as assessed by the investigator, according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in the cohort of patients with PIK3CA‑mutated cancer. A key secondary endpoint was overall survival (OS) in the cohort with PIK3CA‑mutated cancer. Additional secondary endpoints included PFS and OS in the cohort without PIK3CA‑mutated cancer, overall response rate (ORR; complete response or partial response), and clinical benefit rate (CBR; defined as a complete or partial response or as stable disease of greater than or equal to 6 months).

Results obtained from the efficacy analyses demonstrated a clinically meaningful and statistically significant improvement in investigator‑assessed PFS in the Piqray plus fulvestrant treatment group as compared to the placebo plus fulvestrant treatment group, for the cohort of patients with PIK3CA‑mutated cancer. An estimated 35% risk reduction of disease progression or death was observed in the Piqray plus fulvestrant treatment, with an increase in the median PFS of 5.3 months (11.0 months vs. 5.7 months). In addition, the PFS benefit was generally consistent across pre‑planned sensitivity, the supportive and subgroup analyses that included stratification factors, major demographics, prior therapies and other prognostic factors, such as lung/liver metastases and bone lesions only.

At the time of final PFS analysis, OS data in the PIK3CA‑mutated cohort were not mature with 92 (27%) deaths reported, but not detrimental to patients treated with Piqray plus fulvestrant. Treatment with Piqray plus fulvestrant was also associated with marked improvements in ORR and CBR relative to placebo plus fulvestrant. The differential rate in ORR and CBR between the two treatment groups was consistent with the observed gain in PFS. Time to definitive deterioration in ECOG performance status (PS) score was similar between the two treatment groups.

A PFS benefit with Piqray plus fulvestrant treatment was not demonstrated in the PIK3CA non-mutated cohort, indicating a lack of clinical activity in this patient population. In addition, there were no statistical differences of ORR and CBR between the two treatment groups. Therefore, Piqray is not recommended for use in patients with PIK3CA non-mutated HR-positive, HER-2 negative breast cancer.

In conclusion, the pivotal SOLAR‑1 study met its primary endpoint in the PIK3CA mutated cohort, demonstrating a statistically significant and clinically meaningful improvement in PFS in favor of Piqray plus fulvestrant treatment. The combination therapy at the recommended dose offers a valuable new treatment option for patients with HR‑positive, HER2‑negative advanced breast cancer harboring a PIK3CA mutation, with disease progression on or following an endocrine‑based regimen. In the context of the significant clinical benefit observed for this target population with limited therapeutic options, the safety profile of this combination regimen is considered acceptable. The totality of the data support a favorable benefit‑risk profile for Piqray in combination with fulvestrant for the treatment of postmenopausal women and men with HR‑positive, HER2‑negative, PIK3CA‑mutated, advanced breast cancer after disease progression following an endocrine‑based regimen.

Supportive Study

Data from a Phase I/II dose‑escalation and expansion study, X2101, provided further evidence of the efficacy of Piqray plus fulvestrant in a heavily pre‑treated population of patients with PIK3CA-altered advanced breast cancer. In the expansion cohort, 49 previously treated patients with ER‑positive, HER2‑negative, and PIK3CA‑altered metastatic breast cancer were treated with Piqray plus fulvestrant. Study results showed that the median PFS was 9.1 months; ORR and CBR were 28.6% and 44.9%, respectively.

Indication

The New Drug Submission for Piqray was filed by the sponsor with the following indication:

  • Piqray (alpelisib) is indicated for the treatment of postmenopausal women, and men, with hormone receptor‑positive, HER2‑negative advanced breast cancer with a PIK3CA mutation in combination with fulvestrant after disease progression following an endocrine‑inclusive regimen.

Health Canada approved the following indication:

  • Piqray (alpelisib), in combination with fulvestrant, is indicated for the treatment of postmenopausal women, and men, with hormone receptor‑positive, HER2‑negative, PIK3CA-mutated advanced or metastatic breast cancer after disease progression following an endocrine‑based regimen.

For more information, refer to the Piqray Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The overall safety profile of Piqray, in combination with fulvestrant, is based primarily on the pivotal Phase III clinical study SOLAR-1, previously described in the Clinical Efficacy section. Data from the PIK3CA‑mutated and non-mutated cohorts were combined to provide a more robust safety evaluation. In the safety set (number of patients [n] = 571), 283 patients received Piqray in combination with fulvestrant, and 286 patients received placebo in combination with fulvestrant. The median treatment duration in the SOLAR‑1 study was 8.2 months in the Piqray plus fulvestrant cohort and 5.6 months in the placebo plus fulvestrant cohort. In the Piqray plus fulvestrant arm, exposure to fulvestrant was longer than to Piqray (median 8.2 vs 5.6 months, with 59% of patients exposed to fulvestrant for ≥6 months), reflecting that patients who discontinued Piqray continued treatment with fulvestrant.

Overall, Piqray, in combination with fulvestrant, is characterized by a manageable safety profile in patients with HR‑positive, HER2-negative advanced breast cancer. Almost all patients (99.3%) in the Piqray plus fulvestrant cohort (versus 92.0% in the placebo plus fulvestrant cohort) experienced at least one adverse event. The most common adverse events reported in the Piqray plus fulvestrant cohort (≥20% incidence) were hyperglycemia, diarrhea, nausea, decreased appetite, rash, vomiting, decreased weight, stomatitis, fatigue, and asthenia.

Serious AEs were reported more frequently in the Piqray plus fulvestrant group relative to the placebo plus fulvestrant group (34.9% vs. 16.7%). The most common serious adverse reactions reported in ≥1% of the patients in Piqray plus fulvestrant cohort were hyperglycemia, diarrhea, abdominal pain, nausea, acute kidney injury, rash, osteonecrosis of the jaw, maculo‑papular rash, erythema multiforme, hypersensitivity, anemia, pyrexia, stomatitis, mucosal inflammation, dehydration, vomiting and hypokalemia. The following serious adverse reactions were included in a Serious Warnings and Precautions box of the Piqray Product Monograph: hypersensitivity (including anaphylactic reaction), severe cutaneous reactions (including Stevens-Johnson Syndrome), hyperglycemia (including diabetic ketoacidosis), and pneumonitis.

Dose reductions due to adverse events occurred in 57.7% of patients receiving Piqray plus fulvestrant. Permanent discontinuation of Piqray and/or fulvestrant due to adverse events were reported in 25% of patients. The most common adverse events leading to treatment discontinuation of patients treated with Piqray and fulvestrant were hyperglycemia (6%), rash (3%), diarrhea (3%), and fatigue (2%).

Piqray treatment has been shown to be associated with QT prolongation based on nonclinical and clinical data. An analysis of clinical electrocardiogram data from the X2101 study (a supportive study) showed that mean increases from baseline in QTcF were 8.7 msec (90% confidence interval: 4.1, 13.3 msec) in patients treated with Piqray at the clinically recommended dose. Both the mean and the upper limit of 90% confidence interval exceeded the threshold defined in the International Council on Harmonisation E14 guideline - The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non‑Antiarrhythmic Drugs. This QT prolongation finding was captured in the Piqray Product Monograph as a warning regarding concomitant use of Piqray with drugs known to cause QTc prolongation.

Overall, Piqray in combination with fulvestrant is characterized by a manageable safety profile in the intended patient population. The aforementioned major safety findings, clinical monitoring and management were outlined in the finalized Piqray Product Monograph. Data from these studies allowed for an informed assessment of the safety profile of the Piqray plus fulvestrant combination and an evaluation of the overall benefit‑risk in postmenopausal women and men with HR‑positive, HER2‑negative, PIK3CA-mutated, advanced breast cancer after disease progression following an endocrine‑based regimen.

For more information, refer to the Piqray Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Alpelisib (the medicinal ingredient in Piqray) inhibits the α-isoform of PIK3 (wild type and two mutants H1047R, E545K) to a higher degree compared to the other isoforms. In vivo, alpelisib treatment showed dose-dependent tumour growth inhibition in mouse xenograft models of breast cancer. In in vivo studies in estrogen receptor positive (ER+) breast cancer xenograft mouse models, combination of alpelisib and fulvestrant demonstrated increased anti-tumour activity compared to fulvestrant alone. Combination of alpelisib with fulvestrant was also shown to be effective in ER+ breast cancer cell line xenografts progressing on everolimus (mTORC1) treatment or cyclin-dependent kinase (CDK) 4/6 inhibitor treatment. In a secondary pharmacology study, alpelisib caused hyperglycemia and insulin insensitivity in all three species investigated, i.e. mouse, rat and dog.

In a safety pharmacology study, a single oral administration of alpelisib induced a dose-independent increase in systolic and diastolic blood pressure in dogs at all doses tested. In vitro, the half maximal inhibitory concentration (IC50) of alpelisib for inhibition of the human Ether‑à‑go‑go‑Related Gene (hERG) transmission was 9.4 µM, which is similar to the maximum serum concentration (Cmax, 6.8 µM) at the clinically recommended dose of 300 mg. There were no adverse effects on electrocardiogram, respiration, or neurological behavior in animals.

In repeated‑dose studies (up to 13 weeks), administration of alpelisib to rats and dogs resulted in adverse effects in the gastrointestinal tract, hemolymphoid system, skin, and metabolic system. In addition, adverse events in the reproductive system suggest that alpelisib has the potential to impair male and female fertility.

Glucose homeostasis was affected in various species (mice, rats, dogs). These effects in both rats and dogs were correlated with pancreatic histology changes. Other changes related to alpelisib include atrophy in mammary gland and lacrimal glands, odontoblast degeneration, pathological changes in bone density, and in the cornea in dogs. Most alpelisib‑induced toxicities were dose‑dependent and generally reversible after a 4- or 8‑week treatment‑free recovery period.

In both pregnant rats and rabbits, alpelisib treatment during organogenesis was associated with embryo‑fetal death, a reduction in fetal weight and increased fetal malformations below exposures in humans at the recommended clinical dose. Based on these findings in animals and the mechanism of action, alpelisib can cause fetal harm when administered to a pregnant woman.

Overall, the submitted nonclinical data was in accordance with International Council for Harmonisation guidelines and is adequate to support the approval for the oral daily use of Piqray for the proposed indication.

For more information, refer to the Piqray Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Piqray has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 30 months is acceptable when the drug product is stored as recommended.

Proposed limits of drug‑related impurities are considered adequately qualified (i.e. within International Council for Harmonisation limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the materials used in the manufacture of Piqray drug substance or drug product are of human or animal origin.

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