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Pharmacodynamic Biomarkers

Bridged pharmacodynamic biomarkers for safety in the vamorolone clinical program

The vamorolone clinical program relies heavily on use of 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 also monitor efficacy, anticipating later clinical benefit.

The vamorolone program has used existing safety biomarkers that are well-bridged to later clinical outcomes for the following four side effect profiles:

  • 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 (prednisone, deflazacort) are recognized by the body as a form of cortisol, and this creates a strong negative feedback on adrenal production of cortisol. This is called adrenal suppression. 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.
    • Vamorolone has shown about 100-fold less activity in adrenal suppression compared to prednisone, thus improving its safety profile in both mouse studies and human Phase 1 studies.
    • Adrenal suppression is measured in all vamorolone clinical trials using the pharmacodynamic biomarker of morning cortisol levels in the blood.
  • Bone turnover. Prednisone and deflazacort 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 is 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.
  • 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. Glucocorticoid drugs disrupt this process by making muscle less sensitive to insulin – a condition termed insulin resistance. DMD muscles are already struggling with maintaining energy stores, and prednisone and deflazacort likely make the problem worse.
    • 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. This is in part due to the fact that safety biomarkers are shared across all different diseases where glucocorticoids are used. Efficacy (clinical benefit) markers are likely different for different diseases. For example, glucocorticoids cause bone fragility in both boys with DMD, and older people with arthritis, and they are both measured by bone turnover markers. However, efficacy markers in DMD likely come from muscle, and efficacy markers in arthritis likely come from joints.

The CINRG group has recently carried out a systematic study of prednisone and deflazacort treated DMD boys, compared to those that were untreated, to define novel pharmacodynamic biomarkers for efficacy in DMD (Hathout et al. in press). These biomarkers are pro-inflammatory proteins seen in the blood of DMD patients that are then suppressed towards normal levels by corticosteroids. These candidate efficacy biomarkers are measured in the DMD clinical trials of vamorolone to determine if they predict later clinical benefit, and can be utilized for dose finding in the Phase 2a extension study.