Merrimack Pharmaceuticals President and CEO Richard Peters, M.D., Ph.D.
Merrimack Pharmaceuticals President and CEO Richard Peters, M.D., Ph.D.

Merrimack Pharmaceuticals said today it will review its entire development pipeline, including its lead candidate MM-121 (seribantumab), after the monoclonal antibody failed a Phase II trial in patients with non-small cell lung cancer—the company’s second clinical failure in four months.

MM-121 missed its primary endpoint in the Phase II SHERLOC trial (NCT02387216) by failing to improve progression-free survival (PFS) after being added to docetaxel in patients with heregulin positive NSCLC, the company said.

Merrimack did not disclose detailed data, but said it plans to present “observations” from SHERLOC at an unspecified future oncology meeting.

“The data provide a definitive signal that MM-121 does not improve clinical outcomes for patients with non-small cell lung cancer and, in line with this efficient development strategy, we plan to look closely at the data as we assess the continued development of MM-121 and evaluate our pipeline more broadly,” Merrimack president and CEO Richard Peters, M.D., Ph.D., said in a statement.

The failure of SHERLOC is Merrimack’s second clinical setback since June, when the company ceased development of its pancreatic cancer candidate MM-141  (istiratumab) following its failure in a Phase II trial.

Merrimack said it plans to provide the results of its portfolio review, and an update on its development pipeline, on November 7 when it holds its quarterly conference call with analysts to discuss third-quarter results.

The company’s pipeline includes one other clinical candidate, MM-310, a novel antibody-directed nanotherapeutic (ADN) targeting the EphA2 receptor. Merrimack is set to read out data on the solid tumor candidate by year’s end from a Phase I study (NCT03076372) that has been enrolling patients.

Also in Merrimack’s pipeline are several preclinical candidates, including: MM-161, a monoclonal antibody targeting FGFR IIIc-Isoforms; ATRI, a nanoliposome targeting ATR; TRIL, a ligand fusion targeting Death Receptor 4 and Death Receptor 5; BCL2/BCLXL, a nanoliposome targeting BCL2/BCLXL; STIMULI™, a group of multispecific TNF superfamily receptor agonists for immune stimulation; and an undisclosed immuno-oncology candidate.

“Across the board, we are encouraged by the progress we have seen from these programs, which target three distinct areas of focus: growth factor pathways, cellular proliferation and repair, and immuno-oncology,” Dr. Peters reassured analysts August 7 on Merrimack’s quarterly conference call following the release of second-quarter results, according to a transcript by Seeking Alpha.


‘Very Disappointed’

SHERLOC was a randomized, open-label study that enrolled 109 patients with NSCLC, all of whom underwent a biomarker screen for high tumor expression of heregulin, the signal for the HER3 receptor that is prevalent in solid tumors. Patients were also required to have received a prior platinum-based therapy, as well as prior immunotherapy where available and clinically indicated.

The trial’s key secondary endpoints were objective response rate (ORR), time to progression, and overall survival as key secondary endpoints. SHERLOC was launched in February 2015 and completed patient enrollment last month.

Merrimack CMO Sergio Santillana, M.D., M.Sc.
Merrimack CMO Sergio Santillana, M.D., M.Sc.

“We are very disappointed by the outcome of this study, in particular for patients and families facing this difficult diagnosis,” added Merrimack CMO Sergio Santillana, M.D., M.Sc.

MM-121 is a fully human anti-HER3 (ErbB3) monoclonal antibody designed to target phenotypically distinct heregulin positive cancers within solid tumors by blocking the HER3 pathway by preventing the signal between heregulin and the HER3 receptor.

Since heregulin-positive cancer cells are characterized by their ability to escape the effects of targeted, cytotoxic, and anti-endocrine therapies, Merrimack reasoned that identifying heregulin positive cancer cells by RNA in situ hybridization (ISH) would have detected tumors at risk for rapid clinical progression. When used in combination with chemo, MM-121 is designed to block the heregulin/HER3 signaling axis to make these cells more responsive to the effects of the combo, thus delivering improved clinical outcomes, according to the company.

MM-121 received the FDA’s orphan drug designation in November 2017 for the treatment of heregulin positive non-small cell lung cancer.

MM-121 continues to be evaluated in another Phase II trial, SHERBOC (NCT03241810), in which the candidate is being assessed in combination with fulvestrant, versus placebo and fulvestrant, in patients with heregulin positive, hormone receptor-positive, and ErbB2 (HER2) negative, post-menopausal metastatic breast cancer.

The trial’s primary endpoint is PFS, with ORR, time to progression and overall survival as key secondary endpoints.

In February, SHERBOC began enrollment of patients who had progressed after one or two lines of prior systemic therapies for metastatic or locally advanced disease and have received prior CDK inhibitor-based therapy.

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