Advertisement
Sundar Jagannath, M.D., Chief of the Multiple Myeloma Program, Bone Marrowand Blood Stem Cell Transplantation at St. Vincent's Comprehensive CancerCenter in New York, and Ravi Vij, M.D., Associate Professor of Medicine,Division of Oncology, Section of Bone Marrow Transplantation at WashingtonUniversity School of Medicine, presented data from two ongoing Phase 2clinical trials of carfilzomib in relapsed and refractory multiple myelomapatients during the Novel Therapies for Myeloma and Related Disorders oralsession at the 50th Annual Meeting of the American Society of Hematology(ASH). Both Phase 2 clinical trials are being conducted by Proteolix incollaboration with the Multiple Myeloma Research Consortium (MMRC).
Advertisement
Activity in Relapsed and Refractory Multiple Myeloma Patients
Dr. Jagannath presented data from an ongoing, open-label, multi-centerstudy of single-agent carfilzomib in multiple myeloma patients. All patientsin this trial were refractory to their last treatment. Of 39 evaluablepatients, ten (26%) achieved partial or minor responses and an additional 16(41%) achieved stable disease. Importantly, responses have also been durablewith median treatment duration of 240 days, or approximately eight months.
"Patients enrolled in this Phase 2 trial have previously failedbortezomib, lenalidomide, thalidomide, and stem cell transplant. Carfilzomibas a single-agent is well tolerated and has demonstrated encouragingactivity," said Dr. Jagannath.
The most common adverse events reported have been fatigue, anemia andthrombocytopenia. Patients with impaired renal function tolerated the drugand responses were independent of renal status. Treatment with carfilzomibwas associated with a low incidence of peripheral neuropathy, a common sideeffect associated with the approved proteasome inhibitor, bortezomib.Exacerbation of pre-existing peripheral neuropathy was rare and did not resultin dose reductions or discontinuation of therapy. Overall, carfilzomib wasgenerally well tolerated and toxicities were manageable.
These data were presented by Dr. Jagannath in an oral presentation titledInitial Results of PX-171-003, an Open-Label, Single-Arm, Phase 2 Study ofCarfilzomib in Patients with Relapsed and Refractory Multiple Myeloma (MM)(Abstract #864).
Carfilzomib Activity in Relapsed Patients by Prior Exposure to Bortezomib
A second presentation by Dr. Vij described interim results from a Phase 2clinical trial of single-agent carfilzomib in multiple myeloma patientsdesigned to evaluate response rates based on patients' bortezomib treatmenthistory. Patients enrolled in this trial received one to three priortherapies, such as bortezomib, thalidomide, lenalidomide or stem celltransplantation and had subsequently relapsed. A total of 31 patients havebeen enrolled in this study and are currently evaluable for response.
Of fourteen evaluable bortezomib-naive patients, eight (57%) achievedresponses, including one patient with a complete response, two with very goodpartial responses and five with partial responses. Four additional patientsachieved stable disease. Among seventeen patients who have received priortreatment with bortezomib, three (18%) achieved partial responses, one patientachieved a minor response, and ten patients achieved stable disease. Themedian time to disease progression has not yet been established for thisstudy.
According to Dr. Vij, "Single-agent carfilzomib has shown impressive anddurable activity, notably among patients who have failed transplantation andhave not yet received treatment with a proteasome inhibitor. The emergingsafety profile makes this an attractive option in patients who havepre-existing neuropathy. Continued evaluation of carfilzomib in less heavilypre-treated patients is warranted given these promising findings."
Carfilzomib was generally well tolerated among relapsed patients andtoxicities were manageable. The most common adverse events were fatigue,anemia and neutropenia. Two cases of tumor lysis syndrome were observed amongbortezomib-naive patients, and with additional monitoring and managementguidelines no further events have been reported. No treatment-emergent Grade3 or 4 peripheral neuropathy was reported in this study.
Dr. Vij presented these interim data from a study of relapsed patients ina presentation titled Initial Results of PX-171-004, an Open-Label,Single-Arm, Phase 2 Study of Carfilzomib in Patients with Relapsed MultipleMyeloma (MM) (Abstract #865).
"We are encouraged by the data that show that carfilzomib is active andhas been successful in providing durable responses in patients who haverelapsed or who do not respond to currently available treatment options," saidLori A. Kunkel, M.D., Proteolix's Chief Medical Officer. "We believecarfilzomib may have broad application in the treatment of hematologicmalignancies and solid tumors."
Supporting Preclinical Data
In addition to the two oral presentations of Phase 2 clinical data,Proteolix scientists presented results of preclinical studies that furthercharacterize the mechanism and safety profile of carfilzomib. These data werepresented on Sunday, December 7 in two poster presentations: Non-ProteasomalTargets of Proteasome Inhibitors Bortezomib and Carfilzomib (Abstract #2657)and The Selective Proteasome Inhibitor Carfilzomib is Well Tolerated inExperimental Animals with Dose Intensive Administration (Abstract #2765).
Carfilzomib acts by inhibiting the proteasome with a high degree ofselectivity and is structurally and mechanistically distinct from bortezomib.Preclinical studies designed to assess and compare the off-target activity ofbortezomib and carfilzomib indicate that carfilzomib has minimal activity onproteases other than the proteasome. In contrast, bortezomib targets severalserine proteases including Cathepsin G, an enzyme whose inhibition may play arole in neuropathic pain. Proteolix researchers believe that theseobservations may translate into a different and possibly superior safetyprofile for carfilzomib as compared to bortezomib. In support of this notion,chronic administration of carfilzomib is well tolerated in rats and monkeyswith no signs of the significant behavioral and histological neurotoxicitiesthat have been described for bortezomib.
About Multiple Myeloma
According to the American Cancer Society, in 2008, approximately 19,900new cases of multiple myeloma will be diagnosed in the United States. Newlydiagnosed patients have treatment options that include combinationchemotherapeutic agents and stem cell transplantation. While many patientsrespond to treatment, most eventually relapse and require subsequenttreatment. Few patients are ultimately cured of their disease.
About Carfilzomib
Carfilzomib is the first in a new class of highly specific proteasomeinhibitors. Carfilzomib produces specific and sustained inhibition of theproteasome, leading to apoptosis in cancer cells with minimal off-targeteffects. In Phase 1 and Phase 2 clinical trials, carfilzomib has demonstratedsingle-agent activity in hematologic and solid tumors, including multiplemyeloma and renal cancer.
Proteolix is currently conducting a comprehensive clinical developmentprogram evaluating carfilzomib for the treatment of multiple myeloma,including two ongoing Phase 2 clinical trials of single-agent carfilzomib, onein heavily pre-treated relapsed patients who have failed to respond to priortreatment, and a second in relapsed patients stratified by prior treatmentwith bortezomib. A Phase Ib clinical trial of carfilzomib in combination withlenalidomide and dexamethasone in patients with relapsed multiple myeloma isalso ongoing. In addition, based on promising Phase 1 results, Proteolix isconducting a single-agent Phase 2 clinical trial of carfilzomib in patientswith recurrent or advanced solid tumors. For the latest information regardingongoing carfilzomib clinical trials, please visithttp://www.clinicaltrials.gov.
About Proteolix
Founded in December 2003, Proteolix, Inc. is a privately-heldbiopharmaceutical company, headquartered in South San Francisco, dedicated todiscovering, developing and commercializing novel therapeutics that targetprotein degradation pathways for cancer and autoimmune diseases. Proteolix'slead product, carfilzomib, is the first in a new class of highly specificproteasome inhibitors, and is currently in multiple Phase 2 clinical studiesto evaluate its safety and efficacy in hematologic and solid tumormalignancies. Proteolix is also developing a pipeline of novel proteasomeinhibitors, including an oral proteasome inhibitor and a selectiveimmunoproteasome inhibitor. For additional information on Proteolix, pleasevisit http://www.proteolix.com.Contact information Investors: Media Inquiries: Matthew Ferguson BCC Partners Chief Financial Officer Karen L. Bergman or Michelle Corral 650-266-2825 650-575-1509 or 415-794-8662 [email protected]
SOURCE Proteolix, Inc.
