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Lundbeck updates on clinical phase III study for Lu AF35700 in Treatment-Resistant Schizophrenia

Valby, Denmark, 25 October 2018 - H. Lundbeck A/S (Lundbeck) today announced that DAYBREAKi, the first phase III study for Lu AF35700, an investigational, novel, once-daily, oral antipsychotic drug candidate for the potential treatment of treatment-resistant schizophrenia (TRS), did not meet the primary endpoint of statistical superiority vs conventional therapy.

Lu AF35700 was safe and generally well-tolerated in the study with no unexpected adverse events reported.

“TRS constitutes the highest burden of disease within schizophrenia for patients, their families and society and we had with Lu AF35700 hoped to show superiority against conventional therapy”, says Anders Gersel Pedersen, Executive Vice President, Research and Development at Lundbeck; “this is a setback for patients with schizophrenia, but we will continue to advance our pipeline of innovative therapies to meet the needs of patients suffering from psychiatric and neurological diseases.”

DAYBREAK was a multinational, double-blind, randomized, active-controlled phase III study that evaluated the antipsychotic efficacy, safety and tolerability of Lu AF35700 compared to an active-controlled arm over ten weeks in 964 patients with TRS.


The safety and efficacy of Lu AF35700 in patients with TRS was assessed in a 10-week, double-blind, randomised, active-controlled trial. The target TRS population for randomization was patients who met the DSM-5 criteria for schizophrenia who experienced ongoing psychotic symptomatology and demonstrated a lack of satisfactory clinical improvement to at least two different antipsychotics given at an adequate dose and duration.

The study included a single-blinded prospective treatment period of patients with persistent psychotic symptomatology who had at least one adequate and well-documented antipsychotic treatment trial without a satisfactory clinical improvement were treated for 6 weeks with either risperidone (4mg to 6mg/day) or olanzapine (15mg to 20mg/day) to confirm their resistance to antipsychotic treatment.

Patients who did not fulfil the pre-specified response criteria in the prospective treatment period were considered treatment-resistant and were eligible to enter the double-blind treatment period were patients were randomly assigned to 10 weeks of daily treatment with either Lu AF35700 10mg (n=235), Lu AF35700 20 mg (n=232) or to continued treatment with risperidone or olanzapine (n=230).

The primary efficacy endpoint was change from randomisation to Week 10 of the double-blind treatment period in PANSS total score.

About Lu AF35700

Lu AF35700 is an antagonist at dopaminergic, serotonergic, and α adrenergic receptors. Unlike all currently available antipsychotics, Lu AF35700 has higher affinity for the human dopamine D1 receptor than it has for the human dopamine D2 receptor. In TRS, the higher ratio of dopamine D1 vs. D2 receptor activity is hypothesized to result in a beneficial efficacy profile and a tolerability profile without the troublesome side effects associated with extensive dopamine D2 receptor blockade, such as extrapyramidal symptoms.

In November 2015, FDA granted Fast Track designation for Lu AF35700 — a first important step to ensure a potential expedited approval of the compound.

About treatment-resistant schizophrenia (TRS)

Treatment-resistant schizophrenia (TRS) is broadly defined in clinical guidelines as no or minimal clinical improvement in target schizophrenia symptoms following treatment with ≥2 anti-psychotic treatments of adequate dose and durationii, [iii], [iv], [v], [vi]. About one-third of patients with schizophrenia have TRS with persistent core positive symptoms of at least moderate severity despite treatment with antipsychoticsvii, [viii], [ix]. TRS is among the most highly disabling psychiatric disorders for both patients and caregivers, and imposes the greatest impairment in the patients’ community functioning and psychosocial adjustmentx, [xi]. TRS is associated with poor prognosis and functional outcomes, and individuals with TRS are at increased risk of hospitalization, unemployment, homelessness, aggression, imprisonment, substance abuse, violent victimization, and suicidexii, [xiii], [xiv].

About H. Lundbeck A/S

H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) is a global pharmaceutical company specialized in psychiatric and neurological disorders. For more than 70 years, we have been at the forefront of research within neuroscience. Our key areas of focus are Alzheimer's disease, depression, Parkinson's disease and schizophrenia.

Our approximately 5,000 employees in 55 countries are engaged in the entire value chain throughout research, development, manufacturing, marketing and sales. Our pipeline consists of several late-stage development programmes and our products are available in more than 100 countries. We have production facilities in Denmark, France and Italy. Lundbeck generated revenue of DKK 17.2 billion in 2017 (EUR 2.3 billion; USD 2.6 billion).

i NCT02717195: Effect of Lu AF35700 in Patients With Treatment-resistant Schizophrenia (DayBreak)

ii Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;2 Suppl:1-56

iii Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;5:318-78.

iv Howes, OD, McCutcheon, R, Agid, O, et al. 2017. Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guideline on Diagnosis and Terminology. Am J Psychiatry 174, 216–229.

v Howes, OD, McCutcheon, R, Agid, O, et al. 2017. Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guideline on Diagnosis and Terminology. Am J Psychiatry 174, 216–229.

vi National Institute for Health and Care Excellence. nice.org.uk/guidance/cg178.

vii Barnes, et al. Treatment-resistant schizophrenia. In: Hirsch SR and Weinberger D (eds). Schizophrenia (pp 489–516). Oxford 2003: Blackwell Publishing.

viii Conley R, Kelly D. Management of Treatment Resistance in Schizophrenia. Biol Psychiatry. 2001;11:898-911.

ix Pantelis C, Lambert TJ. Managing patients with “treatment-resistant” schizophrenia. Med J Aust. 2003;Suppl:62-6.

x Iasevoli F, Giordano S, Balletta R, Latte G, Formato MV, Prinzivalli E, De Berardis D, Tomasetti C, de Bartolomeis A. Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Prog Neuropsychopharmacol Biol Psychiatry. 2016;34-48.

xi Brain C, Kymes S, DiBenedetti D, Brevig T, Velligan DI. Experiences, attitudes, and perceptions of caregivers of individuals wit treatment-resistant schizophrenia: a qualitative study. BMC Psychiatry 2018; 18:253.

xii Brekke, Prindel, Bae, Long. Risks for individuals with schizophrenia who are living in the community. Psychiatry Serv. 2001; 52:1358-66.

xiii Jones and Castle. Management of treatment resistant schizophrenia: a review article. Afr Psychiatry Rev. 2006;9:17-23

xiv Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;2:63-76


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