At the upcoming ASCO Annual Meeting being held June 3-7 in Chicago, Eisai Co., Ltd. (OTC:ESALF) is expected to report detailed results from its DACO-016 Phase 3 trial of Dacogen® [decitabine] as a frontline treatment for elderly patients [65+ years old] with acute myelogenous leukemia [AML]. As announced less than one year ago, Dacogen’s top-line results did not meet the primary endpoint of superiority over low-dose cytarabine in terms of overall survival in this study, although a trend was reported to be evident.
Shares of SuperGen, Inc. (SUPG), which climbed as high as $2.89 on expectations for positive trial results, reached a new 52-week low of $1.71 in July 2010 following the negative top-line news. SuperGen receives a 20-30% royalty on worldwide sales of Dacogen from its development and commercialization partners – Eisai in North America and Johnson & Johnson (JNJ) outside of North America.
Despite the negative top-line results, shares of SuperGen have since rebounded and reached a new 52-week high in April 2011. Optimism may stem from the fact that both Eisai and Johnson & Johnson are continuing to analyze the data and planning to move forward with North American and European regulatory filings in 2011 based on the primary analysis and secondary endpoints. Accordingly, investors will anxiously await the detailed Phase 3 results being presented on June 6 at ASCO to better gauge the likelihood of FDA approval in AML [Abstract #6504: “Results from a randomized phase III trial of decitabine versus supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed AML”].
Results from the Dacogen study may also be of interest to investors in Cyclacel Pharmaceuticals, Inc. (CYCC), which recently launched a multicenter, randomized, pivotal Phase 3 trial for the company’s sapacitabine oral capsules as a front-line treatment of elderly patients aged 70 years or older with newly diagnosed AML who are not candidates for intensive induction chemotherapy. (Editor's note: Cyclacel is a client of MD Becker Partners.) Unique among drugs available to treat AML patients, sapacitabine is the only oral agent in late-stage clinical development. It is also the only candidate to progress into a pivotal study on the basis of survival data from a randomized Phase 2 study. Historically, sponsors advanced molecules to pivotal development in AML based on Phase 2 studies with primary endpoints of complete remission [CR].
The pivotal Phase 3 study is being conducted under a Special Protocol Assessment [SPA] agreement that Cyclacel reached with the FDA. The primary efficacy endpoint for the study is an improvement in overall survival from either of the two pairwise comparisons [Arm A versus Arm C, or Arm B versus Arm C] in the following three arms consisting of approximately 150 patients per arm:
- Arm A: sapacitabine administered in alternating cycles with Dacogen
- Arm B: sapacitabine administered alone
- Arm C: Dacogen administered alone
Cyclacel is testing the treatment regimen of sapacitabine administered in alternating cycles with Dacogen [Arm A] in an on-going pilot study, with data expected at ASCO 2011 [Abstract #6587: “Phase I/II study of sapacitabine and decitabine administered sequentially in elderly patients with newly diagnosed acute myeloid leukemia”]. Thirty-day and 60-day mortality outcomes from this pilot study may be helpful in determining the odds of success in the Phase 3 pivotal study. To put this in perspective, 30-day mortality in AML patients aged 70 years or older ranged from 17% to 21% in a recently published Phase 3 study [Harousseau JL, et al, Blood, 2009:114:1166]. Accordingly, results from the pilot study that demonstrate thirty-day mortality with sapacitabine is equal or less than 21% could be encouraging for Cyclacel.
The Phase 3 study builds on promising one-year survival observed in elderly patients aged 70 years or older with newly-diagnosed AML or AML in first relapse enrolled in a Phase 2 study of single agent sapacitabine. In a disease setting where patients are typically treated with chemotherapy agents like cytarabine for an average of one to two cycles, patients in Cyclacel’s Phase 2 study achieved a median of 12 cycles of treatment with sapacitabine.
In addition, approximately 45% of patients in the Phase 2 study had transformed into AML after being diagnosed with myelodysplastic syndromes [MDS] and were previously treated with Dacogen or Celgene Corporation’s (CELG) Vidaza® [azacitidine]. Only newly diagnosed AML patients are expected to be enrolled in the ongoing Phase 3 trial, none of whom had been previously treated with Dacogen or Vidaza and none of whom had relapsed, potentially increasing the odds for a successful trial.
Finally, Sunesis Pharmaceuticals, Inc. (SNSS) will also be presenting at ASCO [Abstract #TPS201, “Adaptive design of VALOR, a phase III trial of vosaroxin or placebo in combination with cytarabine for patients with first relapsed or refractory acute myeloid leukemia”]. Unlike the aforementioned frontline trials being conducted under SPA’s, Sunesis is studying vosaroxin in relapsed/refractory AML in an ongoing Phase 3 trial. Approximately 450 patients will be randomized to receive either vosaroxin or placebo in combination with cytarabine.
Cytarabine, a generic chemotherapy drug introduced several decades ago, is already a critical part of the treatment for younger patients with AML who are fit to withstand its toxicity. Unfortunately, several companies that make cytarabine have recently experienced production difficulties and others cannot make the drug fast enough to keep up with demand. This has resulted in a severe shortage of cytarabine that has reportedly affected leukemia clinical trials being run by the Cancer and Leukemia Group B [CALGB]. Accordingly, investors will be looking to Sunesis for an update on enrollment in the VALOR Phase 3 trial to determine whether or not the cytarabine shortage has been a factor.
Beyond the aforementioned investigational therapies, a researcher in the field of oncology noted that newer, targeted agents will be required to advance the treatment of AML: “My personal opinion on AML affecting the elderly population is that the field is in need of a total revamp whereby certain chemotherapy agents need to be combined with targeted therapies to overcome drug resistance and provide meaningful survival data,” said Daruka Mahadevan, M.D. Ph.D., Director, Phase I Program, Arizona Cancer Center. “If you can increase the survival of a 70-year old patient by ten years, that would be a real achievement. Sapacitabine is interesting as it is an oral agent, while vosaroxin in combination of cytarabine may provide short term control – but is unlikely to provide a survival benefit.”
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