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Merrimack: Bispecific Antibody Starts Phase II Gastric Program

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By Randy Osborne
Staff Writer

While investors wait for key data from a Phase II trial with Merrimack Pharmaceuticals Inc.'s HER2 signaling inhibitor MM-121 in breast, ovarian and non-small-cell lung cancer (NSCLC), the company began a Phase II trial with its bispecific antibody, MM-111, which targets the HER2 and HER3 receptors, for advanced gastric, esophageal and gastroesophageal junction (GEJ) cancers.

"The biology seems to be somewhat similar as you move down from the gastrointestinal tract," said Ulrik Nielsen, co-founder and chief scientific officer of Merrimack, noting that the study is structured as two experiments in one. Overexpression of HER2 has been reported in 7 percent to 34 percent of stomach and esophageal cancers, helping cancer to thrive when it binds with HER3 and the protein heregulin. HER3 is linked to an especially poor prognosis in gastric cancer.

The Phase II study is testing MM-111 in two subsets of patients who overexpress HER2. The first group of patients typically would get therapy based on trastuzumab (Herceptin, Roche AG), based on their HER2 score of 2+ or 3+ on the HercepTest and/or their having a positive fluorescence in situ hybridization (FISH) status. These patients will be randomized to get either MM-111 combined with paclitaxel and trastuzumab, or the paclitaxel-and-trastuzumab duo by itself.

Merrimack is enrolling in the second set of patients, those who normally would not get HER2-targeted therapy such as trastuzumab because they have a 2+ HercepTest score with a negative FISH status for the HER2 gene, although some may show elevated HER2 levels. The subjects in this arm will be randomized to get either MM-111 combined with paclitaxel or paclitaxel alone.

"There are two reasons for [the dual structure of the Phase II study]," Nielsen said. "The first one is that we think MM-111 is going to work in [both] populations. Logistically, it's a lot easier to screen for patients. We're going to screen out half or more of the patients in the study, so the more you can include on treatment the better off you are, in terms of enrolling the trial."

The second reason involves a statistical consideration. "You can sort of borrow power across the different groups," Nielsen said. "You can run a smaller trial, and still get high-confidence data, but you're assuming that the groups fare pretty similarly, clinically, at least in the control arm."

Fox Chase Cancer Center in Philadelphia has enrolled the first patient. Up to 60 sites are expected to open in the U.S., Europe, Asia and Africa. "The simulation suggests that we will treat about 180 patients in total, across the four different groups," Nielsen said.

In May, Merrimack enrolled the final patient in its Phase II trial with MM-121 in combination with exemestane (Aromasin, Pfizer) in post-menopausal women with locally advanced or metastatic estrogen receptor-positive and/or progesterone receptor-positive, HER2-negative breast cancer. MM-121, a fully human monoclonal antibody that targets HER3, is being developed in a collaboration with Paris-based Sanofi SA. (See BioWorld Today, Oct. 2, 2009.)

"The idea there is that you now reverse their resistance to the anti-hormonal therapy" by adding MM-121 to the usual care," Nielsen said of the double-blinded, placebo-control trial, expected to report data in the second half of this year.

The arrangement with Sanofi, Merrimack's first major deal, traded rights to the monoclonal antibody for $60 million up front and a potential $470 million in milestone payments, with Merrimack retaining the right to co-promote the product in the U.S., while collecting double-digit royalties. Merrimack is handling development through Phase II proof of concept for each indication.

"We have five ongoing studies, and they're all expected to report out this fall and winter, so it's exciting times," Nielsen told BioWorld Today, adding that Merrimack is "doing a few different things."

Paclitaxel is also the combination drug, given weekly, with MM-121 in the ovarian cancer trial. "We've collected biopsies in over 200 patients in that study," Nielsen said.

Another neoadjuvant breast cancer trial with MM-121 deploys paclitaxel against triple-negative disease in one cohort, and estrogen-receptor / progesterone-receptor-positive patients in another, with both getting the same combination. "That's also a heavily biomarker-driven study," Nielsen said. "In these neoadjuvant studies, you actually treat the patients before you surgically remove the tumor, and we have biopsies both before that, during treatment, and obviously we get tumor specimens from the surgery as well."

All This and Nanoparticles, Too

Guggenheim analyst Bret Holley wrote in a May research report that he was optimistic about MM-121 in breast and ovarian cancers, based on the success of Basel, Switzerland-based Roche AG's success with Perjeta (pertuzumab). MM-121 in Phase I trials, when combined with paclitaxel, garnered a 48 percent overall response rate, and Holley was particularly upbeat about the odds for the compound in ovarian tumors. (See BioWorld Today, June 12, 2012.)

There's also a Phase II trial ongoing with MM-121 combined with Tarceva (erlotinib, Roche AG and Astellas Pharma Inc.) in non-small cell lung cancer, which shows promise, in Holley's view.

Cowen and Co. analyst Eric Schmidt, also in May, wrote that the second half of this year "promises to be a busy time" for Merrimack, with five Phase II or III readouts from MM-121 and another standout: MM-398, the irinotecan-based nanotherapeutic in trials for pancreatic and colon cancer.

MM-398 has "the very simple purpose of delivering a lot more chemotherapeutic to the tumor compared to other places," when given as a second-line therapy after the failure of gemcitabine-based regimens. The 405-patient trial's three arms include 5-FU/leucovorin alone, MM-398 alone, and MM-398 with 5-FU/leucovorin. Analyst Schmidt's consultants see a "decent chance of success" in the difficult indication, he wrote.

Nielsen said that, "historically, 5-FU/leucovorin has been combined a lot with irinotecan, which is on the interior of MM-398, and has done very well recently in pancreatic cancer as part of the FOLFIRINOX [oxaliplatin, irinotecan, fluorouracil and leucovorin] regimen. This regimen looks a little bit like that, but what we think is a much more potent, irinotecan-based ingredient."

Pancreatic tumors, he noted, "are quite dense. They have the stroma around them, with a lot of macrophages that make it hard for drugs to get into the tumor." MM-398 "loads up about 80,000 molecules of irinotecan into a nanoparticle about 100 nm in size," Nielsen said. "We deliberately designed it so it would be taken up by macrophages and we think even, in some cases, that the macrophages will traffic with that nanoparticle before they digest it, and release the active drug to the adjacent tumor cells. We're trying to take advantage of the poor structure of the pancreatic tumors that normally get in your way and use it to actually deliver the drug."

In Phase II trials (without a control arm) 25 percent of patients lived 12 month. Six-month survival totaled about 42 percent, which "compares quite favorably to existing care," he said.

Merrimack also has, at the Phase I stage, MM-302, the first-ever antibody-targeted nanoparticle. "Unlike MM-398, we have added a HER2 antibody on the outside that helps it actively get taken up by HER2-positive tumor cells," with doxorubicin on the inside, Nielsen said. "We've been studying that for some time in HER2-positive breast cancers, and we've been getting nice data that we've presented at a few conferences now."

The class could rival antibody-drug conjugates (ADCs), he said. "If you think about it, those can only carry usually about four drug molecules per antibody to the tumor. It really puts an upper cap on how much drug you can get into the tumor cell to try and kill it. In these nanoparticle-based approaches, we can in one particle have as many as 100,000 molecules of chemotherapy delivered by just, in this case, 50 antibodies. On average, [that's] tens of thousands of molecules delivered by an antibody."

A Phase II study in HER2-positive breast cancer is expected to begin early next year.

Merrimack's pipeline includes eight biologic and nanoparticle-based candidates, six of which have arrived at the clinical stage. The company recently raised $150 million in a financing, and has enough cash to operate into 2015. Merrimack's stock (NASDAQ:MACK) closed Monday at $4.81, down 2 cents.