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Use Of Velcade Widening As Various Trials March On
By Randall Osborne
Editor
When Millennium Pharmaceuticals Inc. nailed down its overseas marketing deal in July 2003 with Ortho Biotech Products LP for the multiple myeloma drug Velcade (approved two months earlier), investors sat up and took notice.
The terms were mighty fine: $15 million up front and as much as $500 million in milestones. And Velcade was turning out to be quite the bullet against a disease that had been anything but easy to attack.
Just invoking the name of the proteasome inhibitor carries weight, and working in a similar scientific space proved appealing last week to Merck & Co. Inc., which entered a research deal with Rigel Pharmaceuticals Inc. for the further investigation of ubiquitin ligases - enzymes that regulate protein degradation within the cell, thus affecting such functions as cell division, a key element in cancer.
The proteasome, noted Donald Payan, vice president and chief scientific officer at Rigel, is "the final disposal apparatus for proteins that are destined to be chewed up - it's where they go to die. We're going further upstream to look at how the system is fine-tuned in selected disease mechanisms."
Velcade, approved in third-line multiple myeloma and under FDA review for the treatment of second-line disease, is not all of the Millennium story, and company officials set aside last Tuesday as its first-ever "research and development day" to update observers on progress with Velcade, as well as the rest of the pipeline.
Analysts at UBS Warburg initiated coverage of the company early this month with a "neutral" rating. Over the summer, SunTrust Robinson Humphrey jumped aboard, calling the stock a "buy." After the meeting with Millennium, Robert Baird & Co. stuck with its "neutral" tag, though analyst Christopher Raymond wrote in a report that he was "impressed" with Velcade's advancement.
Also moving along is the company's other marketed product, Integrilin (eptifibatide, originally from Cor Therapeutics Inc., which merged with Millennium), an anti-clotting agent for acute coronary syndrome, co-promoted with Schering-Plough Corp. Integrilin inhibits the glycoprotein IIb-IIIa.
At this month's American Heart Association Scientific Sessions Symposium 2004 in New Orleans, Millennium said that Integrilin, when compared with bivalirudin, did not meet the primary endpoint of coronary flow reserve, but did demonstrate a statistically significant improvement in myocardial perfusion - encouraging news from the PROTECT trial, designed to match Integrilin against the direct thrombin inhibitor bivalirudin in high-risk patients. Another platelet study, called CLEAR, along with one named CRUSADE, yielded positive results, too.
Most eyes, however, are on Velcade for the moment, a therapy that won accelerated approval only four and a half years from the first human dose, thanks to help from the Multiple Myeloma Research Foundation, which provided funding and other guidance, along with the National Cancer Institute and Dana-Farber Cancer Institute. (See BioWorld Financial Watch, May 19, 2003.)
Investors await a decision from the FDA on accepting Millennium's supplemental new drug application in second-line multiple myeloma. A survey by CancerConsultants Inc. found 50 percent of doctors already are using it in second-line therapy, up from 37 percent three months ago. What's more, data from analysts at Baird show Velcade is surpassing in popularity Celgene Corp.'s Thalomid (thalidomide) plus dexamethasone in second-line patients. Some 37 percent of surveyed doctors said they like Velcade best, vs. 39 percent preferring the treatment known as Thal/Dex.
Millennium told analysts three Phase III trials with Velcade are expected to start in the near term - one in the final quarter of this year or first quarter of next, and two in the first half of 2005. Two of the studies will be carried out in multiple myeloma patients slated for stem cell transplants, which is a sector key to the growth of the drug for front-line therapy. About 34 percent of patients are deemed "transplant eligible." The company also has the EVEREST trial on deck for the first half of 2005, which is a Phase IV study re-treating Velcade patients with a second course of the drug as a single agent.
Non-Hodgkin's lymphoma is another targeted disease for Velcade, specifically follicular/marginal zone lymphoma and mantle-cell lymphoma, known as "indolent" and "aggressive" NHL, respectively. A Phase II study in relapsed/refractory mantle-cell lymphoma is ongoing, with Baird expecting interim data at the American Society of Clinical Oncology meeting in May. In indolent NHL, there's an ongoing Phase II trial testing Velcade plus Rituxan (rituximab, Genentech Inc.), with early data likely also at next year's ASCO meeting.
Millennium also unveiled at its hosted event plans for Velcade against non-small-cell lung cancer. In second-line disease, Baird expects data and a decision on next steps in the fourth quarter of this year related to the Phase II trial of Velcade with docetaxel (Taxotere, Aventis Pharmaceuticals Inc.). In first-line, Millennium is finishing up a Phase II trial giving Velcade with gemcitabine and carboplatin. And in bronchoalveolar carcinoma, the company aims to start a Phase II study with Velcade as a single agent in patients who have relapsed after being treated with an EGFr inhibitor.
Piper Jaffray, which has a "market perform" rating on the stock, said last week in a research note that the analyst firm expects Millennium to go ahead with Phase III trials in NSCLC, although Velcade against breast cancer has been abandoned without fanfare since the drug doesn't seem to work in that indication.
"We talked to some physicians in colorectal cancer just this week and they're not too enthusiastic" in that indication, either, said Phil Nadeau, analyst with SG Cowen & Co., pointing out that the compound seems to work better in hematologic settings than in solid tumors, maybe due to bioavailability issues. Millennium halted a Phase II trial of Velcade in that indication in January.
But he agrees that a Phase III trial is likely in NSCLC.
"My sense from what they said in the past is that they probably will," he told BioWorld Financial Watch, adding that physicians seem interested, but to a modest degree, probably because Velcade is intravenous and "they can get similar levels of activity from some oral drugs."
Farther back in the pipeline is MLN2704. At the ASCO meeting in June, Millennium reported that Phase I data of the drug in patients with progressive metastatic hormone-refractory prostate cancer showed it was well tolerated and produced antitumor activity. The drug, an antibody conjugate, has reached the Phase I/II stage.
At its R&D day, Millennium also touted a pair of chemokine receptor antagonists, MLN3897 and MLN1202, being tested for rheumatoid arthritis and multiple sclerosis. The first is an oral inhibitor of the CCR1 receptor in Phase I trials, with the drug eventually to target moderate RA and relapsing/remitting MS. The second, for the same indications, is in a Phase IIa trial in RA patients.
"I think most investor sentiment is focused on Velcade," Nadeau noted, making it the main growth driver.
"That being said, Millennium is still guiding for break-even and maybe even profitability in 2006. In order to get there, at least in our model, you need to see Integrilin sales growth. We have Velcade going from $59.6 million in 2003 to $300 million in 2006, and Integrilin going from $300 million in 2003 to $370 million in 2006."
Published November 22, 2004
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