Merrimack's GI Cancer Agents Show Promise

Merrimack Pharmaceuticals is combining biology, computing, and engineering in order to gain a comprehensive understanding of the dynamics of different types of cancer and then use that information to develop new therapeutics.

The company says its approach focuses on three biological characteristics of tumors: signaling networks that drive tumor growth; signaling adaptations that occur when tumors become resistant to treatment; and tumor micro-anatomy and micro-environment. Each of these strategies has helped Merrimack develop different biologic agents.

For example, by concentrating on signaling adaptations, the company was able to develop MM-111, a first-in-class bispecific antibody that is able to bind with both specificity and avidity to HER2- and HER3-expressing tumor cells. While the role of HER2 is well established in breast cancer, Merrimack was able to determine that HER3 is a key tumorigenic node involved in many different types of cancer, with involvment in the growth and development of cancers as well as ways in which cancer cells develop resistance to targeted therapies and chemotherapy.

Merrimack Pipeline

Agent

Indication

Description

Target

Phase

MM-121

NSCLC, breast cancer, ovarian cancer

Monoclonal antibody

ErbB3

II

MM-111

Gastric cancer (2nd line, 2 indications)

Bispecific antibody

ErbB3, ErbB2

II

MM-151

Regractory advanced solid tumors

Oligoclonal antibody

EGFR

I

MM-141

Cancer, nonspecific

Bispecific tetravalent antibody

IGF-1R, ErbB3

I

MM-131

Cancer, nonspecific

Multispecific antibody

Undisclosed

Preclinical

MM-398

Pancreatic cancer (2nd line, 2 indications), colorectal cancer, glioma

Nanotherapeutic

Encapsulated irinotecan

III

MM-302

Advanced, HER2+ breast cancer

Antibody-targeted nanotherapeutic

HER2-targeted encapsulated doxorubicin

I

MM-310

Cancer, nonspecific

Antibody-targeted nanotherapeutic

Undisclosed

Preclinical

Source: www.merrimackpharma.com

In August, MM-111 received orphan drug status from the FDA for the treatment of both esophageal cancer and gastric as well as gastroesophageal junction (GEJ) cancers. Estimates vary, but various scientific studies have found that the HER2 cell surface receptor is overexpressed in 7% to 34% of gastric cancers, and HER3 expression is associated with poor prognosis in patients with the disease and perhaps contributes to resistance to current treatment options. A phase II study to assess the efficacy of MM-111 in these tumor types is currently enrolling patients. Another product of Merrimack’s research approach is MM-398, which was developed using the company’s investigations into the micro-anatomy of a tumor, with a focus on how the vasculature, immune system, extracellular factors, and interaction with noncancer cells and neighboring tissues can affect the development of the tumor. MM-398 is a nanotherapeutic that delivers the chemotherapy drug irinotecan via encapsulation in a liposomal sphere. The natural blood flow of the tumor directs the drug to the site of the tumor to minimize exposure of the drug to noncancer cells.

The results of a phase II study of MM-398 in pancreatic cancer were published in August in the British Journal of Cancer. The study met its primary endpoint with 75% of patients surviving at least 3 months, with 25% of patients in the study surviving for at least one year. The median overall survival was 5.2 months, and 50% of patients showed evidence of disease control. A global, randomized, open-label phase III trial called NAPOLI-1 is assessing MM-398 with or without 5-FU and leucovorin versus the control arm of 5-FU and leucovorin in patients with metastatic pancreatic cancer after gemcitabine failure. Enrollment is expected to be completed later this year.

Overall, a total of eight different therapeutic agents are in various stages of development at Merrimack, and while many are in early stages, some of these drugs are being considered for specific tumor types, including non-small cell lung cancer, breast cancer, and colorectal cancer, in addition to the aforementioned tumor types.