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Pharmacodynamic Biomarkers

Bridged pharmacodynamic biomarkers for safety in the vamorolone clinical program

The vamorolone clinical program utilizes pharmacodynamic biomarker measured in small volumes of blood. Pharmacodynamic biomarkers, if carefully characterized and sufficiently bridged to clinical outcomes, can serve as acute and objective read-outs of drug effect. Biomarkers can monitor safety of a drug, detecting safety signals months or years before they become a clinical problem. On the other hand, biomarkers can serve as a measure of efficacy, anticipating later clinical benefit.

Besides using clinical data to study if the investigational drug vamorolone may be safe and effective for DMD, certain safety biomarkers are also being carefully studied that have previously shown to be bridged to later clinical outcomes in other glucocorticoid drugs. It is unknown if vamorolone will also show these outcomes. The early results are summarized below:

  • Adrenal suppression. There are natural day/night patterns of the natural glucocorticoid, cortisol, in blood. Cortisol peaks in early morning hours before waking, and then declines to low levels by Noon. Cortisol is produced by the adrenal glands (adrenal cortex), receiving signals through the hypothalamus – pituitary – adrenal axis (HPA axis). There are negative feedback loops in the HPA axis, so that increasing levels of cortisol begin to shut down further production of cortisol – a process that creates the daily peaks and troughs of cortisol that set our day/night patterns. Pharmacological glucocorticoids are recognized by the body as a form of cortisol, and this creates a strong negative feedback on adrenal production of cortisol;even a single low dose of prednisone leads to adrenal suppression. Adrenal suppression in turn leads to a reduced ability of the adrenal cortex to make cortisol, as well as other steroid hormones such as testosterone.
    • Adrenal suppression is measured in all vamorolone clinical trials using the pharmacodynamic biomarker of morning cortisol levels in the blood.
    • Data from VBP15-002 may be found here: https://www.ncbi.nlm.nih.gov/pubmed/30219580
  • Bone turnover. Glucocorticoids cause changes in bone metabolism that lead to more fragile bones (osteopenia), as well as stunting of growth in children. The side effect of bone fragility is particularly problematic in older individuals with arthritis or other age-related disease, where glucocorticoid treatment can exacerbate osteoporosis. There are extensive interactions between bones and muscle, and when muscles get weak, bones often become weak as well, as is the case in DMD. Two key pharmacodynamic biomarkers are used in studies of bone turnover: osteocalcin (a marker of bone formation), and CTX1 (a marker of bone absorption, or bone loss). Prednisone causes rapid reductions in osteocalcin even at very low doses, and also causes increases in CTX1. The drug-induced reduction in osteocalcin (bone formation) and increases in CTX1 (bone loss) leads to an unfavorable ratio, and this is considered well-bridged to later clinical outcomes of bone fragility.
    • Vamorolone has shown no changes in bone turnover markers, osteocalcin or CTX1, up to 20 mg/kg/day in Phase 1 studies. In contrast, prednisone shows significant changes at just 0.2 mg/kg/day.
    • Bone turnover markers are monitored in all clinical trials of vamorolone.
    • Data from the 2 week VBP15-002 trial may be found here: https://www.ncbi.nlm.nih.gov/pubmed/30219580
    • No decreases in osteocalcin were seen at any dose level in the 24-week VBP15-003 study
  • Insulin resistance. The body transports sugar (glucose) through the blood as a way of sending energy to tissues. To take glucose out of the blood, insulin is secreted by the islet cells of the pancreas, and tissues that need sugar respond to the insulin to take up sugar. One of the tissues that has the highest energy demand is muscle – it needs sugar from the blood to maintain activity and strength. Thus, normal muscle is highly sensitive to insulin, and able to efficiently take up sugar out of the blood, and maintain adequate energy stores in the muscle. Glucocorticoids disrupt this process by making muscle less sensitive to insulin – a condition termed insulin resistance.
    • Vamorolone has shown no evidence of inducing insulin resistance to 20.0 mg/kg/day in Phase 1 trials. In contrast, prednisone induces insulin resistance at 0.2 mg/kg.
    • Insulin resistance is monitored in all vamorolone trials by testing fasting insulin and glucose levels.
  • Immune suppression. Prednisone causes both anti-inflammatory activity and immune suppression. While both anti-inflammation and immune suppression are parts of the immune system, they are considered different. Anti-inflammation is part of the efficacy (benefit) of corticosteroids, and is through transrepression of the innate immunity system (low level, rapid-acting ‘danger signals’ of cells and tissues). Immune suppression refers to suppression of acquired immunity where lymphocytes recognize something foreign in the body, and mount a ‘learned’ immune response to the foreign object. With glucocorticoids, anti-inflammation via innate immunity is of benefit, but immune suppression of acquired immunity may lead to a patient unable to mount an immune response against a virus or bacteria.
    • Vamorolone has shown no evidence of suppression of peripheral blood lymphocytes to 20.0 mg/kg/day in Phase 1 trials (compared to pre-dose levels). In contrast, prednisone leads to reductions in peripheral blood lymphocytes at doses of 0.2 mg/kg
    • Lymphocytes and other blood cell types are monitored in all vamorolone clinical trials as a biomarker for immune suppression.

In summary, by the use of well-established pharmacodynamic safety biomarkers, we are able to monitor safety of the drug through small drops of blood, before clinical symptoms might appear months or years later.

Exploratory pharmacodynamic biomarkers for efficacy in the vamorolone clinical program

While pharmacodynamic biomarkers for safety (side effects) of corticosteroid drugs are well established, biomarkers for clinical benefit (efficacy) have not been well-studied.

The CINRG group carried out a systematic study of prednisone- treated DMD boys, compared to those that were untreated, to define novel pharmacodynamic biomarkers for efficacy in DMD; this study may be found here: https://www.ncbi.nlm.nih.gov/pubmed/27530235).

These biomarkers have been shown to be responsive to glucocorticoids in other inflammatory diseases; this study may be found here: https://www.ncbi.nlm.nih.gov/pubmed/30352204

These candidate efficacy biomarkers are measured in the DMD clinical trials of vamorolone and will be studied to determine if they predict later clinical benefit in vamorolone trials. Biomarker data from the 2-week VBP15-002 trial may be found here: https://www.ncbi.nlm.nih.gov/pubmed/30219580