Summary Basis of Decision for Agamree

The clinical package included 11 studies: 6 Phase I and 5 Phase II (1 pivotal and 4 open-label) studies. Ten of the 11 studies used the Route of Synthesis (ROS) 1 (ROS1) formulation of Agamree and one Phase II study (VBP15-006) used the to-be-marketed ROS2/Fine formulation. All formulations were liquid suspensions for oral administration.

Comparative bioavailability and pharmacology data supported the validity of the modelling used which showed that the ROS1 formulation and the to-be-marketed ROS2/Fine formulation have similar bioavailability under low-fat fed conditions and are bioequivalent under high-fat fed conditions. This was essential to complement the clinical data in justifying the proposed dosage, including a down-titration dose of 4 mg/kg/day (which was not studied systematically) for tolerability issues not managed at higher dosages and a reduced maximum dose of 240 mg daily for patients weighing 40 kg or more.

Clinical Pharmacology

Vamorolone, the medicinal ingredient in Agamree, is a corticosteroid that selectively binds to the glucocorticoid receptor, which triggers anti-inflammatory effects via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) mediated gene transcripts. In addition, vamorolone inhibits the activation of the mineralocorticoid receptor by aldosterone. Due to its specific structure, vamorolone is likely not a substrate for 11ß-hydroxysteroid dehydrogenases. The precise mechanism by which vamorolone exerts its therapeutic effects in patients with Duchenne muscular dystrophy (DMD) is unknown.

The pharmacokinetics of vamorolone was studied in healthy adult volunteers and in patients with DMD aged 2 to less than 4 years, 4 to less than 7 years, and 7 to less than 18 years. The study population was mostly composed of White participants, but also included Black, Asian, and Latino participants.

Vamorolone is well absorbed with a time to maximum dose concentration between 2 and 4 hours and distributes quickly into tissues. In children aged 4 to less than 7 years who received 6 mg/kg/day of vamorolone for 14 days, the observed maximum concentration (C_max) was 970 ng/mL and the area under the concentration-time curve from time 0 to infinity (AUC_inf) was 3,606 ng•h/mL. Similar pharmacokinetic parameters were observed in patients with DMD aged 7 to less than 18 years. The apparent volume of distribution of vamorolone for patients with DMD and a body weight of 20 kg was 162.4 L when taken with a meal. Protein binding was 88.1% in vitro. The major route of elimination is via multiple phase I and phase II metabolic pathways, with subsequent excretion of metabolites into urine and feces. Vamorolone plasma and urine metabolites are formed through direct glucuronidation as well as hydrogenation with subsequent glucuronidation. Unaltered vamorolone represented only 4.4% of the vamorolone-related molecules observed in plasma. The terminal elimination half-life of vamorolone is approximately 2 hours. Drug exposure increased linearly with the dose administered, and no drug accumulation was observed.

Based on a concentration-corrected QT Interval (QTc) study, the maximum recommended human dose of 6 mg/kg/day is unlikely to induce QTc prolongation in patients with DMD. Vamorolone produced an increased heart rate of 10 to 15 beats per minute in healthy volunteers.

The population pharmacokinetic study supported a dose capping at 240 mg/day for patients weighing 40 kg or more. Moderate hepatic impairment (Child-Pugh B) resulted in increased drug exposure. For patients with mild and moderate hepatic impairment, the vamorolone dose should be reduced to 2 mg/kg/day for patients weighing less than 40 kg, or up to 80 mg/day for patients weighing 40 kg or more. Vamorolone was not studied in patients with severe liver impairment and is contraindicated in this population. The impact of renal impairment on vamorolone drug exposure was not studied; however, vamorolone was not excreted intact in urine and renal impairment is unlikely to impact the systemic exposure to vamorolone.

Vamorolone exposure is increased by strong cytochrome P450 (CYP) 3A4 inhibitors. When vamorolone is administered with a strong CYP3A4 inhibitor, the starting dose should be decreased to 4 mg/kg/day for patients weighing 40 kg or less and to a maximum of 160 mg/day for patients weighing more than 40 kg. No dose adjustment is required when used with weak or moderate CYP3A4 inhibitors. No clinically relevant CYP3A4 induction was observed in healthy volunteers. The sponsor plans to provide a complete drug-drug interaction study report for Study SNT-I-VAM-025 as part of a post-approval commitment. The potential for drug-drug-interactions involving uridine diphosphate-glycosyltransferases (UGTs) has not been fully evaluated.

Vamorolone was well tolerated in healthy adults, but several participants presented clinically relevant adrenal events meeting the criterion for acute and chronic adrenal suppression. Signs of hepatic toxicity were also observed in one participant.

Overall, the clinical pharmacology data support the use of Agamree for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Agamree was evaluated in Period 1 (weeks 1 to 24) of the pivotal Phase II, double-blind, placebo- and prednisone-controlled Study VBP15-004. Ambulatory corticosteroid-naïve boys aged 4 to less than 7 years with confirmed DMD were randomized 1:1:1:1 to receive either Agamree 2 mg/kg/day (30 patients), Agamree 6 mg/kg/day (30 patients), placebo (30 patients), or prednisone 0.75 mg/kg/day (31 patients).

The demographic and baseline disease characteristics of the patients were representative of the indication. Most patients were White (83.1%) or Asian (10.2%) and not Hispanic or Latino (95.8%). The mean age was similar across treatment arms at 5.41 years (range: 4 to 7 years). The mean number of months from first onset of symptoms of DMD was approximately 38 months (range: 3 to 77 months). Overall, patients in the Agamree arms had more advanced disease at baseline versus (vs.) patients in the placebo or prednisone arms with a slower Time to Stand Test (TTSTAND) velocity (an early prognostic factor for disease progression and loss of ambulation.), a shortened 6-minute walk test (6MWT) distance, and a lower North Star Ambulatory Assessment (NSAA) score.

The primary efficacy endpoint, the least squares mean change from baseline in TTSTAND velocity at Week 24, showed a statistically significant and clinically meaningful improvement of 0.060 rises/sec (95% confidence interval [CI]: 0.02 to 0.10, p = 0.002) in favour of Agamree 6 mg/kg/day over placebo. A pre-specified hierarchical analysis of relevant secondary endpoints (which were met) consisted of change from baseline in TTSTAND velocity to Week 24 for Agamree 2 mg/kg/day vs. placebo, 6MWT distance for Agamree 6 and 2 mg/kg/day vs. placebo, and Time to Run/Walk 10 meters (TTRW) velocity for Agamree 6 mg/kg/day. No clinically meaningful differences were seen in efficacy at Week 24 for Agamree 2 mg/kg/day compared with 6 mg/kg/day. After 6 months, efficacy differences between Agamree 2 and 6 mg/kg/day were only clinically meaningful for the change in TTSTAND velocity.

Supportive efficacy information was provided from open-label supportive studies designed to assess the clinical safety of Agamree, where exploratory endpoints were used to analyse the clinical efficacy of Agamree. During Period 2 (weeks 24 to 48) of Study VBP15-004, a 24-week double-blind extension phase following Period 1, clinically meaningful improvements in TTSTAND velocity at Week 24 were maintained up to Week 48 in patients who continued on Agamree 6 mg/kg/day. The efficacy results across outcome measures for the Agamree 2 mg/kg/day arm showed clinically significant declines in several efficacy endpoints after Week 24, including TTSTAND velocity, demonstrating that efficacy was not well maintained up to Week 48. However, conclusions of the efficacy analyses at Week 48 are limited as they are exploratory.

Exploratory efficacy data from the 24-week, open-label, multiple-dose, Phase II Study VBP15-003 in 48 ambulatory corticosteroid-naïve boys aged 4 to less than 7 years showed mean improvements in TTSTAND velocity. After completion of Study VBP15-003, 46 out of 48 patients enrolled in Study VBP15-LTE, a 24-month, open-label, multiple-dose, Phase II study in which patients could modify their dosage between 2, 4, and 6 mg/kg/dose. Eleven out of 41 patients (27%) were down-titrated from 6 mg/kg/day to 2 or 4 mg/kg/day due to tolerability issues, mainly excessive weight gain. Efficacy assessed by TTSTAND velocity was maintained up to Month 18 in the group of 23 boys receiving 2 or 6 mg/kg/day, indicating a delay in motor function decline compared with natural history.

In the 12-week Study VBP15-006, the only study designed to assess the safety of Agamree in expanded age groups, exploratory efficacy findings in 20 boys aged 2 to less than 4 years (10 per dose) were dose-dependent. Efficacy was not shown in the 34 patients who were aged 7 to less than 18 years; therefore, the evidence of efficacy in this subpopulation is not robust. However, while there is a lack of clinical evidence of significant efficacy with Agamree in the patients aged 7 to less than 18 years, the underlying pathophysiology of DMD is the same across all ages and stages of disease. Additionally, Agamree shares the same mechanism of action as the corticosteroid class, which has been associated with delayed progression when used after loss of ambulation. Therefore, the extrapolation of efficacy for patients aged 7 years and older is acceptable.

Indication

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

Agamree (vamorolone oral suspension) is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older.

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

Agamree (vamorolone oral suspension) is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 4 years of age and older.

Health Canada revised the indication due to the lack of robust efficacy data and increased risks in patients aged 2 to less than 4 years. As the be benefit-harm-uncertainty profile was considered unfavourable in this age group, the indication was restricted to patients aged 4 years and older.

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

Clinical Safety

The primary safety dataset for Agamree 2 to 6 mg/kg/day is based on a controlled dataset from the 24-week Period 1 of the pivotal Study VBP15-004 described in the Clinical Efficacy section. This includes data from 58 patients aged 4 to less than 7 years exposed to Agamree 2 mg/kg/day (30 patients) or 6 mg/kg/day (28 patients) compared to those who received placebo (29 patients) or prednisone 0.75 mg/kg/day (31 patients). The median duration of exposure was 5.5 months in each arm, with 27 patients from the Agamree 6 mg/kg/day arm treated for 6 months or more.

Adverse drug reactions were reported at a greater incidence in the Agamree 6 mg/kg/day arm (68%) than in the prednisone (45%), Agamree 2 mg/kg/day (33%), or placebo (28%) arms.

The most common adverse drug reactions (Agamree 6 mg/kg/day vs. Agamree 2 mg/kg/day vs. placebo) were cushingoid features (29% vs. 7% vs. 0%), vomiting (14% vs. 17% vs. 7%), abdominal pain (18% vs. 10% vs. 10%), diarrhea (7% vs. 3% vs. 3%), fall (11% vs. 0% vs. 3%), increased weight (11% vs. 0% vs. 3%), vitamin D deficiency (11% vs. 7% vs. 0%), increased appetite (7% vs. 3% vs. 3%), headache (7% vs. 7% vs. 3%), irritability (11% vs. 0% vs. 0%), and cough (7% vs. 10% vs. 3%). Pooled uncontrolled safety data from 163 patients aged 4 to less than 7 years at entry across the supportive studies (with a median duration of exposure of 11 months) was similar to the controlled data.

Dose reductions from 6 to 2 mg/kg/day due to tolerability issues occurred in 27% of patients in the long-term 24-month open-label Study VBP15-LTE, with 10 out of 11 cases being due to excessive weight gain.

As Agamree is a synthetic steroid, with effects mediated by the glucocorticoid pathway, the following were defined as known adverse events of special interest associated with this class of drug: adrenal suppression with potential life-threatening adrenal crisis if treatment is discontinued suddenly, cushingoid features, weight gain, stunted growth, behavioural changes, bone fractures, diabetogenic effects, gastrointestinal symptoms, immune suppression with increased risk of infections, hypertension, cataracts, glaucoma, and hepatotoxicity. During Period 1 of Study VBP15-004, these events were reported more frequently in the Agamree 6 mg/g/day arm (79%) than in the prednisone (77%), placebo (69%), or Agamree 2 mg/kg/day (67%) arms. Dose-dependent adrenal suppression (indicative of adrenal insufficiency and defined as morning cortisol less than 100 nmol/L) was reported in 93% of patients in the Agamree 6 mg/kg/day arm, 74% in the prednisone arm, 26% of patients in the Agamree 2 mg/kg/day arm, and 4% of patients in the placebo arm. Other dose-dependent adverse events of special interest in the pivotal study as well as in supportive and longer-term studies included increased bone fractures and fasting insulin levels. Submitted data also suggest that the proposed dose of Agamree 6 mg/kg/day suppresses bone turnover and decreases bone density.

Additional safety data in 20 pediatric patients aged 2 to less than 4 years and 34 patients aged 7 to less than 18 years receiving Agamree 2 or 6 mg/kg/day were provided from the 12-week open-label Study VBP15-006. Adverse reactions were more common in patients aged 2 to less than 4 years compared with patients aged 4 to less than 7 years treated at the same dose and duration in the pivotal study (100% vs. 71%), with more gastrointestinal disorder events (100% vs. 21%), adrenal suppression (50% vs. 0%), and psychiatric disorders (33% vs. 11%). Data in younger patients were supported by a post hoc analysis in all Agamree-treated patients across studies by age group (less than 5 years or 5 years or older). The safety in boys aged 7 to less than 18 years was similar to the safety profile in the target age group aged 4 to less than 7 years.

Across studies, serious adverse drug reactions included one case of rhabdomyolysis and one case of acute hepatitis suspected of drug-induced liver injury due to time-course and positive rechallenge, both resulting in treatment discontinuation. There were other cases of elevated liver function tests throughout the clinical studies, including some that led to discontinuation of Agamree. Therefore, the risk of drug-induced liver toxicity cannot be excluded.

Since most adverse drug reactions are dose-dependent, risk mitigation by down-titrating from 6 mg/kg/day to 2 or 4 mg/kg/day is recommended. The use of Agamree has been contraindicated in patients with severe liver impairment due to the lack of data in this population, the pharmacokinetic data, and the known class effects of corticosteroids. Pharmacokinetic data in patients with mild or moderate liver impairment support dose adjustments.

Overall, the main limitations of the study database include the restricted study population, the lack of active control beyond 6 months, the short duration of exposure in the open-label design studies for assessing long-term safety, and the exploratory nature of efficacy analyses in the supportive studies. Controlled safety data to confirm the implications of class adverse effects with longer treatment duration are lacking, including adrenal suppression and duration of recovery from adrenal insufficiency after treatment cessation, effect on bone metabolism with long-term risk of fractures, risks of infections due to immunosuppression, impact on glucose homeostasis, behavioural changes, lipid metabolism, hepatotoxicity, glaucoma, and cataracts.

Adverse events observed across studies and laboratory data suggest that Agamree has off-target steroidogenic effects that are proportional to dose, with potential harms similar to the risks associated with the corticosteroid class.

Based on the lack of robust efficacy data and increased risks in patients aged 2 to less than 4 years, the benefit-harm-uncertainty profile is considered unfavourable in this age group, and the indication was restricted to patients aged 4 years and older.

While long-term risks cannot be excluded, in children aged 4 and older, risks are considered manageable with appropriate labelling, safety-related dose reductions, and pharmacovigilance. Appropriate warnings and precautions are in place in the approved Product Monograph for Agamree to address the identified safety concerns.

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

Vamorolone, the medicinal ingredient in Agamree, is a synthetic glucocorticoid in the structural class of synthetic steroidal drugs. Vamorolone differs from traditional glucocorticoids by having a double bond between carbons 9 and 11 and lacking the hydroxyl or carbonyl function on carbon 11 found in all other members of the corticosteroid class.

In vitro, vamorolone has demonstrated anti-inflammatory activity in various animal models, including the Duchenne muscular dystrophy (DMD) mdx mice model. This activity was associated with binding to the glucocorticoid receptor and suppression of the pro-inflammatory nuclear factor-kappa B (NF-κB) signaling pathway. This mechanism is termed “trans-repression”. Unlike other corticosteroids, vamorolone shows limited glucocorticoid response element-driven transcription, suggesting potential for reduced steroid-associated adverse effects, although this has not been confirmed clinically. In vitro, vamorolone inhibited the mineralocorticoid receptor. The pharmacologic activity of vamorolone was consistent with that of a corticosteroid.

Pharmacokinetic studies in mice, dogs, and monkeys demonstrated rapid absorption (time to maximum plasma concentration [T_max] of 1 to 12 hours) and dose-proportional plasma concentration in dogs and monkeys, with more than dose-proportional increases in mice. Bioavailability ranged from 53.2% to 74.5% across species, with widespread tissue distribution, including to the brain. Vamorolone is extensively metabolized, primarily to inactive glucuronides, and is a substrate and inducer of cytochrome P450 (CYP) 3A4. Elimination half-life ranged from 40 minutes in mice to 2.3 hours in dogs.

Repeated-dose studies in mice, dogs, and monkeys were conducted and revealed a consistent profile of various toxicities induced in a dose- and time-dependent manner. The target organs for vamorolone toxicity were the lymphatic system, liver, gallbladder, pancreas, adrenal glands, kidneys, reproductive organs of both sexes, thyroid, salivary glands, skin, and skeletal muscles. The no-observed-adverse-effect level (NOAEL) was 45 mg/kg/day in mice and 2 mg/kg/day in male dogs. The NOAEL in female dogs could not be determined due to the prominent interference of the proposed drug with the ovarian cycle. Adverse effects included adrenal cortical atrophy, increased food consumption, and weight gain, consistent with long-term glucocorticoid administration.

Vamorolone was non-mutagenic and non-genotoxic. Carcinogenicity studies were not conducted, but existing data suggest a low carcinogenic risk. Post-authorization commitments were made to address carcinogenicity, including conducting and providing the results of carcinogenicity studies in adequate animal models based on International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S1B guidelines. Alternatively, justifications may be provided indicating that one or more of these studies are not required based on ICH S1B guidelines. Waiver approval will be subject to a formal assessment.

Vamorolone is intended to treat DMD, which affects almost exclusively male patients and therefore, the standard battery of developmental and reproductive toxicology studies was not conducted. However, in general toxicity studies in dogs, vamorolone affected spermatocytes and the prostate gland in males and eliminated corpora lutea in females, consistent with glucocorticoid-mediated interference of the hypothalamic-pituitary-gonadal axis. Pre- and post-implantation losses were observed at high doses in mice.

Juvenile toxicity studies were conducted in mice and the main target organs were similar to those of adult mice, excepted for mild mandibular salivary gland hypertrophy with decreased mandibular gland weight, which was observed in juvenile mice but not in adults. Vamorolone significantly reduced tibia and/or body length, indicating potential growth retardation at exposures without a safety margin to humans; these effects were considered clinically relevant and adverse. Bone mineral density and structure have not been analyzed, preventing the assessment of a potential risk for direct effects on growth plates and skeleton development.

Cardiac safety was assessed in vitro and in vivo. Vamorolone did not inhibit the human ether-a-go-go-related gene (hERG) potassium channel (a non-Good Laboratory Practice study) and did not affect respiratory or electrocardiogram parameters in dogs up to 50 mg/kg/day, though mild heart rate increases were noted. Neurobehavioral studies showed no effects in mice but reduced activity and impaired limb function in dogs at 50 mg/kg/day. Safety margins based on maximum concentration (C_max) and area under the concentration-time curve (AUC) relative to human exposure at the maximum recommended human dose were minimal in mice and absent in dogs.

Vamorolone was tested in the DMD mouse model with mdx mice (females only) and was compared to the glucocorticoid prednisolone. Compared to prednisolone, vamorolone presented a better profile regarding the negative impacts on muscles: it reduced diaphragm inflammation, had lowered muscle atrophy, and did not evoke cardiac hypertrophy (mild signs of cardiac fibrosis restricted to young animals). Findings regarding skeletal muscles were contradictory, with atrophy observed in dogs and preservation of muscular mass, as well as protection from muscular inflammation and degeneration, found in mice.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Agamree. In view of the intended use of Agamree, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. As described above, the sponsor has committed to conduct in vivo carcinogenicity studies post-authorization or submit a weight of evidence to Health Canada to obtain a waiver for carcinogenicity studies.

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

The quality (chemistry and manufacturing) information submitted for Agamree has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored upright at room temperature (15 ºC to 30 ºC) and in the original carton. Once opened, the drug product may be stored refrigerated up to 3 months in an upright position at a temperature between 2 °C to 8 °C.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

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

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Agamree is of human or animal origin.