Gleevec Gains Simultaneous FDA Approval for Five Rare, Life-Threatening Disorders

November 1, 2006

Gleevec (imatinib mesylate) tablets has receivedFDA approval to treat patients with fiverare, potentially life-threatening disorders,representing the first time that aregulatory authority has ever simultaneouslyapproved one targeted medicinefor so many disorders, according toNovartis, maker of Gleevec.

ROCKVILLE, Maryland--Gleevec(imatinib mesylate) tablets has receivedFDA approval to treat patients with fiverare, potentially life-threatening disorders,representing the first time that aregulatory authority has ever simultaneouslyapproved one targeted medicinefor so many disorders, according toNovartis, maker of Gleevec. The agentpreviously was approved for the treatmentof Philadelphia chromosome-positive(Ph+) chronic myeloid leukemia(CML) and gastrointestinal stromal tumors(GISTs).

Gleevec targets the activity of the tyrosinekinase Bcr-Abl and the receptortyrosine kinase Kit. Researchers havefound that Gleevec also inhibits othertyrosine kinases, including platelet-derivedgrowth factor receptor (PDGFR),which have been shown to be activatedin disease pathways that underlie a numberof rare hematologic diseases, as wellas some solid tumors.

The new approvals are for one solidtumor and four diseases of the blood:

  • Dermatofibrosarcoma protuberans(DFSP), a type of tumor that begins as ahard lump found in the skin of the chest,abdomen, or leg, which grows slowly andusually does not metastasize. Usually, surgerysuccessfully removes the tumor, butabout half the time, the tumor returns.In one uncontrolled study and five publishedcase reports, the overall responserate to Gleevec was 83% with a completeresponse rate of 39%. The responses weredurable and led to surgical resection ofthe residual tumor in a number of cases.The overall complete response rate toGleevec and surgical resection was 67%.Relevant target: PDGFR.

Gleevec is indicated for adult patientswith unresectable, recurrent, and/ormetastatic DFSP at a dose of 800 mg/d.

  • Relapsed or refractory Ph+ acute lymphoblasticleukemia (ALL), a rapidly progressiveleukemia. Among 43 relapsed/refractory Ph+ ALL patients in a phase IIstudy of Gleevec, 8 (19%) had a complete hematological response (CHR) and15 (35%) had a major cytogenetic response(MCR).

Gleevec is indicated as a single agentfor the treatment of adult ALL patientsat a recommended dose of 600 mg/d.

  • Myelodysplastic/myeloproliferativediseases (MDS/MPD). These are diseasesin which too many of certain types ofblood cells--monocytes, platelets, fibroblasts,red blood cells--are made in thebone marrow. They include chronicmyelomonocytic leukemia (CMML),atypical Ph-negative CML (aCML), Bcr-PDGFR-positive CML, and MPD associatedwith eosinophilia.

Of a total population of 31 patientstreated for MDS/MPD with Gleevec, 14(45%) achieved a CHR and 12 (39%) an MCR. Of the 16 patients with a translocationassociated with PDGFR gene rearrangement,all had a hematologic response(13 CHR), and 12 had an MCR.Relevant target: PDGFR.Gleevec is indicated for adults withMDS/MPD associated with PDGFR generearrangements at a dose of 400 mg/d.

  • Hypereosinophilic syndrome/chroniceosinophilic leukemia (HES/CEL), whichis characterized by the persistent overproductionof eosinophils, often leadingto organ damage. Historically, patientswith HES/CEL have shown no detectablechromosomal abnormality. Among 61patients positive for FIP1L1-PDGFRafusion kinase, all (100%) had a CHR toGleevec vs 21% of those who were negativefor this fusion kinase. Overall, 107 of176 patients (61%) had a CHR.

Gleevec is indicated for HES/CEL at adose of 400 mg/d. For HES/CEL patientswith demonstrated FIP1L1-PDGFRa fusionkinase, a starting dose of 100 mg/d isrecommended.

  • Aggressive systemic mastocytosis(ASM), which is marked by the presenceof too many mast cells. Of a total populationof 28 patients treated for ASM withGleevec, 8 (29%) achieved a CHR and 9(32%) a partial hematologic response(61% overall response rate). Relevant targets:PDGFR, Kit. Gleevec is indicatedfor adults with ASM without the D816Vc-Kit mutation or with unknown c-Kitmutational status at a recommended doseof 400 mg. For patients with ASM associatedwith eosinophilia, a starting dose of100 mg/d is recommended.