Sometimes when a drug hits the market, it can take on a life of its own. Researchers start using their imaginations—and their own grant money—to pursue applications the drugmaker itself might never have envisioned. And sometimes, those researchers make important new discoveries, which can provide the company with a running start on a potentially lucrative opportunity.
One of those stories is happening now at Seattle Genetics.
The Bothell, WA-based cancer drug developer (NASDAQ: SGEN) said this month that it is pushing ahead with the final stage of clinical trials to test its brentuximab vedotin (Adcetris) for patients with cutaneous T-cell lymphoma (CTCL). The company agreed to invest in the 124-patient study after seeing that researchers, operating independently at MD Anderson Cancer Center and Stanford University, both ran trials suggesting the Seattle Genetics drug could be an important new advance for CTCL. If the company and its partner, Cambridge, MA-based Millennium Pharmaceuticals, can confirm what the researchers saw in those smaller trials, then it could pave the way to an FDA approval of the drug for a third type of lymphoma. That could open the door to treating another 1,000 new patients a year in the U.S., expanding the number of people eligible to get the drug by about 35 percent.
Cutaneous T-cell lymphoma comes in a lot of different forms, and although it doesn’t usually kill people, it is painful and disfiguring. It’s a disease in which cancerous immune system cells migrate to the skin, causing nasty lesions. There are a few treatments out there, such as topical immune suppressors, radiation, or chemotherapy. There are also more targeted drugs like Eisai Pharmaceuticals’ bexarotene (Targretin), Merck’s vorinostat (Zolinza), or Celgene’s romidepsin (Istodax). But once patients progress past the early rounds of therapy, no treatments have shown tumor shrinkage rates beyond about 35 percent, much less an ability to spur long-term remissions. The Seattle Genetics drug, in the hands of the Stanford and MD Anderson researchers, boosted the response rate up to more than 65 percent, and in one study showed the remissions lasted at least six months and counting. That’s the kind of data that prompted Seattle Genetics to make CTCL one of its more promising new corporate R&D priorities.
“We’ve talked to the doctors extensively, and we are thrilled with the activity they are seeing,” says Seattle Genetics CEO Clay Siegall. “This is the most active drug in CTCL they’ve ever seen.”
Seattle Genetics won FDA approval for brentuximab vedotin back in August, originally as a treatment for relapsed forms of Hodgkin’s lymphoma and anaplastic large cell lymphoma (ALCL). But for years, the company has seen those two conditions as just a starting point. The drug is designed to hit a marker known as CD30 on the surface of cells. Hodgkin’s and ALCL are known to carry the CD30 marker, so there was a good scientific rationale to try the drug first on those patients.
What was less clear to Seattle Genetics, or anybody else, was just how many other cancers have CD30 markers on them, or how prevalent the CD30 markers need to be for the new drug to make a difference. Basically, once Seattle Genetics proved that it had a hammer for CD30, scientists suddenly started looking more aggressively for that nail. Published literature says about half of CTCL patients have tumors expressing the CD30 marker, which made it appear worth exploring, but not necessarily a slam dunk for Adcetris to show anti-tumor activity. “We spent time looking, but the literature was kind of sketchy,” Siegall says. “Before Adcetris was approved, nobody cared that much about CD30.”
Now, the race is on to find CD30 on all kinds of tumor types, and cutaneous T-cell lymphoma is just now emerging as one of the promising new uses. There are so many expansion studies underway, both company-sponsored and investigator-sponsored, that Siegall is predicting Adcetris could exceed $1 billion in peak annual sales. While the small studies done by investigators aren’t designed to generate enough proof to win FDA approval, they do enable the company to skip ahead in development and run quick, relatively low-risk clinical trials that could expand the potential market for the product.
One of these key studies came to Seattle Genetics in January, when a researcher at MD Anderson Cancer Center reported that 11 of 17 evaluable patients (65 percent) on the company’s drug had significant shrinkage of their tumors and skin lesions. Seven of the 11 responses were graded as complete remissions, meaning researchers couldn’t see any evidence of skin lesions or tumors. Adverse events were mostly mild diarrhea, chest tightness, hair loss, and numbness/tingling in the extremities.
That finding was confirmed earlier this month by a researcher at Stanford University who reported that 12 of 16 patients (75 percent) had what is considered a partial remission. None of them were graded as complete remissions, although that’s partly because of the scoring system used in the study. “If the lesion is 99.9 percent gone, it’s still hard to say that’s a complete response,” Siegall says. Side effects again were consistent with previous studies, although one patient had a severe case of nerve damage in the fingers and toes, the company said.
Even without claiming the tumors went away completely, the finding is still striking, because they were very sick patients who had gotten a median of six prior rounds of therapy. And even though they were quite sick, the partial remissions lasted at least six months for 68 percent of the patients. Side effects were consistent with other studies.
Those trials were enough for Seattle Genetics and its partner, Millennium, to go ahead and invest their own time and money in a pivotal stage study of 124 patients, which will compare brentuximab vedotin to standard chemotherapy. The main goal—agreed upon by Seattle Genetics, Millennium and U.S. regulators—will be to show the new drug offers an advantage in tumor shrinkage for at least four months.
Based on the strong early signs that the drug is working for CTCL, it’s likely that word will spread among physicians looking to enroll patients in the upcoming study, putting even a little more wind in Seattle Genetics’ sails. “We believe the Phase III will enroll quickly with data potentially in late 2013,” said analyst Jason Kantor of RBC Capital Markets, in a note to clients May 10.
While Seattle Genetics can’t legally market its drug to physicians for a use that isn’t approved by the FDA, physicians are free to prescribe a drug to any patient they think might benefit. And it’s possible that as more clinical trial data rolls in, physicians could add brentuximab vedotin to treatment guidelines for CTCL patients, even before FDA approval. If that happens, it would make it easier for doctors to secure reimbursement from insurers if they prescribe it, Siegall says.
Besides the recent studies reported by Stanford and MD Anderson researchers, I count seven more investigator-sponsored clinical trials that underway or about to get started. Investigators have decided to pursue their own ideas for how to best use brentuximab vedotin in studies at City of Hope Medical Center in Duarte, CA, Northwestern University in Evanston, IL, Memorial Sloan-Kettering Cancer Center in New York, Dana-Farber Cancer Institute in Boston, and the University of North Carolina in Chapel Hill.
Not all of these trials will pan out, of course. Researchers are running these trials precisely to find out if the drug will work. But here’s a list of the investigator-sponsored trials going on with Adcetris, which all represent some potential avenues for growth.
|Site||Investigator||Patient Population||No. of Patients to Enroll||Target Completion Date|
|City of Hope Medical Center||Robert Chen||Salvage therapy for Hodgkin’s, before stem cell transplant||37||Dec. 2014|
|Memorial Sloan-Kettering Cancer Center||Allison Moskowitz||Transplant eligible, relapsed Hodgkin’s||46||January 2014|
|UNC Lineberger Comprehensive Cancer Center||Steven Park||Chemotherapy, followed by Adcetris, in previously untreated Hodgkin’s patients||15||April 2013|
|Stanford University||Youn Kim||Cutaneous T-cell lymphoma patients with Mycosis fungoides and Sezary syndrome.||18||July 2013|
|Massachusetts General Hospital||Yi-Bin Chen||Acute graft-versus-host disease that resists steroids.||28||June 2014|
|Massachusetts General Hospital/Dana-Farber Cancer Institute||Jeremy Abramson||Limited-stage Hodgkin’s lymphoma, testing Adcetris in combination with the AVD chemotherapy combo.||28||April 2014|
|Northwestern University||Leo Gordon||Older patients with untreated Hodgkin’s lymphoma, getting a combo of Adcetris and AVD chemotherapy.||48||May 2016|
|MD Anderson Cancer Center||Madeleine Duvic||Cutaneous forms of Anaplastic Large Cell Lymphoma, Mycosis Fungoides, Extensive Lymphomatoid Papulosis.||58||June 2014|
|University of Cologne||Peter Borchmann||Advanced classical Hodgkin’s lymphoma||100||June 2013|
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