Three Late-Stage Leukemia Company Previews for ASCO

At the upcoming ASCO Annual Meeting being held June 3-7, 2011, in Chicago, Illinois, Eisai Co., Ltd. (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 America 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 Monday, June 6, 2011 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.  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 sixty-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, thirty-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 1-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 1 to 2 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.”

Investment Opportunities with Five Frontline Therapies for AML

Acute myelogenous leukemia [AML] is a fast-growing cancer of the blood and bone marrow.  Unformed cells called myeloblasts, or “blasts,” reside in the bone marrow and normally become a particular kind of cell – a white blood cell, red blood cell, or platelet.  In AML, abnormal blasts produce white blood cells that do not function properly.  They do not fight infections and, as they build up, they inhibit the production of normal white blood cells, red blood cells, and platelets that the body needs.

Standard frontline therapy for AML patients under the age of 60 consists of cytarabine  [AraC] combined with an anthracycline [such as daunorubicin or idarubicin] in what is commonly referred to as the 7+3 regimen.  While 45% of elderly patients with AML [70+ years old] achieved a complete response [CR] using this regimen, there was no improvement in overall survival and more than a third of patients died within the first eight weeks of treatment according to a recent study published in the journal Blood[i].  This is consistent with the CR rates of 40%–60% with conventional chemotherapy and disease-free survival of less than 20% at three years referenced in the literature[ii].

Since more than half of AML cases occur in patients over 60 years old, there is a need to develop better frontline therapies in this setting.  With five agents being investigated as frontline therapy for elderly AML patients in late-stage trials, the purpose of this article is to compare and contrast these programs – several of which have near-term catalysts for investors.

Hypomethylating Agents

SuperGen, Inc. (SUPG), Eisai Co. Ltd. (ESALF), and Johnson & Johnson (JNJ)

On June 30, 2010, preliminary results from a Phase III trial of Dacogen® [decitabine] as a frontline treatment for elderly patients [65+ years old] with AML were released.  While Dacogen did not meet the primary endpoint of overall survival, a trend was reported to be evident.  However, the failure to demonstrate an improvement in overall survival was surprising given the favorable Phase II results and the fact that the comparator arm received low dose AraC instead of the aforementioned 7+3 regimen.  Low dose AraC predominantly works in patients with favorable cytogenetics, so it should have been relatively easy for Dacogen to demonstrate a survival benefit.

Shares of SuperGen, which climbed as high as $2.89 on expectations for positive trial results, reached a new 52-week low of $1.71 in July.  Supergen receives a 20-30% royalty on worldwide sales of Dacogen from its development and commercialization partners – Eisai in North America and Johnson & Johnson outside of North America.

While investors appear to be discounting approval of Dacogen as a frontline therapy for elderly AML, there may be reasons for optimism.  For example, both Eisai and Johnson & Johnson are continuing to analyze the data and planning to move forward with North America and European regulatory filings in 2011 based on the primary analysis and secondary endpoints.  In addition, the Phase III study was conducted under a special protocol assessment [SPA] with the U.S. Food and Drug Administration [FDA].

Celgene Corporation (CELG)

In view of Dacogen’s negative Phase III trial results, investors may be skeptical about Vidaza® [azacitidine], another hypomethylating agent currently approved for the treatment of myelodysplastic syndromes [MDS], a pre-cancerous condition that can often progress to AML.  According to ClinicalTrials.gov [Identifier NCT01074047], Celgene is currently enrolling patients in a Phase III, multicenter, randomized, open-label, study of Vidaza versus conventional care regimens for the frontline treatment of elderly patients [65+ years old] with AML.

In December 2008, the European Commission granted marketing authorization for Vidaza as a treatment for patients with higher-risk MDS, chronic myelomonocytic leukemia [CMML], and MDS that transforms into AML with a blast percentage of 20-30% in the peripheral blood or bone marrow.  While Vidaza demonstrated a clinically relevant increase in median survival of 9.4 months [24.4 vs. 15 months] in these settings[iii], it is unclear how the drug will work in AML de novo patients with a higher blast percentage [greater than 50%] that represent half of the elderly patient population.  In view of the fact that Dacogen is more myelosuppressive than Vidaza [see Table 1], and for this reason may be preferred over Vidaza for off-label use in AML, the recent failure of Dacogen only adds to this uncertainty.

Table 1. Percentage of Patients with Myelosuppression from Prescribing Information

Adverse Event Dacogen Vidaza
Anemia 82.0% 69.5%
Neutropenia 90.0% 32.2%
Thrombocytopenia 89.0% 65.5%

Monoclonal Antibodies

Seattle Genetics, Inc. (SGEN)

Seattle Genetics is developing SGN-33 [lintuzumab], an unconjugated IgG1 antibody for the treatment of AML.  Lintuzumab has been shown to induce cell death by both complement and/or antibody-directed cellular cytotoxicity, or as a direct effect of the engagement of the CD33 receptor, which is expressed in most leukemic blast cells but also in normal hematopoietic cells.

In a Phase II study in relapsed/refractory AML patients, single agent lintuzumab demonstrated efficacy in patients with advanced AML; however, the positive effects were confined to patients with low disease burden [blast percentage 5% to 30%].  This suggested that additional development of this agent would be best achieved by combining lintuzumab with chemotherapy.  However, while the addition of lintuzumab to salvage induction chemotherapy was safe, it did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML in a subsequent Phase III trial[iv].

Seattle Genetics is now conducting a 210 patient Phase IIb study in frontline treatment of elderly patients [60+ years old] with AML with results expected in the August to October 2010 timeframe.  See ClinicalTrials.gov [Identifier NCT00528333] for more information.

While lintuzumab relies on a different mechanism of action, investor’s are understandably skeptical about the success of another anti-CD33 monoclonal antibody in AML.  In June 2010, Pfizer, Inc. (PFE) agreed to withdraw Mylotarg® [gemtuzumab ozogamicin] from the U.S. market, effective October 15.  Mylotarg is an IgG4 monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins.  Developed by Wyeth, the drug was fast-tracked to treat patients ages 60 and older with recurrent AML who were not candidates for other chemotherapy.  The FDA approved Mylotarg in May 2000 based upon a surrogate endpoint due to the fact it treated relapsed disease with no other viable therapy.

Four years later, a confirmatory trial was begun to confirm the results of the 142 patients who participated in the three previous clinical trials.  The 2004 trial showed that adding Mylotarg to existing chemotherapy for the treatment of AML provided no benefit and even showed a higher death rate.

Nucleoside Analogs

Genzyme Corporation (GENZ)

In September 2009, the FDA’s Oncologic Drugs Advisory Committee [ODAC] voted 9 to 3 that a randomized, controlled trial is needed to support the proposed label expansion for Clolar® (clofarabine) as a frontline treatment for elderly [60+ years old] patients with AML.  Consistent with the decisions for both Johnson & Johnson’s Zarnestra® [tipifarnib] and Vion Pharmaceuticals’ Onrigin® [laromustine], the committee determined that single-arm clinical study results were not sufficient for approval.

Despite the setback, Genzyme stated in a press release that the company remains committed to the clinical development of clofarabine in this patient population and that the drug is being investigated in clinical trials by most of the leading AML experts and major cooperative leukemia investigation groups in the United States and Europe.

Beyond the frontline setting, Genzyme is also conducting a randomized Phase III trial comparing clofarabine in combination with AraC to AraC alone in relapsed and refractory adult AML patients 55 years old or older [ClinicalTrials.gov Identifier NCT00317642]. Results are expected in 2011.

Note: At the time of writing, Sanofi-Aventis (SNY) has offered to acquire Genzyme for $69 per share.

Cyclacel Pharmaceuticals, Inc. (CYCC)

Cyclacel is developing sapacitabine for the treatment of AML, MDS and non-small cell lung cancer [NSCLC].  Sapacitabine is unique among the frontline, elderly AML landscape as it represents the only oral agent in late-stage clinical development and the only product candidate to demonstrate a survival benefit in a randomized study.

In December 2009, Cyclacel reported interim results from an ongoing Phase II study involving 60 patients aged 70 or older with either untreated AML [80%] or AML in first relapse [20%] randomized across three dosing schedules of sapacitabine [ClinicalTrials.gov Identifier NCT00590187].  The three-day dosing schedule in Arm C was selected for further clinical development in elderly patients with de novo AML based on a 1-year survival rate of 30% and an overall response rate of 35%.

In the first quarter of 2010, Cyclacel submitted a SPA request for a randomized, registration-directed, Phase III study of sapacitabine in elderly patients with AML and, pending the response, expects to initiate a pivotal Phase III study in 2010.

Summary

While many companies are developing therapies for AML [see Table 2], there is a need to focus on better frontline therapies for elderly patients given the lack of efficacy and significant toxicity associated with the current 7+3 treatment regimen.  Investors will be watching the following catalysts to help handicap which of the five product candidates [decitabine, azacitidine, clofarabine, sapacitabine, or lintuzumab] will win the race and become the first agent approved by the FDA in this setting:

  • Phase IIb results for lintuzumab expected in the August to October 2010 timeframe
  • FDA response to SPA request for Phase III study of sapacitabine; initiation of pivotal Phase III study in 2010
  • Supplemental new drug application [sNDA] for decitabine by March 31, 2011 and subsequent response from FDA
  • Results from frontline clofarabine clinical trials by AML experts and major cooperative leukemia investigation groups in the United States and Europe; relapsed/refractory AML Phase III results in 2011
  • Phase III results for azacitidine expected around 2013

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Table 2. Late-stage Therapeutic Landscape for AML

Sponsor(s) Route Class SPA Setting Comments
Dacogen® (decitabine) Supergen, Eisai, Johnson & Johnson i.v./s.c. Hypomethylating agents Yes Frontline and relapsed/refractory Failed overall survival endpoint versus low-dose ara-C in frontline elderly AML (≥65), expect to file with FDA on secondary endpoints in March 2011.  Phase 3 trial underway in relapsed/refractory setting.
Vidaza® (azacitidine) Celgene Corp s.c. Hypomethylating agents No Frontline Phase 3 study underway (NCT01074047)
Clolar® (clofarabine) Genzyme Corp i.v. Nucleoside analogs No Frontline Rejected by FDA in elderly AML (≥60) due to single-arm
Mylotarg® (gemtuzumab ozogamicin) Pfizer/Wyeth i.v. Monoclonal antibodies n/a Relapse/refractory Accelerated approval, but withdrawn from market
Lintuzumab Seattle Genetics i.v. Monoclonal antibodies No Frontline Phase 2b data from 210 pts expected late August to October 2010 timeframe
Sapacitabine Cyclacel Pharma oral Nucleoside analog Pending Frontline Phase 2 demonstrated 30% survival in elderly AML (≥70); SPA pending
Vosaroxin (a.k.a. voreloxin) Sunesis Pharma (SNSS) i.v. Topoisomerase II inhibitors No Relapse/refractory Pivotal Phase 3 being planned
Zarnestra™ (tipifarnib) Johnson & Johnson oral Farnesyltransferase inhibitors No Frontline Rejected by FDA in elderly AML (≥60) due to single-arm, subsequent randomized study failed ‘09
Onrigin™ (laromustine) Vion Pharma i.v. Alkylating agents No Frontline Rejected by FDA in elderly AML (≥60) due to single-arm
Lestaurtinib Cephalon (CEPH) oral Tyrosine kinase inhibitors No Relapse/refractory Failed Phase 2 reported ASH ‘09
AC220 Ambit Biosciences/Astellas Pharma oral Tyrosine kinase inhibitors No Relapse/refractory Entered pivotal Phase 2, single-arm trial in December 2009

References


[i] Kantarjian H, Ravandi F, O’Brien S, Cortes J, Faderl S, Garcia-Manero G, Jabbour E, Wierda W, Kadia T, Pierce S, Shan J, Keating M, Freireich EJ.  Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010 Jul 28. [Epub ahead of print]

 

[ii] Amadori S, Suciu S, Willemze R, Mandelli F, Selleslag D, Stauder R, Ho A, Denzlinger C, Leone G, Fabris P, Muus P, Vignetti M, Hagemeijer A, Beeldens F, Anak O, De Witte T; EORTC leukemia group; GIMEMA leukemia group.  Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups.  Haematologica. 2004 Aug;89(8):950-6.

[iii] Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C, Greenheld W.  Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Health Technol Assess. 2010 May;14 Suppl 1:69-74.

[iv] Eric J. Feldman, Joseph Brandwein, Richard Stone, Matt Kalaycio, Joseph Moore, Julie O’Connor, Nancy Wedel, Gail J. Roboz, Carole Miller, Raj Chopra, Joseph C. Jurcic, Randy Brown, W. Christopher Ehmann, Philip Schulman, Stanley R. Frankel, Daniel De Angelo, David Scheinberg.  Phase III Randomized Multicenter Study of a Humanized Anti-CD33 Monoclonal Antibody, Lintuzumab, in Combination With Chemotherapy, Versus Chemotherapy Alone in Patients With Refractory or First-Relapsed Acute Myeloid Leukemia. Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4110-4116.