Summary Basis of Decision for Pemazyre

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 Pemazyre is located below.

Recent Activity for Pemazyre

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Pemazyre, a product which contains the medicinal ingredient pemigatinib. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-06-07

Drug Identification Number (DIN):

  • DIN 02519933 – 4.5 mg pemigatinib, tablet, oral administration
  • DIN 02519941 – 9 mg pemigatinib, tablet, oral administration
  • DIN 02519968 – 13.5 mg pemigatinib, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DIN 02519933) market notification

Not applicable

Date of first sale: 2022-01-06

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02519941) market notification

Not applicable

Date of first sale: 2021-11-30

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02519968) market notification

Not applicable

Date of first sale: 2021-11-26

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 242569

2020-09-10

Issued NOC under NOC/c Guidance 2021-09-17

NOC issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Pemazyre

Date SBD issued: 2022-02-16

The following information relates to the New Drug Submission for Pemazyre.

Pemigatinib

Drug Identification Number (DIN):

  • DIN 02519933 - 4.5 mg pemigatinib, tablet, oral administration
  • DIN 02519941 - 9 mg pemigatinib, tablet, oral administration
  • DIN 02519968 - 13.5 mg pemigatinib, tablet, oral administration

Inc.yte Corporation

New Drug Submission Control Number: 242569

 

On September 17, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Incyte Corporation for the drug product Pemazyre. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

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-harm-uncertainty profile of Pemazyre is favourable for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Clinical effectiveness of Pemazyre is based on overall response rate and duration of response from a single-arm Phase II trial (Study FIGHT-202) in patients with specific FGFR2 rearrangements.

Treatment with Pemazyre should be initiated following confirmation of an FGFR2 fusion or rearrangement using a validated test.

 

1 What was approved?

 

Pemazyre, a protein kinase inhibitor, was authorized for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Clinical effectiveness of Pemazyre is based on overall response rate and duration of response from a single-arm Phase II trial in patients with specific genetic alteration in FGFR2.

Treatment with Pemazyre should be initiated following confirmation of an FGFR2 fusion or rearrangement using a validated test.

Data regarding the use of Pemazyre in patients younger than 18 years of age have not been submitted to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use.

Of the 146 patients treated with Pemazyre in Study FIGHT-202, 46 (31.5%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Pemazyre 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.

Pemazyre 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.

Pemazyre (4.5 mg, 9 mg, and 13.5 mg pemigatinib) is presented as a tablet. In addition to the medicinal ingredient, the tablet also contains magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

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 Pemazyre Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Pemazyre approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Pemazyre is favourable for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Pemazyre was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Cholangiocarcinoma is a highly malignant invasive carcinoma that originates from bile duct epithelial cells. The prognosis for cholangiocarcinoma is generally poor owing to the aggressive nature of the disease, the paucity of effective treatment options, and the late stage at which the disease is typically diagnosed. The 5-year survival rate by the American Joint Committee on Cancer stage is 50% for Stage I, 30% for Stage II, 10% for Stage III, and 0% for Stage IV.

Surgery is the preferred treatment option for patients with cholangiocarcinoma. However, most patients have advanced-stage disease at the time of diagnosis, and only 35% are eligible for surgical resection with curative intent. For patients with advanced-stage or unresectable cholangiocarcinoma, the median overall survival with standard of care chemotherapy is less than one year. There are currently no Health Canada-approved drugs for the treatment of patients with cholangiocarcinoma in the second-line setting.

Fibroblast growth factor/fibroblast growth factor receptor (FGFR) fusions are a reported genetic modification most commonly in intrahepatic cholangiocarcinoma, and have been identified as an early driver of oncogenic events in this disease. The FGFR2 fusions are present in an estimated 10 to 16% of patients with intrahepatic cholangiocarcinoma.

Pemigatinib (the medicinal ingredient in Pemazyre) is a small molecule kinase inhibitor of FGFR1, 2, and 3. It inhibits FGFR phosphorylation and signaling and selectively decreases cell viability in cancer cell lines with activating FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements. These genetic alterations in FGFR genes result in activation of FGFR signaling that supports the proliferation and survival of malignant cells.

Pemazyre has been shown to be efficacious in adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. The market authorization with conditions was based primarily on efficacy and safety data from one single-arm Phase II trial, Study FIGHT-202. The efficacy population consisted of 107 patients with previously treated locally advanced or metastatic cholangiocarcinoma, and who had an FGFR2 gene fusion or non-fusion rearrangement, as determined by a clinical trial assay. Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact. Patients received Pemazyre in 21-day cycles consisting of 13.5 mg once daily oral dosing for 14 days, followed by 7 days off therapy. Pemazyre was administered until disease progression or unacceptable toxicity.

After a median duration of therapy of 6.0 months, and median duration of efficacy follow-up of 15.4 months, there was a clinically meaningful confirmed objective response rate, as assessed by the independent review committee, of 35.5% (95% confidence interval: 26.5%, 45.4%) including 3 complete responses and 35 partial responses. The study achieved the predetermined threshold for a positive outcome, which required the lower limit of the 95% confidence interval for the objective response rate to exceed 15%.

The detected responses appeared durable, with a median duration of response of 9.1 months (95% confidence interval: 6.0 months, 14.5 months), as assessed by the independent review committee. Historically, this patient population has a poor prognosis. Published literature results from various second line therapies indicate that in advanced cholangiocarcinoma, the objective response rate for second line or later treatments is 10% or less. Furthermore, the overall survival rate for this patient population is estimated to be 5 to 6 months. In this context, the reported objective response rate of 35.5% and duration of response of 9.1 months demonstrate a clinically meaningful benefit. Subgroup analyses, while not statistically significant, demonstrated consistent, favourable objective response rate data, with the 95% confidence interval of each participant group within the subgroups overlapping the 95% confidence interval for all participants with the qualifying FGFR2 fusion or rearrangement. Overall, these efficacy data from Study FIGHT-202 provide promising evidence of a clinically meaningful benefit of Pemazyre in the proposed indication; however, these data remain to be confirmed by the reported efficacy obtained in the ongoing randomized Phase III Study INCB54828-302.

The primary safety data from the Phase II Study FIGHT-202 (number of patients [n] = 146) and integrated safety data from across the studies in the clinical development program (n = 466), revealed a consistent safety profile for Pemazyre. However, only the data from the 146 patients from the FIGHT-202 trial were included in the final Pemazyre Product Monograph.

In Study FIGHT-202, the most common treatment-emergent adverse event was hyperphosphatemia, which was reported in 60% of patients. Hyperphosphatemia is an expected adverse event due to the pharmacodynamic effects of pemigatinib. Adverse events of hyperphosphatemia were primarily managed by dose interruption (1.4%), dose reduction (0%), and phosphate-lowering therapy (18.5%), when necessary. Phosphate elevations did not appear to be associated with any clinical sequelae.

Serious treatment-emergent adverse events occurred in 45% of patients. The most common serious adverse events, reported in more than 3% of patients, were abdominal pain, pyrexia, cholangitis, and pleural effusion. Dose interruptions and dose reductions due to adverse events occurred in 43% and 14% of patients, respectively; most commonly due to stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, and fatigue. Adverse events of Grade 3 or higher were experienced in 64% of patients. The most frequently reported adverse event (Grade 3 or higher) was hypophosphatemia. This event frequently occurred during the 7-day off-treatment phase of the recommended dose regimen.

Serous retinal detachment events are known adverse events associated with FGFR2 inhibitors, and led to Pemazyre discontinuation in 0.4% of patients, dose interruption in 1.7% of patients, and dose reduction in 0.4% of patients in Pemazyre clinical trials. Routine monitoring including optical coherence tomography to detect asymptomatic serous retinal detachment was not performed in the Pemazyre clinical trials. Therefore, the incidence of asymptomatic serous retinal detachment with Pemazyre is unknown. Baseline ophthalmological exams and routine monitoring for eye disorders were important risk mitigation measures implemented in Study FIGHT-202, and have been included as recommendations in the Pemazyre Product Monograph.

Overall, the safety profile of Pemazyre is considered acceptable, given the target patient population and seriousness of the disease, with adverse events typically manageable by dose reduction, temporary treatment discontinuation, and/or standard medical care. The Pemazyre Product Monograph includes recommendations regarding adverse event monitoring and dose modifications, as well as reference to physician education materials pertaining to the diagnosis and management of serous retinal detachment.

Additional safety data will be assessed when the final report of the ongoing, randomized Phase III confirmatory trial is submitted to Health Canada, as part of the conditions under the NOC/c Guidance.

A Risk Management Plan (RMP) for Pemazyre was submitted by Incyte Corporation 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 Pemazyre Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Pemazyre was accepted.

Overall, the data from Study FIGHT-202 provided promising evidence of clinical effectiveness and demonstrated a favourable benefit-risk profile for the target patient population. The identified safety issues can be managed through labelling and sufficient monitoring. Appropriate warnings and precautions are in place in the Pemazyre Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Pemazyre will be ongoing. Further evaluation will take place upon the submission of the final report of the ongoing randomized Phase III Study INCB54828-302.

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 Pemazyre?

 

The New Drug Submission (NDS) for Pemazyre was filed under the Notice of Compliance Pathway. Subsequent review of the NDS for Pemazyre led to the decision to issue the sponsor market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

 

Submission Milestones: Pemazyre

Submission Milestone Date
New Drug Submission filed 2020-09-17
Screening  
Screening Acceptance Letter issued 2020-10-15
Review  
Review of Risk Management Plan completed 2021-05-26
Quality evaluation completed 2021-07-28
Non-clinical evaluation completed 2021-07-30
Labelling review completed 2021-07-29
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: 2021-08-06
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking) 2021-08-17
Clinical/Medical Evaluation complete 2021-09-02
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance 2021-09-17

 

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

 

4 What follow-up measures will the company take?

 

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to submit to Health Canada:

  • As a Supplement to a New Drug Submission - Confirmatory (SNDS-C), the final report for the confirmatory study entitled: INCB54828-302 - A Phase III, open label, randomized, active controlled, multicenter study to evaluate the efficacy and safety of pemigatinib versus gemcitabine plus cisplatin chemotherapy in first-line treatment of participants with unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangement.

The expected date of trial completion is June 2026. The final report submission is anticipated to be completed by December 2026.

 

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

 

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.

The PAAT for Pemazyre is found above.

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

The medicinal ingredient in Pemazyre, pemigatinib, is an oral fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor of FGFR 1, 2 and 3. Genetic alterations in FGFR genes result in activation of FGFR signaling that supports the proliferation and survival of malignant cells. Pemigatinib inhibits FGFR phosphorylation and signaling, and selectively decreases cell viability in cancer cell lines with activating FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements. In FGFR-activated cancer cell lines, the concentration required for 50% inhibition (IC50) was less than 2 nM. In pre-clinical studies, pemigatinib exhibited anti-tumor activity in mouse xenograft models of human tumours with FGFR 1, 2, or 3 activation including a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR 2-Transformer-2 beta homolog (TRA2b) fusion protein.

In non-clinical studies, in vitro, pemigatinib demonstrated concentration-dependent and reversible inhibition of FGFR 1, 2 and 3 with IC50 values from 0.39 to 1.2 nM. In vivo, pemigatinib inhibited tumour growth in a dose-dependent manner in an FGFR2-amplified human gastric tumour xenograft model in mice and rats.

No clinically meaningful effects on the respiratory or central nervous systems were observed, and pemigatinib did not cause QTc prolongation or any changes in other cardiovascular parameters.

Species-shared (rats and monkeys) toxicities included hyperphosphatemia, soft tissue and vascular mineralization, physeal dysplasia of the femur, cartilage sternum and teeth (rats only), and liver enzyme elevation. In most cases, the severity and frequency of these toxicities was greater in rats than monkeys.

Pemigatinib was teratogenic, and induced 100% embryo-fetal mortality in rats at exposures significantly lower than human exposure at the recommended clinical dose.

Pemigatinib was not mutagenic in vitro or in vivo. Overall, the pharmacology/toxicology profile of pemigatinib, given its intended use, is considered acceptable to support this New Drug Submission.

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

Clinical Efficacy

The efficacy of Pemazyre was primarily based on the evaluation of data from a multicentre, open-label, single-arm Phase II study (FIGHT-202). The efficacy population consisted of 107 patients with previously treated locally advanced or metastatic cholangiocarcinoma, who had an FGFR2 gene fusion or non-fusion rearrangement as determined by a clinical trial assay. Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact. Patients received Pemazyre in 21-day cycles consisting of 13.5 mg once daily oral dosing for 14 days, followed by 7 days off therapy. Pemazyre was administered until disease progression or unacceptable toxicity.

The median duration of treatment was 6.0 months, and the median duration of efficacy follow-up was 15.4 months. The follow-up duration was considered reasonable to establish evidence of efficacy for Pemazyre in the target patient population, given that the overall prognosis in this patient population remains poor, with overall response rates from various second line therapies that are reported to be less than 10% in advanced cholangiocarcinoma, and patient estimated survival is only 5 to 6 months.

The major efficacy outcome measures of Study FIGHT-202 were objective response rate and duration of response, as determined by independent review committee using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

Results derived from Study FIGHT-202 showed that there was a clinically meaningful confirmed objective response rate of 35.5% (95% confidence interval: 26.5%, 45.4%) including three complete responses and 35 partial responses. These results achieved the predetermined threshold for a positive outcome, which required the lower limit of the 95% confidence interval for the objective response rate to exceed 15%.

The detected responses appeared durable, with a median duration of response of 9.1 months (95% confidence interval: 6.0 months, 14.5 months), as assessed by the independent review committee. Subgroup analyses, while not statistically significant, demonstrated consistent, favourable objective response rate data, with the 95% confidence interval of each participant group within the subgroups overlapping the 95% confidence interval for all participants with the qualifying FGFR2 fusion or rearrangement.

Historically, this patient population has a poor prognosis, in which overall response rates from various second line therapies are reported to be less than 10%, and estimated survival is only 5 to 6 months. In this context, the reported objective response rate of 35.5% and duration of response of 9.1 months demonstrate a clinically meaningful benefit.

Overall, efficacy data from Study FIGHT-202 provide promising evidence of a clinically meaningful benefit of Pemazyre for the proposed indication. However, time-to-event endpoints from an ongoing randomized Phase III trial (INCB54828-302) are required to confirm the clinical benefit suggested by the reported efficacy from this single-arm Phase II trial.

Indication

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

Pemazyre (pemigatinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor 2 (FGFR2) fusion or other rearrangement.

Clinical effectiveness of Pemazyre is based on overall response rate and duration of response from a single-arm Phase II trial in patients with specific FGFR2 rearrangements.

Treatment with Pemazyre should be initiated following confirmation of a susceptible genetic alteration using a validated test.

Upon review of the submission, Health Canada revised the proposed indication to reflect the requirement for confirmation of an FGFR2 fusion or rearrangement (instead of the more general requirement for a susceptible genetic alteration) using a validated test. Accordingly, Health Canada approved the following indication:

Pemazyre (pemigatinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Clinical effectiveness of Pemazyre is based on overall response rate and duration of response from a single-arm Phase II trial in patients with specific FGFR2 rearrangements.

Treatment with Pemazyre should be initiated following confirmation of an FGFR2 fusion or rearrangement using a validated test.

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

Clinical Safety

The safety of Pemazyre was evaluated in 146 patients from the Phase II Study FIGHT-202, regardless of FGFR2 genetic alteration status. Study FIGHT-202 is described in the previous Clinical Efficacy section. Integrated safety data from patients treated with Pemazyre monotherapy across the studies in the clinical development program (number of patients [n] = 466) revealed a consistent safety profile of Pemazyre. However, only the data from the 146 patients from Study FIGHT-202 were included in the safety labelling in the final Pemazyre Product Monograph.

In Study FIGHT-202, the most common adverse reactions were consistent with other FGFR2 inhibitors. Hyperphosphatemia was the treatment-emergent adverse event reported with the highest frequency at 60%. Adverse events of hyperphosphatemia were primarily managed by dose interruption (1.4%), dose reduction (0%), and phosphate-lowering therapy (18.5%). Phosphate elevations were not associated with any clinical sequelae in Study FIGHT-202.

Other common adverse reactions (greater than or equal to 15%) include alopecia, diarrhea, fatigue, nail toxicity, dysgeusia, nausea, constipation, stomatitis, dry mouth, decreased appetite, vomiting, dry eye, arthralgia, abdominal pain, hypophosphatemia, dry skin, peripheral edema, decreased weight, headache, urinary tract infection, dehydration, hypercalcemia, and palmar-plantar erythrodysaesthesia syndrome.

Dose interruptions and dose reductions due to adverse events occurred in 43% and 14% of patients, respectively. The adverse events that most commonly led to dose modifications were stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, and fatigue. Serious adverse events occurred in 45% of patients. Grade 3 and Grade 4 adverse events were reported in 64% of patients. The most frequently reported Grade 3 and Grade 4 adverse event was hypophosphatemia; frequently reported during the 7-day off-treatment phase of the recommended dose regimen. None of the events were serious, or led to discontinuation or dose reduction. Management of this adverse event includes recommendations in the Pemazyre Product Monograph to discontinue phosphate-lowering therapy and diet during Pemazyre treatment breaks or if serum phosphate level falls below the normal range.

Serous retinal detachment events are known adverse events associated with FGFR2 inhibitors, and led to the discontinuation of Pemazyre in 0.4% of patients, a dose interruption in 1.7% of patients, and a dose reduction in 0.4% of patients. Routine monitoring including optical coherence tomography to detect asymptomatic serous retinal detachment was not performed in Pemazyre clinical trials; therefore, the incidence of asymptomatic serous retinal detachment with Pemazyre is unknown. However, baseline ophthalmological exams and routine monitoring for eye disorders were important risk mitigation measures in Study FIGHT-202, and are included as recommendations in the Pemazyre Product Monograph. Reference in the Pemazyre Product Monograph to available physician education materials regarding the diagnosis and management of serous retinal detachment is an additional measure important for appropriate management of this risk.

Overall, the safety profile of Pemazyre is considered acceptable. The adverse events can be adequately managed by dose reduction, temporary treatment discontinuation and/or standard medical care. The Pemazyre Product Monograph includes recommendations regarding adverse event monitoring and dose modifications, as well as reference to physician educational materials pertaining to the diagnosis and management of serous retinal detachment.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Pemigatinib, the medicinal ingredient in Pemazyre, is a small molecule kinase inhibitor of fibroblast growth factor receptor (FGFR) 1, 2, and 3. Pemigatinib inhibits FGFR phosphorylation and signaling and selectively decreases cell viability in cancer cell lines with activating FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements.

In vitro, pemigatinib demonstrated concentration-dependent and reversible inhibition of FGFR1, FGFR2 and FGFR3 with IC50 (the concentration required for 50% inhibition) values from 0.39 to 1.2 nM. In vivo, pemigatinib inhibited tumour growth in a dose-dependent manner in an FGFR2-amplified human gastric tumour xenograft model in mice and rats.

No clinically meaningful effects on the respiratory or central nervous systems were observed, and pemigatinib did not cause QTc prolongation or any changes in other cardiovascular parameters.

Species-shared (rats and monkeys) toxicities included hyperphosphatemia, soft tissue and vascular mineralization, physeal dysplasia of the femur, cartilage sternum and teeth (rats only), and liver enzyme elevation. In most cases, the severity and frequency of these toxicities was greater in rats than monkeys.

Pemigatinib was teratogenic, and induced 100% embryo-fetal mortality in rats at exposures significantly lower than human exposure at the recommended clinical dose.

Pemigatinib was not mutagenic in vitro or in vivo.

Overall, the pharmacology/toxicology profile of pemigatinib, given its intended use, is considered acceptable to support this New Drug Submission. The key non-clinical findings and related risks are properly labelled in the Pemazyre Product Monograph.

For more information, refer to the Pemazyre 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 Pemazyre 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. The drug product is stored at room temperature (15 ºC to 30 ºC).

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 (i.e., excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. None of the excipients used in the formulation of Pemazyre is of human or animal origin.

 

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