Acacia Pharma Initiates Phase 3 Combination Prophylaxis Study With APD421 in Post-Operative Nausea & Vomiting (PONV)

CAMBRIDGE, England, April 21, 2015 /PRNewswire/ --

Acacia Pharma Ltd ("Acacia Pharma" or "the Company"), the supportive care company developing products for US and international markets, announces the initiation of a Phase 3 study investigating APD421 in combination with standard anti-emetics, in the prevention of post-operative nausea & vomiting (PONV) in high-risk patients. PONV remains a clinically significant problem in patients undergoing surgery, despite the availability of a range of anti-emetic medications. International consensus guidelines recommend the use of multiple anti-emetics to prevent PONV in high-risk patients.

The study is taking place in approximately 30 leading institutions in the USA, France, and Germany and aims to recruit up to 1,200 surgical patients at high-risk of suffering PONV over the next 6-12 months. The trial compares APD421 plus a standard anti-emetic (for example ondansetron or dexamethasone), against placebo plus the same standard anti-emetic. The primary endpoint is no vomiting or retching and no requirement for anti-emetic rescue medication in the first 24 hours after surgery. The incidence and severity of nausea are also being studied. Further studies are planned to investigate the use of APD421 in the treatment of established PONV, with the aim of seeking FDA regulatory approval and bringing the product onto the US market.

Data generated by Acacia Pharma in Phase 2 and Phase 3 clinical trials indicate that APD421, its proprietary low dose intravenous formulation of the marketed dopamine antagonist amisulpride, is an effective, safe anti-emetic. The Company believes that a drug with these characteristics can be used to manage PONV:

• prophylactically in combination with standard anti-emetics (eg 5HT₃ antagonists and/or corticosteroids) in high-risk patients, and
• to rescue patients with PONV despite prior prophylaxis with non-dopamine-antagonist anti-emetics.

Dr Gabriel Fox, Acacia Pharma's Chief Medical Officer commented: "We have already demonstrated the benefit of APD421 when used on its own to prevent PONV. The aim of this study is to show that APD421 is safe and effective when used in combination with other anti-emetics having different mechanisms of action, in patients at high risk of getting PONV. The study is one of the largest PONV studies ever undertaken and is being conducted by many of the world's leading PONV experts in Europe and the US."

Amisulpride is also being developed by Acacia Pharma as APD403 for the prevention of chemotherapy induced nausea & vomiting (CINV).

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 

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 high-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.