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Le sperimentazioni farmacologiche in corso: A che punto siamo?
- 1. AICH, Roma 9 maggio 2015 Le sperimentazioni farmacologiche in corso: A che punto siamo? Marina Frontali, Anna Rita Bentivoglio
- 2. PRIDOPIDINE
- 3. PERCHE LA PRIDOPIDINA? La Dopamina è un neurotrasmettitore importante nel SNC Coinvolta nella regolazione del movimento, dell’umore Le vie dopaminergiche sono mal funzionanti in molte malattie del SNC, ad esempio la Malattia di Parkinson e la schizofrenia, oltre che nella HD
- 4. PRIDOPIDINA Meccanismo d’azione modulatore dopamina, antagonista D2 lega recettori D2 in "stato attivo” rapida cinetica di dissociazione dai recettori antagonismo stato-dipendente del recettore D2. Due studi di fase III sono stati condotti con Pridopidina, MermaiHD5 e HART6
- 5. PRIDOPIDINA Risultati Fallito endpoint primario (miglioramento UHDRS motor subscore) Qualche beneficio negli endpoint secondari (TMS), dosaggio di 90 mg/die Minimo effetto clinico di stabilizzazione delle funzionalità motorie, replicato in 2 studi, effetto dose dipendente Pridopidina sicura e ben tollerata Basandosi su queste informazioni, TEVA ha progettato un nuovo studio di fase II/III (PRIDEHD) per esplorare un nuovo intervallo di dose: 45, 67.5, 90, e 112,5 mg due volte/die, utilizzando UHDRS-TMS come endpoint primario
- 7. SPERIMENTAZIONE PRIDOPIDINA IN ATTO Italy Teva Investigational Site 30083 Recruiting Firenze, Italy Teva Investigational Site 30080 Recruiting Milano, Italy Teva Investigational Site 30082 Recruiting Napoli, Italy Teva Investigational Site 30081 Recruiting Pozzilli (IS), Italy Dosi 45, 67.5, 90,112,5 MG/DI
- 8. PRINCIPALI CRITERI DI INCLUSIONE Test HD 36 CAG o più Pazienti M e F > 20 anni, insorgenza dopo i 18 Punteggio a TMS >25 e a scala indipendenza <90 Le donne devono accettare di assumere contraccettivi per tutta la durata dello studio Pazienti capaci di dare consenso scritto e di assumere la terapia Disponibilità del caregiver ad accompagnare il paziente Peso corporeo > 50 kg
- 9. PRINCIPALI CRITERI DI ESCLUSIONE Cardiopatia rilevante Assunzione di tetrabenazina nelle 6 settimane precedenti l’inizio dello studio Crisi epilettiche negli ultimi 5 anni Altre patologie che a giudizio dello sperimentatore possono influenzare i risultati o impedire al paziente di partecipare allo studio Pazienti che assumono o potrebbero assumere antiaritmici di classe I, antipsicotici, o antidepressivi triciclici Pazienti che assumono o potrebbero assumere farmaci che vengono metabolizzati da CYP2D6
- 10. PERCHE IL LAQUINIMOD? • Farmaco sperimentato nella Sclerosi Multipla • Nei trial registrativi per questa malattia non associato a riduzione delle poussée e neppure del carico lesionale (potere anti-infiammatorio) • Riduzione della disabilità (potere neuroprotettivo) • Attivo su meccanismi comuni a molte malattie nella cascata di eventi che porta alla morte cellulare • Meccanismo non completamente chiaro • Presumibilmente neuroprotezione con azione anti- eccitotossica da glutammato
- 11. SPERIMENTAZIONE LAQUINIMOD IN ATTO http://www.fiercebiotech.com/story/teva- tries-laquinimod-huntingtons-after-repeated- ms-woes/2014-08-15 Italy Teva Investigational Site 30143 Not yet recruiting Firenze, Italy Teva Investigational Site 30098 Recruiting Milano, Italy Teva Investigational Site 30100 Not yet recruiting Milano, Italy Teva Investigational Site 30097 Not yet recruiting Napoli, Italy Teva Investigational Site 30099 Not yet recruiting Pozzilli, Italy http://ir.tevapharm.com/phoenix.zhtml?c=739 25&p=irol-newsArticle&ID=1860274
- 12. PRINCIPALI CRITERI DI INCLUSIONE Test genetico positivo (36-49 CAG) o diagnosi clinica con test durante lo screening Pazienti M/F tra 21 e 55 anni con insorgenza dopo i 18 Le donne in età fertile devono assumere contraccettivi da 30 giorni prima del trattamento a 30 giorni dopo l’ultima dose Pazienti con punteggio di 5 o più al TMS Pazienti capaci di fornire consenso scritto per lo studio, di accettare prelievi di sangue e di assumere farmaci con costanza Pazienti deambulanti e in condizioni di arrivare al centro per tutta la durata dello studio Disponibilità di un caregiver di assistere il paziente durante lo studio I pazienti che assumono antidepressivi devono mantenere lo stesso dosaggio da 30 giorni prima alla fine dello studio
- 13. PRINCIPALI CRITERI DI ESCLUSIONE Uso di farmaci immunosoppressivi o citotossici entro i 12 mesi dall’inizio dello studio Uso precedente di laquinimod Uso di inibitori o induttori di CYP3A4 entro le due settimane dalla randomizzazione, di tetrabenazina o antipsicotici nei 30 giorni precedenti la sperimentazione. Donne incinte o in allattamento Altre patologie che a giudizio dello sperimentatore possono influenzare i risultati o impedire al paziente di partecipare allo studio (es. infarto, scompenso cardiaco, malattia polmonare acuta) nei 6 mesi precedenti lo studio) • Patologie neurologiche diverse da HD, patologie apparato digerente che riducono l’assorbimento del farmaco, renali, insufficienza epatica o cirrosi, positività per HIV, • Patologie tumorali (nei 5 anni precedenti), analisi alterate che possano pregiudicare la partecipazione
Editor's Notes
- Eligibility Ages Eligible for Study: 21 Years and olderGenders Eligible for Study: BothAccepts Healthy Volunteers: NoCriteria Inclusion Criteria: Diagnosis of HD based on the presence of >/= 36 CAG repeats Male or female age ≥21 years, with an onset of HD after 18 years' old. Females of child bearing potential have to be compliant in using adequate birth control throughout the duration of the study Body weight ≥50 kg Sum of >/= 25 points on the UHDRS-TMS and UHDRS Independence Score below 90% Able and willing to provide written informed consent prior to any study related procedure. Willing to provide a blood sample for genetic analyses Willing and able to take oral medication and able to comply with the study specific procedures. Ambulatory, being able to travel to the study centre, and judged by the investigator as likely to be able to continue to travel for the duration of the study. Availability and willingness of a caregiver, informant or family member to accompany the patient to the clinic at study, and the suitability of the caregiver should be judged by the investigator. Other criteria apply, please contact the investigator for more information.
- Exclusion Criteria: Patients with clinically significant heart disease at the screening visit Treatment with tetrabenazine within 6 weeks of study screening Patients with a history of epilepsy or of seizures within the last 5 years Have other serious medical illnesses in the opinion of the investigator may put the patient at risk when participating in the study or may influence the results of the study or affect the patient's ability to take part in the study Patients receiving medications (within the last 6 weeks prior to screening) that have been proven to prolong QT interval or who may require such medications during the course of the study such as but not limited to non allowed anti psychotic medications, tricyclic antidepressants and/or Class I antiarrhythmics Patients receiving medications (within the last 6 weeks prior to screening) that are metabolized by CYP2D6 and have the potential of reducing seizure threshold Other criteria apply, please contact the investigator for more information
- Criteria
- Inclusion Criteria: Documentation of prior positive genetic testing for HD, or a clinical diagnosis of symptomatic HD Presence of 36-49 CAG repeats, inclusive, in the huntingtin gene based on centralized CAG testing during screening. Male or female between 21-55 years of age, inclusive, with an onset of HD at or after 18 years of age Women of child-bearing potential (women who are not post menopausal or who have undergone surgical sterilization) must practice an acceptable method of birth control for 30 days before taking the study treatment, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment was administered. A sum of >5 points on the UHDRS TMS at the screening visit Able and willing to provide written informed consent prior to any study related procedure being performed at the screening visit. Patients with a legal guardian should be consented according to local requirements Willing to provide a blood sample at the screening visit Willing and able to take oral medication and able to comply with the study specific procedures Ambulatory, being able to travel to the study centre, and judged by the investigator as likely to be able to continue to travel for the duration of the study Availability and willingness of a caregiver, informant, or family member to provide input at study visits. A caregiver is recommended to be someone who attends to the patient at least 2 to 3 times per week for at least 3 hours per occasion, and the suitability of the caregiver should be judged by the investigator For patients taking allowed antidepressant medication, the dosing of medication must have been kept constant for at least 30 days before baseline and must be kept constant during the study Additional criteria may apply, please contact the investigator for more information
- Exclusion Criteria: Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azatioprine within 12 months prior to screening Previous use of laquinimod Use of moderate/strong inhibitors of cytochrome P450 (CYP)3A4 within 2 weeks prior to randomization Use of inducers of CYP3A4 within 2 weeks prior to randomization Pregnant or breastfeeding Subjects with a clinically significant or unstable medical or surgical condition that may put the patient at risk when participating in the study or may influence the results of the study or affect the patient's ability to take part in the study, as determined by medical history, physical examinations, ECG, or laboratory tests. Such conditions may include: A major cardiovascular event (e.g. myocardial infarction, acute coronary syndrome, de-compensated congestive heart failure, pulmonary embolism, coronary revascularization) that occurred during the past 6 months prior to randomization Any acute pulmonary disorder A central nervous system (CNS) disorder other than HD that may jeopardize the subject's participation in the study, including such disorders that are demonstrated on the baseline magnetic resonance imaging (MRI) (based on local read) A gastrointestinal disorder that may affect the absorption of study medication Renal disease Cirrhotic patients with moderate or severe hepatic impairment Known human immunodeficiency virus (HIV) positive status. Patients will undergo an HIV test at screening per local requirements, if applicable Any malignancies, excluding basal cell carcinoma, in the 5 years prior to randomization Any clinically significant, abnormal, screening laboratory result which in the opinion of the investigator, affects the patients' suitability for the study or puts the patient at risk if he/she enters the study Unsuitable for MRI (e.g, claustrophobia, metal implants) Alcohol and/or drug abuse within the 6 months prior to screening, as defined by Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition Text Revision (DSM IV TR) criteria for substance abuse Patients with active suicidal ideation during the past month as measured by a most severe suicide ideation score of 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or 5 (Active Suicidal Ideation with Specific Plan and Intent) on the baseline screening Columbia-Suicide Severity Rating Scale (C-SSRS) or subjects who answer "Yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) if the attempt or acts were performed within 1 year of screening, or subjects who, in the opinion of the investigator, present a serious risk of suicide Patients with known intracranial neoplasms, vascular malformations, or intracranial hemorrhage Known drug hypersensitivity that would preclude administration of laquinimod or placebo, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate Swallowing difficulties that would preclude administration of laquinimod or placebo capsules Treatment with any investigational product within 12 weeks of screening or patients planning to participate in another clinical study assessing any investigational product during the study. - Patients in noninterventional and/or observational studies will not be excluded from participating in this study Treatment with tetrabenazine within 30 days of the study baseline visit Treatment with antipsychotic medication within 30 days of the study baseline visit Additional criteria may apply, please contact the investigator for more information