Summary Basis of Decision for Uptravi

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 Uptravi is located below.

Recent Activity for Uptravi

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.

Post-Authorization Activity Table (PAAT) for Uptravi

Updated: 2024-03-01

The following table describes post-authorization activity for Uptravi, a product which contains the medicinal ingredient selexipag. 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.

Drug Identification Numbers (DINs):

DIN 02451158 - 200 mcg, selexipag, tablet, oral administration

DIN 02451166 - 400 mcg, selexipag, tablet, oral administration

DIN 02451174 - 600 mcg, selexipag, tablet, oral administration

DIN 02451182 - 800 mcg, selexipag, tablet, oral administration

DIN 02451190 – 1,000 mcg, selexipag, tablet, oral administration

DIN 02451204 – 1,200 mcg, selexipag, tablet, oral administration

DIN 02451212 – 1,400 mcg, selexipag, tablet, oral administration

DIN 02451220 – 1,600 mcg, selexipag, tablet, oral administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 258347

2021-11-03

Issued NOC 2022-04-21

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 254080

2021-06-23

Issued NOC 2021-11-24

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 245598

2020-10-26

Issued NOC 2021-10-05

Submission filed as a Level II – Supplement (Safety) to update the PM with pediatric clinical pharmacokinetic information in patients 6 years of age or older. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Action and Clinical Pharmacology section of the PM. An NOC was issued.

SNDS # 242543

2020-08-06

Issued NOC 2021-07-21

Submission filed as a Level II – Supplement (Safety) to update the PM with long-term survival and safety data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trial section of the PM. An NOC was issued.

SNDS # 247479

2020-12-14

Issued NOC 2021-05-03

Submission filed as a Level I – Supplement to update the blister pack labels and remove the Actelion name (logo). The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 229725

2019-07-15

Issued NOC 2020-06-23

Submission filed as a Level I – Supplement to update the PM with the addition of a new dosing recommendation with co-administration of Uptravi and moderate cytochrome P450 2C8 inhibitors. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

Drug product (DIN 02451182) market notification

Not applicable

Date of first sale: 2020-03-23

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 (DINs 02451158, 02451174, 02451190) market notification

Not applicable

Date of first sale: 2020-03-17

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 02451204) market notification

Not applicable

Date of first sale: 2020-01-08

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 02451212) market notification

Not applicable

Date of first sale: 2020-01-06

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 02451166) market notification

Not applicable

Date of first sale: 2019-12-16

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 02451220) market notification

Not applicable

Date of first sale: 2019-11-08

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

SNDS # 229156

2019-06-26

Issued NOC 2019-08-20

Submission filed as a Level I – Supplement to update the carton labels, package insert, and PM to remove the Actelion name (logo). The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 226279

2019-03-28

Cancellation Letter Received 2019-05-01

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety and efficacy information. The changes were not in scope of an NC but were considered to be Level I changes. The sponsor cancelled the submission administratively.

NDS # 221143

2018/10/18

Issued NOC 2018/11/23

Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Actelion Pharmaceuticals Ltd. to Janssen Inc. An NOC was issued.

NC # 205182

2017/05/01

Issued No Objection Letter 2017/08/04

The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Contraindications, Warnings and Precautions, and Drug Interactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 201926

2017/01/13

Issued No Objection Letter 2017/04/18

The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions, and Drug Interactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 193755

2016/03/29

Issued No Objection Letter 2016/06/22

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Dosage and Administration section of the Product Monograph (PM). The submission was reviewed and a No Objection Letter was issued.

Drug product (DINs) 02451158, 02451166, 02451174, 02451182, 02451190, 02451204, 02451212, 02451220 market notification

Not applicable

Date of first sale: 2016/04/21

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

NDS # 182114

2015/02/13

Issued NOC 2016/01/20

Notice of Compliance issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Uptravi

Date SBD issued: 2016-03-03

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

Selexipag, 200 µg, 400 µg, 600 µg, 800 µg, 1,000 µg, 1,200 µg, 1,400 µg, and 1,600 µg, Tablets, oral

Drug Identification Number (DIN):

  • DIN 02451158 - 200 µg, selexipag, tablet, oral
  • DIN 02451166 - 400 µg, selexipag, tablet, oral
  • DIN 02451174 - 600 µg, selexipag, tablet, oral
  • DIN 02451182 - 800 µg, selexipag, tablet, oral
  • DIN 02451190 - 1,000 µg, selexipag, tablet, oral
  • DIN 02451204 - 1,200 µg, selexipag, tablet, oral
  • DIN 02451212 - 1,400 µg, selexipag, tablet, oral
  • DIN 02451220 - 1,600 µg, selexipag, tablet, oral

Actelion Pharmaceuticals Ltd.

New Drug Submission Control Number: 182114

 

On January 20, 2016, Health Canada issued a Notice of Compliance to Actelion Pharmaceuticals Ltd. for the drug product Uptravi.

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 Uptravi is favourable for the long-term treatment of idiopathic pulmonary arterial hypertension (iPAH), heritable pulmonary arterial hypertension (HPAH), PAH associated with connective tissue disorders and PAH associated with congenital heart disease, in adult patients with World Health Organization (WHO) functional class (FC) II-III to delay disease progression. Disease progression included: hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance associated with either worsened PAH symptoms or need for additional PAH-specific treatment).

Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

 

1 What was approved?

 

Uptravi, a prostacyclin receptor agonist, was authorized for the long-term treatment of idiopathic pulmonary arterial hypertension (iPAH), heritable pulmonary arterial hypertension (HPAH), PAH associated with connective tissue disorders and PAH associated with congenital heart disease, in adult patients with World Health Organization (WHO) functional class (FC) II-III to delay disease progression. Disease progression included: hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance associated with either worsened PAH symptoms or need for additional PAH-specific treatment).

Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

Of the total number of patients in the clinical study of Uptravi for PAH, 18% were 65 years of age and older. There was limited clinical experience in patients over the age of 75 years; therefore Uptravi should be used with caution in this population.

The safety and efficacy of Uptravi in children less than 18 years have not yet been established.

Uptravi is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Uptravi was approved for use under the conditions stated in the Uptravi Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Uptravi (200 µg, 400 µg, 600 µg, 800 µg, 1,000 µg, 1,200 µg, 1,400 µg, and 1,600 µg selexipag) is presented as a tablet. In addition to the medicinal ingredient, the eight strengths of selexipag contain the following non-medicinal ingredients:

List of Non-medicinal Ingredients
Strength Non-medicinal ingredients
200 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide yellow, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
400 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide red, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
600 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide black, iron oxide red, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
800 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide black, iron oxide yellow, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
1,000 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
1,200 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide black, iron oxide red, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
1,400 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide yellow, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, titanium dioxide;
1,600 µg carnauba wax, corn starch, D-mannitol, hydroxypropyl cellulose, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, low substituted hydroxypropyl cellulose, magnesium stearate, propylene glycol, 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 Uptravi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Uptravi approved?

 

Health Canada considers that the benefit/risk profile of Uptravi is favourable for the long-term treatment of idiopathic pulmonary arterial hypertension (iPAH), heritable pulmonary arterial hypertension (HPAH), PAH associated with connective tissue disorders and PAH associated with congenital heart disease, in adult patients with World Health Organization (WHO) functional class (FC) II-III to delay disease progression. Disease progression included: hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance associated with either worsened PAH symptoms or need for additional PAH-specific treatment).

Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

Pulmonary arterial hypertension is a specific form of pulmonary hypertension, a condition characterised by increased blood pressure in the pulmonary vasculature. The disease is characterised by progressive deterioration in pulmonary and cardiac function usually resulting in increasing shortness of breath and exercise intolerance. It is a rare and incurable disease, despite the considerable progress that has been made with respect to the underlying disease mechanisms involved, as well as advances in pharmacotherapy of the condition. Several medications in three different pharmacological categories are currently approved for its treatment.

Although Uptravi (selexipag) is classified as a selective prostacyclin receptor agonist, its action is similar to other prostacyclin drugs already approved for the treatment of PAH, though it is more potent and has an active metabolite 37 times more potent than the parent drug. The efficacy of this drug results from the actions of this primary metabolite. As with other prostacyclins, use of selexipag results in vasodilation of the pulmonary vasculature which are constricted in patients with PAH, thus relieving some of the symptoms of PAH and delaying, to some degree, the progression of the disease. Treatment with selexipag does not cure the disease, nor do any of the currently approved PAH medications.

Uptravi has been shown to be efficacious in patients with PAH having the physical limitations and symptoms according to WHO FC II-III. The market authorization was based on a multicentre, long-term (a median follow-up of 1.5 years for the Uptravi group and 1.2 years for the placebo group), double-blind, placebo-controlled, parallel-group, event-driven Phase III pivotal study in 1,156 patients with symptomatic (WHO FC I-IV) PAH. Use of Uptravi (whether used by itself or concomitantly with either or both of two other PAH-specific drugs) was evaluated in terms of delaying the occurrence of progression of the disease, need for hospitalization for worsening of PAH, or death. Statistically significant and clinically meaningful delays in both disease progression and the need for hospitalization for worsening of PAH compared to the placebo-treated group occurred. However, use of Uptravi had no effect on overall mortality.

Considering the very serious nature of the disease being treated, no significant safety concerns were demonstrated in any of the studies submitted, including the pivotal randomized and placebo-controlled study. Anaemia, hyperthyroidism, and hypotension were the potential harms noted in the course of the pivotal study. Overall, Uptravi was seen as having a favourable risk-benefit profile, with very specific benefits to patients coupled with no significant risk.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal study are positive and the benefits of Uptravi therapy are considered to outweigh the potential risks. Uptravi has an acceptable 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 Uptravi Product Monograph to address the identified safety concerns.

This New Drug Submisssion 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 Uptravi?

 

Submission Milestones: Uptravi

Submission Milestone Date
Pre-submission meeting: 2015-01-14
Submission filed: 2015-02-13
Screening  
Screening Acceptance Letter issued: 2015-03-27
Review  
Biopharmaceutics Evaluation complete: 2016-01-08
Quality Evaluation complete: 2016-01-18
Clinical Evaluation complete: 2015-12-23
Labelling Review complete: 2016-01-19
Notice of Compliance issued by Director General: 2016-01-20

 

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 Uptravi?

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

Summary Basis of Decision documents (SBDs) for PAAT for Uptravi 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 Basis for Decision

Clinical Pharmacology

Uptravi (selexipag) is an oral, selective, prostacyclin receptor (IP receptor) agonist. Selexipag is hydrolysed to yield its active metabolite which is approximately 37-fold more potent than selexipag. Selexipag and the active metabolite are high-affinity IP receptor agonists with a high selectivity for the IP receptor versus (vs.) other prostanoid receptors. Stimulation of the IP receptor by selexipag and its active metabolite leads to vasodilatory as well as anti-proliferative and anti-fibrotic effects. Decreased expression of IP receptors and decreased synthesis of prostacyclin contribute to the pathophysiology of pulmonary arterial hypertension (PAH).

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Uptravi for the specified indication.

A comparative bioavailability study was conducted to bridge the clinical formulation (200 μg film-coated tablet used to dose patients up to 1,600 μg twice a day) with the intended commercial strengths (200 µg, 400 µg, 600 µg, 800 µg, 1,000 µg, 1,200 µg, 1,400 µg, and 1,600 µg tablets). The results of the study demonstrated that the proposed commercial tablet formulation exhibited comparable bioavailability to the Phase III tablet formulation.

In addition, Health Canada conducted a review of a comparative bioavailability study designed to evaluate the effect of food on the bioavailability of selexipag (parent compound) and the active metabolite. The results of the study demonstrated that in the presence of food, the exposure to selexipag after a single dose of 400 μg was increased by 10% in Caucasian subjects and decreased by 15% in Japanese subjects, whereas exposure to the active metabolite was decreased by 27% (Caucasian subjects) and 12% (Japanese subjects). More subjects reported adverse events after administration in the fasted state than in the fed state. The sponsor proposed administration of Uptravi (selexipag) with or without food with a provision of improved tolerability when taken with food. The wording in the Uptravi Product Monograph is supported by the submitted data.

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

Clinical Efficacy

The clinical efficacy of Uptravi (selexipag) was evaluated in a multicentre, long-term (a median follow-up of 1.5 years for the Uptravi group and 1.2 years for the placebo group), double-blind, placebo-controlled, parallel-group, event-driven Phase III study in 1,156 patients with symptomatic (World Health Organization [WHO] functional class [FC] I-IV) pulmonary arterial hypertension (PAH). Patients were randomized to either placebo (Number of patients [n] = 582) or Uptravi (n = 574) twice a day. The dose was increased at weekly intervals by increments of 200 µg given twice a day to determine the individualised maintenance dose (200-1,600 µg twice a day).

The primary study endpoint was the time to first occurrence of a morbidity or mortality (MM) event up to end of treatment, defined as a composite of death (all causes); or hospitalisation for PAH; or progression of PAH resulting in need for lung transplantation or balloon atrial septostomy; or initiation of parenteral prostanoid therapy or chronic oxygen therapy; or other disease-progression events (patients in WHO FC II or III at baseline) confirmed by a decrease in 6-minute walk distance (6MWD) from baseline (≥ 15%) and worsening of WHO FC or (patients in WHO FC III or IV at baseline) confirmed by a decrease in 6MWD from baseline (≥15%) and need for additional PAH-specific therapy. All events were confirmed by an independent adjudication committee, blinded to treatment allocation.

The mean age was 48.1 years (range 18-80 years of age), with the majority of patients being Caucasian (65.0%) and female (79.8%). Approximately 1%, 46%, 53% and 1% of patients were in WHO FC I, II, III and IV, respectively, at baseline.

Idiopathic or heritable PAH was the most common aetiology in the study population (58%) followed by PAH due to connective tissue disorders (29%), PAH associated with congenital heart disease with repaired shunts (10%), and PAH associated with other aetiologies (drugs and toxins [2%] and HIV [1%]).

At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of a specific therapy for PAH, either an endothelin receptor antagonist(ERA) (15%) or a phosphodiesterase type 5 (PDE-5) inhibitor (32%) or both an ERA and a PDE-5 inhibitor (33%).

The overall median double-blind treatment duration was 63.7 weeks for the placebo group and 70.7 weeks for the Uptravi group.

The study met its primary objective by demonstrating a significant risk-reduction in the occurrence of a first MM event up to end of treatment. Uptravi-treated patients compared with placebo had a clinically and statistically significant relative 40% risk reduction in the time to first occurrence of a MM episode in all groups studied (hazard ratio [HR] Uptravi vs. placebo 0.60, 99% confidence interval [CI] 0.46,0.78 p<0.0001) at 3 years. The absolute risk reduction was 15.8% at 3 years. As measured by actual number of events, a MM event was recorded in 140 (24.4%) patients in the Uptravi group as compared to 212 (36.6%) patients in the placebo group.

Hospitalisation for worsening of PAH was the most frequently confirmed first MM event, occurring in 71 (12.4%) Uptravi-treated patients compared to 96 (16.5%) in the placebo group. Disease progression as the first event was confirmed for 32 (5.6%) patients in the Uptravi group compared to 94 (14.4%) in the placebo group. Treatment with Uptravi as compared to placebo had no statistically significant effect on overall survival (all-cause death) up to study closure, after a median follow-up of 1.9 years. At study closure, the number of fatal events was similar in the Uptravi (100 patients, 17.4%) and placebo groups (105 patients, 18.0%).

Approximately 80% of patients were receiving one or two additional PAH specific drugs. However, sub-group analysis showed that efficacy was observed in patients treated with Uptravi as monotherapy (HR 0.57, 99% CI 0.33, 1.03, p = 0.0068). Statistically significant efficacy was also shown in patients treated with Uptravi plus other PAH-specific drugs (PDE-5 inhibitors or ERAs) or with triple therapy, that is (i.e.), selexipag + PDE-5 + ERA.

Treatment with Uptravi provided positive results with the secondary efficacy endpoint, change from baseline to Week 26 of treatment in the 6-minute walk distance measured at trough. In the past, improvements in this parameter formed the basis for approval of PAH drugs. Overall, treatment with Uptravi showed a median 12 metre improvement over placebo. While statistically significant (99% CI: 1, 24, p = 0.0027) this increase is not seen as having any clinical significance. However, treatment-naïve patients (i.e., no PAH specific drugs at baseline) had a much greater improvement (34 metres, 99% CI: 10, 63, p = 0.0027) which is seen as being both statistically and clinically significant, supporting the efficacy of Uptravi as monotherapy.

Indication

During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was the following.

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH, WHO Group I) in patients with WHO functional class II-IV to delay disease progression. Disease progression included: death, hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance [6MWD] associated with either worsened PAH symptoms or need for additional PAH-specific treatment).

Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders and PAH associated with congenital heart disease.

Upon review, it was determined that there was lack of supporting efficacy data for PAH patients with WHO FC I and IV. The following revised indication was recommended by Health Canada.

Uptravi is indicated for the long-term treatment of idiopathic pulmonary arterial hypertension (iPAH), heritable pulmonary arterial hypertension (hPAH), PAH associated with connective tissue disorders and PAH associated with congenital heart disease, in adult patients with WHO functional class (FC) II-III to delay disease progression. Disease progression includes: hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance [6MWD] associated with either worsened PAH symptoms or need for additional PAH specific treatment).

Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

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

Clinical Safety

The clinical safety of Uptravi (selexipag) was primarily evaluated in the pivotal long-term, Phase III placebo-controlled study described in the Clinical Efficacy section. This study enrolled 1,156 patients with symptomatic PAH. The mean treatment duration was 76.4 weeks (median 70.7 weeks) for patients treated with Uptravi vs. 71.2 weeks (median 63.7 weeks) for patients on placebo. The exposure to Uptravi was up to 4.2 years.

The most commonly reported adverse drug reactions were related to the pharmacological effects of Uptravi. Headache was the most frequently reported reaction (65.2% Uptravi, 31.5% placebo), followed by diarrhea (42.4% vs. 18.4%), nausea (33.4% vs. 18.2%), jaw pain (25.7% vs. 5.7%), vomiting (18.1% vs.8.5%), pain in the extremity (16.9% vs. 7.6%), myalgia (16.0% vs. 5.9%), flushing (12.2% vs. 4.9%), and arthralgia (10.8% vs.7.6%). These reactions were more frequent during the dose titration phase. The majority of these reactions were of mild to moderate intensity.

The most frequently reported serious adverse events (SAEs) were PAH worsening (14.4% Uptravi, 22.0% placebo) and right ventricular failure (5.9% Uptravi, 7.1% placebo). The most frequently reported adverse event leading to discontinuation of study drug was PAH worsening (13.6% Uptravi, 23.4% placebo). The proportion of patients who discontinued due to right ventricular failure was 2.4% in the Uptravi group and 4.0% in the placebo group.

The most frequently reported SAEs with fatal outcome were PAH worsening (3.3% Uptravi, 2.8% placebo) and right ventricular failure (1.2% Uptravi, 1.0% placebo). Other reported SAEs with fatal outcome included sudden death (0.9% Uptravi, 0.7% placebo), cardiopulmonary failure (0.5% Uptravi, 0.2% placebo), acute right ventricular failure (0.3% Uptravi, 0.5% placebo), and acute renal failure (0.3% Uptravi, 0.5% placebo). Reports of SAEs with fatal outcome reported in 2 or more patients in either group were primarily associated with PAH and its associated co-morbidities. Similar distributions of cause of death were observed within each group. There was no association between the number of SAEs with fatal outcome and the Uptravi dose.

Hypotension was reported in 5.9% of the patients in the Uptravi group and 3.8% in the placebo group. Four patients (0.7%) each in the Uptravi and placebo groups had SAEs of hypotension.

Hyperthyroidism was reported in 9 patients (1.6%) in the Uptravi group, compared to no cases in the placebo group. Seven of the 9 cases (1.2%) were of mild intensity and 2 (0.4%) of moderate intensity.

The proportion of patients who had at least 1 adverse event denoting anemia or decreased hemoglobin was 10.4% in the Uptravi group compared to 8.0% in the placebo group. Anemia SAEs were reported for 6 Uptravi-treated patients (1.0%) and 3 placebo-treated patients (0.5%). No patient discontinued treatment due to an anemia adverse event.

With respect to overall safety, considering the serious nature of the disease being treated, no serious safety concerns were noted in the course of the various studies submitted with the submission. Principal adverse events encountered in patients treated with Uptravi were typical prostacyclin-associated adverse events, and were dose-related, such as headache, flushing, gastrointestinal symptoms and pain manifestations. These events were usually not serious, but were very common. Uptravi showed no evidence of drug-induced hepatic injury or any potential for QT prolongation. A slight tendency for hypotension, hyperthyroidism, and mild anemia was noted in patients receiving the drug; the need to monitor patients for these events was noted in the Uptravi Product Monograph. Appropriate warnings and precautions are in place in the approved Uptravi Product Monograph to address the identified safety concerns.

Overall, Uptravi was seen as favourable in the treatment of certain forms of PAH. It provides additional options of PAH-specific drugs that can be used by physicians treating patients with those forms of the disease. The results obtained in the pivotal study are seen as being both statistically and clinically meaningful.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

A number of non-clinical studies were submitted investigating the molecular mechanism, functionality, pharmacodynamics, pharmacokinetics, and toxicology of Uptravi (selexipag) in rodent and non-rodent species. It was demonstrated that selexipag and its main metabolite bound with high affinity and high selectivity to prostacyclin receptors compared to other prostanoid receptors in all species studied. Both compounds were potent agonists at the human prostacyclin receptor. Pharmacological actions on platelets, arterial pulmonary endothelium and vascular smooth muscle cells ranged from vasodilation, decreased mean arterial pressure, and decreased pulmonary arterial pressure to inhibition of platelet aggregation and inhibition of fibrosis.

The safety pharmacology program revealed that there were no major issues identified at a low and moderate dose while secondary effects on the central nervous system, cardiovascular system, gastrointestinal tract, and kidney were observed only at the highest dose tested. The results of the toxicological studies did not show safety issues with selexipag or its main metabolite.

Overall, no outstanding safety concern was observed with Uptravi at the intended therapeutic dose range. The results of the non-clinical studies as well as the potential risks to humans have been included in the Uptravi Product Monograph.

For more information, refer to the Uptravi 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 Uptravi 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 36 months is acceptable when the drug product is stored at 15-30°C.

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

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

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

None of the excipients (including magnesium stearate) are of human or animal origin. They are either synthetic and/or of vegetable origin.

 

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