Vamorolone

Vamorolone is a dissociative corticosteroid that selectively binds to the glucocorticoid receptor, which triggers anti-inflammatory effects via inhibition of NF-kB mediated gene transcripts, but leads to less transcriptional activation of other genes. In addition, vamorolone inhibits the activation of the mineralocorticoid receptor by aldosterone. Due to its specific structure, vamorolone is likely not a substrate for 11β-hydroxysteroid dehydrogenases and is therefore not subject to local tissue amplification. The precise mechanism by which vamorolone exerts its therapeutic effects in patients with DMD is unknown.

Vamorolone produced a dose-dependent decrease in morning cortisol levels in the clinical studies. A dose-dependent increase in haemoglobin, haematocrit values, erythrocytes, leukocyte counts and lymphocyte counts was observed with in clinical studies with vamorolone. No relevant changes in mean neutrophil counts or immature granulocytes were observed. High density lipoprotein (HDL) cholesterol and triglycerides values increased in a dose-dependent manner. There was no relevant effect on glucose metabolism up to 30 months of treatment.

Unlike corticosteroids, vamorolone did not result in a reduction of bone metabolism as measured by bone turnover markers, nor in a significant reduction in lumbar vertebral bone mineralisation parameters by Dual-Energy X-Ray Absorptiometry (DXA) after 48 weeks in the clinical studies. The risk for bone fractures in patients with DMD treated with vamorolone has not been established.

Absorption

Vamorolone is well absorbed and distributes quickly into tissues. After oral administration with food, the median T_max is about 2 hours (range 0.5 to 5 hours).

Effect of food

Co-administration of vamorolone with a meal reduced C_max by up to 8% and delayed T_max by 1 hour, relative to administration under fasting conditions. The overall systemic absorption as measured by AUC was increased by up to 14% when vamorolone was taken with food. In the Chinese adult population, AUCinf and C_max increased by 24% and 25% respectively and the median T_max was delayed by 3 hours with a high fat meal. It is unlikely that this food effect will pose a safety concern. Although food does not significantly alter the overall bioavailability of vamorolone, consistent co-administration with food may reduce variability in bioavailability.

Distribution

The apparent volume of distribution of vamorolone for a DMD patient with a body weight of 20 kg taking vamorolone is 28.5 L based on the population PK analysis. Protein binding is 88.1% in vitro. The blood to plasma ratio is approximately 0.87.

Biotransformation

Vamorolone is metabolised via multiple Phase I and Phase II pathways, such as glucuronidation, hydroxylation, and reduction. The main plasma and urine metabolites are formed through direct glucuronidation as well as hydrogenation with subsequent glucuronidation. The involvement of specific UGT and CYP enzymes in the metabolism of vamorolone has not been conclusively demonstrated.

Elimination

The major route of elimination is by metabolism with subsequent excretion of metabolites into urine and faeces. Vamorolone clearance for a DMD patient with a body weight of 20 kg taking vamorolone is 58 L/h based on the population PK analysis. The terminal elimination half-life of vamorolone in children with DMD is approximately 2 hours.

Approximately 30% of vamorolone dose is excreted in faeces (15.4% unchanged) and 57% of vamorolone dose is excreted in urine as metabolites (<1% unchanged). The major metabolites in urine are glucuronides.

Linearity/non-linearity

The PK are linear and vamorolone exposure increases proportionally with either single or multiple doses. Vamorolone does not accumulate with repeated administration.

Special populations

Hepatic impairment

The effect of moderate hepatic impairment (Child-Pugh class B) of vamorolone was studied in humans. Vamorolone C_max and AUC_0inf values were approximately 1.7- and 2.6-fold higher in subjects with moderate hepatic impairment compared to age, weight and sex matched healthy adults. Vamorolone dose should be reduced in patients with moderate hepatic impairment to 2 mg/kg/day for patients up to 40 kg and to 80 mg for patients with a body weight of 40 kg and above

Based on the available data, the increase in vamorolone exposure is proportional to the severity of hepatic dysfunction. Patients with mild hepatic impairment (Child-Pugh class A) are not expected to have a significant increase in exposure and therefore no dose adjustment is recommended. There is no experience with vamorolone in patients with severe hepatic impairment (Child-Pugh class C) and vamorolone should not be administered to these patients.

Renal impairment

There is no clinical experience in patients with renal impairment. Vamorolone is not excreted unchanged via the kidney, and increases in exposure due to renal impairment are considered unlikely.

Paediatric population

Following oral administration, vamorolone exhibits dose-dependent pharmacokinetics in paediatric patients aged 2 to <18 years. Exposure (C_max and AUC) increases with dose; however, no accumulation is observed with once-daily dosing. Tmax occurs at 2 hours across all age groups. The elimination half-life (t_1/2) is approximately 2 hours, indicating consistent and rapid clearance. The pharmacokinetic parameters are summarised in table 1 and table 2.

Table 1. Pharmacokinetics parameters across age range after single dose:

¹ Data derived from Study 2: A phase 2 open-label, multiple dose study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of vamorolone in boys ages 2 to <4 years and 7 to <18 years with Duchenne Muscular Dystrophy (DMD).
² Data derived from Study 3: A phase 2a open-label, multiple ascending dose study to assess the pharmacokinetics of vamorolone in boys with Duchenne Muscular Dystrophy (DMD).
³ For the age group of 2 to <4 years, the sampling is sparse. For this reason, the AUC presented is AUC_0-6.
ND, not determined.

Table 2. Pharmacokinetics parameters across age range after multiple dose (2 weeks):

¹ Data derived from Study 2: A phase 2 open-label, multiple dose study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of vamorolone in boys ages 2 to <4 years and 7 to <18 years with Duchenne Muscular Dystrophy (DMD).
² Data derived from Study 3: A phase 2a open-label, multiple ascending dose study to assess the pharmacokinetics of vamorolone in boys with Duchenne Muscular Dystrophy (DMD).
³ For the age group of 2 to <4 years, the sampling is sparse. For this reason, the AUC presented is AUC_0-6.
ND, not determined.

Repeat-dose toxicity

Repeated vamorolone administration resulted in transient increases of triglycerides and cholesterol as well as liver enzymes in mice and dogs. Focal hepatic inflammation/necrosis observed in both species might have developed secondary to the hepatocellular hypertrophy and vacuolation containing glycogen and lipid accumulations that likely reflect the stimulation of gluconeogenesis.

Long-term vamorolone dosing also caused adrenal cortex atrophy in mice and dogs, which are ascribable to the known suppression of the hypothalamic-pituitary-adrenal axis by glucocorticoid agents.

The primary anti-inflammatory activity of vamorolone further accounted for mild to moderate lymphocyte depletion in spleen, thymus and lymph nodes of both species. The adverse liver and adrenal gland findings and the lymphoid changes in mice and dogs developed with no safety margins to the MRHD based on AUC.

Genotoxicity and carcinogenicity

Vamorolone did not exert any genotoxic potential in the standard test battery. Carcinogenicity studies have not been conducted with vamorolone, but the absence of pre-neoplastic lesions in long-term toxicity studies and experience with other glucocorticoid agents do not suggest a particular carcinogenic hazard.

Reproductive and developmental toxicity

No standard reproductive and developmental toxicity studies have been performed. An exploratory embryo-foetal developmental study with vamorolone in mice showed higher foetal and litter incidences of cleft palate at exposures similar to the human exposure at the MRHD indicative of a teratogenic effect of vamorolone. Vamorolone did not adversely affect the development of sperm and reproductive tissues in the chronic toxicity study in mice. Following chronic dosing in dogs, incompletely reversible spermatocyte/spermatid degenerations were observed in testes leading to oligospermia and germ cell debris in epididymides. Furthermore, the prostate glands were reduced and contained less secretory product.

In female animals, long-term repeated dosing in dogs additionally resulted in partially reversible bilateral absence of corpora lutea in the ovaries. The inhibition of male and female fertility is attributable to the known interference of long-term glucocorticoid treatment with the hypothalamus-pituitary-gonadal axis and developed without AUC-based safety margin to humans at the MRHD.

Juvenile toxicity

The main target organs of vamorolone in male and female juvenile mice overlap with those of adult mice such as adrenal cortical atrophy and vamorolone-related adverse hepatocellular degeneration/necrosis.

Vamorolone-related effects exclusively observed in juvenile mice were non-adverse tibia and body lengths reductions in male and female animals and were attributed to the induction of slower growths. In addition, acinar cell hypertrophy of mandibular salivary glands were detected in female animals. Whereas growth retardation is a well known effect associated with glucocorticoid treatment of children, the relevance of the salivary gland findings for children is unknown. At the no observed adverse effect level (NOAEL) for general toxicity in male and female juvenile mice, no safety margin with respect to human exposure at the MRHD exists.