DuoCort

A Patients who are unable to produce enough cortisol to meet their own needs are said to have adrenal insufficiency. Adrenal insufficiency is a life-threatening, but readily treatable hormonal deficiency. Adrenal insufficiency can occur for various reasons. Cortisol deficiency is another term for adrenal insufficiency.

It is the same as primary adrenal insufficiency. It occurs when the adrenal gland is the source of the inability to produce enough cortisol to meet the body´s needs.

We have two adrenal glands that are situated just above each kidney. The gland is divided into two separate parts. The adrenal core produces stress hormones (catecholamines, such as adrenaline) as part of the nervous system. The adrenal cortex produces steroid hormones. The most abundant and important is cortisol. The others are aldosterone, a salt-and water conserving hormone, and DHEA, a weak androgen.

Primary adrenal insufficiency, also called Addison’s disease, is caused by the gradual destruction of the adrenal cortex by the body’s own immune system. Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed.

About 80 percent of reported cases in the developed world are caused by autoimmune disorders and the numbers are rising with the increase in the incidence of autoimmune diseases. There are other causes of primary adrenal insufficiency, including tuberculosis and defective development of the adrenal glands.

Secondary adrenal insufficiency is more common than primary adrenal insufficiency and occurs when the pituitary and hypothalamus are unable to stimulate and regulate the adrenal glands to produce sufficient amounts of cortisol. The most common causes are benign tumours of the pituitary.

Cortisol is necessary for the functioning of almost every part of the body, such as glucose and fuel metabolism, immune function, muscle and skeletal function, connective tissue and brain function. It is also central to the body’s ability to prepare for and handle stress, either physical or emotional.

Excesses or deficiencies of this crucial hormone can lead to various physical symptoms and diseases. Lack of cortisol can for example give:

• Low blood sugar
• Low blood pressure
• Decreased appetite and weight loss
• Fatigue and muscle weakness

Deficiency of cortisol leads to ill health that can be life threatening if not treated.

Cortisol plays important roles in the regulation of:

• blood pressure and cardiovascular function
• the use of proteins, carbohydrates, and fats
• bone density
• growth
• kidney function
• the immune system
• the effect of insulin in breaking down carbohydrates for energy

The chronic forms of adrenal insufficiency (primary and secondary adrenal insufficiency) require life-long therapy.

For patients with primary or secondary adrenal insufficiency treatment is essential to survival and well-being.

Treatment of adrenal insufficiency involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced with hydrocortisone, the synthetic form of our natural cortisol and sometimes with other corticosteroids.

Patients with primary adrenal insufficiency, Addison’s disease, also need replacement with a salt-conserving hormone due to lack of aldosterone. Replacing adrenal andogens is less well documented.

Cortisol is replaced with hydrocortisone or cortisone acetate, the synthetic form of our natural cortisol and sometimes with other corticosteroids, such as, prednisone or dexamethasone.  Normal, or physiologiscal, cortisol production in the body follows a distinct 24-hour pattern with high levels just before waking in the morning, tapering off over the day and ending with a cortisol-free interval at night. Currently available products are unable to deliver replacement therapy in a way that adequately mimics this normal pattern of cortisol release.  Furthermore, current therapy is 30-40 years old and the only treatment innovation for decades has been to better define patients’ individual doses and to give two or three daily administrations in order to crudely mimic the normal pattern of cortisol. Current research indicates that patients may be suffering higher rates of mortality and disease than previously thought, likely contributed to by the non-physiological medications to which they now have access.

1. Existing administration forms cannot adequately mimic the normal 24 hour pattern of cortisol in the body and this result in too-high and too-low levels at different times of the day, which can adversely affect patients’ well-being.
   Multiple daily dosing can result in failure to fully comply with treatment, exposing the patient to risk.
   
   
2. By virtue of the dosage forms, patterns of administration, type of glucocorticoid used and patient needs and preferences, the total daily dose of glucocorticoid replacement is too high in some patients.
   
   
3. The primary aim in all endocrinology is to achieve hormone replacement with an endogenous hormone and to perform it as physiologically as possible. A hydrocortisone formulation that could more adequately mimic the normal profile of cortisol with a simpler dosing regimen would therefore be a step forward in improving cortisol replacement therapy.
   

Patients with adrenal insufficiency can suffer from obesity, cardiovascular disease, other long-term side effects and higher rates of mortality. We believe that the solution to the problem is a truly once-a-day therapy that better mimics the body’s own release pattern of cortisol.

Replacement of cortisol is very difficult.  We know that both too much and too little is bad for health. Missed doses and too little during an intercurret illness may lead to high fever, diarrhoea, a drop in blood pressure and a critical illness called adrenal crisis. Too high doses over a long period of time can induce obesity and its related disorders such as hypertension and diabetes. As there is no blood test or urinary test that can be used to see whether the dose and regime of cortisol replacement is adequate, careful clinical evaluation must be done by the treating physician in collaboration with the patient. A once daily administration that better mimics the body’s own serum cortisol profile should make the treatment easier and thereby safer.

DuoCort´s new product is a once daily, dual-release hydrocortisone tablet to be used as replacement therapy for patients with adrenal insufficiency.

The new therapy will:

• More closely mimic the natural biological rhythm of cortisol.
• Be a convenient once-daily medication which may improve compliance compared to multiple daily dose therapy
• Have a higher initial cortisol exposure after tablet intake than current therapy.

It is a single tablet combining both rapid release and extended release characteristics. In order to better mimic the normal cortisol release profile, the new dual-release tablet is administered in the morning on an empty stomach with a glass of water.  It achieves rapid onset of part of the total dose, followed by the slow release of the remainder of the dose over the rest of the day.

In healthy subjects the body´s normal cortisol production follows a distinct daily pattern. This means that cortisol levels vary during the 24 hour day. The cortisol levels are highest in the early morning hours, peak at around 7am, decline during the day to their lowest point which occurs by midnight and the early phase of sleep. This normal rhythm is controlled by the human body clock which is set according to light and dark exposure. In addition to this normal rhythm, cortisol secretion increases in response to any stress, whether physical or psychological.

You want a replacement treatment to mimic this normal rhythm as closely as possible in order keep the body’s rhythms as close to normal as possible and thereby improve body function and well-being.  Today’s therapy cannot adequately mimic this rhythm.  A once daily treatment also offers a more convenient alternative for patients and may improve compliance, which is important to keeping cortisol at the right level during the whole day and safer when there is less risk of missing a dose.

Morning fatigue is a big problem for around 40% of AI patients. DuoCort´s new product has a higher initial cortisol exposure after tablet intake, than currently available tablets.

It is currently in late-stage clinical trials in Europe. DuoCort have submitted an application for marketing authorisation in Europe.

The Phase I trial evaluated the safety and pharmacokinetics of the new hydrocortisone tablets in healthy volunteers.

The data shows that both t5 mg and 20 mg dual-release hydrocortisone tablets were safe and well tolerated.  The novel dual-release formulation showed a rapid increase in cortisol levels after single-dose administration, the dose was well absorbed and it had similar bioavailability to the oral hydrocortisone in the literature. Moreover, the data showed no risk of dose accumulation. The release profile closely resembled the physiological one, including the natural nocturnal cortisol free interval.

DuoCort have submitted an application for marketing authorisation in Europe mid 2010. Other countries will follow as quickly as the regulatory requirements can be fulfilled.

The new dual release product has an orphan drug designation both in the US as well as in the EU.  Orphan Drug legislation provides incentives to encourage the development and marketing of medicines for rare diseases such as adrenal insufficiency, including access to regulatory assistance during the development phase, reduced filing fees, and market exclusivity.

To recoup the investment in pharmaceutical and clinical research and other investments required to get an innovative drug like the DuoCort product approved and on the market, its price will most likely be higher than existing drugs for cortisol replacement, which have been on the market for years and have had very little invested in them in recent decades.  Pricing, however, is something that will be decided together with pricing and drug reimbursement authorities at the time of approval.

We are currently exploring a range of commercialisation options.