Acacia Pharma Initiates Second Pivotal Phase 3 Treatment Study with Baremsis™ (APD421) in Post-Operative Nausea & Vomiting (PONV)

CAMBRIDGE, England, March 21, 2016 /PRNewswire/ --

NDA filing expected in second half of 2016 

Acacia Pharma Group plc ("Acacia Pharma"), the supportive care company developing products for US and international markets, announces the initiation of its second pivotal Phase 3 treatment study, investigating BAREMSIS^™ (amisulpride injection, formerly APD421) in surgical patients who develop post-operative nausea & vomiting (PONV), despite having received antiemetic prophylaxis before surgery.

International consensus guidelines recommend that surgical patients who develop PONV should be treated with an antiemetic with a different mechanism of action from any antiemetic given before surgery for the prevention of PONV. Currently two classes of antiemetics are predominantly given prophylactically in an attempt to prevent PONV. These are 5HT₃ antagonists (usually ondansetron) and corticosteroids (usually dexamethasone). A safe and effective third antiemetic mechanism is therefore required to treat subsequent PONV and BAREMSIS, a dopamine antagonist antiemetic, could fulfil this need.

This second Phase 3 treatment trial compares two doses of BAREMSIS against placebo in post-surgical patients who develop PONV despite prior antiemetic prophylaxis. The study is taking place in leading institutions in the USA, Canada, France and Germany and aims to recruit around 560 patients. The primary endpoint is the successful resolution of the episode of PONV, with no recurrence of vomiting or requirement for further antiemetic rescue in the 24-hour period after treatment.

Dr Julian Gilbert, CEO said: "Up to 40% of surgical patients who receive a preventative antiemetic prior to surgery, still develop PONV which extends hospital stays, can lead to readmissions and subsequently increases healthcare costs. Unfortunately, the PONV treatment options currently available to anaesthetists for these patients are limited due to the extensive prophylactic use of 5HT₃ antagonists and corticosteroids. We believe that BAREMSIS, a dopamine antagonist antiemetic that we have already shown to be safe and effective in preventing PONV, could provide the solution to this problem and this study is designed to investigate its use in treatment."

A Phase 3 treatment study of BAREMSIS in around 560 surgical patients who develop PONV and who have not received prior prophylaxis is ongoing, and Acacia Pharma has already successfully completed two Phase 3 prophylaxis studies showing that BAREMSIS is safe and effective at preventing PONV, when given either alone or in combination with other antiemetics, prior to surgery. These three studies, along with the study we have announced the initiation of today, will complete the efficacy package Acacia Pharma aims to submit to the US FDA as part of its BAREMSIS New Drug Application (NDA) in the second half of 2016, looking to gain approval for the treatment and prophylaxis of PONV alone and in combination, a novel and unique label if approved.

NOTES TO EDITORS  

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, by 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 lead project, BAREMSIS™ 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) has successfully completed one Phase 2 dose-ranging study in patients receiving highly emetogenic chemotherapy. 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. Management, Gilde Healthcare, Lundbeckfond Ventures, Novo A/S and F-Prime Capital are the Company's key shareholders. Acacia Pharma is based in Cambridge, UK and has US operations in Indianapolis, IN. http://www.acaciapharma.com

About BAREMSIS 

BAREMSIS (formerly 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 for any use in the US.

Data generated by Acacia Pharma indicate that BAREMSIS is an effective, safe, dopamine antagonist antiemetic. 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 treat patients that have not responded to PONV prophylaxis with a 5HT₃ antagonist alone or in combination.

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 hospital, particularly 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:

• Being female
• Being a non-smoker
• Having a prior history of PONV or motion sickness
• An 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