Macrogenics Inc. is taking a further step into Asia as it joins with I-Mab Biopharma (Shanghai) Co. Ltd. in a collaboration and license agreement to develop and commercialize enoblituzumab, an immune-optimized, anti-B7-H3 monoclonal antibody.

Macrogenics receives $15 million up front, with development and regulatory milestone payments of up to $135 million. I-Mab will pay tiered, double-digit royalties ranging from the midteens to 20% based on annual net sales. I-Mab receives regional development and commercialization rights in mainland China, Hong Kong, Macau and Taiwan.

Last November, Macrogenics entered a collaboration and license agreement with Shanghai-based Zai Lab Ltd. involving its immuno-oncology programs for margetuximab, an immune-optimized anti-HER2 monoclonal antibody currently being evaluated in a phase III metastatic breast cancer trial; MGD-013, a bispecific molecule designed to provide coordinate blockade of PD-1 and LAG-3 for the potential treatment of a range of solid tumors and hematological malignancies; and an undisclosed multispecific molecule in preclinical development. Macrogenics received $25 million up front and may receive up to $140 million in potential development and regulatory-based milestone payments in that deal. In addition, Zai will pay Macrogenics double-digit royalties on annual net sales of the assets.

The I-Mab deal didn't help the stock as Macrogenics (NASDAQ:MGNX) closed down 1.86% on Thursday. In early February, the shares got a massive boost from positive results of the phase III Sophia study of margetuximab in HER2-positive metastatic breast cancer patients.

Rockville, Md.-based Macrogenics CEO Scott Koenig told BioWorld the search that resulted in the I-Mab collaboration was competitive, and Macrogenics chose I-Mab because it was committed to building a portfolio of biologics with a focus in immune-oncology.

"They bring complementary development resources for the China market and have a track record of rapidly progressing development projects in their territory," he added. "They are also well-capitalized and successfully raised approximately $370 million in the past three years."

For the Macrogenics deal, I-Mab plans to lead regional studies in its territories and participate in global studies conducted by Macrogenics. Macrogenics plans to begin a phase II study of enoblituzumab in combination with MGA-012 (also known as INCMGA-0012), an investigational anti-PD-1 antibody that Macrogenics licensed to Incyte Corp., in patients with squamous cell carcinoma of the head and neck in the second half of 2019.

I-Mab focuses on immuno-oncology and immuno-inflammation. Its pipeline includes three molecules that the company expects to reach clinical development in the U.S. by the end of this year. In April, it entered a collaboration with Roche Holding AG, of Basel, Switzerland, to evaluate its CD73 antagonist, TJD-5, in combination with Tecentriq (atezolizumab). Roche will supply atezolizumab for use in the clinical study, with rights to data generated in the study belonging jointly to the companies.

Late last December, I-Mab out-licensed China rights to its GLP-1 Fc protein, known as TG-103, to treat diabetes to CSPC Pharmaceutical Group Co. Ltd. for ¥150 million (US$21.7 million). As part of the deal, CSPC paid ¥15 million up front to I-Mab to obtain the exclusive license and will pay another ¥135 million based on the development progress of TG-103 in China as well as royalties. Under the terms, CSPC will be granted the exclusive rights for the development and commercialization of TG-103 for all indications in China, and I-Mab will provide the necessary technical support. (See BioWorld, Dec. 26, 2018.)

Early data positive

Enoblituzumab is an investigational Fc-optimized monoclonal antibody (MAb) that targets B7-H3, a member of the B7 family of immune regulator proteins. B7-H3 is widely expressed by a number of different tumor types and may play a key role in regulating the immune response to various types of cancer. There is no currently approved agent targeting B7-H3.

Spurring on Macrogenics' phase II were positive data from its phase I open-label, dose-escalation study of enoblituzumab in combination with Keytruda (pembrolizumab, Merck & Co. Inc.), an anti-PD-1 MAb, in patients with select solid tumors. The study is an evaluation of the safety of the combination when administered to patients with B7-H3-expressing melanoma, squamous cell carcinoma of the head and neck (SCCHN), non-small-cell lung cancer (NSCLC) and urothelial cancer. The study also evaluated potential antitumor activity, pharmacokinetics and pharmacodynamics of the combination. A total of 133 patients were treated in the study and the data cut-off date was Oct. 12, 2018.

The combination of enoblituzumab and pembrolizumab demonstrated acceptable tolerability in patients treated to date, with any adverse event of grade 3 or above occurring in 27.1% of patients. The rate of immune-related adverse events experienced in the study was comparable to that observed in patients who receive anti-PD-1 as monotherapy.

In the SCCHN dose-expansion cohort, of the response-evaluable patients who had not previously received anti-PD-1 or anti-PD-L1 therapy, six of 18 (33.3%) had confirmed partial responses (PRs). For the subset of patients with B7-H3 tumor expression of 10% or greater, six of 15 (40%) had confirmed PRs. Objective response rates ranging from 13% to 16% have previously been reported in SCCHN patients treated with anti-PD-1 alone.

In the NSCLC dose-expansion cohort, of the response-evaluable patients who had not previously received anti-PD-1 or anti-PD-L1 therapy and who were PD-L1-negative (i.e., PD-L1<1%), five of 14 (35.7%) had confirmed PRs. Objective response rates ranging from 8% to 17% have previously been reported in PD-L1-negative NSCLC patients treated with anti-PD-1 alone.

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