FDA Answers sNDA For Spectrum's Fusilev With "Complete Response"

If two therapies perform similarly in a head-to-head trial, can a sponsor use the failed superiority data to claim non-inferiority? Spectrum hopes so.

FDA issued a "complete response" letter to Spectrum Pharmaceuticals on the supplementary NDA to use Fusilev (levoleucovorin) in treatment of advanced colorectal cancer, saying Spectrum has not made the case that the foliate analog is non-inferior to the current standard leucovorin.

At issue is whether data from the 12-year-old Phase III study submitted to support the sNDA can be used to show non-inferiority, since the trial was designed as a head-to-head superiority test. The two therapies performed fairly equally in the study.

"FDA said we failed to show non-inferiority, even though we think we did," a spokesman said. Spectrum hopes to meet with regulators to clarify the situation by the end of the year, he said.

The pivotal study was a randomized, parallel, active-control, open-label trial conducted in 1997 by the Mayo Clinic in patients with advanced metastatic colorectal cancer. Patients received 5-FU with either Fusilev or d-leucovorin daily. There was no statistically significant difference in overall survival between Fusilev and leucovorin (13 months versus 12.3 months), progression free survival (5.7 months versus 5.8 months) or objective tumor response rates (13.6% versus 15.6%).

The primary endpoint of the study was to show superiority to generic leucovorin, and it failed to meet that endpoint, the spokesman said. However, Spectrum submitted the data to show levoleucovorin is non-inferior to leucovorin.

Levoleucovorin is the pharmacologically active isomer of leucovorin (or folinic acid). Leucovorin is made up of two isomers, which means Fusilev offers the advantage of injecting only half the dose necessary for leucovorin, Spectrum argues. Leucovorin is a common part of chemotherapy regimens, combined with 5-fluorouracil and oxaliplatin in FOLFOX or with 5-FU and irinotecan in FOLFIRI as an adjuvant to increase the effectiveness of 5-FU.

Fusilev has already been approved by FDA, cleared in March 2008 for rescue after high-dose methotrexate therapy in osteosarcoma. It is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and inadvertent overdose of folic acid antagonists.

New indication is part of Spectrum's expansion in oncology

Fusilev is one of two approved oncologics in the Irvine, Calif., drug maker's portfolio, and the firm has been pursuing label expansions for both. Spectrum just finished dealing with a "complete response" on an extended indication for Zevalin (ibritumomab tiuxetan) to include first-line treatment of follicular non-Hodgkin's lymphoma in patients who achieve a partial or complete response to first-line chemotherapy, ultimately gaining approval Sept. 4. The radiotherapeutic antibody was initially approved in 2002 for patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma.

Spectrum gained Zevalin from Seattle-based Cell Therapeutics Inc. in March, when CTI sold out it's half of a joint venture between the two firms (Also see "CTI Bags Cash, Turns Its Back On Zevalin" - Pink Sheet, 16 Mar, 2009.).

Spectrum signaled a change of course away from it's roots in the generics business in 2008, when it jettisoned what it deemed noncore assets - a portfolio of injectable generic drugs for which it held ANDAs - to focus on its late-stage clinical programs in oncology ( [See Deal] ).

In addition to its label expansion projects, the lead candidate in Spectrum's oncology pipeline is a synthetic bio-reductive prodrug in studies against non-invasive bladder cancer. EOquin (apaziquone) began Phase III studies in 2007. Spectrum licensed the drug to Allergan in October 2008 in an exclusive development and commercialization deal that paid Spectrum $41.5 million upfront ( [See Deal] ).

The company also has three drugs in Phase II: ozarelix, for treatment of prostate cancer and benign prostatic hypertrophy; ortataxel, for taxane-refractory solid tumors; and satraplatin, an oral oncologic for non-small cell lung cancer.

Spectrum's stock was trading at $5.09 at close Oct. 8, down $1.12 from the night before. The 52 week high is $10 dollars, the low, 55 cents, making this not the worst day in the firm's financial memory.

In September the company netted $47.5 million through the registered direct offering of 6.6 million common shares at $7.55 (market average) to existing investors. The company also issued 90-day warrants at $7.55 to purchase 2.65 million shares ( [See Deal] ).

-Shirley Haley ([email protected])