Clolar Launching For Pediatric ALL; Genzyme, FDA Discussing Adult Studies

Genzyme will employ a sales force of less than 10 to launch Clolar for pediatric acute lymphoblastic leukemia in January.

"Genzyme expects to make Clolar commercially available as quickly as possible in January," the company said announcing the Dec. 28 accelerated approval.

The sales force, which will target pediatric oncologists at cancer centers across the country, is limited by the small patient population eligible for treatment with Clolar (clofarabine).

Genzyme's approval announcement cites an estimate by Cancer Metric that 2,700 new pediatric ALL patients are diagnosed each year.

This figure does not represent the market for Clolar since the drug is indicated only for third-line use.

"Clolar is indicated for the treatment of pediatric patients one to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens," labeling states.

Genzyme plans to expand its newly created oncology sales force incrementally as the drug is approved in additional indications.

The company is in discussions with FDA concerning Clolar's late stage development for adult leukemia and is conducting Phase I studies in solid tumor cancers.

Labeling includes the adult dose determined from a Phase II study in highly refractory and/or relapsed patients with hematologic malignancies.

Bioenvision, holder of ex-U.S. rights to Clolar, recently announced the results of a study of first-line monotherapy in 30 acute myeloid leukemia patients over 60 years of age. The trial demonstrated an overall response rate three-fold greater than standard of care.

Genzyme acquired Clolar as part of its recently approved merge with Ilex.

Genzyme has a relatively limited time frame in which to develop additional indications. With seven years of orphan drug exclusivity and six months of pediatric exclusivity, Genzyme's marketing protection for clofarabine extends until June 28, 2012. The composition of matter patent expires in 2009; the company also has a method of cancer treatment patent which expires in 2014.

One of Genzyme's first tasks following approval of Clolar will be to redesign its confirmatory trial for the treatment of pediatric ALL.

"Please submit a new protocol for a study to show clofarabine clinical benefit in children with ALL within two months of the date of this letter," FDA's approval letter states.

"Your proposed Phase III study to be possibly conducted by the [Children's Oncology Group] does not appear to have a realistic chance of showing a clinical benefit of clofarabine in children with ALL in first relapse," the letter states.

At the Dec. 1 advisory committee review of Clolar, FDA Division of Oncology Drug Products Director Richard Pazdur expressed concern that Ilex (now Genzyme) had not yet met with the agency to discuss its confirmatory trial design (¹ (Also see "Accelerated Approval Requests Based On Low Efficacy Frustrate FDA" - Pink Sheet, 13 Dec, 2004.), p. 37).

FDA granted the product accelerated approval on the basis of induction of complete responses in a clinical trial. The agency's accelerated approval mechanism has received considerable attention recently due to the failure of AstraZeneca's Iressa (gefitinib) to show a survival benefit in confirmatory trials.

Clolar was approved based on a single-arm study of 49 relapsed/refractory pediatric patients with ALL at a single dose.

In the trial, six patients (12.2%) achieved a complete remission, four (8.2%) achieved complete remissions without platelet recovery and five achieved a partial remission.

Ilex submitted the chemistry, manufacturing and controls section of its rolling NDA Oct. 22, 2003. The company completed its submission March 31, 2004.

FDA later extended the priority review deadline to Dec. 30 after the company submitted data on 14 additional patients (² 'The Pink Sheet' Aug. 30, 2004, In Brief).

Clolar's approved indication follows the recommendation of FDA's Oncologic Drugs Advisory Committee. The committee voted 9-6 in favor of the indication and 14-1 against approval for pediatric acute myelogenous leukemia (³ (Also see "Ilex Clolar Advisory Committee Splits On Pediatric Leukemia Approvals" - Pink Sheet, 6 Dec, 2004.), p. 22).