A Phase 1, Single-Center, Open-Label, Dose Optimization Study of ABP-700 in Healthy, Adult Subjects

ABP-700 is an intravenous (IV) anesthetic being developed for monitored
anesthesia care (MAC) and/or general anesthesia in patients undergoing
diagnostic or therapeutic procedures.
The highly dynamic nature of surgical and procedural intervention, as well as
the short duration of these procedures, demands the development of potent yet
rapidly reversible anesthetic agents. Ideally, the pharmacokinetics (PK) and
pharmacodynamics (PD) of these anesthetic agents should be better matched to
the procedures being performed. In general, currently used agents are either
too long-acting or not easily titratable to the desired level of effect. The
result is a clear unmet need for more effective drugs with a higher therapeutic
index that exhibit a predictable PK/PD relationship and allow precisely
tailored control of sedation and anesthesia. Newer sedative/anesthetic drugs
that are potent, have minimal hemodynamic effects and reduced toxicities, and
have a PK/PD profile that enables them to be more readily titratable are highly
desired to meet these evolving patient and healthcare needs.
ABP-700 is a newly developed, potent, positive allosteric modulator of the
GABAA receptor. Its mechanism of action is via potentiation of GABAA receptor
activation producing its sedative and anesthetic effects. ABP-700 contains an
ester bond that was precisely designed to undergo rapid hydrolysis in the body
by nonspecific tissue esterases that produce an inactive carboxylic acid
metabolite. This chemical approach has been used previously in approved drugs
such as remifentanil, esmolol, and clevidipine, resulting in rapid inactivation
of pharmacologic activity and a unique PK profile.
ABP-700 has been extensively characterized in a series of non-GLP and GLP in
vitro and in vivo pharmacology, PK, genotoxicity and safety pharmacology
studies, as well as pilot and definitive acute toxicology studies. Taken
together, these studies satisfy the guidelines established by the European
Medicines Agency guidance: "ICH guideline M3(R2) on non-clinical safety studies
for the conduct of human clinical trials and marketing authorization for
pharmaceuticals* (December 2009).

Primary objectives:
- to assess the safety and tolerability of bolus doses of ABP-700 in the
presence of pre-medications commonly used in the monitored anesthesia care
(MAC) setting.
- to optimize bolus dosing of ABP-700 in combination with pre-medications.

Secondary objectives:
- to characterize the pharmacokinetics (PK) of ABP-700.
- to assess the pharmacodynamics (PD) of ABP-700.
- to investigate dose response and PK/PD relationships.

This study will be conducted at QPS in the Netherlands using a dedicated
treatment room that is equipped similarly to the operating rooms used in the
University Medical Center Groningen, i.e. monitoring is present
(heart/lungs/circulation), as well as respiratory support including ventilation
and intubation equipment. A Crash Cart is also available in this room at all
times. The Crash Cart is identical to the one available in the Intensive Care
Unit of the UMCG and contains all required drugs and equipment required to
conduct acute, emergent cardiac-pulmonary resuscitation. Prior to dosing, the
specific treatment room used for the study is checked and cleared for use by an
Investigator.
During the conduct of the study, the Principal Investigator or one of two
Sub-Investigators from the Department of Anesthesiology will be present during
administration until recovery of the subject. In addition, a nurse anesthetist
(*Anesthesie Medewerker*) will also be present. The anesthesia team will
conduct the study using the same standards of clinical care as used in the UMCG
Operating Room.
Subjects will participate in only 1 cohort and will receive only one dose.
This study will be an open-label, parallel, bolus dose study. Up to twenty (20)
cohorts of 4 subjects each are planned for evaluation. Each cohort will receive
either a single or repeat bolus dose of ABP-700. All subjects assigned to a
cohort will receive the same pre-treatment of an opiate or benzodiazepine.
The maximum bolus dose for any given cohort will not exceed 0.75 mg/kg. In
cohorts where multiple bolus doses are administered, the total dose may not
exceed 0.75 mg/kg. The rate and interval of bolus administration of ABP-700
will be defined for each cohort.
Safety will be monitored and the level of sedation/anesthesia will be assessed
throughout the study. Venous serial blood samples will be collected for the PK
assessment of ABP-700.
In order to consider a dosing paradigm optimized it must be tested in the
following sequence and not at any time meet the defined stopping criteria:
1. Initial Cohort (4 subjects)
2. Repeat Cohort (4 subjects)
3. Expansion Cohort (8 subjects, 2 cohorts of 4 subjects

The study will start with a screening. At the screening a physical examination
will take place and a few other standard medical assessments will be performed
(ECG,vital signs). Furthermore a blood and urine sample will be taken for
laboratory tests and an alcohol breathtest and drug screen will be done.

During the stay in the clinic the subject will receive (a pre-treatment
medication and) the research medication once on Day 1. Safety will be monitored
and sedation/anesthesia will be assessed throughout the study. Venous serial
blood samples will be collected. The subjects will be asked for possible side
effects on regular basis.

Finally, a follow-up visit will take place.

The study drug has been previously tested in 85 humans and was generally well
tolerated. A number of side-effects, possibly linked to use of the study drug,
were reported. The most common side effect (occurring in more than 5% of
ABP-700 treated subjects) were involuntary muscle movements
(twitching and uncontrollable movements), hyperventilation, tachycardia,
restlessness, increased blood pressure, hiccups, abnormal respiration,
decreased oxygen saturation, euphoric feeling, gagging, generalized myoclonus,
headache, injection site reaction, itching eyelid, motoric restlessness,
nausea, respiratory pauses, snoring, tachypnea, vasovagal reaction (low blood
pressure, bradycardia), vomiting, yawning and emergence delirium. These
side-effects are all consistent with the mechanism of action observed with this
type of medication.

The most reported side-effects of fentanyl are: respiratory depression (too
shallow or slow breathing, shortness of breath, short periods of not
breathing), skeletal and chest muscle rigidity and slow heart rate. If
respiratory distress occurs it may sometimes be necessary to give naloxone, a
socalled antidote, to counteract the effects of fentanyl (an antidote is a
substance to counteract injurious effects).

The most reported side-effects of sufentanil citrate are: respiratory
depression and muscle stiffness.

The most reported side-effects of remifentanil are: loss of consciousness,
apnea, muscle rigidity and tachycardia.

The most reported side-effects of midazolam are: headache, nausea, drowsiness,
vomiting, hiccups, coughing and pain, redness and hardening of the skin after
injection.

The dose levels of ABP-700 and premedication are selected on the basis of
research results in animals and humans. The risk to health at these dose levels
is limited but you may experience one of the above mentioned side-effects or
other symptoms not previously reported. Your health will be closely monitored
during the trial to minimize these risks.

All drugs have a potential risk of causing an allergic reaction, which if not
treated promptly, could become life threatening. You will be closely monitored
for any allergic reactions and emergency treatment will be provided as needed.

In total, approximately 64.8 mL of blood will be drawn. The blood collection
procedure is not dangerous, but may cause discomfort or bruising. Occasionally,
fainting or an infection at the blood sampling site can occur.

Your health and possible side-effects from the medication will be closely
monitored by the research physicians. If you develop any symptoms during the
trial, you will be treated by the research physicians. If new information about
the safety of the study drug becomes available, you will be informed as soon as
possible. You can decide at this point whether you want to continue with the
study. If your safety or well-being is in danger, you will be withdrawn from
the study immediately.

If you notice changes in your physical or mental state or you are experiencing
side-effects during or after the end of the treatment period, please inform the
research physician or nurses immediately. This is also applicable when you
experience symptoms when you are not in the clinic. This is important for your
own safety and for the quality of the research. You will be given an emergency
card containing information about the trial and contact details.