Lu AF35700 / Lundbeck, Jiangsu NHWA Pharma - LARVOL DELTA

Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D and D receptors. (PubMed, Eur J Pharmacol) - "The D-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors."

Journal • CNS Disorders • Psychiatry • Schizophrenia • FOS

Efficacy and safety of Lu AF35700 in treatment-resistant schizophrenia: A randomized, active-controlled trial with open-label extension. (PubMed, Schizophr Res) - P3 | "Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS."

Clinical • Journal • CNS Disorders • Pain • Psychiatry • Schizophrenia

Distal kinetic deuterium isotope effect: Phenyl ring deuteration attenuates N-demethylation of Lu AF35700. (PubMed, Bioorg Med Chem Lett) - "The N-demethylation of zicronapine (7) and three of its deuterated analogs 8 - 10 has been studied in human in vitro metabolism systems. Additional deuteration of the N-methyl group, which as mentioned had shown no effect in isolation, further decreased the rate of the N-demethylation reaction (compound 10vs.9). This paper presents and discusses this unprecedented 'distal kinetic isotope effect' that was observed when incubating the test compounds with human liver microsomes or recombinant human CYP450 liver enzymes."

Journal

New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics. (PubMed, Neurosci Biobehav Rev) - "Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses...BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal."

Adverse events • Clinical • Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Experimental Serotonergic Agents for the Treatment of Schizophrenia. (PubMed, J Exp Pharmacol) - "Particularly, AVN-211, LuAF-35700 and Brilaroxazine are currently under clinical development. Moreover, some compounds showed some pro-cognitive and antipsychotic-like properties in animal models, while other agents showed contradictory effects in improving symptoms and were removed from the development program. Although some serotonergic drugs seem promising for improving the treatment of schizophrenia, further studies regarding the pathophysiological mechanisms of schizophrenia and novel compounds as well as high-quality trials are necessary in order to improve schizophrenia outcomes."

Journal • Review • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

Experimental Serotonergic Agents for the Treatment of Schizophrenia (Dovepress) - "We identified 17 experimental serotonergic agents, under study for their potential use in schizophrenia treatment. Particularly, AVN-211, LuAF-35700 and Brilaroxazine are currently under clinical development. Moreover, some compounds showed some pro-cognitive and antipsychotic-like properties in animal models, while other agents showed contradictory effects in improving symptoms and were removed from the development program....Further studies regarding the pathophysiological mechanisms of schizophrenia and novel compounds as well as high-quality trials are necessary in order to improve schizophrenia outcomes."

Review • CNS Disorders • Schizophrenia

Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. (PubMed, CNS Spectr) - "Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved..."

Journal • CNS Disorders • Schizophrenia

DayBreak: Effect of Lu AF35700 in Patients With Treatment-resistant Schizophrenia (clinicaltrials.gov) - P3; N=964; Completed; Sponsor: H. Lundbeck A/S; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • CNS Disorders • Schizophrenia

Pharmacokinetics of Lu AF35700 in Subjects With Renal Impairment (clinicaltrials.gov) - P1; N=32; Recruiting; Sponsor: H. Lundbeck A/S; Trial completion date: May 2018 ➔ Oct 2018; Trial primary completion date: May 2018 ➔ Oct 2018

Trial completion date • Trial primary completion date • Biosimilar • Renal Disease

Investigational Dopamine Antagonists for the Treatment of Schizophrenia (SIRS 2020) - "Brexpiprazole and cariprazine, which were agents listed as ‘investigational dopamine antagonists,’ have just received FDA approval...However, three other agents, including BL-1020, ITI-007, and JNJ-37822681, have solid published data showing their efficacy and the potential to provide enhanced safety than the currently available atypical antipsychotics. Other agents such as L-THP, Lu AF35700, S33138, and SB- 773812 are currently under vigorous investigation...Thus, it may become the first new pharmacotherapy, after clozapine, for patients with treatment-resistant schizophrenia if the phase III trial shows positive results...However, much as ‘all roads lead to Rome’ all the studied agents to date lead to alteration of dopamine receptors, either in the form of agonist/partial agonist or antagonist activity. Thus, the development of agents with dopamine antagonist properties will and should continue, unless a novel agent with an extradopaminergic mechanism, with its..."

Flexible-dose, Long-term Safety Study of Lu AF35700 in Adult Patients With Schizophrenia (clinicaltrials.gov) - P3; N=528; Completed; Sponsor: H. Lundbeck A/S; Active, not recruiting ➔ Completed

Clinical • Trial completion

Pharmacokinetics of Lu AF35700 in Subjects With Renal Impairment (clinicaltrials.gov) - P1; N=23; Terminated; Sponsor: H. Lundbeck A/S; Trial completion date: Feb 2020 ➔ Jul 2019; Recruiting ➔ Terminated; Trial primary completion date: Feb 2020 ➔ Jul 2019; New data; the study was terminated based on new efficacy data

Clinical • Trial completion date • Trial primary completion date • Trial termination

Study Evaluating the Effect of Multiple Doses of Itraconazole on the Drug Lu AF35700 in Healthy Young Men and Women (clinicaltrials.gov) - P1; N=21; Completed; Sponsor: H. Lundbeck A/S; Recruiting ➔ Completed; Trial completion date: Apr 2019 ➔ Jul 2019

Clinical • Trial completion • Trial completion date

Rational and targeted development of NW-3509, a glutamate modulator for the treatment of patients with poor/ non-response to antipsychotics (SIRS 2019) - "...These findings support the hypothesis that patients with decreased/non response are unlikely to respond to dopaminergic/ serotoninergic blockade, as noted in failed studies with marketed drugs (risperidone, olanzapine, aripiprazole) or putative antipsychotics (Lu AF35700) that act through non-dopaminergic mechanisms, but may respond to glutamate antagonists...The combination of ineffective doses of NW-3509 and marketed antipsychotics, including clozapine, demonstrated significant effects in animal models of positive and negative symptoms...Neuroimaging techniques assessing cortico-striatal connectivity, the Striatal Connectivity Index, that differentiates patients with schizophrenia who are likely to respond to dopaminergic D2 antagonist treatment versus those patients less likely to respond (Sarpal et Al, JAMA Psych 2015; Sarpal et al, Am J Psych 2015) will be performed at selected centers to characterize these patients. Positive results for evenamide , a selective..."

Clinical

Pharmacokinetics of Lu AF35700 in Subjects With Renal Impairment (clinicaltrials.gov) - P1; N=32; Recruiting; Sponsor: H. Lundbeck A/S; Trial completion date: Feb 2019 ➔ Feb 2020; Trial primary completion date: Feb 2019 ➔ Feb 2020

Clinical • Trial completion date • Trial primary completion date

Efficacy of Lu AF35700 in Patients With Early-in-disease or Late-in-disease Treatment-resistant Schizophrenia (clinicaltrials.gov) - P3; N=120; Terminated; Sponsor: H. Lundbeck A/S; N=817 ➔ 120; Trial completion date: Sep 2020 ➔ Feb 2019; Active, not recruiting ➔ Terminated; Trial primary completion date: Sep 2020 ➔ Feb 2019; aaa

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination

Study With Lu AF35700 in Healthy Men and Women in Fasting and Fed State (clinicaltrials.gov) - P1; N=10; Completed; Sponsor: H. Lundbeck A/S; Recruiting ➔ Completed; N=20 ➔ 10

Clinical • Enrollment change • Trial completion

Anew: Efficacy of Lu AF35700 in Patients With Early-in-disease or Late-in-disease Treatment-resistant Schizophrenia (clinicaltrials.gov) - P3; N=817; Active, not recruiting; Sponsor: H. Lundbeck A/S; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed