During the Clinical and Research Excellence (CARE) Awards, the ‘Clinical Trial Result of the Year’ award will recognize a group for their exceptional contribution to an area with unmet medical need. However, the task could seem disconcerting as thousands of clinical data were released during 2016 and any that were deemed positive do contribute to an existing medical field. To highlight some of the notable achievements from last year, Biomedtracker data was reviewed to identify instance of top-line data that positively affected the likelihood of approval (LOA)  of the trial’s drug, resulting in a total of 34 top-line events. Epidiolex for Dravet syndrome and SAGE-547 for severe postpartum depression (PPD) stuck out from the rest because both show high promise in markets where there are no other FDA approved treatment options available.
However, this search excluded trial results for already approved drugs in their primary indication. Since noteworthy trial results aren’t limited to investigational drugs, I’ll cover some key achievements of drugs already on the market in a later blog.
Epidiolex significantly reduces convulsive seizures in children and young adults
In March 2016, top-line results of the Phase II/III study in patients with Dravet syndrome showed that Epidiolex achieved the primary endpoint of a significant reduction in convulsive seizures, over a 14-week period, compared with a placebo. Epidiolex is GW Pharmaceuticals’ oral liquid formulation of a highly purified extract of plant-derived cannabidiol (CBD), a non-psychoactive molecule from the cannabis plant. These positive results affirm positive data published in 2015 from a physician-led expanded access program in treatment-resistant epilepsy, and support GW Pharmaceuticals’ plans to file a new drug application (NDA) of Epidiolex [ ], which has both orphan drug designation and fast track designation from the U.S. Food and Drug Administration (FDA) in the treatment of Dravet syndrome.
The Phase II/III (GWPCARE1 PART B; ClinicalTrials.gov identifier: NCT02091375) study randomized 120 patients into two arms - Epidiolex 20mg/kg/day (n=61) and placebo (n=59). Patients taking Epidiolex achieved a median reduction in monthly convulsive seizures of 39% compared to 13% of patients in the placebo group, which was highly statistically significant (p=0.0123) .
These positive trial results are noteworthy due to their high impact on this patient population since Epidiolex is the first drug candidate in this space to demonstrate a clinically significant effect. Also, on average, patients were taking approximately 3 anti-epileptic drugs (AED), having previously tried and failed an average of more than 4 other AEDs. Biomedtracker increased its likelihood of approval (LOA) by 10% based on these results, placing it 15% above the average baseline rate of approval .
The Dravet Syndrome Foundation reports that patients with Dravet syndrome face a 15-20% mortality rate due to SUDEP (Sudden Unexplained Death in Epilepsy), prolonged seizures, seizure-related accidents such as drowning, and infections . Dravet syndrome is one of the most severe and difficult-to-treat types of epilepsy and Epidiolex will have a huge impact for children who suffer from this disease.
Results of SAGE-547 point to a new understanding of severe postpartum depression and will influence future development of therapies in this disease area
On July 12, 2016, Sage Therapeutics (who won a CARE award in 2016 for ‘Most Innovative Clinical Trial Design’) saw its stock price increase by 37.3% based on positive Phase II (202A; ClinicalTrials.gov identifier: NCT02614547) results of SAGE-547 for women with PPD, a market where there are no other available FDA approved treatment options . SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABA-A receptors and is being developed as an adjunctive therapy for a variety of central nervous system (CNS) disorders. The drug also has breakthrough therapy designation and fast track designation from the FDA in the treatment of PPD.
Rapid reversal and robust changes in Hamilton Depression Rating Scale (HAM-D) scores may represent a significant advancement for the treatment of post-partum depression and an increased awareness of its underlying pathology. In June 2015, data from a separate Phase II study, albeit only in four patients, provided strong proof-of-concept for the administration of a GABA-A receptor positive allosteric modulator as an adjunctive therapy. During pregnancy, there is a large increase in progresterone-derived neurosteroids that leads to a tonic inhibition and subsequent down regulation of GABA-A receptor delta subunits. Following pregnancy, there is a rapid reversal of this process. However, inability to modulate these delta-containing GABA-A receptors is associated with depression-like behavior in the post-partum period .
In July 2016, top-line results of the Phase II 202A study showed that SAGE-547’s rapid onset of action was associated with relief for women who suffer from the debilitating symptoms of PPD. SAGE-547 achieved the primary endpoint of a significant reduction in the HAM-D score compared to placebo at 60 hours (10 evaluable patients), representing a greater than 20-point mean reduction in the depression scores, with a greater than 12-point difference from placebo . Biomedtracker increased its LOA by 5% based on these results, placing it 12% above the average baseline rate of approval .
These results are potentially transformative for PPD treatment and will serve as a paradigm shift in how this disease is understood and treated. The statistically significant, clinically meaningful decrease in HAM-D associated with SAGE-547 compared to placebo at only 24 hours and maintenance of the magnitude of this effect throughout 30 days, are notable and further support the company proposed mechanism of action (MOA) of rapid, highly beneficial restoration of acute GABA imbalance in PPD patients. As many as 85% of childbearing women report mild and transient mood disturbances during the first week postpartum and the American Academy of Pediatrics (AAP) estimates that more than 400,000 infants are born each year to mothers who are depressed [10,11].
If approved, both Epidiolex and SAGE-547 will significantly change and impact patient care in areas where there are huge unmet medical needs. For the second part of this blog, I’ll examine drugs that have been approved by the FDA, but whose continuing studies and promising data are contributing to overall disease pathology and are improving the standards of care.
For more information about the Clinical and Research Excellence (CARE) Awards, including how to book a table or sponsorship opportunities, please visit clinicalresearchexcellence.com
The LOA of a drug represents the average probability of FDA approval for marketing in the U.S. for the specified disease group based on the historical performance of drugs in the same development phase.
Ellis L. (2016) Dravet Syndrome Indication Will Set GW Pharma Apart On US Epilepsy Market. Scrip.
GW Pharmaceuticals (2016) GW Announces New Epidiolex® (CBD) Positive Phase 3 Data in Dravet Syndrome and Lennox-Gastaut Syndrome.
Biomedtracker, January 2017.
Dravet Syndrome Foundation. What is Dravet Syndrome?
Jackson M. (2016) Sage Drug Could Help Take Stigma Out Of Postpartum Depression. Scrip.
Biomedtracker, January 2017.
Sage Therapeutics (2016) Sage Reports Positive Top-line Results Including Demonstration of 30-Day Durability from Phase 2 Clinical Trial of SAGE-547 in Severe Postpartum Depression.
Biomedtracker, January 2017.
Ross LE, Murray BJ, Steiner M (2005) Sleep and perinatal mood disorders: a critical review. J Psychiatry Neurosci, 30(4), 247–256.
American Academy of Pediatrics (2015) Available at: http://downloads.aap.org/DOFA/Clark%20Costello%20Postpartum%20Depression%20Endorsement.pdf