Acacia Pharma Announces Positive Phase 3 Results For APD421 in Post-Operative Nausea & Vomiting (PONV)

CAMBRIDGE, England, October 7, 2014 /PRNewswire/ --

Acacia Pharma announces positive Phase 3 results with APD421 for the management of post-operative nausea & vomiting (PONV). The data generated demonstrated a statistically significant reduction in the incidence of PONV with APD421 compared to placebo in adult surgical patients at moderate to high risk of suffering PONV (PONV is defined as any episode of emesis or use of antiemetic rescue medication in the first 24 hours after surgery). This condition is a clinically significant problem despite the availability of a range of antiemetic medications. In particular, there remains a clear need for improved options for combination prophylaxis in the highest risk patients, and rescue therapy.

Two double-blind, placebo controlled, Phase 3 studies were conducted in 19 major centres in the US, France and Germany, and recruited a total of 689 surgical patients with two or more of the four validated "Apfel risk factors" for PONV, of whom 626 were evaluable per protocol. APD421 was significantly superior to placebo (p=0.005), giving a relative risk reduction (RRR) of 19.4% in the incidence of PONV.  There was no significant difference in the rate of adverse events between APD421 and placebo. Detailed data from these studies will be presented at an upcoming scientific meeting and/or submitted for publication in a peer-reviewed journal.

Acacia Pharma's CEO, Dr Julian Gilbert, commented: "A significant number of patients suffer from PONV despite routine use of prophylactic antiemetics, predominantly 5HT₃s and corticosteroids, increasing healthcare costs and reducing patient satisfaction. There is a clear need for an efficacious, safe antiemetic with a different mechanism of action for use in combination prophylaxis in the highest risk patients, and to rescue patients who suffer PONV despite receiving prophylaxis. Our clinical data indicate APD421 is an effective dopamine antagonist antiemetic, which has the potential to become a mainstay of therapy, contributing greatly to the well-being of patients following surgery."

Dr Gabriel Fox, Acacia Pharma's CMO, added: "Dopamine antagonists were a popular and very efficacious option for anaesthetists seeking to prevent PONV, until the emergence of safety concerns such as heart rhythm disturbances and movement disorders. Acacia Pharma set out to develop an effective and safe dopamine antagonist to add back into the armamentarium of antiemetics for the management of PONV. We believe we are on the way to achieving this goal, having completed three studies with many of the world's leading experts in PONV, providing statistically significant evidence of the benefit of APD421 in PONV without the safety issues previously seen with this class of drugs."

The company has engaged J.P. Morgan Cazenove to advise the Board on its strategic options.

About PONV 

PONV 

Post-operative nausea & vomiting (PONV) is a common complication of surgery which is distressing to patients and increases healthcare costs. In untreated patients, the incidence of vomiting is ~30%, the incidence of nausea is ~50% and the PONV rate in high-risk surgical patients is up to 80%^[1]. PONV is reported by patients as one of the most troublesome of all post-operative complications^[2].

PONV can lead to prolonged discharge times and unanticipated hospital admissions (increasing healthcare costs)^[1] and to the possibility of reduced healthcare provider income as a consequence of Medicare's Hospital Readmissions Reduction Program and the pay-for- performance payment system in the Hospital Value-Based Purchasing (VBP) Program, in the US^[3]. The objective of PONV management, therefore, is to decrease the incidence of PONV, reducing patients' length of stay in the post-anaesthesia care unit (PACU) and avoiding hospital readmission, thereby reducing healthcare costs; and reducing patient distress, improving overall satisfaction, thereby optimising provider income through improved patient outcomes.

PONV risk factors 

A simplified risk scoring system has been developed by Apfel et al. to assess the risk of PONV in surgical patients^[4]. The four "Apfel risk factors" are:

• Female
• Non-smoker
• Prior history of PONV or motion sickness
• Expected use of post-operative opioid analgesia.

Each of these four risk factors independently contributes around 20% risk of PONV. Patients with two "Apfel risk factors" are considered at moderate risk of PONV, while those with three or four are considered at high risk. A patient with all four risk factors has up to an 80% chance of PONV in the absence of effective prophylaxis.

Guidelines for the management of PONV 

Prophylaxis 

It is recommended that surgical patients are prescribed prophylactic antiemetics alone or in combination, according to their risk of PONV. Those considered at moderate risk of PONV should be given at least one prophylactic antiemetic and those at high risk of PONV, should be given multiple antiemetics of different mechanisms of action to optimise efficacy^[1].

Rescue 

It is recommended that when a patient who has received antiemetic prophylaxis suffers PONV, an antiemetic from a different mechanism of action to that given prophylactically, is used to provide rescue treatment^[1]. Repeating the mechanism given prophylactically confers no additional benefit^[5].

Current management of PONV  

Two classes of drugs are predominantly used for the management of PONV: 5HT₃ antagonists (eg ondansetron); and corticosteroids (eg dexamethasone). Ondansetron and dexamethasone have been investigated in many clinical studies and generally deliver a relative risk reduction (RRR) in the incidence of PONV of 15-30%^{[2],[ 6],[ 7]}.

Prophylaxis 

The majority of surgical patients receiving prophylaxis are given a 5HT₃ antagonist alone or in combination with a corticosteroid^[8]. However, Acacia Pharma believes that drug choices are limited in the highest risk patients where a third antiemetic of a different mechanism is required.

Rescue 

Up to 40% of patients experience PONV, requiring rescue medication, despite the routine use of prophylactic antiemetics^[2]. The majority of surgical patients have been given a prophylactic 5HT₃ antagonist^[8] therefore precluding their use for rescue^[1]. Dexamethasone (a corticosteroid) has a slow onset of action and is not recommended for rescue^[1].  Therefore Acacia Pharma believes antiemetic choices for rescue are extremely limited.

Unmet need for a dopamine antagonist for PONV 

Droperidol (a dopamine antagonist) was previously considered the drug of choice for PONV management until it received a boxed warning for QT-interval prolongation^[9]. A boxed warning is the most serious form of warning issued by the U.S. Food and Drug Administration for prescription drug products. The boxed warning and concerns about its side effect profile have severely limited the use of droperidol as an antiemetic^[8].

Therefore there is currently no safe, effective, dopamine antagonist antiemetic available for anaesthetists to:

• Add to the most prevalent prophylactic regimen of a 5HT₃ antagonist plus a corticosteroid, in the highest risk patients.
• Rescue patients having previously been given prophylaxis with a 5HT₃ antagonist (alone or in combination).

^[1]Gan et al, Anesthesia & Analgesia (2014) 118 1 85-113

^[2]Apfel et al, N Engl J Med (2004) 350 2441-51

^[3]http://www.medicare.gov/hospitalcompare/linking-quality-to-payment.html

^[4]Apfel et al, Anesthesiology (1999) 91 109-118

^[5]Kovac et al, J Clin Anesth (1999) 11 453-459

^[6]Fortney et al,  Anesthesia & Analgesia (1998) 86 731-738

^[7]Gan et al. Anesthesia & Analgesia (2011) 112 4 804-812

^[8]Habib & Gan, J Clin Anesth (2008) 20 35-39

^[9]Gan et al, Anesthesia & Analgesia (2007) 105 6 1615-1628

About APD421 

APD421 comprises a low dose intravenous formulation of the marketed dopamine antagonist amisulpride, which Acacia Pharma has repurposed for the completely new, patent-protected use of management of PONV. Amisulpride is currently indicated for the management of psychoses, and is given at high doses in oral form. Amisulpride is not available in any form, for any use, in the US.

Data generated by Acacia Pharma indicate that APD421 is an effective, safe, dopamine antagonist. The company believes that a drug with these characteristics can be used prophylactically in combination with 5HT₃ antagonists and/or corticosteroids in the highest risk patients and to rescue patients that have not responded to PONV prophylaxis with a 5HT₃ antagonist alone or in combination.

Amisulpride is also being developed by Acacia Pharma as APD403 for the prevention of chemotherapy induced nausea & vomiting (CINV) and is currently being investigated in a Phase 2 dose-ranging study.

About Acacia Pharma 

Acacia Pharma is developing supportive care product opportunities for post-surgical and cancer patients. Patients and healthcare professionals urgently need new and improved interventions in these rapidly expanding, yet poorly served, areas of supportive care, to improve treatment outcomes and patients' quality of life.

Acacia Pharma has generated its pipeline of product opportunities using a commercially driven approach to product discovery identifying completely new uses for marketed drugs, a process termed repurposing. This strategy leads to opportunities with a higher probability of success and enables more rapid development. All of Acacia Pharma's repurposed programmes are optimised for their new use using a new route of delivery and dose that are appropriate for the new indication identified, thereby differentiating them from the original marketed product.

The company's lead project, APD421 for post-operative nausea & vomiting (PONV), has generated positive results in Phase 3 clinical studies. Its sister project, APD403 for chemotherapy induced nausea & vomiting (CINV) is under investigation in a Phase 2 dose-ranging study. In addition, the company has completed a Phase 2 study with APD515 for xerostomia (dry mouth) in advanced cancer patients and a Phase 2a study with APD209 for cancer cachexia (muscle wasting).

Acacia Pharma is led by an experienced management team, members of which have successfully built and exited life sciences companies. Management, Gilde Healthcare, Lundbeckfond Ventures, Novo A/S and Fidelity Biosciences are the Company's key shareholders. Acacia Pharma is based in Cambridge, UK. http://www.acaciapharma.com 

SOURCE Acacia Pharma