Product
Treanda

Approval Date
March 20, 2008

Release Date
April 2008

Companies
Cephalon Inc.


Indication
Indicated for the treatment of chronic lymphocytic leukemia(CLL).

Active Ingredient
Bendamustine hydrochloride

Agency Roster
Ignite Health (Interactive)
LyonHeart

MarketingStrategy/Execution
Cephalon has been conducting traditional pre-launchactivities for Treanda, the first new therapy approved for the treatment ofchronic lymphocytic leukemia (CLL) since 2001. Those include having presentingdata from several studies at the American Society of Hematology meeting lastDecember and running professional advertisements. Ads will continue through theend of the pre-marketing phase, scheduled to conclude in April with theproduct’s availability. The oncology franchise consists of about 100field-based personnel, including reps, reimbursement staff and medical scienceliaisons. Cephalon says it’s continuing to study Treanda, and that’s a goodthing. Although its safety hasn’t been questioned, more data are needed to convinceoncologists of the drug’s superiority over existing first-line CLL treatments.An sNDA for Treanda use in relapsed indolent non-Hodgkin’s lymphoma (NHL) hasbeen filed, with a decision expected by October.

Physician Outlook
Cephalon, Inc.’s cytotoxic chemotherapy TREANDA(bendamustine) was recently approved for the treatment of patients with chroniclymphocytic leukemia (CLL), and offers another effective treatment option forthis indolent but incurable disease. TREANDA is thought to combine twomechanisms of action commonly used by cytotoxics in CLL, acting both as apurine analog and as an alkylating agent, and has been available for severalyears in Germany under the trade name Ribomustin (Mundipharma).

In a randomized, multi-center, pivotal study in treatment-naïvepatients with CLL, TREANDA was shown to produce higher rates of overallresponse (59% vs. 26%) and complete response (8% vs. < 1%) than oralchlorambucil, with a median duration of response of 18 months vs. 6 months forchlorambucil. The most common adverse effects with TREANDA weremyelosuppression, fever, nausea, and vomiting, and rates of infection wereconsidered low. However, TREANDA has not been compared to fludarabine(Fludara, Bayer), which is the most common chemotherapy used in the initialtreatment of CLL, typically in combination with rituximab (Rituxan, Genentech).

TREANDA has also shown significant efficacy, both alone andin combination with rituximab, in patients refractory to rituximab-containingregimens, and thus represents an important additional option for this group ofpatients. It is also under study for indolent non-Hodgkin’s lymphoma andmantle-cell lymphoma (for which it is already approved in Germany).

— Michael Galvin, Ph.D., Senior VP, GfK V2

Also in the Pipeline(According to Adis R&D Insight)
Drug: HL 275/HMR 1275
Manufacturer: Sanofi-Aventis
Indication:  ChronicLymphocytic Leukaemia
Active Ingredient:Alvocidib
Phase: III

Drug: Genasense
Manufacturer: Genta
Indication:  ChronicLymphocytic Leukaemia
Active Ingredient:Oblimersen
Phase: Preregistration

Drug: HuMax CD20
Manufacturer: Genmab
Indication:  ChronicLymphocytic Leukaemia
Active Ingredient:Ofatumumab
Phase: III

Drug: Nipent
Manufacturer: Pfizer/National Cancer Institute
Indication:  ChronicLymphocytic Leukaemia
Active Ingredient:Pentostatin
Phase: III

Drug: MabThera
Manufacturer: Biogen Idec
Indication:  ChronicLymphocytic Leukaemia
Active Ingredient: Rituximab 
Phase: III
Source: Wolters Kluwer Health

Recent MM&MCoverage
CompanyNews

Pharmacology
Bendamustine is a bi-functional mechlorethamine derivative.Mechlorethamine and its derivatives dissociate into electrophilic alkylgroups. These groups form covalent bonds with electron-richnucleophilic moieties. The bifunctional covalent linkage can lead tocell death via several pathways. The exact mechanism of action ofbendamustine remains unknown. Bendamustine is active against bothquiescent and dividing cells.

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity.

Clinical Trials
The safety and efficacy of bendamustine were evaluated in anopen-label, randomized, controlled multicenter trial comparingbendamustine to chlorambucil. The trial was conducted in 301previously-untreated patients with Binet Stage B or C (Rai Stages I-IV)CLL requiring treatment. Patients were randomized to receive eitherbendamustine 100mg/m2 IV on Days 1 and 2 or chlorambucil 0.8mg/kgorally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints ofobjective response rate and progression-free survival were calculatedusing a pre-specified algorithm based on NCI working group criteria forCLL. The results of this study demonstrated a significantly higher rateof overall response (59% vs. 26%) and a significantly longerprogression-free survival (18 months vs 6 months) for bendamustinecompared to chlorambucil.

Adverse Reactions
Neutropenia, pyrexia, thrombocytopenia, nausea, anemia, leukopenia,vomiting, asthenia, fatigue, malaise, dry mouth, somnolence, cough,constipation, headache, mucosal inflammation, stomatitis, increasedbilirubin, increased AST or ALT; infection, infusion reactions(discontinue if severe), tumor lysis syndrome, skin reactions (ifsevere or progressive, withhold dose or discontinue).

Adults
Give by IV infusion over 30 minutes. 100mg/m2 on Days 1and 2 of a 28-day cycle, up to 6 cycles. May give allopurinolprophylactically for those at high risk of tumor lysis syndrome. Delaytreatment for Grade 4 hematologic toxicity or clinically significant≥Grade 2 non-hematologic toxicity. Hematologic toxicity (≥Grade 3):reduce dose to 50mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Non-hematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m2on Days 1 and 2 of each cycle. Subsequent cycles: may consider dosere-escalation. Severe renal impairment (CrCl <40mL/min) or moderateto severe hepatic impairment: not recommended.

Children
Not recommended.

Precautions
Myelosuppression; monitor leukocytes, platelets, hemoglobin,neutrophils closely; restart treatment based on ANC and platelet countrecovery. Renal or hepatic impairment. Monitor for infection, infusionreactions, tumor lysis syndrome. Pregnancy (Cat.D); avoid use. Nursingmothers: not recommended.

Interactions
May be potentiated or antagonized by CYP1A2 inhibitors, inducers.