Summary Basis of Decision (SBD) for Ondexxya

As outlined in the What steps led to the approval of Ondexxya? section, during the review of the clinical component of the New Drug Submission for Ondexxya, the foreign reviews completed by the European Medicines Agency and the United States Food and Drug Administration were used as added references as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Andexanet alfa, the medicinal ingredient in Ondexxya, is a recombinant modified human factor Xa (FXa) protein that lacks procoagulant or anticoagulant activity. A point mutation (serine → alanine) in the catalytic triad prevents it from cleaving prothrombin, whereas a deletion of the membrane binding gamma‑carboxyglutamic acid domain prevents formation of the prothrombinase complex.

Andexanet alfa is an antidote for apixaban and rivaroxaban and competitively binds these FXa inhibitors in the plasma, freeing-up endogenous FXa to resume its normal function in hemostasis.

In addition to reversing the anticoagulant effect of drugs that target FXa, andexanet alfa binds to tissue factor pathway inhibitor (TFPI), an endogenous naturally occurring anticoagulant that normally circulates at low concentrations in plasma. Tissue factor pathway inhibitor binds reversibly to FXa, and the resulting TFPI‑FXa complex inhibits the tissue factor‑factor VIIa complex, which plays a key role in activation of the tissue factor pathway leading to thrombin generation. When andexanet alfa binds to TFPI, circulating TFPI concentrations are reduced, which may lead to increased thrombin generation and increased risk of thrombosis.

The rapid action of andexanet alfa and its equally rapid elimination formed the basis of the recommended dosage regimens. The pharmacokinetic and pharmacodynamic analyses showed that when andexanet alfa was infused first as a bolus dose, and immediately thereafter as a continuous infusion, the anticoagulant concentration was sufficiently lowered two minutes after the bolus dose ended, and stayed lowered for the duration of the subsequent continuous infusion. Given the short half-life of andexanet alfa, the unbound anticoagulant concentration rapidly increased to expected levels (within 2 to 3 hours) upon cessation of dosing.

Although there is a linear relationship between the amount of drug delivered and the subsequent reduction of anticoagulant concentration, the current dosing protocol of Ondexxya is predominantly based on clinical study observations and clinical decisions, rather than on stoichiometric relationships between the various chemical species that lead to blood coagulation.

The submitted population pharmacokinetic analysis consisted of three models with a similar design and a number of conceptual relationships which could be associated with bias. Therefore, these models should be interpreted with caution.

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

Clinical Efficacy

The efficacy of Ondexxya was evaluated in two studies (14‑503 and 14‑504) conducted in healthy volunteers and in one study (14‑505) conducted in patients who presented with an acute major bleeding episode while receiving either apixaban or rivaroxaban.

Study 14-503 (apixaban reversal study in healthy volunteers)

This was a Phase III randomized, double-blind, placebo-controlled clinical study designed to demonstrate the ability of Ondexxya to reverse apixaban‑induced anticoagulation in healthy volunteers. The study consisted of two consecutive parts. Each part evaluated a different dosing regimen of Ondexxya: a bolus only (Part 1) and a bolus followed by a continuous infusion (Part 2). In both parts of the study, patients were randomized in a 3:1 ratio to receive Ondexxya or placebo.

For both parts, subjects began the study by receiving apixaban 5 mg orally every 12 hours for 3.5 days to achieve steady-state levels. Subsequently subjects in Part 1 received a single bolus dose of Ondexxya 400 mg intravenously (IV) (number of subjects [n] = 24) or placebo (n = 9). Subjects in Part 2 received a single bolus dose of Ondexxya 400 mg IV immediately followed by a single Ondexxya 480 mg infusion delivered at a rate of 4 mg/min (n = 24) or placebo (n = 8). For both parts, the bolus dose was given to subjects 3 hours after receiving the last apixaban dose (i.e., at the approximate steady‑state maximum plasma concentration for apixaban).

Parts 1 and 2 evaluated the efficacy of andexanet alfa in reversing apixaban anti‑coagulation. The primary outcome was the percent change from baseline in anti‑FXa activity at the nadir. The review focused on Part 2 of the study as it is representative of the proposed clinical use of Ondexxya. Secondary efficacy endpoints included the proportion of patients with an 80% or greater reduction in anti‑FXa activity from baseline to nadir, the change from baseline in free apixaban concentration at the nadir, and an evaluation of thrombin generation restoration.

The results from study 14‑503 demonstrated that Ondexxya reduced anti‑FXa activity from baseline to nadir more effectively than a placebo. At the nadir, the median change in anti‑FXa was ‑92.73% (range: ‑96.3%, ‑83.4%) for Ondexxya‑treated subjects compared to ‑33.01% (range: ‑40.1%, ‑24.1%) for placebo‑treated subjects. The estimate of shift was ‑59.50% (95% confidence interval [CI]: ‑64.10%, ‑55.17%), which was statistically significant (p<0.0001). Notably, near maximum reductions in anti‑FXa activity were observed at the end of bolus dosing and sustained until the end of Ondexxya infusion. Results of the secondary endpoints were supportive of the findings of the primary outcome.

Study 14-504 (rivaroxaban reversal study in healthy volunteers)

This clinical study was nearly identical in design to study 14‑503, with the exception that subjects were randomized in a 2:1 ratio to receive Ondexxya or placebo. In Part I there were 27 subjects in the Ondexxya group versus 14 subjects in the placebo groups; Part II included 26 subjects in the Ondexxya group versus 13 subjects in the placebo group. In addition, the study tested a higher dosage regimen of Ondexxya than administered in 14‑503: 800 mg delivered as an IV bolus followed by 960 mg delivered by IV infusion at a rate of 8 mg/min. Ondexxya was administered 4 hours after the last dose of rivaroxaban.

The results from study 14‑504 demonstrated that Ondexxya was effective at reducing the anti‑FXa activity of rivaroxaban with an estimated median (range) change of ‑96.62% (‑100.0%, ‑91.0%) from baseline at the nadir. In contrast, anti‑FXa activity was changed by a median of ‑45.46% (‑68.3, ‑27.8) in placebo‑treated patients at the nadir, which was due to the cessation of rivaroxaban treatment. Results of the secondary endpoints were supportive of the findings of the primary outcome.

Study 14-505 (patients with acute major bleeding and a history of FXa inhibitor use)

This clinical trial was a Phase IIIb/IV, open-label, single‑arm study conducted in adult patients who were experiencing an acute major bleeding episode and had recently received either apixaban, rivaroxaban, edoxaban, or enoxaparin. Patients who participated in the study were considered to be in need of urgent reversal of anticoagulation. The definition of major bleeding was based on the International Society of Thrombosis and Haemostasis definition.

In total, 477 patients were enrolled in the study and efficacy was based on two co‑primary endpoints. The first co‑primary endpoint evaluated the percentage decrease in anti‑FXa activity following Ondexxya treatment (in a manner similar to that described for studies 14-503 and 14-504). The second co‑primary endpoint was the proportion of patients who achieved a hemostatic efficacy rating of excellent/good after receiving Ondexxya treatment. Hemostatic efficacy was assessed by an independent endpoint adjudication committee who considered predefined criteria to rate hemostatic efficacy as good/excellent or poor/none. The efficacy analysis set included 347 patients who had an evaluable baseline anti-FXa level, met prespecified bleeding criteria, and had a baseline anti-FXa level of ≥ 75 ng/mL (apixaban or rivaroxaban patients) or ≥ 40 ng/mL (edoxaban patients) or ≥ 0.25 IU/mL (enoxaparin patients).

The study population was predominantly (over 90%) older than 65 years of age and male (54.3%). The anticoagulant received was apixaban in 51.4% of patients and rivaroxaban in 36.5% of patients.

Ondexxya dosing regimens were as described for study 14-503 (low-dose) and 14-504 (high‑dose). The appropriate dosing regimen for each patient was selected depending on the specific prior anticoagulant, the dose of the anticoagulant received, and the time since receiving the last dose of anticoagulant.

The study demonstrated reductions in anti‑FXa activity were similar to the reductions seen in healthy volunteers ( approximately 90% at the nadir). The activity‑time profile for anti‑FXa was also similar between this study (14‑505) in patients treated with a direct oral anticoagulant (DOAC) and the two studies (14-503 and 14-504 ) in healthy volunteers with an over 90% median reduction in activity that occurred rapidly and was sustained until the end of infusion after which time the anti‑FXa activity rose rapidly. In terms of hemostatic efficacy, a rating of excellent/good was achieved by 80% of patients evaluated (95% CI: 75.3%, 84.1%). The result was statistically superior to the prespecified success rate of 50% and remained superior in an analysis that included all patients regardless of whether they were included in the efficacy analysis set.

Overall, the clinical data provides promising evidence of efficacy including a robust effect on a pharmacodynamic marker for efficacy that is reasonably likely to predict a benefit. As the Ondexxya submission was evaluated under the Notice of Compliance with Conditions (NOC/c) Guidance, additional efficacy and safety data will be assessed when the final report of the confirmatory study (Protocol 18‑513) is submitted.

Indication

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

Ondexxya (andexanet alfa) is indicated for adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to acute major bleeding, including life-threatening bleeds.

To support safe and effective use of the product, Health Canada approved the following indication:

Ondexxya (andexanet alfa) is indicated for adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

Ondexxya has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.

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

Clinical Safety

The safety of Ondexxya was evaluated in healthy volunteers and in patients presenting with acute major bleeding while receiving an FXa inhibitor (see Clinical Efficacy section).

Healthy volunteer analysis

In total, 417 healthy subjects were included in the pooled Ondexxya (all doses) analysis set and 156 subjects were included in the pooled placebo analysis set. Of the 417 healthy subjects treated with Ondexxya, 143 received only bolus doses (ranging from 90 mg to 800 mg) and 274 received bolus doses (ranging from 400 mg to 800 mg) followed by continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes (ranging from 480 mg to 960 mg). Treatment-emergent adverse events (TEAEs) occurred in 46.8% of Ondexxya‑treated healthy subjects compared to 43.6% of placebo‑treated healthy subjects. Two subjects experienced infusion‑related reactions that led to discontinuation of Ondexxya. No deaths were observed among healthy volunteers. One serious adverse event (nephrolithiasis) occurred in one subject who was treated with Ondexxya. The event occurred 25 days after dosing and was considered unlikely to be related to Ondexxya treatment.

Patients with acute major bleeding and a history of FXa inhibitor use

In study 14‑505, (carried out in 477 patients presenting with acute major bleeding while under treatment with an FXa inhibitor and requiring rapid reversal of anticoagulation), 72.5% of patients experienced one or more TEAEs. Severe TEAEs occurred in 33.9% of patients, 5.4% had life‑threatening TEAEs, and 17% of patients died. Notably, life‑threatening acute major bleeds are associated with a high mortality rate. In addition, patients who discontinue DOAC treatment and undergo DOAC reversal become exposed to underlying risk factors for thromboembolic and ischemic events. Thromboembolic and ischemic TEAEs were commonly observed. These events included stroke (6.9%), myocardial infarction (3.6%), deep vein thrombosis (3.4%), pulmonary embolism (1.9%) and atrial thrombosis (1.0%). The most common TEAEs observed in patients who experienced an acute major bleeding episode were urinary tract infections (10.5%), pneumonia (8.2%), delirium (4.4%), hypotension (4.0%), and pyrexia (4.0%). The occurrences of serious adverse events were similar between patients who received rivaroxaban or apixaban at baseline.

As the Ondexxya submission was evaluated under the Notice of Compliance with Conditions (NOC/c) Guidance, additional safety data will be assessed when the final report upon completion of Protocol 18‑513 is submitted.

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

The in vitro studies submitted demonstrate that andexanet alfa (the medicinal ingredient in Ondexxya) binds to direct factor Xa (FXa) inhibitors with high affinity. Andexanet has no significant interaction with other major plasma coagulation proteins, except for tissue‑factor pathway inhibitor (TFPI). The andexanet‑TFPI interaction may enhance reversal of the FXa inhibitor-induced inhibition of thrombin generation, but it has minimal effect on thrombin generation in the absence of an FXa inhibitor. In animal models, andexanet alfa did not demonstrate a pro‑ or anticoagulant effect. Reversal of anticoagulation following the administration of andexanet alfa was only observed in animals treated with FXa inhibitors. In rats, andexanet alfa administered alone did not affect the hematology profiles, and no serious adverse effects or evidence of thrombogenicity were reported.

Central nervous system and respiratory safety pharmacology studies of andexanet alfa were conducted in male rats at doses up to and including the maximum dose considered feasible as an intravenous bolus (30 mg/kg). There were no adverse findings in either set of studies. Additionally, cardiovascular safety was evaluated in cynomolgus monkeys, and no adverse effects were found on electrocardiogram parameters or blood pressure.

Andexanet alfa was well tolerated in both rats and monkeys. Testing at doses up to 60 mg/kg/day did not elicit any serious adverse effects in the presence or absence of FXa inhibitors. Coagulation parameters were evaluated and showed increased levels of D‑dimer and thrombin-antithrombin III-complexes (TAT) in monkeys, both of which were attenuated by co‑administration with FXa inhibitors.

Overall andexanet alfa appears to be well‑tolerated at an exposure that is 2 to 3‑fold higher than that observed with the highest dose intended for human clinical use.

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

Andexanet alfa (the medicinal ingredient in Ondexxya) is a recombinant modified version of human factor Xa (FXa) designed to retain high binding affinity for both direct and indirect (antithrombin III [ATIII]‑dependent) FXa inhibitors. It has a molecular weight of approximately 41 kDa. The modified protein lacks catalytic activity due to the replacement of the active site serine with an alanine, thereby ensuring andexanet alfa is unable to cleave and activate prothrombin, and thus removing the procoagulant activity of native FXa. Andexanet alfa has also been engineered without the gamma-carboxyglutamic acid (Gla) domain, preventing incorporation into the prothrombinase complex. Andexanet alfa therefore acts as an FXa decoy molecule by binding to the FXa inhibitors and preventing them from interacting with the native FXa molecule, thereby restoring the activity of native FXa and sequestering the FXa inhibitors.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that andexanet alfa consistently exhibits the desired characteristic structure and biological activity. Impurities and degradation products arising from manufacturing and storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Andexanet alfa (the drug substance) is a recombinant protein produced by genetically engineered Chinese hamster ovary cells (CHO). The manufacture is based on a master and working cell bank system. Both the master and working cell banks are thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The process for the manufacture of andexanet alfa starts with growing a cell culture from the working cell banks until the recombinant protein is expressed and secreted into the culture medium. Subsequently, the cell culture fluid is harvested and purified through a series of chromatographic and filtration steps. The final drug substance is then dispensed into polyethylene terephthalate glycol bottles, stored frozen, and shipped to the drug product manufacturer.

The process for the manufacture of the drug product (Ondexxya) consists of thawing the drug substance, pooling, sterile filtration, aseptic filling, and lyophilization of the bulk drug product. The vials are then capped with a rubber stopper and aluminum overseal. The lyophilized drug product is then stored at 2 °C to 8 °C until it is shipped to the packaging site.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of andexanet alfa with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The quality of the drug substance (andexanet alfa) is assessed against respective release specifications, which includes tests to assess identity, purity, potency, and other relevant characteristics of the drug substance. The associated analytical methods and method validations are deemed sufficient and acceptable. Together with the available batch data, the justification of specifications and stability results confirm that the proposed manufacturing process consistently yields drug substance of acceptable quality.

The quality of Ondexxya drug product lots is routinely assessed against release specifications. The associated analytical methods, reference standards, and method validations were provided and deemed sufficient and acceptable. Most of the quantitative analytical methods used are the same for the drug substance and drug product. Overall, the available batch data, statistical analyses, justification of specifications, and stability results confirm that the proposed manufacturing process consistently yields drug product of acceptable quality.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 48 months at 2 °C to 8 °C for Ondexxya is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The andexanet alfa purification process includes viral clearance steps and purification steps with viral clearance capabilities. All identified viral clearance steps were evaluated for viral clearance capacity with a suitable set of model viruses. Overall, the drug substance manufacturing process provides an acceptable level of viral clearance.