Summary Basis of Decision for Albrioza

Clinical Pharmacology

The mechanism by which sodium phenylbutyrate and ursodoxicoltaurine (the medicinal ingredients in Albrioza) exert their therapeutic effect in patients with amyotrophic lateral sclerosis (ALS) is unknown. In vitro, the combination of sodium phenylbutyrate and ursodoxicoltaurine may reduce neuronal cell death. Activity could be attributed to sodium phenylbutyrate, ursodoxicoltaurine, their metabolites, or derivatives.

The rationale for the use of sodium phenylbutyrate and ursodoxicoltaurine for treatment of ALS was based on the publication history of each entity in the treatment of various neurological disorders, including ALS. The sponsor proposed specific mechanistic pathways by which each component may contribute to the actions of the combination, but these remain speculative.

Phenylbutyrate is an aromatic short‑chain fatty acid approved in Canada for reduction of elevated plasma ammonia in urea cycle disorders. It is rapidly metabolized, primarily in the liver, to phenylacetate, another aromatic short‑chain fatty acid. Phenylacetate (also an endogenous compound from gut flora), is in turn rapidly metabolized to phenylacetylglutamine, which is excreted by the kidneys.

Ursodoxicoltaurine is a naturally‑occurring bile acid (secondary and hydrophilic), as are the two derivatives: ursodeoxycholic acid and glycoursodeoxycholic acid. As with all bile acids, these entities are subject to extensive enterohepatic circulation, such that under physiological conditions less than 10% of the total bile acid pool reaches systemic circulation. In Canada, ursodiol is approved for treatment of cholestatic liver diseases. Additionally, the injectable bile acid deoxycholic acid is approved for reduction of submental fat.

In support of clinical pharmacology of the combination product, the sponsor provided two reports:

• a single‑dose, fed versus fasted pharmacokinetic study in healthy adult volunteers (number of patients [n] = 14); and
• sparse sampling in ALS patients (n = 89) in the pivotal Phase II safety and efficacy study: one sample collected at 12‑ and 24‑week visits, either 1 hour or 4 hours post‑dose.

A population pharmacokinetic model was developed based on the above studies. The model supported predictions of the exposure of sodium phenylbutyrate and phenylacetate in ALS patients, including:

• mean maximum observed serum concentration (C_max) at steady state of 131 μg/mL for sodium phenylbutyrate and 24 μg/mL for phenylacetate;
• elimination from circulation by 6 hours post‑dose;
• saturable non‑linear kinetics for phenylacetate metabolism;
• a significant increase (~100%) in both sodium phenylbutyrate and phenylacetate exposure with fasting, and in phenylacetate exposure (~50%) with low body weight (<70 kg compared to >70 kg). There is potential for additivity when both factors occur together.

Plasma concentrations of ursodoxicoltaurine and derivatives were generally within reported ranges but high variability precluded identification of covariate effects (age, bodyweight, sex, or antibiotic use). No population pharmacokinetic analysis was performed for ursodoxicoltaurine derivatives, in view of the extensive enterohepatic recycling.

A thorough QT study was not performed. The sponsor is expected to complete and submit results from the planned sub-study of QTc interval prolongation and Albrioza exposure in a total of at least 50 participants.

Secondary pharmacology showed the potential for “off target” effects for both sodium phenylbutyrate and ursodoxicoltaurine and their respective metabolites and derivatives, via multiple receptor/organ systems. Consideration was given to: decades of use as products for hepatic‑related disorders; considerable literature reporting use in humans for other purposes (and established adverse reactions); and the endogenous nature of the compounds.

During the review, there were noted gaps in the clinical pharmacology program that included the following:

• no exposure‑response data, which precluded dose optimization;
• no dedicated intrinsic (e.g., hepatic/renal impairment) or extrinsic factor (e.g., drug‑drug interaction) pharmacokinetic studies to inform dosing recommendations;
• no assessment of the effect of combined versus individual active pharmaceutical ingredients;
• no assessment of drug interaction potential between the two components;
• whether, and to what extent, the metabolite phenylacetate and derivatives of parent entities (ursodiol, glycoursodeoxycholic acid) contribute to the primary pharmacology.

Uncertainties stemming from these were considered with the totality of data, disease context and patient population, and addressed with appropriately conservative and precautionary wording in the Albrioza Product Monograph. As part of the conditions in keeping with the provision of the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide additional information  to address some of the noted gaps identified in the current clinical pharmacology program.

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

Clinical Efficacy

The efficacy of Albrioza for the treatment of amyotrophic lateral sclerosis (ALS) was based on a single Phase II study (Centaur) conducted in American patients with ALS. The Centaur study aimed to assess whether Albrioza plus standard of care could provide superior outcomes to standard of care alone. For patients who completed the Centaur study, an open‑label extension (OLE) was added and was also included to assess the long‑term safety of Albrioza.

Centaur study

This study was a 24‑week randomized, double‑blind placebo‑controlled study conducted in patients with familial or sporadic ALS as defined by the World Federation of Neurology revised El Escorial criteria. The Centaur study enrolled a total of 137 patients from 25 sites in the United States of America.

The study design consisted of patients randomized 2:1 to receive either Albrioza (n = 89) or placebo (n = 48) treatment for 24 weeks (Intent‑to‑Treat [ITT] population). Two of the patients randomized to the Albrioza treatment group did not receive a follow up efficacy assessment; therefore, the modified ITT (mITT) population included 135 patients, with 87 patients in the Albrioza treatment group and 48 patients in the placebo treatment group.

Once randomized, patients received the contents of one sachet of either Albrioza or placebo, once daily for the first 3 weeks based on their assigned treatment group. After 3 weeks of treatment, the dose was increased to one sachet twice daily, if well‑tolerated.

Baseline disease characteristics were generally comparable between the two treatment groups; 95% were Caucasian, the median age was 57.7 years (age range: 18 years to less than 80 years old), and 68% were males. Thirty percent of patients in the Albrioza treatment group were bulbar onset patients versus 21% in the placebo treatment group. Patients enrolled had a slow vital capacity greater than 60% of predicted capacity and ALS symptom onset within 18 months. On average, patients were diagnosed with ALS six months prior to study baseline with an approximate time of 13.5 months since the onset of first symptom.

The primary efficacy endpoint was a comparison of the rate (i.e., slope) of reduction in the ALS Functional Rating Scale‑Revised (ALSFRS‑R) total scores between Albrioza plus standard of care versus standard of care alone, from baseline to Week 24 in the mITT population. The ALSFRS‑R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is then scored from 0 to 4, with higher scores representing greater functional ability.

Secondary endpoints were also included that consisted of the rate of decline of muscle strength based on the Accurate Test of Limb Isometric Strength (ATLIS), biomarkers of neuronal death, measure of lung function based on the slow vital capacity, and survival (composite of time to death, tracheostomy, permanent assisted ventilation, and hospitalization).

Based on ALSFRS-R, results obtained from the Centaur study demonstrated that the primary efficacy endpoint was met. When comparing the placebo and Albrioza treatment groups, the results showed the decline in ALSFRS‑R scores from baseline was statistically significantly less in the Albrioza‑treated patients as compared to placebo‑treated patients over a 24‑week period (2.32‑point absolute estimated difference with shared baseline model, p = 0.03). The estimated mean rates of ALSFRS‑R score were ‑1.24 points per month with Albrioza and -1.66 points per month with placebo (0.42 point difference/month; p = 0.03). The post‑hoc ITT analysis, including the 137 randomized patients, was similar to the mITT analysis. Furthermore, the effect of Albrioza was conserved in sensitivity analyses when correcting for the effects of concomitant use of background ALS standard of care therapies (riluzole and/or edaravone) with no significant difference between Albrioza used alone or with edaravone, riluzole, or both. Yet, none of the secondary endpoints reached statistical significance against placebo.

Although data from the single Phase II Centaur study are promising, as the primary efficacy endpoint was met, the results are not substantial or persuasive. Certain issues were identified with the study conduct and analyses which limit the interpretability and robustness of the results. Some of these issues include: small patient sample size, short study duration, higher rate of use of riluzole and edaravone in the placebo group, higher rate of post-baseline initiation of edaravone or riluzole in the Albrioza treatment group, assumption of linearity of functional decline over time in the primary efficacy slope analysis (which is not established), potential unblinding due to gastrointestinal events and bitter taste, considerable missing data at Week 24, and significant patient discontinuation. Of note, numerically more Albrioza‑treated patients than placebo‑treated patients discontinued due to adverse events and disease progression and a higher percentage of placebo‑treated patients completed the study. In addition, results of the primary endpoint were modest, the secondary endpoints did not reach statistical significance, there was no account for loss of data due to death rate in the primary analysis, tracheostomy and hospitalizations were included in the definition of survival without assessing deaths alone, and no survival benefit was found at 24 weeks. Furthermore, as evidence was based on a population with a recent diagnosis and good respiratory function, efficacy in patients with more advanced disease could not be determined.

Given the issues noted above, Health Canada determined that further evidence from a placebo‑controlled study in a larger population is needed to confirm clinical benefits. As such, Amylyx Pharmaceuticals Inc. has committed to providing the final report for the confirmatory Phase III placebo‑controlled Albrioza study with the aim of supporting a clinical benefit.

Open‑Label Extension

An ongoing OLE of up to 132 weeks was added for patients who completed the 24-week Centaur study. The primary objective of the OLE was to assess the long‑term safety of Albrioza. A total of 56 patients from the Albrioza treatment (RA) group and 34 patients from the placebo treatment (RP) group were enrolled in the OLE and treated with Albrioza.

The secondary endpoints included, in hierarchical order, the rate of decline in ALSFRS-R score, rate of key study events (death, tracheostomy, permanent assisted ventilation, hospitalization), rate of progression in upper and lower ATLIS scores, rate of progression in slow vital capacity, rate of progression in ALSFRS-R domains, and rate of progression in ATLIS total score.

Based on ALSFRS-R, results obtained from the OLE showed that the rate of decline was significantly less in the RA group as compared to the RP group. In addition, patients treated with Albrioza earlier and longer retained greater functioning than those with initiation of Albrioza delayed by 24 weeks. Other measures were generally not significant.

However, although the primary efficacy endpoint was met and data from the OLE show promise, some issues were noted in terms of the interpretability and robustness of the data collected. These issues included: the open‑label study design, low participation rate (66%) from the controlled phase, high rate of discontinuation, significant missing data from discontinuations (only 40% with Week 48 ALSFRS‑R measurements) and deaths during study (15% to 20% mortality by Week 48) which were not included in the functional analyses. Moreover, linearity assumption for efficacy endpoints over a longer period was uncertain, death alone was not pre‑specified and use of tracheostomy and hospitalizations in the survival analysis has limitations, and these events were not collected in survival follow‑up.

Efficacy conclusion

Overall, the data derived from the single Phase II Centaur study and the OLE are considered promising rather than substantial. The issues identified in both studies in regard to conduct and analyses limit the interpretability and robustness of the results. Furthermore, as evidence is based on a restricted ALS population with a more recent diagnosis and good respiratory function, efficacy in patients with more advanced disease cannot be determined. Therefore, it was determined that further evidence from a placebo‑controlled clinical study conducted in a larger population is needed to confirm the clinical benefits.

Based on the benefit‑harm‑uncertainty profile of the product, a decision was made to issue the sponsor market authorization under the NOC/c Guidance in recognition of the promising but unconfirmed evidence of clinical effectiveness. Amylyx Pharmaceuticals has committed to providing the final report for the confirmatory Phase III placebo‑controlled study to verify the clinical benefit.

Indication

The New Drug Submission for Albrioza was filed by the sponsor with the following indication, which Health Canada subsequently approved:

• Albrioza (sodium phenylbutyrate/ursodoxicoltaurine) is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS).

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

Clinical Safety

The clinical safety of Albrioza was evaluated in a single Phase II, 24-week study (Centaur) and its long‑term OLE of up to 132 weeks. Details of both studies have been previously described in the Clinical Efficacy section.

In the Centaur study, the most common treatment‑related treatment‑emergent adverse events (TEAEs) included: diarrhea (placebo = 10%; Albrioza = 18%), nausea (placebo = 4%; Albrioza = 9%), constipation (placebo = 4%; Albrioza = 8%), abdominal discomfort/pain/pain upper (placebo = 2%; Albrioza = 11%), fatigue (placebo = 2%; Albrioza = 8%), proteinuria (placebo = 4%; Albrioza = 6%), decreased appetite (placebo = 4%; Albrioza = 7%), dizziness (placebo = 2%; Albrioza = 6%), and somnolence (placebo = 0%; Albrioza = 3%). A total of six drug‑related TEAEs in 5 patients in the Albrioza treatment group (diverticulitis, diarrhea, nephrolithiasis, depression and fatigue, and nausea) and in 2 patients in the placebo treatment group (diarrhea and nephrolithiasis) were assessed as serious and/or severe. Overall, 5 (6%) patients in the Albrioza treatment group and 2 (4%) patients in the placebo treatment group died during the 24‑week study, the majority from respiratory failure/arrest. Three of these 5 patients were Albrioza-treated patients and 2 were placebo‑treated patients.

The most common adverse events in the OLE included fall (19%), nausea (14%) and diarrhea (13%). Overall, the adverse events observed in the population studied were consistent with symptoms related to ALS progression or the most common side effects of Albrioza. A total of 17 serious adverse events were reported in 14 (16%) patients. Overall, 5 patients died prior to week 24. The cause of death among these 5 patients included respiratory failure (2 patients), ALS, cardiac arrest, and disease progression.

An imbalance in treatment‑emergent cardiac events and electrocardiogram abnormalities was observed between treatment groups (Albrioza vs. placebo), with all cardiac events occurring in the Albrioza treatment group. A total of 14 Albrioza‑treated patients had a total of 17 events (8 cardiac events, 9 electrocardiogram abnormalities, with 3 patients experiencing both events). Of those, 8 patients had a total of 11 events in the Centaur study (6 cardiac events, 5 electrocardiogram abnormalities, with 3 patients experiencing both events), and 6 patients in the OLE study (2 cardiac events and 4 electrocardiogram abnormalities). Cardiac events considered as possibly related to Albrioza treatment included atrial fibrillation (2 events), palpitations (2 events), atrioventricular block first degree, bundle branch block left, left anterior hemiblock, tachycardia, and intraventricular conduction delay. There was one serious event of cardiac death in the OLE.

Cardiac arrhythmias and atrial fibrillation are considered as important safety risks with Albrioza treatment. These potential cardiac risks have been included in the Albrioza Product Monograph and also the Risk Management Plan for Albrioza.

Overall, the benefit of Albrioza therapy seen in the Centaur 24‑week study and the OLE are considered to outweigh the potential risks for the intended population of patients with ALS. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Albrioza Product Monograph to address the identified safety concerns. Furthermore, as part of the conditions in the issuance of a Notice of Compliance under the NOC/c Guidance, safety monitoring of the use of Albrioza will be ongoing. Further evaluation will take place upon the submission of the requested conditions after they become available.

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