West Coast Editor
Though not the magic bullet that many might once have hoped for, a special protocol assessment (SPA) can bolster chances for approval, and Innovive Pharmaceuticals Inc.'s SPA for a Phase II trial with tamibarotene for third-line relapsed or refractory acute promyelocytic leukemia could help in an indication where Cephalon Inc.'s Trisenox (arsenic trioxide) already has planted a second-line flag.
"We're hoping to get the [new drug application] package done and filed by the end of next year," said Steven Kelly, president and CEO of New York-based Innovive. "We've already identified about 35 sites," and the company likely can enroll one patient per site every nine months, if not sooner.
Innovive's stock (OTCC BB:IVPH) closed Friday at $2.55, down 20 cents.
The study will be known as STAR-1, and will test Innovive's oral synthetic retinoid in acute APL patients who've previously been given all-trans-retinoic acid (ATRA), sold as Vesanoid by Basel, Switzerland-based F. Hoffmann-La Roche Ltd., and Trisenox for their disease, a subtype of acute myeloid leukemia.
APL is caused by a chromosomal translocation - t(15;17) - which fuses the promyelocytic leukemia gene with the retinoic acid receptor alpha (RARalpha) gene, holding up myeloid cells at the promyelocytic stage, which makes promyelocytes proliferate and gather in bone marrow and blood, replacing normal cells. ATRA targets the PML-RARalpha fusion gene, and tamibarotene is a new RARalpha agonist.
Oral ATRA combined with chemotherapy is the current first-line standard of care for APL, but the drug can cause potentially fatal retinoic acid syndrome in up to 25 percent of patients, due to the fast increase in white blood cells. Also, ATRA-caused remissions usually don't last long, and patients often fail to respond to the second course of treatment.
The next step is usually intravenous Trisenox, but that compound brings the risk of toxicity and irregular heartbeat. For patients who do not respond to ATRA and Trisenox, there is no standard of care.
In the tamibarotene trial, 50 adults with relapsed or refractory APL after treatment with those two compounds will be enrolled as outpatients, and will take tamibarotene tablets at a dose of 6 mg/m2 daily. The primary endpoint is durable complete response.
"Typically, if you can maintain it for 28 days, that's considered a durable response," Kelly said, and the FDA has agreed in the SPA. He noted that the company will follow patients every three months for a year, and then every six months afterward, to keep measuring response.
Secondary objectives of the trial are to determine the rates of morphologic leukemia-free state, partial response, cytogenetic complete response and molecular complete response, as well as safety, tolerability and pharmacokinetics.
Innovive's SPA, like those gained by other companies, is an agreement between the firm and the FDA on the study's design, endpoints and analysis of data. The pact is intended to strengthen the likelihood that, if the trial achieves prespecified results, those results would serve as the main basis for an efficacy claim.
But the SPA is no guarantee. Last month, an FDA advisory panel turned thumbs-down on GPC Biotech Inc.'s satraplatin for second-line, hormone-refractory prostate cancer, turning away data from a Phase III trial conducted under an SPA deal. (See BioWorld Today, July 25, 2007.)
In a move that hurt GPC, partner Pharmion Corp., and licensee Spectrum Pharmaceuticals Inc., the Oncology Drugs Advisory Committee decided 12-0 to recommend that the agency wait for the overall survival results from the pivotal trial with satraplatin, rather than accept progression-free survival data alone.
And the month before, Encysive Pharmaceuticals Inc. lost 43.4 percent of its stock value on word of the Houston-based company's third approvable letter for Thelin (sitaxsentan) 100 mg tablets for pulmonary arterial hypertension (PAH). (See BioWorld Today, June 19, 2007.)
Encysive, which also conducted its Phase III trial under an SPA agreement, is taking the matter to a formal dispute resolution. Meanwhile, the firm has retained Morgan Stanley to help figure out the next steps.
Kelly said Innovive's investors at meetings lately have asked, "Are you getting a real SPA or . . . ?" and the company has done as much as possible to cover its bases with the FDA on primary and secondary endpoints. "We've also agreed with the FDA that we would use this study in combination with studies that were done in Japan," where tamibarotene already is approved. "I'm pretty pleased," he added.
Elsewhere in the general space, Ziopharm Oncology Inc., of New York, has the Phase II-stage ZIO-101 (darinaparsin), a small molecule, organic arsenic formulation, for multiple myeloma, liver cancer and hematological cancers. At the 11th International Myeloma Workshop in Kos, Greece, in late June, Ziopharm also offered preclinical data indicating that ZIO-101 may have activity in myeloma patients who have failed treatment with arsenic trioxide.
"We wouldn't consider that competitive," Kelly said - not only because ZIO-101 is targeting solid tumors, but also because studies already have shown ATRA and arsenic could work together. "They're unique mechanisms [of action, with] non-overlapping toxicities." Just what the doctor ordered in oncology, he noted.
Also in the pipeline, Innovive has INNO-206 (formerly DOXO-EMCH), a prodrug for doxorubicin, undergoing Phase II trials in small-cell lung cancer. INNO-206 is the (6-Maleimidocaproyl) hydrazone of doxorubicin, which means doxorubicin is attached to an acid sensitive linker to boost efficacy, has lower side effects and reaches tumors faster.
Undergoing Phase I studies at Sloan Kettering Cancer Center in New York is INNO-305, also known as WT1 heteroclitic peptide immunotherapy, made up of long and short synthetic peptides derived from WT1 and mixed with adjuvant to induce T-cell responses.
Innovive also has INNO-406 (formerly known as NS-187), an oral, dual Bcr-Abl and Lyn-kinase inhibitor. A study published in 2005 in the journal Blood found the compound 25 to 55 times more potent than imatinib mesylate (Gleevec, Novartis AG) in vitro, and at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl bearing tumors. INNO-406 has shown activity in 12 of 13 imatinib-resistant cell lines. A Phase I dose escalation, safety and tolerability study is ongoing at sites in the U.S., Germany and Israel. Innovive believes the drug could work against chronic myeloid leukemia or acute lymphocytic leukemia.