DNL.L Regulatory News (DNL)

8 October 2018

Diurnal Group plc

("Diurnal" or the "Company")

Headline data for Chronocort® European Phase III clinical trial

Diurnal Group plc (AIM: DNL), the specialty pharmaceutical company targeting patient needs in chronic endocrine (hormonal) diseases, announces headline data from the Chronocort® pivotal Phase III clinical trial in Europe for adults with congenital adrenal hyperplasia (CAH). Both regimens used in the trial - regular adjustment of Chronocort® and conventional glucocorticoid doses according to endocrine response and symptoms (with the adjustments being mandated by a blinded physician) - controlled androgens (sex hormones) over a 24-hour period. The stated primary objective of the protocol was to demonstrate superiority of Chronocort® to conventional therapy in endocrine control over the 24-hour period: as titration of conventional therapy achieved control as good as titration of Chronocort®, the primary objective of the trial was not met.

Chronocort® achieved control on a lower overall dose of glucocorticoid with fewer patients requiring rescue therapy (sick day rules). The modified release formulation of Chronocort®, designed to provide overnight cortisol release, eliminated the early morning peak in androgen levels seen using conventional therapy. 

The implications of the overall trial results, including interim data from the ongoing long-term dosing study, will be discussed with the regulatory authorities.

Martin Whitaker, Chief Executive Officer of Diurnal, commented:

"We are surprised by these results, following our previously successful Phase II clinical trial in CAH. However, these initial results confirm the concept of Chronocort®, that early morning control of androgens can be achieved with a modified release preparation of hydrocortisone. We will now analyse the full data set from this trial, along with interim data from the ongoing Chronocort® long-term dosing study, to determine next steps in Chronocort® development, and discuss these with the regulatory authorities. We will provide an update on these plans to the market in due course, including any impact on our development of Chronocort® in the US, where we recently initiated a pivotal Phase III study in CAH, focussed particularly on morning control of androgens. We remain confident that Chronocort® will be a valuable treatment option for CAH patients."

The Phase III trial was designed in agreement with the European Medicines Agency (EMA) and conducted in a total of 122 patients with CAH across seven countries and 11 clinical trial sites. Patients being treated for CAH with combinations of generic steroids (standard-of-care) were enrolled on the trial and randomised to either Chronocort® on a twice-daily regime or continued their standard of care regimen.

CAH is an orphan condition caused by a block in cortisol production, an essential adrenal steroid hormone required for healthy life. A lack of cortisol in turn causes the over-production of male steroid hormones (androgens). Cortisol deficiency and over-production of androgens can lead to increased mortality, infertility and severe development defects, including ambiguous genitalia, precocious puberty and short stature. Sufferers, even if treated, remain at risk of death through an adrenal crisis. The condition is estimated to affect a total of approximately 47,000 patients in Europe, with over 400,000 in the rest of the world.

This announcement contains inside information for the purposes of Article 7 of Regulation (EU) 596/2014 (MAR).

Notes to Editors

Chronocort® Phase II trial

Data from the Chronocort® Phase II trial demonstrated that the trial met its primary endpoint of fully characterising the pharmacokinetic profile of Chronocort® in 16 male and female adult subjects with CAH. The results showed Chronocort® provides circadian levels of the stress hormone, cortisol, similar to the healthy population mimicking the overnight rise in cortisol levels, such that patients wake with a normal cortisol level.

In addition, the secondary objective of examining the effect of Chronocort® on the morning biochemical efficacy markers of the disease showed a significant reduction in the morning levels of 17-hydroxyprogesterone (the main androgen) in patients after six months on Chronocort (median 70nmol/l vs 5.65nmol/l p= 0.014) with 94% of values in the normal or optimal range compared to 31% before Chronocort® therapy. Chronocort® was well-tolerated during the six-month trial. The trial was reported in the Journal of Clinical Endocrinology and Metabolism (Mallappa et al JCEM 2014).

About Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is an orphan condition caused by deficiency of adrenal enzymes, most commonly 21-hydroxylase. This enzyme is required to produce the adrenal steroid hormone, cortisol. The block in the cortisol production pathway causes the over-production of male steroid hormones (androgens), which are precursors to cortisol. The condition is congenital (inherited at birth) and affects both sexes. The cortisol deficiency and over-production of male sex hormones can lead to increased mortality, infertility and severe development defects including ambiguous genitalia, premature (precocious) sexual development and short stature. Sufferers, even if treated, remain at risk of death through an adrenal crisis.

Current therapy for CAH uses a variety of generic steroids (hydrocortisone, dexamethasone and prednisolone). Approximately two-thirds of CAH patients are estimated to have poor disease control, leading to elevated androgen levels. The condition is estimated to affect a total of approximately 47,000 patients in Europe, with over 400,000 in the rest of the world.

About Chronocort®

Chronocort® is a modified release preparation of hydrocortisone that has been designed to mimic the circadian rhythm of cortisol when given in a twice-a-day "toothbrush" regimen (last thing at night before sleep and first thing in the morning on waking) to control androgen excess and chronic fatigue in patients with diseases of cortisol deficiency. The first planned indication for Chronocort® is CAH in adults. Chronocort® has been extensively studied in humans having completed four Phase I trials, a Phase II trial in 16 CAH patients in the US in 2014, and a Phase III trial in 122 CAH patients in Europe.

In Europe, Chronocort® has been granted Orphan Drug Designation in the treatment of CAH, which, if confirmed at marketing authorisation, provides market exclusivity for 10 years. The market authorisation of Chronocort® in Europe is anticipated in 2020.

About Diurnal Group plc

Founded in 2004, Diurnal is a UK-based specialty pharma company developing high quality products for the global market for the life-long treatment of chronic endocrine conditions, including Congenital Adrenal Hyperplasia and Adrenal Insufficiency. Its expertise and innovative research activities focus on circadian-based endocrinology to yield novel product candidates in the rare and chronic endocrine disease arena.

For further information about Diurnal, please visit www.diurnal.co.uk

Date of Preparation Oct 2018 Code: CH EU-EU-0050