idalopirdine (Lu AE58054) / Lundbeck, Otsuka, Eli Lilly, Denovo - LARVOL DELTA

In-silico Design, ADMET Screening, Prime MM-GBSA Binding Free Energy Calculation and MD Simulation of Some Novel Phenothiazines as 5HT6R Antagonists Targeting Alzheimer's Disease. (PubMed, Curr Comput Aided Drug Des) - "The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders. (PubMed, Biomolecules) - "Several 5-HT receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing...Masupirdine, a selective 5-HT receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Psychiatry • Schizophrenia

Novel difluoromethyl-containing 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)-1H-indole scaffold as potent 5-HTR antagonists: Design, synthesis, biological evaluation, and early in vivo cognition-enhancing studies. (PubMed, Bioorg Med Chem) - "Herein, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)- 1H-indole derivatives were designed and synthesized via hybridization strategy of idalopirdine and SB-271046. Finally, C14 could efficiently reverse the scopolamine induced emotional memory deficits in novel object recognition assay in rats. Thus, we propose C14 might be considered as a new cognition-enhancing agent and the further studies are now underway in our laboratory."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Alzheimer's Disease: Efficacy of Mono- and Combination Therapy. A Systematic Review. (PubMed, J Geriatr Psychiatry Neurol) - "Three trials found that a combination of ChEI with additional memantine provides a slight benefit for patients with moderate to severe AD over ChEI monotherapy and placebo...Approaches with idalopirdine, atorvastatin or vitamin supplementation in combination with ChEI have not proven effective and have not been retried since. Fluoxetine and ST101 have shown partial benefits in combination with ChEI over ChEI monotherapy and placebo...Longer trials are needed. No major cognitive benefit is missed, if solely appropriate ChEI monotherapy is initiated."

Clinical • Combination therapy • Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia

Denovo Biopharma In-Licenses Late-Stage Alzheimer's Disease Asset from Lundbeck (PRNewswire) - “Denovo Biopharma…announced it has licensed global rights for idalopirdine from H. Lundbeck A/S, including all rights to develop, manufacture and commercialize idalopirdine for all indications. Lundbeck received options to re-acquire idalopirdine for predetermined undisclosed financial terms, with Denovo and Lundbeck sharing China rights in the event Lundbeck's options are exercised and Denovo retaining all global rights in the event Lundbeck's options are not exercised…Idalopirdine (now DB109) is an oral antagonist of the serotonin (5-HT6) receptor, which is primarily expressed in the brain and is hypothesized to be involved in Alzheimer's Disease, schizophrenia, and other indications.”

Licensing / partnership • Alzheimer's Disease • CNS Disorders • Schizophrenia

Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT receptor antagonist with therapeutic interest in Alzheimer's disease. (PubMed, Eur J Med Chem) - "The latter will deliver after hydrolysis, compound 6, a potent 5-HT receptors antagonist (K = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory."

Journal • Alzheimer's Disease • CNS Disorders

Serotonin Type 6 and 7 Receptors as a Novel Therapeutic Target for the Treatment of Schizophrenia. (PubMed, Neuropsychiatr Dis Treat) - "SGS-518, ABT-354, Lu AE58054, SB-742,457, S-518, AVN-211, AVN-322, SYN-114 and SYN-120 are serotonin 6 receptor antagonists and aripiprazole-controlled release serotonin 7 receptor agonists under clinical trial for schizophrenia. Thus, research on novel drugs that act on serotonin 6 and 7 receptors likely facilitates the intervention into schizophrenia patients seeking better quality of life in the future."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Recent updates in the Alzheimer's disease etiopathology and possible treatment approaches: a narrative review of current clinical trials. (PubMed, Curr Mol Pharmacol) - "The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are the widely chosen targets. It is predicted that some FDA-approved drugs such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR could also use in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggesting approaches for the clinical trial design for this devastating disease in the near future."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • Immunology

Recent development of piperazine and piperidine derivatives as antipsychotic agents. (PubMed, Mini Rev Med Chem) - "In this direction various antipsychotic drugs have been synthesized at laboratory level and few are under clinical trial studies such as Lu AE58054, PF-04802540, ORG25935, DMXB-A, Bitopertin and ABT-126. In the present review, we include the studies related to the effect of different substituents on piperidine/piperazine derivatives and their anti-psychotic activity. Various series of synthesized compounds by different researchers with piperidine/piperazine nucleus have been reviewed and diagrammatically represented in the form of SAR (structure activity relationships) which will help to the scientists for the development of potential lead compounds."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Antagonism of the 5-HT6 receptor - Preclinical rationale for the treatment of Alzheimer's disease. (PubMed, Neuropharmacology) - "...This manuscript summarizes the scientific rationale for the use of 5-HT receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT receptor antagonist idalopirdine (Lu AE58054)...Collectively, the current evidence suggests that 5-HT6 receptor antagonism adds a unique, complementary mechanism of action to that of AChEIs. The facilitation of multiple neurotransmitters and neuronal activity in brain regions that mediate cognition, and the synergy with AChEIs, are proposed to mediate the procognitive effects of 5-HT6 receptor antagonists in AD patients."

Journal • Preclinical • Review • Alzheimer's Disease • Biosimilar

Reducing falls in Parkinson's disease: Interactions between donepezil and the 5-HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. (PubMed) - Eur J Neurosci - "Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait."

Journal • Alzheimer's Disease • Biosimilar • Gene Therapies • Parkinson's Disease

Alzheimer’s Drugs and Medicare: A case for pre-approval discussions (Pink Sheet - Informa) - "Idalopirdine and RVT-101...are expected to launch in March and October 2018...According to Informa’s Biomedtracker database, a top-line data read out for idalopirdine is due between now and March 31, 2017 and top-line data for RVT-101 are expected between July 31, 2017 and Dec. 31, 2017."

Anticipated launch • Anticipated P3 data: top line • Alzheimer's Disease

Pharmacokinetics Properties of Single Oral Dosing of Lu AE58054 in Subjects With Hepatic Impairment (Mild and Moderate) and in Healthy Subjects (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: H. Lundbeck A/S

New P1 trial • Biosimilar

STARSHINE: Study of Lu AE58054 in Patients With Mild - Moderate Alzheimer's Disease Treated With Donepezil (clinicaltrials.gov) - P3; N=932; Completed; Sponsor: H. Lundbeck A/S; Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • Biosimilar

"JAMA Editor's Audio Summary: Idalopirdine for Dementia, Anesthesia Handovers During Surgery, Screening for Scoliosis, and more - https://t.co/K9jk3DkdbE" (@JAMA_current)

Alzheimer's Disease • Biosimilar • CNS Disorders

Axovant confidence 'not swayed' after rival Alzheimer's drug fails (Investor's Business Daily) - "Lundbeck, however, had changed the dosing scheme for its idalopirdine to once daily to cut down on liver toxicity concerns, a departure from phase two in which patients received 90 milligrams each day. In phase three, Lundbeck tested 10 milligrams, 30 mg and 60 mg....Axovan's confidence was 'not swayed' by Lundbeck's failure, Evercore analyst Mark Schoenebaum wrote in a report. He says the company plans to file a new drug application with the U.S. Food and Drug Administration by the end of 2017."

Anticipated NDA • Clinical protocol • Alzheimer's Disease

Lundbeck gives up on Alzheimer's drug, rival to Axovant pill (Reuters) - "The failure of Lundbeck's two latest Phase III trials is not a huge surprise, since the company and its Japanese partner Otsuka had already announced disappointing results from another late-stage trial in September. Taken together, Lundbeck said on Wednesday, the trials 'do not demonstrate efficacy to support a regulatory submission'."

Pipeline update • Alzheimer's Disease

Deals of the week: Pfizer management updates thoughts on split (Pink Sheet - Informa) - In March 2013, the companies launched Abilify Maintena (aripiprazole depot) which is set to lose patent protection in 2015; Lu AE58054 is expected to begin three phase III trials later this year involving 2,500 patients for Alzheimer’s disease.

Anticipated new P3 trial • Launch • Patent • Alzheimer's Disease • Schizophrenia

Lundbeck says Alzheimer's late-stage study fails (Reuters) - "The company said both doses of its drug idalopirdine failed to improve symptoms of the disease measured on a scale called ADAS-cog in the study named Starshine....The Copenhagen-based company said both doses of idalopirdine, being developed with Japan's Otsuka Pharmaceutical Co Ltd, also failed to meet the secondary goals of the study. Lundbeck said two other late-stage studies of its experimental drug would continue as planned and it expected data from the two studies in the first quarter of 2017."

Anticipated P3 data • P3 data • Alzheimer's Disease

"Top Upcoming Biopharma Events in 2016: *save this tweet*" - ‏@CashRocket

Anticipated P3 data • Alzheimer's Disease

Bloomberg news Lundbeck in talks with possible Alzheimer’s drug partners (Businessweek) - Lundbeck failed to win recommendation from EU for Acrescent (combination of memantine and donepezil), after company had negative results; P3 trial for AE58054 is expected to begin by Q4 2012; Lundbeck is talking with several potential partners to help develop the drug and will announce partner by H1 2013

Anticipated licensing / partnership • European regulatory • Trial initiation date • Alzheimer's Disease

Bioequivalence Study of Idalopirdine Tablets 60 mg (clinicaltrials.gov) - P1; N=30; Completed; Sponsor: H. Lundbeck A/S; Recruiting -> Completed

Trial completion • Biosimilar

Efficacy and safety of idalopirdine for Alzheimer's disease: a systematic review and meta-analysis. (PubMed, Int Psychogeriatr) - "Idalopirdine is not effective for AD patients and is associated with a risk of elevated liver enzymes and vomiting. Although idalopirdine might be more effective at high doses and in moderate AD subgroups, the effect size is small and may be limited."

Journal • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Dementia

Lundbeck sees sharp rise in net profit, cautions on year ahead (The Wall Street Journal) - "Lundbeck says: "First quarter is positively impacted by the expansion of the alliance with Otsuka...co-development and co-commercialization right for Lu AE58054 has initiated an upfront payment to Lundbeck of DKK 284 Million"."

Commercial • Alzheimer's Disease • Schizophrenia

Idalopirdine, a selective 5-HT6 receptor antagonist, reduces food intake and body weight in a model of excessive eating. (PubMed, Metab Brain Dis) - "Moreover, an anorectic action was not caused by abnormalities of the gastrointestinal tract, such as nausea. The obtained results indicate that idalopirdine reduces caloric intake and could be considered for further tests as a potential treatment of obesity."

Journal • Biosimilar • Obesity