Lanicemine (DB11889): A Comprehensive Pharmacological and Clinical Development Profile

1. Introduction to Lanicemine

1.1. Overview and Chemical Properties

Lanicemine is an investigational small molecule drug, identified by the DrugBank Accession Number DB11889, which has been the subject of numerous clinical trials, primarily focusing on its potential as a treatment for depressive disorders.[1] Its Chemical Abstracts Service (CAS) Registry Number is 153322-05-5 for the free base form.[2]

Lanicemine is known by several synonyms, reflecting its journey through different stages of development and by various research groups. These include AZD6765, its development code under AstraZeneca; AR-R 15896AR, an earlier development designation; (αS)-phenyl-2-pyridineethanamine, its chemical name; and BHV-5500, the code used by Biohaven Pharmaceuticals.[1] The dihydrochloride salt form of Lanicemine is also documented, with CAS Number 153322-06-6.[19]

The molecular formula for the free base of Lanicemine is C13​H14​N2​.[1] Its average molecular weight is approximately 198.269 g/mol, often rounded to 198.27 g/mol.[1] The dihydrochloride salt form has a molecular weight of 271.19 g/mol.[19]

In its physical form, Lanicemine free base has been described as a neat oil.[2] The dihydrochloride salt is typically an off-white to light yellow solid.[19] Regarding solubility, the free base form is soluble in organic solvents such as ethanol, dimethyl sulfoxide (DMSO), and dimethylformamide. The dihydrochloride salt exhibits good solubility in DMSO and water, with aqueous solubility reported as ≥100 mg/mL.[2] Specific solubility data indicates approximately 20 mg/mL in ethanol, 30 mg/mL in DMSO, and 5 mg/mL in dimethylformamide for the free base, and ≥100 mg/mL in water and 240 mg/mL in DMSO (requiring sonication) for the dihydrochloride salt.[2]

Table 1: Lanicemine Identifiers and Basic Properties

Property	Value	Reference(s)
DrugBank ID	DB11889	1
Primary CAS Number	153322-05-5 (free base)	2
Other CAS Number	153322-06-6 (dihydrochloride salt)	19
Molecular Formula	C13​H14​N2​ (free base)	1
Molecular Formula	C13​H16​Cl2​N2​ (dihydrochloride salt)	19
Molecular Weight	~198.27 g/mol (free base)	1
Molecular Weight	271.19 g/mol (dihydrochloride salt)	19
Synonyms	AZD6765, AR-R 15896AR, (αS)-phenyl-2-pyridineethanamine, BHV-5500	1
Type	Small Molecule	1
Physical Appearance	Neat oil (free base); Off-white to light yellow solid (dihydrochloride)	2

1.2. Development History Overview

Lanicemine's development path has been marked by shifts in therapeutic focus, reflecting an evolving understanding of its pharmacological profile and clinical potential. Initially, the compound was investigated by Astra Arcus USA, which later became part of AstraZeneca.[5] The early research explored its utility as a neuroprotective agent; however, this line of development was discontinued in 2007.[9]

Subsequently, AstraZeneca repurposed Lanicemine (as AZD6765) for the treatment of severe and treatment-resistant depression.[4] This shift was largely influenced by the emerging understanding of the rapid antidepressant effects of ketamine, another N-methyl-D-aspartate (NMDA) receptor antagonist. The hypothesis was that Lanicemine, with its distinct "low-trapping" characteristic at the NMDA receptor, might offer similar rapid antidepressant efficacy but with a more favorable side effect profile, particularly with respect to psychotomimetic and dissociative effects commonly associated with ketamine.[7] Despite some promising early-phase clinical data, AstraZeneca terminated the development of Lanicemine for depression in 2013 after larger Phase IIb studies failed to meet their primary efficacy endpoints.[4]

Following AstraZeneca's discontinuation, the rights to Lanicemine were acquired or further developed by Biohaven Pharmaceuticals, which designated it as BHV-5500.[4] Biohaven's strategy involved exploring Lanicemine for different neurological and neuropsychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and various pain syndromes.[5] This indicated a continued belief that its unique NMDA receptor interaction profile could be therapeutically relevant in conditions beyond depression, particularly where a better safety margin than traditional NMDA antagonists was desirable. In October 2022, Pfizer completed its acquisition of Biohaven Pharmaceuticals.[5] The current development status of Lanicemine under Pfizer's stewardship is not clearly detailed in the available information, suggesting it may be in very early exploratory stages, under review, or potentially deprioritized. This trajectory, from neuroprotection to depression and then to other CNS disorders like PTSD and pain, exemplifies a common pattern in pharmaceutical research and development. The repurposing of compounds often occurs as scientific understanding of their mechanisms of action and potential therapeutic windows evolves. Even after initial setbacks in one indication, a compound's unique pharmacological properties may hold promise for other conditions, particularly if a differentiated safety or efficacy profile can be established.

2. Mechanism of Action and Pharmacology

2.1. NMDA Receptor Antagonism

Lanicemine's primary pharmacological action is as an N-methyl-D-aspartate (NMDA) receptor antagonist.[1] It functions as a non-selective, voltage-dependent NMDA channel blocker, interacting with sites within the ion channel pore.[2]

The binding affinity (Ki​) of Lanicemine for the NMDA receptor is reported to be in the range of 0.56-2.1 μM.[2] Its potency, measured as the half-maximal inhibitory concentration (IC50​), is approximately 4-7 μM in Chinese Hamster Ovary (CHO) cells expressing NMDA receptors and 6.4 μM in Xenopus oocyte electrophysiology assays.[19] In mouse cortical slices, an IC50​ of 10.8 μM was observed for the reduction of epileptiform discharges.[9]

A distinguishing characteristic of Lanicemine is its "low-trapping" property within the NMDA receptor channel. Compared to ketamine, which exhibits approximately 86% channel trapping, Lanicemine demonstrates a lower propensity for trapping, around 54%.[22] This means that Lanicemine dissociates more readily from the channel upon cessation of agonist binding or channel closing. Theoretically, this low-trapping mechanism could lead to a more selective blockade of NMDA receptors on neurons with high levels of tonic activity, such as certain cortical interneurons, while relatively sparing physiological, phasic NMDA receptor activity elsewhere.[4] This characteristic, along with its rapid reversibility (fast off-rate), was hypothesized to contribute to its improved safety and tolerability profile, particularly a reduction in psychotomimetic effects compared to higher-trapping NMDA antagonists like ketamine.[12]

Regarding NMDA receptor subunit selectivity, studies suggest that Lanicemine, similar to ketamine, does not exhibit strong selectivity between NR2A- and NR2B-containing NMDA receptors.[3] While some research describes it as non-selective [2], other investigations have compared its qEEG profile to those of NR2B-selective negative allosteric modulators (NAMs), noting distinct differences, which indirectly supports its non-selective channel blocking mechanism rather than subtype-specific allosteric modulation.[9]

2.2. Comparison with Ketamine

Lanicemine was often benchmarked against ketamine due to their shared primary target, the NMDA receptor, and ketamine's established rapid antidepressant effects. However, key differences in their interaction with the receptor and resulting clinical profiles were central to Lanicemine's development rationale.

Table 3: Comparison of Lanicemine and Ketamine Properties

Feature	Lanicemine	Ketamine	Reference(s)
Primary Mechanism	Low-trapping NMDA channel blocker	High-trapping NMDA channel blocker	4
NMDA Channel Trapping (%)	~54%	~86%	22
Psychotomimetic Effects (e.g., CADSS, BPRS)	Minimal / Significantly less than ketamine	Prominent	4
Dissociative Effects	Minimal / Significantly less than ketamine	Prominent	4
Antidepressant Efficacy (Clinical Trials)	Initial promise, but failed to show consistent superiority over placebo in larger trials	Rapid and robust, but often transient; esketamine approved	10
Gamma-EEG Effects	Dose-dependent ↑; similar magnitude to ketamine at equipotent cortical activation doses	Dose-dependent ↑; coupled with locomotor activity in rodents	6
NR2 Subunit Selectivity	Similar lack of NR2A vs. NR2B selectivity	Similar lack of NR2A vs. NR2B selectivity	3

The development of Lanicemine was predicated on the hypothesis that its low-trapping NMDA channel blockade would dissociate the desired antidepressant effects from the undesirable psychotomimetic and dissociative side effects characteristic of ketamine.[4] Clinical data largely supported the improved tolerability aspect; studies consistently reported fewer and milder dissociative symptoms (measured by the Clinician Administered Dissociative States Scale - CADSS) and psychotomimetic effects (measured by the Brief Psychiatric Rating Scale - BPRS) with Lanicemine compared to ketamine.[22] For example, a Phase I study directly comparing the two showed that Lanicemine did not significantly increase CADSS total scores, whereas ketamine did.[22]

Despite this improved side effect profile, Lanicemine's antidepressant efficacy proved inconsistent in larger clinical trials. While early, smaller studies suggested rapid but often less robust or sustained antidepressant effects compared to ketamine [8], subsequent, larger Phase IIb trials failed to demonstrate superiority over placebo.[10] This outcome suggests that the specific NMDA receptor interactions or downstream signaling pathways crucial for robust antidepressant effects might be more complex or perhaps intrinsically linked to those that also produce acute psychological disturbances. Alternatively, Lanicemine's particular interaction profile, while safer, may not have engaged the critical antidepressant pathways as effectively or for a sufficient duration as higher-trapping agents like ketamine, especially in the context of high placebo response rates observed in these challenging patient populations.

Pharmacodynamic studies using quantitative electroencephalography (qEEG) showed that both Lanicemine and ketamine induce dose-dependent elevations in spontaneous gamma-band EEG power in rodents and humans, a marker often associated with cortical disinhibition and NMDA receptor target engagement.[6] In human subjects, 150 mg of Lanicemine produced gamma-EEG effects comparable in magnitude to those seen with 0.5 mg/kg of ketamine, suggesting similar levels of cortical target engagement at these doses.[22] However, in rodent models, a notable difference emerged: only ketamine's gamma-EEG changes were tightly coupled with increases in locomotor activity, implying that Lanicemine might influence these neural networks without causing the broader systems-level disruptions characteristic of ketamine.[19] The fact that similar cortical target engagement, as measured by qEEG, did not translate into comparable clinical antidepressant efficacy for Lanicemine highlights a significant translational challenge in CNS drug development. It suggests that either gamma-EEG is not a sufficiently nuanced surrogate for the specific type of NMDA receptor modulation required for robust antidepressant effects, or that other pharmacological properties of ketamine (e.g., its higher trapping efficiency or effects on other receptor systems) are critical for its superior efficacy in depression.

Furthermore, studies on global brain connectivity (GBC) in depressed patients indicated that ketamine, but not Lanicemine at a 100mg dose, significantly increased GBC in multiple prefrontal cortex clusters, both during infusion and at 24 hours post-treatment. Although Lanicemine showed numerical trends in the same direction, the lack of statistical significance suggests a potentially weaker or different impact on these large-scale brain networks compared to ketamine.[28]

2.3. Other Pharmacological Effects

Beyond its primary investigation in depression, Lanicemine has been evaluated for other CNS activities:

• Anticonvulsant Activity: Early preclinical research by Palmer et al. (1999) demonstrated that AR-R 15896AR (Lanicemine) possessed anticonvulsant properties. It was effective in preventing tonic seizures induced by various chemoconvulsants (4-aminopyridine, bicuculline, strychnine) and excitatory amino acids (N-methyl-DL-aspartic acid, kainic acid), as well as seizures induced by maximal electroshock (MES) in rodents. Notably, it was ineffective in two kindling models of epilepsy and did not exhibit proconvulsant properties, distinguishing it from some other NMDA antagonists.[9]
• Cognitive Effects: The cognitive effects of Lanicemine have yielded mixed observations. A study using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in nonhuman primates reported non-specific impairment in a list-based delayed match-to-sample task with AZD6765.[9] Conversely, clinical trials in depression generally reported no clinically meaningful adverse effects on cognition at therapeutic doses.[22] This discrepancy may relate to species differences, dose levels, or the specific cognitive domains assessed.
• Affective Bias Modulation: More recent preclinical work (published in 2025) has explored Lanicemine's impact on affective biases in rats. These studies indicate that Lanicemine can acutely attenuate negative affective biases, with sustained effects observed at higher doses. This line of research investigates whether the sustained modulation of such biases could correlate with therapeutic effects in mood or anxiety disorders and how the ion-trapping properties of different NMDA antagonists might influence these outcomes.[41]

3. Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) of Lanicemine have been characterized, primarily through a human study utilizing [14C]-labeled Lanicemine.

3.1. Absorption

In most clinical trials evaluating its antidepressant and anxiolytic potential, Lanicemine was administered intravenously (IV).10 This route ensures complete bioavailability.

Exploration of oral administration was limited. Early preclinical work by Palmer et al. (1999) indicated that orally administered AR-R 15896AR rapidly entered the rat brain.9 A Phase 1 clinical trial (NCT00963365) assessing single and multiple ascending oral doses in healthy subjects was planned by AstraZeneca but was subsequently withdrawn, so comprehensive human oral bioavailability data is lacking.9

3.2. Distribution

The distribution of Lanicemine has been investigated in humans using a single 150 mg IV dose of [14C]-Lanicemine in healthy male subjects, as reported by Sangster et al. (2014).43 The volume of distribution at steady state (Vss) for unchanged Lanicemine was 161 L, suggesting a moderate degree of tissue distribution beyond the plasma compartment. For total radioactivity, the Vss was 117 L.

Analysis of whole blood-to-plasma radioactivity ratios, which ranged from 0.72 to 0.93 across various time points, indicated that radioactivity was more concentrated in the plasma/extracellular fluid than within blood cells. The calculated percentage of radioactivity associated with red blood cells was low, ranging from 20.6% to 38.2%.43

Preclinical data in rats showed rapid brain penetration after oral administration.9

3.3. Metabolism

The metabolism of Lanicemine was characterized in the same human [14C]-Lanicemine study.43 Unchanged Lanicemine was found to be the major circulating component, accounting for 66% of the total radioactivity area under the curve (AUC0-∞) in plasma.

Ten metabolites were identified in urine. The most abundant single metabolite detected in excreta was an O-glucuronide conjugate of Lanicemine (designated M1 in urine in some reports), which accounted for approximately 11% of the administered radioactive dose.

In plasma, several circulating metabolites were identified, each constituting less than 4% of the total plasma radioactivity. These included a para-hydroxylated metabolite (referred to as M1 in plasma), an O-glucuronide (M2 in plasma), an N-carbamoyl glucuronide (M3 in plasma), and an N-acetylated metabolite (M6 in plasma).44 The primary biotransformation pathways appear to involve hydroxylation, O-glucuronidation, N-carbamoyl glucuronidation, and N-acetylation. Detailed information on the specific enzymes involved (e.g., cytochrome P450 isoforms or UDP-glucuronosyltransferases) was not available in the provided summaries and would require access to the full study publication.43

3.4. Excretion

Lanicemine and its metabolites are primarily eliminated via renal excretion.43 In the human [14C]-Lanicemine study, a mean of 93.8% of the administered radioactive dose was recovered in urine over a 240-hour collection period. Fecal excretion was a minor pathway, accounting for only 1.9% of the dose.

A significant portion of the drug is excreted as unchanged Lanicemine, which constituted 37.0% of the total dose found in urine. The majority of urinary excretion occurred relatively rapidly, with approximately 90% of the dose recovered in urine within 72 hours post-dose.43

3.5. Pharmacokinetic Parameters

Key pharmacokinetic parameters for Lanicemine following a single 150 mg IV infusion of [14C]-Lanicemine in healthy male subjects were reported by Sangster et al. (2014).[43]

Table 4: Summary of Lanicemine Pharmacokinetic Parameters in Humans (150 mg IV dose)

Parameter	Value	Unit	Reference(s)
Mean Cmax​ (Lanicemine)	1270	ng/mL	43
Mean Tmax​ (Lanicemine)	1.0	h	43
Mean Terminal Elimination Half-life (t1/2​) (Lanicemine)	~16	h	43
Apparent Clearance (CL) (Lanicemine)	8.3	L/h	43
Volume of Distribution at Steady State (Vss​) (Lanicemine)	161	L	43
Primary Excretion Route	Urine	% of dose	43
Radioactivity Recovered in Urine	93.8	% of dose	43
Unchanged Lanicemine in Urine	37.0	% of dose	43

The pharmacokinetic profile of Lanicemine, characterized by a terminal half-life of approximately 16 hours and low clearance (8.3 L/h), is generally consistent with intermittent intravenous dosing regimens, such as those employed in the clinical trials for depression (e.g., three times a week or weekly infusions).[11] The observation that the parent drug is the predominant circulating species, with metabolites present at lower concentrations, simplifies the interpretation of its pharmacodynamic effects, as these are likely primarily driven by Lanicemine itself rather than by active metabolites with potentially different pharmacological profiles.[43] Despite these seemingly favorable pharmacokinetic characteristics, which did not appear to be a fundamental impediment to the dosing strategies used, Lanicemine ultimately did not demonstrate sufficient efficacy in larger depression studies. This suggests that the limitations encountered were more likely related to its pharmacodynamic properties (e.g., insufficient engagement of the necessary antidepressant pathways at well-tolerated doses, or the intrinsic nature of its "low-trapping" mechanism being less effective for robust antidepressant effects) or to challenges inherent in clinical trial design for treatment-resistant depression, such as high placebo response rates, rather than a fundamentally unsuitable pharmacokinetic profile for the intended intravenous use.

4. Clinical Development for Depression and Related Disorders

Lanicemine, primarily under the development code AZD6765 by AstraZeneca, underwent an extensive clinical program evaluating its efficacy and safety for Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD).[1]

4.2. Key Clinical Trials by AstraZeneca (as AZD6765)

AstraZeneca conducted a series of clinical trials to assess Lanicemine's potential as an antidepressant.

• Phase I Study (NCT01130909 / D2285M00008): This randomized, double-blind, four-way crossover study in healthy male subjects compared single intravenous (IV) doses of Lanicemine (75 mg and 150 mg) with ketamine (0.5 mg/kg) and placebo. The 150 mg dose of Lanicemine produced gamma-EEG effects comparable to ketamine, indicating similar cortical target engagement. Crucially, Lanicemine was associated with significantly fewer dissociative symptoms, as measured by the Clinician Administered Dissociative States Scale (CADSS), than ketamine.[13]
• Phase IIA Study (NCT00491686 / D6702C00001): This exploratory trial evaluated a single 100 mg IV dose of Lanicemine in patients with TRD. The primary endpoint, change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 24 hours post-infusion, did not show a statistically significant difference from placebo, largely due to a high placebo response. However, trends favoring Lanicemine were observed at 1 hour and 72 hours post-infusion, with the antidepressant-like effect peaking at 72 hours. The drug was well tolerated, with no clinically meaningful psychotomimetic or cognitive effects reported.[9]
• Phase IIB Study (NCT00781742 / Study 9): This adjunctive therapy trial investigated multiple IV infusions of Lanicemine (100 mg or 150 mg, three times per week for three weeks) in patients with moderate-to-severe MDD who had a history of poor response to antidepressants. Both doses of Lanicemine demonstrated a statistically significant greater improvement in MADRS total score at week 3 compared to placebo. The 100 mg dose showed an onset of efficacy as early as week 2, and this effect persisted for up to 5 weeks post-treatment (2 weeks after the last infusion). Lanicemine was generally well-tolerated, with minimal dissociative effects. This study provided the strongest evidence for Lanicemine's antidepressant potential at the time.[9]
• Phase IIB Study (NCT01482221 / Study 31 / CONCERT): This larger, longer-term adjunctive therapy study evaluated Lanicemine (50 mg or 100 mg IV) administered via 15 infusions with decreasing frequency over 12 weeks in MDD patients with inadequate treatment response. The primary endpoint was the change in MADRS total score from baseline to week 6.
• Efficacy Failure: Contrary to the promising results of Study 9, neither the 50 mg nor the 100 mg dose of Lanicemine demonstrated superiority over placebo on the primary endpoint or any secondary efficacy measures.[10] At week 6, the MADRS total score change from baseline was -13.18 for placebo, -14.37 for Lanicemine 50 mg, and -14.40 for Lanicemine 100 mg.
• Reasons for Failure: The primary reason cited for the failure to demonstrate efficacy was an unusually high placebo response rate. The 13.18-point decrease in MADRS score in the placebo group at week 6 was substantial and made it difficult to show a statistically significant drug-placebo difference. Post-hoc analyses suggested that patients with greater baseline depression severity or those with baseline suicidal ideation might have shown a numerically superior response to Lanicemine.[11] Differences in study design compared to Study 9, such as longer duration, lack of a placebo run-in, and a larger number of study sites, may have contributed to the high placebo effect.[33]
• The negative outcome of this trial, and potentially another (PURSUIT study), led AstraZeneca to discontinue the development of Lanicemine for depression in 2013.[4]
• Other Phase I Studies:
• NCT00785915: A single and multiple ascending dose study in healthy Japanese and Caucasian subjects was completed, but specific results beyond completion are not detailed in the provided information.[9]
• NCT00963365: A Phase I study investigating oral single and multiple ascending doses in healthy subjects was planned but subsequently withdrawn by AstraZeneca.[9]
• Phase II Study (NCT00986479): This study, often attributed to Zarate et al. (2013), involved a single IV infusion of Lanicemine in patients with TRD. It reported rapid but short-lived antidepressant effects without significant psychotomimetic side effects, similar to the findings of NCT00491686.[9]

Table 2: Summary of Key Lanicemine Clinical Trials for Depression (AstraZeneca)

Trial ID (NCT)	Phase	Sponsor	Indication	Key Design (Dose, Duration, Comparator)	Primary Endpoint	Key Efficacy Outcome (vs Placebo)	Key Safety Finding (Psychotomimetic/Dissociative Effects)	Reference(s)
NCT01130909	I	AstraZeneca	Healthy Volunteers	Single IV: Lanicemine 75mg, 150mg; Ketamine 0.5mg/kg; Placebo	qEEG, Safety	N/A (EEG effects comparable to ketamine at 150mg)	Significantly less than ketamine (CADSS)	13
NCT00491686	IIA	AstraZeneca	TRD	Single IV: Lanicemine 100mg vs Placebo	MADRS change at 24h	Not significant at 24h (high placebo); trend at 72h (-5.7 MADRS)	No clinically meaningful effects	9
NCT00781742 (Study 9)	IIB	AstraZeneca	MDD (inadequate response)	Adjunctive IV: Lanicemine 100mg or 150mg vs Placebo (3x/week for 3 weeks)	MADRS change at Wk 3	Significant improvement: 100mg: -5.5 MADRS; 150mg: -4.8 MADRS	Minimal, not different from placebo	9
NCT01482221 (Study 31 / CONCERT)	IIB	AstraZeneca	MDD (inadequate response)	Adjunctive IV: Lanicemine 50mg or 100mg vs Placebo (15 infusions over 12 weeks, decreasing frequency)	MADRS change at Wk 6	Not significant (high placebo response)	Generally well tolerated, low psychotomimetic/dissociative AEs	10
NCT00986479	II	AstraZeneca	TRD	Single IV: Lanicemine vs Placebo	MADRS change	Rapid but short-lived antidepressant effects	No psychotomimetic effects	9

4.3. Safety and Tolerability in Depression Trials

Across its depression clinical trial program, Lanicemine was generally reported as well tolerated.10

The most consistently reported adverse event (AE) was dizziness, which was typically mild to moderate in severity and often occurred around the time of infusion.21 Other common AEs included nausea, somnolence, and headache.21

Serious adverse events (SAEs) were infrequent. For example, in the large Study 31 (NCT01482221), SAEs were reported in 3.0% of patients receiving Lanicemine compared to 4.0% in the placebo group.11

A critical aspect of Lanicemine's safety profile was the consistently low incidence and severity of psychotomimetic and dissociative effects, especially when compared to ketamine. Measurements using the CADSS generally showed no clinically meaningful increase in dissociative symptoms for Lanicemine relative to placebo.[22] Similarly, assessments with the BPRS indicated no significant psychotomimetic effects.[22] While some AEs potentially related to dissociative-type events (e.g., depersonalization, illusion) or psychotomimetic symptoms (e.g., visual hallucination) were reported, they were generally mild, infrequent, and did not typically lead to study discontinuation.[22]

Cardiovascular effects were also monitored. Lanicemine infusions were associated with modest and transient increases in supine systolic and diastolic blood pressure, particularly with higher doses (100-150 mg). These changes generally resolved spontaneously and were not accompanied by notable ECG abnormalities.[12]

Cognitive function assessments in human depression trials generally did not reveal clinically meaningful adverse effects of Lanicemine.[22]

The development of Lanicemine for depression aimed to separate the antidepressant activity of NMDA receptor antagonists from their often-limiting psychotomimetic side effects. While Lanicemine largely achieved the goal of improved tolerability with significantly fewer acute psychological disturbances than ketamine, this did not translate into consistent and robust antidepressant efficacy in larger, more definitive trials. This outcome suggests that the neurobiological mechanisms underlying the strong and rapid antidepressant effects of compounds like ketamine might be closely intertwined with those that also produce acute psychotomimetic or dissociative phenomena. Alternatively, the specific "low-trapping" mechanism of Lanicemine, while enhancing safety, may not have engaged the critical antidepressant pathways with sufficient potency or duration to overcome the high placebo responses often seen in treatment-resistant depression populations, or to match the efficacy of higher-trapping agents.

5. Clinical Development for Other Indications (Post-AstraZeneca)

Following the discontinuation of Lanicemine for depression by AstraZeneca, Biohaven Pharmaceuticals (later acquired by Pfizer) explored its potential as BHV-5500 in other CNS indications, notably Post-Traumatic Stress Disorder (PTSD) and pain.

5.1. Post-Traumatic Stress Disorder (PTSD) (as BHV-5500 by Biohaven)

A Phase 1b trial (NCT03166501) investigated Lanicemine (100 mg IV, administered as three infusions over a 5-day period) in individuals with PTSD symptoms and physiological evidence of hyperarousal.[5] The study, with data collection up to November 2019 and published by Sanacora et al. in 2022, found Lanicemine to be safe and well-tolerated in this population. No serious adverse events were reported, and cardiovascular effects were limited to modest, transient increases in blood pressure. There was no increase in suicidal ideation.[12]

The primary outcome, change in Anxiety Potentiated Startle (APS) T-score after three infusions, was not met; there was only a 38% probability that Lanicemine outperformed placebo. However, an interesting acute effect was observed: after the first infusion, there was a 90% chance that Lanicemine attenuated the APS T-score. This acute effect was not sustained after three infusions, possibly due to habituation to the startle paradigm over multiple sessions.[12]

Target engagement was demonstrated through qEEG, with Lanicemine increasing resting-state gamma band power, most robustly after the first infusion. Exploratory analyses of PTSD symptoms suggested a potential benefit for hyperarousal; at Day 8 (3 days after the third infusion), there was a 93% chance that Lanicemine reduced scores on CAPS-5 Criterion E (hyperarousal symptoms) compared to placebo, with a moderate-to-large effect size (Cohen’s d=0.75).[12] The authors concluded that these preliminary findings supported further investigation of selective NMDAR modulators for PTSD, particularly for hyperarousal symptoms.

5.2. Pain (as BHV-5500 by Biohaven/Pfizer)

Biohaven also initiated development of BHV-5500 (Lanicemine) for various pain indications, focusing on formulation development for potential use in combination studies with its Kv7 ion channel platform.[5] Target indications mentioned included Complex Regional Pain Syndrome, post-herpetic neuralgia, and diabetic peripheral neuralgia.[26] As of November 2022, AdisInsight reported "Early research in Pain in USA (unspecified route)" for Lanicemine.[5]

The strategic shift by Biohaven towards these more specific CNS conditions likely aimed to leverage Lanicemine's established human safety profile and its differentiated "low-trapping" NMDA receptor mechanism. This profile could be particularly advantageous for chronic conditions like neuropathic pain or disorders such as PTSD, where the side effect burden of traditional NMDA antagonists like ketamine might limit their utility. However, the acquisition of Biohaven by Pfizer in October 2022 has introduced uncertainty regarding the current development status of Lanicemine for these indications. Recent pipeline updates from Pfizer and the divested Biohaven Ltd. entity (focusing on non-migraine assets) in 2024 and early 2025 do not prominently feature Lanicemine/BHV-5500, suggesting that its development may be in very early stages, under internal review, or potentially deprioritized.[11] This underscores the ongoing challenge of identifying the optimal clinical niche for compounds with complex mechanisms of action, even those with established safety records.

6. Drug Interactions

Information from DrugBank indicates that Lanicemine, due to its activity as a CNS agent and NMDA receptor antagonist, has the potential for numerous pharmacodynamic interactions.[1] The primary concern is an increased risk of CNS depression when Lanicemine is co-administered with other CNS depressant medications. This includes a wide range of drug classes such as benzodiazepines (e.g., Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam), opioids (e.g., Alfentanil, Buprenorphine, Butorphanol), sedative-hypnotics (e.g., Chloral hydrate, Zolpidem), antipsychotics (e.g., Acetophenazine, Amisulpride, Asenapine, Benperidol, Bromperidol, Clothiapine), tricyclic antidepressants (e.g., Amitriptyline, Butriptyline, Clomipramine), antihistamines with sedative properties (e.g., Brompheniramine, Carbinoxamine, Clemastine), muscle relaxants (e.g., Baclofen, Carisoprodol), and other agents like Agomelatine, Apomorphine, Apronal, Articaine, Azelastine, Benactyzine, Brivaracetam, Buspirone, Cabergoline, Cannabidiol, Carbamazepine, and Clidinium.[1]

Additionally, DrugBank suggests a potential for increased adverse effects when Lanicemine is combined with Acenocoumarol or the selective serotonin reuptake inhibitor (SSRI) Citalopram.[1] It is important to note that many of these listed interactions are likely predicted based on pharmacological class effects rather than specific clinical drug-drug interaction studies conducted with Lanicemine. The clinical development program for Lanicemine did not progress to a stage where extensive formal interaction studies would typically be conducted.

7. Regulatory Status and Development History

7.1. Timeline of Development

Lanicemine's development began under Astra Arcus USA, later AstraZeneca, with the code AZD6765. Initial investigations focused on neuroprotection, but this was discontinued in 2007.[5] The focus then shifted to major depressive disorder and treatment-resistant depression. Despite some positive early-phase results, AstraZeneca terminated the development program for depression in 2013. This decision followed the failure of key Phase IIb studies (notably NCT01482221, also known as the CONCERT study, and potentially the PURSUIT study) to demonstrate statistically significant efficacy over placebo, often attributed to high placebo response rates in these challenging patient populations.[4]

Subsequently, Biohaven Pharmaceuticals acquired or initiated development of the compound, renaming it BHV-5500. Biohaven's efforts were directed towards new indications, primarily PTSD and various pain syndromes.[4] In October 2022, Pfizer completed its acquisition of Biohaven Pharmaceuticals.[5]

7.2. Current Status (as of late 2024/early 2025)

The most recent specific update on Lanicemine's development status comes from AdisInsight, dated November 5, 2023, which indicated its highest development phase as "Research" for the indication of Pain. Development for CNS disorders, Epilepsy, and Stroke was listed as discontinued.[5] A Biohaven Ltd. corporate update from November 2022 (Q3 results) mentioned ongoing formulation development work for BHV-5500 (Lanicemine) for pain indications, intended for use in combination studies with their Kv7 platform.[26]

However, publicly available pipeline information from Pfizer (dated April 29, 2025) and recent pipeline updates from Biohaven Ltd. (the entity post-Pfizer acquisition focusing on non-migraine assets, with updates into early 2024/2025) do not prominently feature Lanicemine or BHV-5500.[11] This lack of recent disclosure suggests that if development is ongoing under Pfizer, it is likely at a very early, non-disclosed stage, under strategic review, or has been deprioritized.

7.3. Regulatory Approvals and Designations

Lanicemine has not received regulatory approval from the FDA or EMA for any indication. Its development for depression was halted before reaching pivotal Phase III registration trials.[4] No specific regulatory designations like Fast Track or Orphan Drug status for Lanicemine were mentioned in the provided research materials.

8. Summary and Future Outlook

8.1. Recap of Lanicemine's Profile

Lanicemine (DB11889, AZD6765, BHV-5500) is a small molecule, low-trapping NMDA receptor antagonist. It was initially investigated for neuroprotection and then extensively for major depressive disorder and treatment-resistant depression, with the aim of providing ketamine-like rapid antidepressant efficacy but with a superior safety profile, particularly fewer psychotomimetic and dissociative side effects.

Pharmacologically, Lanicemine binds to the NMDA receptor channel pore with low-to-moderate affinity and exhibits less channel trapping than ketamine. This characteristic was hypothesized to contribute to its better tolerability. Preclinical and early clinical studies supported this, showing target engagement (e.g., similar gamma-EEG effects to ketamine at equipotent cortical activation doses) and significantly reduced psychotomimetic and dissociative symptoms compared to ketamine. Its pharmacokinetic profile in humans, following intravenous administration, includes a terminal half-life of approximately 16 hours, low clearance, and primary renal excretion of the parent drug and its metabolites (mainly an O-glucuronide).

Despite the promising safety profile and some positive signals in early-phase depression studies, larger Phase IIb trials failed to demonstrate consistent and statistically significant antidepressant efficacy over placebo. High placebo response rates in these trials were a significant confounding factor. Consequently, AstraZeneca discontinued its development for depression in 2013.

8.2. Potential Future Research Directions or Applications

Following its discontinuation for depression, Biohaven Pharmaceuticals explored Lanicemine (as BHV-5500) for other CNS indications, including PTSD and neuropathic pain. The rationale was that its differentiated NMDA modulation and established human safety profile might be advantageous in these conditions. A Phase 1b trial in PTSD showed some encouraging signals for hyperarousal symptoms and confirmed target engagement, although the primary endpoint related to anxiety-potentiated startle was not met after multiple infusions. For pain, development focused on formulation for potential combination therapies.

The current status of Lanicemine development under Pfizer, following its acquisition of Biohaven, is unclear from recent public disclosures. While some very early preclinical research continues to explore its mechanisms (e.g., effects on affective biases in animal models [15]), its prominence in Pfizer's publicly detailed pipeline is minimal, suggesting it may not be a high-priority program at present.

8.3. Challenges and Opportunities

The development history of Lanicemine illustrates several key challenges in CNS drug development. The primary challenge was the inability to translate an improved safety profile and evidence of target engagement into robust clinical efficacy for depression, particularly in the context of the high placebo response rates common in psychiatric clinical trials. This raises fundamental questions about the translatability of preclinical models and the precise nature of NMDA receptor modulation required for antidepressant effects.

The "low-trapping" hypothesis for NMDA antagonists appears validated for improving the psychotomimetic safety profile relative to higher-trapping agents like ketamine. However, Lanicemine's journey suggests that this specific modification might also attenuate the very interactions necessary for strong, rapid antidepressant activity, or that the therapeutic window for such effects is very narrow and difficult to consistently achieve in heterogeneous patient populations.

An opportunity might still exist if a specific patient population or a niche indication can be identified where Lanicemine's unique pharmacological profile—combining NMDA receptor modulation with a good tolerability profile—offers a distinct advantage over existing treatments or other investigational agents. Its potential utility in certain pain states or specific symptom domains of PTSD, where chronic dosing and tolerability are paramount, was the focus of Biohaven's strategy. However, the successful clinical validation and advancement of Lanicemine in any new indication would require substantial further investment and positive trial outcomes, the likelihood of which is currently uncertain given the limited visibility of the program within Pfizer's current pipeline priorities. The story of Lanicemine serves as a pertinent case study on the complexities of developing novel CNS therapeutics, particularly those targeting the NMDA receptor system.

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