On April 16, 2018 Only a couple weeks after Takeda Pharmaceuticals reported it was interested in buying Shire, Shire sells its oncology business to France’s Servier for $2.4 billion (Press release, BioSpace, APR 16, 2018, View Source [SID1234525333]).

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It’s possible the sale will make Shire less desirable for Takeda, since Shire’s oncology business was part of the rationale for buying the company. It’s also possible it will make it more desirable by dropping the price slightly. Reuters notes, "The [Servier} deal suggests there is value locked up within Shire’s portfolio—despite a dismal share price performance in the past two years—as its management braces for a possible $50-billion bid battle with Japan’s biggest drugmaker."

Shire has suggested the proceeds from the sale may be returned to shareholders via a buyback. It also indicated that further sales of non-strategic assets were a possibility.
Shire is making it clear that is began looking to sell its oncology business in December and began the sale process in January. In other words, they want it understood that they didn’t quickly sell off the cancer unit to fend off an unwanted Takeda acquisition.

Under UK acquisition laws, Takeda has until April 25 to announce an official bid. The market value of Shire is about $47 billion. Reuters writes, "Buying Shire would be transformational for Takeda but would be a huge financial stretch, since the company is worth around $10 billion more than the Japanese group. Shire also had debt of around $19 billion as of the end of 2017."

Shire’s oncology business includes products such as Oncaspar (pegaspargase), part of a multi-agent treatment for acute lymphoblastic leukemia (ALL) and ex-U.S. rights to Onivyde (irinotecan pegylated liposomal formulation), part of a multi-agent treatment for metastatic pancreatic cancer after gemcitabine-based therapy, and Calaspargase Pegol (Cal-PEG), which is currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of ALL and early stage immuno-oncology pipeline collaborations.

"This transaction is a key milestone for Shire, demonstrating the clear value embedded in our portfolio," said Flemming Ornskov, Shire’s chief executive officer, in a statement. "While the Oncology business has delivered high growth and profitability, we have concluded that it is not core to Shire’s longer-term strategy. We will continue to evaluate our portfolio for opportunities to unlock further value and sharpen our focus on rare disease leadership with selective disposals of non-strategic assets."
Last year the Oncology business created revenues of $262 million.

If Takeda does make an official bid for Shire, this sale might make it slightly more affordable. Last year Takeda acquired Ariad Pharmaceuticals for $4.7 billion. "Shire’s decision to buy back shares may also indicate a positive view of the bid, since increasing shareholder returns would make it easier to get approval for a deal, Kazuyoshi Saito, a senior analyst for Iwai Cosmo Securities Co." told Bloomberg in a phone interview. "I have an impression that Takeda and Shire are heading in the same direction," Saito said.

Meanwhile, buying Shire’s oncology business bolster’s Servier’s presence in oncology. Olivier Laureau, Servier Group President, said in a statement, "The acquisition of Shire’s oncology franchise enables Servier to meet its strategic ambitions to become a global key player in oncology. As an essential step in the evolution of the Group, this acquisition allows us to establish a direct commercial presence in the United States, the world’s leading pharmaceuticals market, and to strengthen our portfolio of marketed products in the territories where Servier is already present. Our goal is to bring these treatments to greater numbers of cancer patients around the world. We thoroughly look forward to welcoming Shire’s oncology teams who will join Servier after the closing."

On April 16, 2018 Humanigen, Inc. (OTCQB: HGEN), a biopharmaceutical company pursuing cutting-edge science to develop its proprietary monoclonal antibodies for immunotherapy and oncology treatments, reported it has signed an agreement with The University of Texas MD Anderson Cancer Center to begin investigator-led research on lenzilumab and its potential to support chimeric antigen receptor T cell (CAR-T) therapy (Press release, Humanigen, APR 16, 2018, View Source [SID1234525348]). Lenzilumab is a first-in-class Humaneered recombinant monoclonal antibody that targets and is an antagonist of soluble granulocyte-macrophage colony-stimulating factor (GM-CSF).

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Preclinical work assessing lenzilumab’s action on one of the mechanisms in the inflammatory cascade induced by CAR-T will proceed in parallel with a planned study that could potentially qualify as a registration study, testing lenzilumab as a potential prophylaxis for neurotoxicity induced by CAR-T therapy. Neutralization of circulating GM-CSF has the potential to blunt or prevent an inflammatory cascade that can result in serious and life-threatening CAR-T-induced side effects – neurotoxicity and Cytokine Release Syndrome.

"With this agreement, we are excited that the team at MD Anderson Cancer Center is beginning to investigate lenzilumab’s potential to make groundbreaking CAR-T therapy safer, better and more routine," said Cameron Durrant, M.D., chairman and chief executive officer of Humanigen. "CAR-T science has moved quickly in the past few years with the two currently marketed CAR-T therapies having been approved based on single Phase 1/2 studies. We look forward to adding to the burgeoning, cutting-edge science studying lenzilumab as a potential critical CAR-T support therapy."

The preclinical study will measure the ability of lenzilumab to block patient CD19-CAR-T cells-treatment-derived GM-CSF induction of human leukocyte antigen-DR (HLA-DR) expression on CD14+ monocytes. It will assess the inhibitory effect of lenzilumab on GM-CSF-induced HLA-DR expression on CD14+ cells, plus other phenotypic and functional monocyte assays.

About Lenzilumab

Lenzilumab is a first-in-class, novel Humaneered recombinant monoclonal antibody designed to target and neutralize circulating granulocyte-macrophage colony-stimulating factor (GM-CSF), the myeloid inflammation factor involved in the recruitment of myeloid cells to a tumor and a central actor in leukocyte differentiation, autoimmunity and inflammation. There is also extensive evidence linking GM-CSF expression to serious and potentially life-threatening side effects in chimeric antigen receptor T-cell (CAR-T) therapy, such as neurotoxicity and Cytokine Release Syndrome (CRS). Humanigen is working with leading CAR-T experts to develop lenzilumab as a potential prophylactic treatment to minimize neurotoxicity associated with CAR-T cancer therapy. In addition, lenzilumab is currently being evaluated as a potential treatment for rare leukemias in a phase 1 trial (NCT02546284) in patients with chronic myelomonocytic leukemia (CMML) with additional potential in juvenile myelomonocytic leukemia (JMML), a rare pediatric cancer. In previous clinical trials, lenzilumab has shown to be safe and well-tolerated in more than 100 patients, including those with rheumatoid arthritis, asthma and healthy volunteers. It is a potent inhibitor of GM-CSF in vivo.

On April 16, 2018 Bristol-Myers Squibb Company (NYSE: BMY) reported two-year overall survival (OS) data from CheckMate -141, a Phase 3 open-label, randomized trial evaluating Opdivo (nivolumab) compared with investigator’s choice chemotherapy (cetuximab, docetaxel or methotrexate) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) after failure on platinum-based therapy (Press release, Bristol-Myers Squibb, APR 16, 2018, View Source [SID1234525334]). Patients treated with Opdivo experienced a 32% reduction in the risk of death after a minimum two years of follow-up (HR 0.68; 95% CI: 0.54 to 0.86), with a median OS of 7.7 months (95% CI: 5.7 to 8.8) compared with 5.1 months (95% CI: 4.0 to 6.2) for standard chemotherapy. The two-year survival rate for Opdivo was 16.9% (95% CI: 12.4 to 22.0) versus 6.0% (95% CI: 2.7 to 11.3) for standard chemotherapy. The safety profile for Opdivo at two-year follow-up was consistent with previous analyses from the study.

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These data will be presented today as an oral presentation (Abstract #CT116) at 4:35 PM CDT, N Hall C (Level 1) during the Updates in Immuno-Oncology Trials session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago.

"The introduction of Immuno-Oncology has the potential to change the treatment landscape of squamous cell carcinoma of the head and neck, compared with the standard of care," said Robert L. Ferris, M.D., Ph.D., a cancer immunotherapist and Director, UPMC Hillman Cancer Center, Pittsburgh, PA. "The sustained overall survival benefit demonstrated by nivolumab in this study is encouraging in SCCHN, which historically has a median survival of less than six months."

The sustained Opdivo OS benefit was observed across PD-L1 expressors and non-expressors in patients with recurrent or metastatic SCCHN. At the two-year follow-up in patients treated with Opdivo whose tumors had PD-L1 expression ≥ 1%, risk of death was reduced by 45% (HR 0.55; 95% CI: 0.39 to 0.78). For patients treated with Opdivo whose tumors had PD-L1 expression <1%, risk of death at two years was reduced by 27% (HR 0.73; 95% CI: 0.49 to 1.09) versus standard chemotherapy.

"Opdivo is the only I-O treatment for squamous cell carcinoma of the head and neck to have shown a significant overall survival benefit versus chemotherapy at the primary analysis. These two-year follow-up data show a sustained long-term overall survival benefit for patients, across PD-L1 expression levels and regardless of HPV status," said Shinta Cheng, M.D., Ph.D., development lead, Bristol-Myers Squibb. "These data showing the durability of this benefit reinforce our ongoing commitment to continuing research with the hope of delivering what matters most to patients fighting cancer: long-term survival."

There were no statistically significant differences between the two arms for PFS (HR 0.87; 95% CI: 0.68 to 1.11) for Opdivo and investigator’s choice, respectively. The safety profile of Opdivo with a two-year follow-up was consistent with previous analyses and with prior studies of Opdivo in patients with melanoma and non-small cell lung cancer. Grade 3-4 treatment-related adverse reactions occurred in 15.3% of patients receiving Opdivo versus 36.9% of patients receiving investigator’s choice.

About CheckMate -141 (Abstract #CT116)
CheckMate -141 is a global phase 3, open-label, randomized trial evaluating Opdivo versus investigator’s choice chemotherapy in patients with recurrent or metastatic SCCHN who had tumor progression during or within six months of receiving platinum-based therapy administered in the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. Patients were included regardless of their HPV or PD-L1 status. Patients were randomized 2:1 to receive Opdivo 3 mg/kg intravenously over 60 minutes every two weeks (n=240), or investigator’s choice (n=121) of methotrexate 40 to 60 mg/m2 intravenously weekly, docetaxel 30 to 40 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly. The primary endpoint is OS. The trial’s secondary endpoints include progression-free survival (PFS) and objective response rate (ORR).

About Head & Neck Cancer
Cancers that are known as head and neck cancers usually begin in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth, the nose and the throat. Head and neck cancer is the seventh most common cancer globally, with an estimated 400,000 to 600,000 new cases per year and 223,000 to 300,000 deaths per year. The five-year survival rate is reported as less than 4% for metastatic Stage IV disease. Squamous cell carcinoma of the head and neck (SCCHN) accounts for approximately 90% of all head and neck cancers, with global incidence expected to increase by 17% between 2012 and 2022. Risk factors for SCCHN include tobacco and alcohol consumption. The human papillomavirus (HPV) infection is also a risk factor leading to rapid increase in oropharyngeal SCCHN in Europe and North America. Quality of life is often impacted for SCCHN patients, as physiological function (breathing, swallowing, eating, drinking), personal characteristics (appearance, speaking, voice), sensory function (smell and hearing), and psychological/social function can be affected.

On April 16, 2018 Leap Therapeutics, Inc. (NASDAQ:LPTX) reported that presented nonclinical and clinical data on DKN-01, Leap’s anti-DKK1 monoclonal antibody, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting (Press release, Leap Therapeutics, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342693 [SID1234525349]). The presentation highlighted the immunomodulatory activity of DKN-01 in nonclinical experiments and preliminary results from the dose escalation phase of the clinical study evaluating DKN-01 in combination with the Merck (known as MSD outside the United States and Canada) anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in patients with advanced esophagogastric cancer.

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Nonclinical Data:
Nonclinical studies demonstrated the activity of DKK1 inhibition in enhancing innate immunity and the potential for combination with immune checkpoint inhibitors. mDKN-01, the murine form of DKN-01, reduced myeloid-derived suppressor cells (MDSCs), increased PD-L1 levels on MDSCs, and enhanced expression of T-cell chemoattractants. These innate mechanisms, promoting an inflammatory tumor microenvironment, are complementary to immune checkpoint inhibition. In a syngeneic tumor model, mDKN-01 had additive activity with anti-PD-1 therapy as compared to either antibody administered alone.

Clinical Data:
Preliminary results from the dose escalation phase of the clinical study evaluating the combination of DKN-01 and KEYTRUDA in patients with advanced esophagogastric cancer demonstrated that the combination was well tolerated with early signals of clinical activity:
Four out of five patients enrolled at the highest tested dose of DKN-01 were naïve to anti-PD-1/PD-L1 therapy and evaluable for response. One patient had a partial response with a 66% reduction in target tumor volume. This patient had progressed on two prior systemic therapies and had a tumor that was known to be KRAS amplified, microsatellite stable (MSS), and PD-L1 negative; a phenotype typically less responsive to anti-PD-1 therapy. Three patients had stable disease, two of whom remain on study through at least four cycles.

Two patients enrolled in the escalation phase were refractory to anti-PD-1/PD-L1 therapy and currently have had a best response of stable disease. One of these patients also had a tumor that was KRAS amplified, MSS, and PD-L1 negative and has been on study for six cycles with an initial 10% reduction in tumor burden.
The DKN-01 and KEYTRUDA expansion combination continues to enroll patients who are naïve to anti-PD-1/PD-L1 therapy (n=40) and patients who are refractory to anti-PD-1/PD-L1 therapy (n=15).

On April 16, 2018 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported that the Company’s randomized, Phase 2b METRIC Study of glembatumumab vedotin compared to Xeloda (capecitabine) in patients with metastatic triple-negative breast cancers that overexpress gpNMB failed to meet its primary endpoint, progression-free survival (PFS) as assessed by an independent, central reading of patient scans (Hazard ratio = 0.95; median PFS: glembatumumab vedotin 2.9 months vs. Xeloda 2.8 months; p=0.76) (Press release, Celldex Therapeutics,APR 16, 2018, View Source [SID1234525681]). There was no significant advantage for glembatumumab vedotin in key secondary endpoints, including overall response rate, duration of response and overall survival. The glembatumumab vedotin safety profile was consistent with prior experience.

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"Triple-negative breast cancer is a very difficult disease to treat, and we are extremely disappointed for patients that the METRIC Study was not successful," said Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics. "On behalf of Celldex, I want to express our gratitude to the METRIC investigators, patients and families who participated in this study. Based on these results, we have also made the decision to discontinue the glembatumumab vedotin program across all indications and are currently prioritizing our pipeline, which includes five candidates in ongoing clinical studies. In line with this, we are evaluating our operational and workforce needs to extend our financial resources and direct them to continued pipeline advancement. Once we solidify these plans, we intend to update investors."

Celldex’s clinical-stage pipeline includes the following compounds:

Varlilumab, a CD27 agonist, currently completing a Phase 2 study in combination with Opdivo in multiple indications with data expected to be presented at multiple medical meetings in 2018;
CDX-3379, an ErbB3 inhibitor, which is expected to complete enrollment in the first stage of a Phase 2 study in combination with Erbitux in head and neck cancer during the third quarter of 2018;
CDX-014, a TIM-1 targeted agent, which is actively enrolling patients in a Phase 1 study in renal cell and ovarian clear cell carcinomas;
CDX-1140, a CD40 agonist, which is actively enrolling patients in a Phase 1 study in various solid tumors; and,
CDX-301, a dendritic cell mobilizer, currently being studied in an investigator-sponsored study in combination with radiation therapy in advanced non-small cell lung cancer. Data from this study were presented in a plenary session at the AACR (Free AACR Whitepaper) Annual Meeting on Sunday, April 15, 2018.
Celldex believes its pipeline prioritization and organizational restructuring efforts will extend financial resources beyond the guidance issued in the Company’s year-end 2017 earnings press release and associated filings. The Company plans to provide revised guidance in its first quarter 2018 financial results in early May.

Webcast and Conference Call
Celldex executives will host a conference call at 8:00 a.m. ET today to discuss topline METRIC results. The conference call will be webcast live over the internet and can be accessed by going to the "Events & Presentations" page under the "Investors & Media" section of the Celldex Therapeutics website at www.celldex.com. The call can also be accessed by dialing (866) 743-9666 (within the United States) or (760) 298-5103 (outside the United States). The passcode is 7786951.

A replay of the call will be available approximately two hours after the live call concludes through April 23, 2018. To access the replay, dial (855) 859-2056 (within the United States) or (404) 537-3406 (outside the United States). The passcode is 7786951. The webcast will also be archived on the Company’s website.

About METRIC
The METRIC study is a randomized Phase 2b study of glembatumumab vedotin in patients with metastatic triple-negative breast cancers that overexpress gpNMB. In this indication, overexpression is defined as greater than or equal to 25% of tumor cells testing positive for gpNMB. Patients were randomized 2 to 1 to either glembatumumab vedotin or to capecitabine, also known by the tradename Xeloda, as a comparator. In total, 327 patients were enrolled into METRIC. The primary endpoint of the study is progression-free survival (PFS), which is defined as the time from randomization to the earlier of disease progression, assessed based on an independent, central reading of patient scans, or death due to any cause. The study called for 203 progression events for evaluation of the primary endpoint. The sum of the data, including the secondary endpoints of response rate, overall survival, duration of response and safety, are also important in assessing clinical benefit.

About Glembatumumab Vedotin
Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect.

Xeloda is a registered trademark of Genentech, Inc. Opdivo is a registered trademark of Bristol-Myers Squibb. Erbitux is a registered trademark of Eli Lilly & Co.