Verso ASH 2012: Array Biopharma (ARRY)

Ieri Array ha illustrato in conferenza stampa gli abstract che saranno presentati ad ASH12, l’American Society of Hematology. Il mercato ha preso bene la notizia ed il rischio che la conferenza fosse stata indetta per mettere una pezza a dati zoppicanti è stato fugato. Come immaginavo il motivo di fanfara e riflettori scaldati a dovere riguarda principalmente la possibile individuazione di un biomarker per la scelta dei pazienti da arruolare in una possibile fase 3 registrativa. Tenendo conto che mancano i dettagli, si può dire comunque che anche i dati relativi al tasso di risposta non sono male.

ARRY 520 in combinazione con desametasone in pazienti affetti da mieloma multiplo refrattari a Velcade, Revlimid e desametasone ha fornito un tasso di risposta del 28%, dato simile, fa notare Array (ARRY) a quello di farmaci come pomalidomide o carfilzomib in pazienti meno pretrattati.

ARRY‑520 è attualmente impiegato in 3 studi clinici:

1. In fase 2 in combinazione con desametasone a basso dosaggio in pazienri con MM refrattario a Revlimid (lenalidomide), Velcade (bortezomib) e desametasone.
2. In fase 1b in combinazione con Velcade e desametasone in pazienti con MM recidivo o refrattario.
3. In fase 1b in combinazione con Kyprolis (carfilzomib) in pazienti  con MM recidivo o refrattario a Velcade.

Dati positivi in questi trial porterebbero a determinare una strada verso la richiesta di autorizzazione, previa ovviamente una fase 3 ben riuscita. A queste possibilità si aggiunge anche quella determinata dal possibile impiego della glicoproteina alfa 1 acida (AAG) come biomarker per la scelta dei pazienti, altro argomento che sarà oggetto di un abstract ad ASH12. Nello stesso gruppo di pazienti pesantemente pretrattati e refrattari che ha ottenuto il 28% di tasso di risposta, quelli con valori di AAG non elevati hanno avuto un tasso di risposta ancora migliore: il 33%.

Capitolo ARRY-614. La nuova formulazione impiegata su pazienti con sindromi mielodosplastiche a rischio basso e intermedio 1 ha ottenuto un 68% di tasso di risposte ematologiche, il che suona come un netto miglioramento rispetto al 38% ottenuto sempre da Array (ARRY) in uno studio precedente con simile popolazione ma somministrando il più alto dosaggio possibile del farmaco nella vecchia formulazione.

Ecco gli abstract:

ARRY 520 

Title:  The Novel KSP Inhibitor ARRY-520 Is Active Both with and without Low-Dose Dexamethasone in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide: Results From a Phase 2 Study
Date:  Monday, December 10, 2012
Time:  11:30 a.m. ET (oral presentation)
Room:  Georgia World Congress Center, Thomas Murphy Ballroom 2-3
Summary:  Patients with relapsed refractory multiple myeloma (RRMM) refractory to both IMiD and proteasome inhibitor therapy have a poor prognosis with median survival of as little as 6 months.  New drugs with clinically meaningful activity in this population are needed. ARRY-520 is a novel agent with a distinct mechanism of action relative to other myeloma drugs and shows promising clinical activity both alone and combined with dexamethasone in RRMM.  Notably, in patients with triple-refractory MM, ARRY-520 + LoDex has shown a preliminary 28% overall response rate (≥MR), with a manageable safety.  These data are comparable to those reported for pomalidomide or carfilzomib in less heavily pretreated patients.

Title:  Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma
*Inclusion of additional patients and updated data for this trial will be presented during the presentation at ASH.
Date:    Monday, December 10, 2012
Time:    6:00 PM – 8:00 p.m. ET
Room:  Georgia World Congress Center, Hall B1-B2
Summary:  The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting.

Title:  Identification of Alpha 1-Acid Glycoprotein (AAG) As a Potential Patient Selection Biomarker for Improved Clinical Activity of the Novel KSP Inhibitor ARRY-520 in Relapsed and Refractory Multiple Myeloma (MM)
Date:  Saturday, December 8, 2012
Time:  5:30 PM – 7:30 p.m. ET
Room: Georgia World Congress Center, Hall B1-B2
Summary:  Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies.  In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520.  In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs.  We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose.

ARRY-614 – Dual p38/Tie2 inhibitor for Myelodysplastic Syndromes (MDS):
Array will also be presenting the following abstract from a Phase 1 clinical trial in patients with MDS using an optimized formulation of ARRY-614 with improved plasma exposure and lower inter-subject variability:
Title:  Role of p38 MAPK and Tie2 in the Pathogenesis of MDS and Their Inhibition by Dual Inhibitor ARRY-614
Date:  Sunday, December 9, 2012
Time:  6:00 PM – 8:00 p.m. ET
Room:  Georgia World Congress Center, Hall B1-B2
Summary:  In cell-based assays, ARRY-614 inhibits both p38-mediated HSP27 phosphorylation (IC₅₀ = 1 nM) and Tie2-dependent AKT phosphorylation (IC₅₀ = 13 nM). Cellular IC₅₀ values, corrected for plasma protein binding, and preliminary pharmacokinetic parameters were used to predict inhibition of these targets in patients. Analysis of the highest administered dose (1200 mg QD) of ARRY-614 as a powder-in-capsule (PiC) formulation in the Phase 1 clinical study predicted robust suppression of phospho-p38 (≥ 50% for 24 hours), consistent with bone marrow and plasma biomarker findings. However, partial inhibition of Tie2 (≥ 50% for 17.1 hours) was predicted. In a second Phase 1 clinical study, an optimized ARRY-614 formulation has demonstrated decreased intra- and inter-patient variability and increased peak plasma concentrations. With this new formulation, peak plasma concentrations of the 400 mg QD cohort were ~50% higher than those of the 1200 mg QD PiC formulation cohort, possibly affording more extensive Tie2 inhibition. These observations suggest that inhibition of both p38 and Tie2 may be important for the effects of ARRY-614 in MDS patients. The ongoing Phase 1 dose escalation trial of the optimized ARRY-614 formulation may further our understanding of the contributions of these targets to the pathogenesis of MDS.

Due piccole note in chiusura. La prima è che nel preparare il documento con le scadenze di Array (ARRY) che avete potuto scaricare settimana scorsa ho inavvertitamente confuso crizotinib con carfilzomib, chiedo scusa, farò in modo di correggere il documento per i futuri download il prima possibile. Seconda cosa che riguarda sempre carfilzomib, l’aggiornamento dei dati di ARRY 520 ed il farmaco in questione sarà materiale interessante durante il congresso.