07 October 2014
Acacia Pharma Announces Positive Phase 3 Results for APD421 in PONV
Cambridge, UK – 7th October 2014: 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.
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 patients4. The four “Apfel risk factors” are:
- 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
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).
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 treatment1. Repeating the mechanism given prophylactically confers no additional benefit5.
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).
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.
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 rescue1. 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
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