PSA Rising, February 22, 2005. Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) today announced results from a phase I clinical trial of MLN2704 in patients with advanced hormone-refractory prostate cancer. These results were presented at the 2005 Prostate Cancer Symposium taking place this week in Orlando, Fl.
The findings from this first in human MLN2704 single ascending dose trial indicated the molecule was well tolerated and produced sustained anti-tumor activity, including one patient who achieved a durable partial response in measurable disease for 11 months, as well as a sustained prostate specific antigen (PSA) decline of more than 50 percent. This patient received 14 doses prior to measurable disease progression at 47 weeks.
MLN2704 is composed of a deimmunized monoclonal antibody (MLN591) directed at prostate specific membrane antigen (PSMA) conjugated to the chemotherapeutic agent DM1.
"We are encouraged by these findings with MLN2704 in prostate cancer, and we are continuing to assess the dose and schedule," said David Schenkein, M.D., senior vice president, clinical research, Millennium.
"These results allow us to continue to pursue this important area of unmet medical need, and we are hopeful that further development can lead to new therapeutic options for patients with hormone-refractory prostate cancer."
Interim data from the Company's ongoing multiple ascending dose trial evaluating MLN2704 in patients with prostate cancer has been accepted for presentation at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO) scheduled for May 13-17 in Orlando, Fl.
Also presented at the meeting were results from two VELCADE studies in patients with progressive hormone-refractory prostate cancer: a phase I/II clinical trial of VELCADE in combination with docetaxel and a phase II study of VELCADE with and without steroids. The findings from the study evaluating VELCADE(R) (bortezomib) for Injection and 40mg docetaxel in combination weekly indicated the combination was well tolerated and showed promising activity.
Specifically, in the higher VELCADE dose cohort, there were two partial responses in 18 patients with measurable disease and there were confirmed PSA declines of at least 50 percent in 36 percent of the 28 evaluable patients.
VELCADE is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S.; Ortho Biotech and Janssen-Cilag are responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for Japan.
"We are continuing to evaluate the data from the VELCADE trials in the prostate cancer population to better assess and understand the activity we have seen in these and past trials," said Dr. Schenkein. "We anticipate finalizing our evaluation and determining next steps in prostate cancer with VELCADE later this year in collaboration with our partner, Johnson & Johnson Pharmaceutical Research & Development, L.L.C."
MLN2704 in patients with advanced androgen independent metastatic prostate cancer; updated results
A single ascending dose phase I study of MLN2704, led by Howard I. Scher, M.D. at Memorial Sloan-Kettering, New York and Mario Eisenberger, M.D. at Johns Hopkins Oncology Center, Maryland enrolled 23 patients and examined the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics and immunogenicity of MLN2704. Patients received MLN2704 at doses ranging from 18 to 343mg/m2. Responses in patients with measurable disease were evaluated based on the RECIST (Response Evaluation Criteria In Solid Tumors) criteria and confirmed four to six weeks after the first documentation of a complete or partial response. In addition, anti-tumor activity was evaluated based on a sustained PSA decline of at least 50 percent confirmed by two separate measurements at least four weeks apart. Dose escalation continued if no dose-limiting toxicity was observed. Investigators reported the following results:
- Of 11 patients with measurable disease, one patient treated with a 264mg/m2 dose, achieved a durable partial response, including a PSA decline of more than 50 percent. This patient received 14 doses prior to measurable disease progression at 47 weeks;
- One additional patient, treated with a 343mg/m2 dose, achieved a PSA decline of more than 50 percent that persisted for 24 weeks;
- Four patients achieved stable disease;
- Toxicities greater than grade three occurred in three patients including an episode of uncomplicated febrile neutropenia with lymphopenia and leukopenia, lymphopenia, and a transient grade three elevation in hepatic transaminases. No grade four toxicities were observed; and
- No immunogenicity was observed despite repeat dosing.
VELCADE® (bortezomib) for Injection in combination with docetaxel in patients with advanced androgen independent prostate cancer
A phase I/II study of VELCADE in combination with docetaxel, being led by Robert Dreicer, M.D., at the Cleveland Clinic Foundation, Cleveland, OH, examined the dose-limiting toxicities, maximum tolerated dose, and the effects on PSA levels of VELCADE and docetaxel, both given weekly for two out of three weeks, in patients with advanced androgen-independent prostate cancer. Two dose levels were expanded into phase II cohorts, one with VELCADE 1.3mg/m2 and docetaxel 40 mg/m2, the second with VELCADE 1.6mg/m2 and docetaxel 40 mg/m2.
Anti-tumor responses in patients with measurable disease were evaluated based on the RECIST criteria and confirmed four to six weeks after the first documentation of a complete or partial response. In addition, anti-tumor activity was evaluated based on a sustained PSA decline of more than 50 percent confirmed by two separate measurements at least four weeks apart.
Investigators reported the following results:
- In the cohort in which patients were treated with VELCADE 1.3mg/m2 and docetaxel 40 mg/m2:
- Of 25 evaluable patients, six patients (24 percent) achieved a confirmed PSA decline of more than 50 percent of which four patients achieved a confirmed PSA decline of at least 90 percent; and
- 100 percent of the 13 patients with measurable disease achieved either partial remission or stable disease, specifically three achieved partial remission.
- In the cohort in which patients were treated with VELCADE 1.6mg/m2 and docetaxel 40 mg/m2:
- Of 28 evaluable patients, 10 (36 percent) had a PSA decline of more than 50 percent;
- 78 percent of 18 patients with measurable disease achieved partial remission or stable disease, specifically two patients achieved partial remission.
- Adverse events observed included fatigue, gastrointestinal events, neuropathy, and hematologic toxicities.
VELCADE in combination with prednisone in patients with advanced androgen independent prostate cancer
A phase II study of VELCADE, led by Michael Morris M.D. and Howard I. Scher, M.D. at Memorial Sloan-Kettering, New York, NY enrolled 30 patients and examined the efficacy of VELCADE in patients with progressive androgen independent metastatic prostate cancer. Patients were treated in two groups, the first 12 patients receiving VELCADE 1.5mg/m2 twice weekly for two out of three weeks at induction with daily prednisone 10mg, and the next 18 patients receiving VELCADE 1.3mg/m2 on the same schedule at induction with prednisone 10mg upon progression. All patients received VELCADE 1.6 mg/m2 weekly as maintenance. Antitumor activity was evaluated based on imaging and measurement of PSA decline at six and twelve weeks. Investigators reported the following results from pooled cohorts:
- Of nine patients with measurable disease, two patients achieved stable PSA and stable scans at 12 weeks;
- Two patients had a stable PSA at 12 weeks but progressed radiographically;
- One patient in the higher dose group demonstrated a partial response on scans but PSA continued to rise; and
- Side effects included hematologic, metabolic and hepatic side effects, neuropathy, syncope, diarrhea and fatigue.
About MLN2704
MLN2704 is composed of a deimmunized monoclonal antibody (MLN591) directed at prostate specific membrane antigen (PSMA) conjugated to the chemotherapeutic agent DM1. MLN2704 binds to PSMA, which is rapidly internalized into the cell delivering a lethal dose of chemotherapy directly to prostate cancer cells. Unlike the enzyme PSA which circulates in the blood, PSMA is a protein expressed on the cell surface of virtually all prostate cancer cells and its abundance on the cell surface increases as the disease progresses and becomes refractory to hormonal therapy. PSMA has little expression in normal tissues.
In April 2001, Millennium entered into an agreement with BZL Biologics, L.L.C., for the joint development and commercialization of antibody-based therapeutics targeting PSMA. Millennium currently has exclusive development and worldwide marketing rights to these products.
To develop MLN2704, Millennium conjugates the chemotherapeutic agent DM1 -- licensed from ImmunoGen, Inc. (Nasdaq: IMGN) -- to the MLN591 antibody, which targets PSMA. DM1 was developed by ImmunoGen specifically for antibody-directed delivery to tumor cells.
In December 2003, MLN-2704 was granted "Fast Track" status by FDA and has been selected for the Continuous Marketing Application Pilot 2 program. This latter innovative program is designed to facilitate scientific exchange and speed approval time.
About VELCADE(R) (bortezomib) for Injection
VELCADE is approved for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. The effectiveness of VELCADE is based on response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in survival.
VELCADE(R) (bortezomib) for Injection is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, orthostatic hypotension, congestive heart failure, gastrointestinal adverse events, thrombocytopenia, and tumor lysis syndrome.
Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.
In 228 patients who were treated with VELCADE 1.3 mg/m2/dose in phase II studies, the most commonly reported adverse events were asthenic conditions (65%), nausea (64%), diarrhea (51%), decreased appetite including anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%), pyrexia (36%), vomiting (36%), and anemia (32%). Fourteen percent of patients experienced at least one episode of Grade 4 toxicity, with the most common toxicities being thrombocytopenia (3%) and neutropenia (3%). A total of 113 (50%) of the 228 patients experienced Serious Adverse Events (SAEs) during studies. The most commonly reported SAEs included pyrexia (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), dehydration (5%), and nausea (4%).
For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-( 866)-VELCADE (1-866-835-2233).
About Millennium
Millennium Pharmaceuticals, Inc., a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a novel cancer product, co- promotes INTEGRILIN(R) (eptifibatide) Injection, a market-leading cardiovascular product, and has a robust clinical development pipeline of product candidates. The Company's research, development and commercialization activities are focused in three therapeutic areas: oncology, cardiovascular, and inflammation. By applying its knowledge of the human genome, its understanding of disease mechanisms, and its industrialized drug discovery platform, Millennium is seeking to develop breakthrough products.
This press release contains "forward-looking statements," including statements about the Company's discovery and development of products. Various
important risks may cause the Company's actual results to differ materially from the results indicated by these forward-looking statements, including:
adverse results in its drug discovery and clinical development programs; failure to obtain patent protection for its discoveries; commercial limitations
imposed by patents owned or controlled by third parties; the Company's dependence upon strategic alliance partners to develop and commercialize
products and services based on its work; difficulties or delays in obtaining regulatory approvals to market products and services resulting from its
development efforts; product withdrawals; competitive factors; difficulties or delays in manufacturing the Company's products; government and third party
reimbursement rates; the commercial success of VELCADE and INTEGRILIN; achieving revenue consistent with internal forecasts; and the requirement
for substantial funding to conduct research and development and to expand commercialization activities. For a further list and description of the risks and
uncertainties the Company faces, see the reports it has filed with the Securities and Exchange Commission. The Company disclaims any intention or
obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
Edited by J. Strax, February 22, 2005
