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March 26, 2018

Top 10 Immuno-Oncology Collaborations

Companies Partner Up as New Therapies Blossom Into Blockbusters

Top 10 Immuno-Oncology Collaborations

The total value of all 10 ranked collaborations is approximately $34.513 billion, a nearly 32% jump from the combined total of last year’s top 10 immuno-oncology collaborations. [Martin Barraud/Getty Images]

  • Many of the best-selling drugs marketed in recent years have been cancer immunotherapies. Celgene’s immunomodulatory treatment Revlimid® (lenalidomide) finished last year as the third best-selling prescription drug with $8.187 billion in sales, while Bristol-Myers Squibb racked up $4.948 billion from Opdivo® (nivolumab) and another $1.244 billion from Yervoy® (ipililumab). Merck & Co. generated $3.809 billion from Keytruda® (pembrolizumab), more than doubling its 2016 sales thanks to a series of new indications.

    Those cancer immunotherapies commanded close to a combined $20 billion-plus in sales last year as they blossomed into mature billion-dollar-sales-plus “blockbuster” drugs. Roche/Genentech’s Tecentriq® (atezolizumab) is halfway to blockbuster status with CHF 487 million ($510 million) in 2017 sales. So, it’s little surprise that biopharmas are eager to at least replicate and ultimately surpass those results by forging ahead with partnerships to develop new immuno-oncology treatments, as well as add sales to existing ones through new indications.

    Below is GEN’s updated list of the top 10 immuno-oncology collaborations, ranked by dollar value as disclosed by the companies in regulatory filings, press announcements, and other public statements. Each collaboration is listed by partner names, value, and date announced, followed by a summary and updates provided by the companies since their launch announcements.

    The total value of all 10 ranked collaborations is approximately $34.513 billion, a nearly 32% jump from the $26.233 billion combined total of the 10 deals that made up last year’s GEN list of Top 10 Immuno-Oncology Collaborations, a reflection of just how much importance biopharmas are placing in cancer immunotherapies. So too is the fact that two of the top three collaborations on this list were launched this year—not to mention the escalating amount of upfront dollars in the top 10 deals: That number has zoomed 59% from the $2.743 billion paid at the outset of last year’s top 10 deals, to $4.368 billion for this year’s top 10 immuno-oncology collaborations. Indeed, all 10 deals on this year’s list are valued at $2 billion or more—compared with 6 of last year’s top 10.

    Another reflection of the rising value of partnerships: While last year’s No. 10 collaboration was worth up to $1.242 billion, this year’s No. 10 partnership was worth potentially 21% more, up to $1.5 billion. This year’s list also shows a shift in immuno-oncology from the creation and announcement of billion-dollar partnerships, to more clinical activity within those alliances.

    Collaborations that combine immuno-oncology and other areas are only ranked based on the immuno-oncology portion of the deals—a situation that applies to just one deal on this list.

  • #10. Servier and Pieris

    Value: Up to €1.7 billion ($2.1 billion) for Pieris, including €30 million ($37 million) upfront

    Date announced: January 5, 2017

    Summary: Servier agreed to partner with Pieris to co-develop Pieris’ PRS-332 and up to seven other immuno-oncology bispecific drug candidates. Companies agreed to initially pursue five bispecific therapeutic programs. These are led by the preclinical bispecific checkpoint inhibitor PRS-332, a programmed cell death protein 1 (PD-1)-targeting therapy consisting of an anti-PD-1 antibody genetically fused to a Pieris Anticalin® protein targeting an undisclosed checkpoint target co-expressed on exhausted T cells. Also included are four immuno-oncology bispecific drug candidates that may combine antibodies from the Servier portfolio with one or more of Pieris’ Anticalin proteins.

    Pieris retains all U.S. commercial rights, with Servier having commercial rights elsewhere in the world. Servier and Pieris also agreed to allow for expansion of their collaboration by up to three additional therapeutic programs.

    Updates: In its Form 10-K Annual Report for 2017, filed March 15, Pieris included among key elements of its strategy “Advancing PRS-332 to development candidate nomination and initiate IND-enabling activities,” adding that PRS-332 “is currently undergoing preclinical evaluation together with Servier.” The four other immuno-oncology bispecific drug candidates have been defined and are in preclinical phases, Pieris said.

  • #9. Sanofi and Regeneron

    Value: Up to $2.17 billion for Regeneron, including $640 million upfront

    Date announced: July 28, 2015

    Summary: Sanofi and Regeneron agreed to jointly develop REGN2810 [since renamed cemiplimab], a programmed cell death protein 1 (PD-1) inhibitor then in Phase I, and launch clinical trials in 2016 with new therapeutic candidates based on ongoing preclinical programs. The partners committed to spend $325 million each toward developing cemiplimab.

    Updates: Regeneron said February 8 it expects during the first quarter to complete a rolling BLA submission to the FDA seeking authorization of cemiplimab—with the company also anticipating a decision by the agency on that application. In December 2017, Regeneron and Sanofi announced positive top-line results from the pivotal Phase II EMPOWER-CSCC trial assessing cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), saying that the treatment demonstrated an overall response rate of 46.3%. Also in December, Regeneron and ISA Pharmaceuticals said they will jointly fund and conduct clinical trials assessing cemiplimab in combination with ISA’s ISA101, an immunotherapy targeting human papillomavirus type 16 (HPV16)-induced cancer, in patients with cervical cancer and head-and-neck cancer. The value of that collaboration has not been disclosed.

    In September 2017, cemiplimab received the FDA’s Breakthrough Therapy designation for the treatment of adults with metastatic CSCC and adults with locally advanced and unresectable CSCC. Also last year, Phase III studies were launched to evaluate cemiplimab in non-small cell lung cancer (NSCLC) and in cervical cancer, a potentially pivotal Phase II study in basal cell carcinoma was initiated, and Regeneron launched collaborations of undisclosed values with Inovio Pharmaceuticals and SillaJen. Regeneron and Inovio will study combinations of cemiplimab with Inovio’s INO-5401 T-cell activating immunotherapy encoding multiple antigens and INO-9012, an immune activator encoding IL-12, in patients with newly diagnosed glioblastoma multiforme. Regeneron and SillaGen will assess cemiplimab with SillaGen’s oncolytic vaccinia virus Pexa-Vec in patients with previously treated metastatic or unresectable renal cell carcinoma.

  • #8. Novartis and Xencor

    Value: Up to $2.56 billion-plus, including $150 million upfront

    Date announced: June 28, 2016

    Summary: Novartis agreed to co-develop two Xencor T-cell-engaging XmAb bispecific antibodies, XmAb®14045 for acute myeloid leukemia (AML) and XmAb®13676 for B-cell malignancies.  The companies agreed to share costs for the worldwide development of both candidates, with Xencor maintaining U.S. commercialization rights and Novartis having ex-U.S. commercialization rights.

    Novartis also received worldwide rights to develop and commercialize additional proprietary bispecific molecules against up to four proprietary target pairs selected by Novartis, if available for non-exclusive license and not subject to a Xencor internal program. For each of the four, Novartis agreed to pay Xencor up to $250 million in development, regulatory, and sales milestone payments. Novartis additionally gained a worldwide nonexclusive license to use Xencor's XmAb Fc technologies—specifically Cytotoxic, Xtend, and Immune Inhibitor Fc domains—to research, develop, commercialize, and manufacture antibodies against up to 10 targets, also if available for non-exclusive license and not subject to a Xencor internal program. For each of the 10, Novartis agreed to pay Xencor up to $76 million in development, regulatory, and sales milestones.

    Xencor is also eligible to receive tiered, low-double-digit royalties for sales of XmAb14045 and XmAb13676 outside the U.S., and mid-single-digit tiered royalties for worldwide sales of the four bispecific molecules—unless Xencor opts in on development of one of these molecules and share in the costs and U.S. profit—as well as low-single-digit royalties on global sales of XmAb Fc molecules.

    Updates: XmAb14045 is in a Phase I open-label, multiple-dose, dose escalation study to assess safety, tolerability, and preliminary antitumor activity in AML. Initial data is expected this year, “pending alignment with Novartis on timing of disclosure,” Xencor stated in its Form 10-K Annual Report for 2017, filed February 28. According to that filing, XmAb13676 is in a Phase I, open-label, multiple-dose, dose escalation study to assess safety, tolerability, and preliminary antitumor activity in B-cell malignancies, with initial data expected in 2018 or 2019, also pending agreement with Novartis on timing.

    Xencor also disclosed that in 2017, it completed delivery of one bispecific antibody candidate for development through a global discovery program.

  • #7. Celgene and Jounce Therapeutics

    Value: Up to $2.6 billion-plus for Jounce, including $225 million upfront, and a $36 million equity investment by Celgene

    Date announced: July 19, 2016

    Summary: Celgene received options to develop and commercialize jointly cancer immunotherapies that include Jounce’s lead candidate JTX-2011, a monoclonal antibody targeting ICOS (the Inducible T cell CO-Stimulator), and other cancer immunotherapies. Celgene gained options from Jounce for up to four of its early-stage programs to be selected from a defined pool of B cell-, regulatory T cell-, and tumor-associated macrophage targets emerging from the Jounce Translational Science Platform; and an additional option to share JTX-4014, Jounce’s PD-1 product candidate, equally with Jounce. The collaboration agreement has an initial term of four years, which may be extended up to three additional years.

    Updates: JTX-2011 last year entered the Phase II portions of the Phase I/II ICONIC trial, assessing JTX-2011 as monotherapy and in combination with Bristol-Myers Squibb’s Opdivo® (nivolumab) in multiple solid tumors. Preliminary efficacy data is expected to be reported in the second quarter. Two Phase II combination-therapy cohorts, gastric cancer and triple negative breast cancer, have met the target enrollment with completion of at least one efficacy assessment. Preliminary efficacy data in these tumor types for have been submitted as an abstract for the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Jounce said March 8.

    Also this year, a new combination study assessing JTX-2011 and a CTLA-4 inhibitor program is expected to be launched within ICONIC. Additionally, Jounce plans to file an IND application, in 2018 for JTX-4014, its internal anti-PD-1 antibody.

  • #6. Merck KGaA and Pfizer

    Value: Up to $2.85 billion for Merck KGaA, including $895 million upfront

    Date announced: November 17, 2014

    Summary: Merck KGaA agreed to jointly develop and commercialize its PD-L1 checkpoint inhibitor  MSB0010718C [since renamed Bavencio® (avelumab) and also known as PF-06834635] with Pfizer, both as a single agent and in various combinations with the companies’ oncology therapies.

    Updates: On February 15, Merck KGaA and Pfizer acknowledged that Bavencio failed the Phase III JAVELIN Lung 200 trial comparing avelumab to docetaxel in patients with unresectable, recurrent, or metastatic non-small cell lung cancer (NSCLC) whose disease progressed after treatment with a platinum-containing doublet therapy. Bavencio missed its primary endpoint of improving overall survival in patients with programmed death ligand-1-positive (PD-L1+) (1% or higher) tumors, though a higher proportion of chemotherapy patients crossed over to immune checkpoint inhibitors outside the study than previously reported in post-platinum immunotherapy clinical trials, which the companies say may have confounded this trial outcome.

    Last year, Bavencio won accelerated approval from the FDA in two indications. Those indications were advanced or metastatic urothelial cancer (mUC; granted May 9, 2017) and intravenous use, for adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC; granted March 23, 2017)—the first treatment approved for the rare, aggressive form of skin cancer. MCC approval has also been granted by the European Union (on September 21, 2017), as well as by Japan, Switzerland, and most recently Canada (on February 22). In December 2017, the FDA granted its Breakthrough Therapy designation for Bavencio in combination with Pfizer’s Inlyta® (axitinib) for treatment-naïve patients with advanced renal cell carcinoma.

    In its Form 10-K Annual Report for 2017, Pfizer disclosed that as of December 31, 2017, it made $140 million in milestone payments to Merck KGaA for approvals of avelumab received in 2017 for MCC in the U.S., the E.U., and Japan; and for mUC in the U.S.

  • #5. Pfizer, Cellectis, and Servier

    Value: Up to $2.885 billion for Cellectis, including $80 million upfront

    Date announced: June 18, 2014

    Summary: Pfizer and Cellectis agreed to develop Chimeric Antigen Receptor T-cell (CAR-T) cancer immunotherapies directed at select targets using the French biotech’s CAR-T platform technology. Pfizer has exclusive rights to develop and commercialize CAR-T cancer therapies directed at a total of 15 targets of its choosing. Both companies agreed to work together on preclinical research for four of 12 additional targets to be selected by Cellectis, with Pfizer having the right of first refusal to the four. In return, Pfizer agreed to fund R&D costs for the 15 targets, and a portion of R&D costs associated with four other Cellectis-selected targets. Cellectis is eligible for payments tied to achieving development, regulatory, and commercial milestone payments of up to $185 million per product resulting from the Pfizer-selected targets, and tiered royalties on net sales of any products commercialized by Pfizer.

    In November 2015, Servier acquired exclusive rights from Cellectis for UCART19, for up to $338 million-plus. Servier then granted exclusive rights to Pfizer to develop and commercialize UCART19 in the U.S.—in a deal whose value has not been disclosed—while retaining rights elsewhere in the world.

    Updates: On March 8, the companies said they will present results from the two Phase I trials with UCART19 during the European society for Blood and Marrow Transplantation (EBMT) Annual Meeting, to be held March 18–21 in Lisbon, Portugal.

    According to abstracts available online, in one study in adults with relapsed/refractory (r/r) B-ALL, UCART19 showed an acceptable safety profile and promising results with 5 of 7 patients achieving molecular remission and proceeding to a second stem cell transplant. In the second study, assessing UCART19 in five children with r/r B-ALL who were CD19+, two patients died 7 and 8 months after UCART19 infusion, respectively; one patient died 2.5 months after MSD allo-SCT from transplant-related complications; and the other two patients achieved remission.

  • #4. Bristol-Myers Squibb (BMS) and CytomX Therapeutics

    Value: Up to $2.888 billion for CytomX, including $200 million upfront1

    Date announced: March 20, 2017

    Summary: In an expansion of an up-to-$1.242 billion, up-to-four target cancer immunotherapy collaboration announced May 27, 2014, BMS and CytomX agreed to discover up to eight additional targets—six oncology targets, two non-oncology—using CytomX’s Probody™ drug discovery platform. CytomX granted BMS exclusive worldwide rights to develop and commercialize the eight targets. In return, BMS agreed to pay CytomX $200 million upfront, plus research funding, and up to $448 million per candidate tied to achieving development, regulatory, and sales milestones, plus tiered royalties from the mid-single digits to low-double digits on net sales of each product commercialized by BMS.

    Updates: The first Probody therapeutic to advance to the clinic through the collaboration, BMS-986249, is under study in a Phase I/II trial (NCT03369223) launched during the fourth quarter. The trial is designed to evaluate BMS-986249 alone and in combination with BMS’ Opdivo® (nivolumab) in solid tumors that are advanced and have spread. The trial began following IND clearance of BMS-986249, for which CytomX earned a $10 million milestone payment from BMS during Q4 2017. Earlier last year, BMS selected all four oncology targets called for under the original agreement—BMS-986249 and three other programs that have yet to enter clinical studies.

  • #3. Bristol-Myers Squibb (BMS) and Nektar Therapeutics

    Value: Up-to-$3.6 billion-plus, including $1.8 billion upfront

    Date announced: February 14, 2018

    Summary: The companies will partner to co-develop Nektar’s lead immuno-oncology program NKTR-214 in combination therapies  with BMS’ marketed cancer immunotherapy Opdivo® (nivolumab), as well as with both Opdivo and BMS’ other marketed cancer immunotherapy blockbuster drug, Yervoy® (ipilimumab), in more than 20 indications across nine tumor types. Those tumor types include melanoma, renal cell carcinoma, non-small-cell lung cancer (NSCLC), bladder cancer, and triple-negative breast cancer. Pivotal studies in renal cell carcinoma and melanoma are expected to be initiated in mid-2018. BMS and Nektar also agreed to study additional combination therapies with other anticancer agents originating from either company, and/or third parties.

    Updates: The deal has led to speculation by one analyst that BMS may soon acquire Nektar. “The collaboration announced on Feb. 14 between BMS and Nektar remains the most important news for Nektar investors in our opinion and we think the deal could lead to an eventual take-out,” observed Difei Yang of Mizuho Securities. Yang cited positive first data announced late last year from the PIVOT-02 Phase I/II study assessing the Opdivo/NKTR-214 combination, as well as the ongoing PROPEL Phase I/II study assessing NKTR-214 with Opdivo and Roche/Genentech’s Tecentriq® (atezolizumab), a study whose estimated primary completion date is December 2018. “With PROPEL data expected in 2H18, we think a scenario where BMS makes a move before the readout of NKTR-214 in combo with Keytruda and Tecentriq is a plausible one.”

  • #2. Merck & Co. and Eisai

    Value: Up to $5.77 billion, including $300 million upfront

    Date announced: March 8, 2018

    Summary: Merck & Co. will partner with Eisai to codevelop its marketed cancer treatment Lenvima® (lenvatinib mesylate) for additional oncology indications, both alone and in combination with Merck’s Keytruda® (pembrolizumab). Eisai and Merck agreed to jointly launch new clinical studies evaluating the Lenvima/Keytruda combination in 11 potential indications covering six types of cancer—endometrial cancer, non-small-cell lung cancer (NSCLC), hepatocellular carcinoma, head and neck cancer, bladder cancer, and melanoma—as well as a “basket” trial targeting multiple unspecified cancer types. The announcement comes two months after the companies won the FDA’s Breakthrough Therapy designation for a Lenvima/Keytruda combination in advanced and/or metastatic renal cell carcinoma (RCC), based on a 63% overall response rate and other positive results in an ongoing Phase Ib/II trial (Study 111/KEYNOTE-146).

    Updates: At a news conference announcing the collaboration, Nikkei reported, Eisai CEO Haruo Naito said Merck's global marketing muscle would enable Lenvima to blossom into a billion-dollar blockbuster: “We expect to attain triple the sales we could manage alone.” During the first nine months of Eisai’s current fiscal year (April–December 2017), Lenvima generated ¥23.477 billion ($220.4 million), Eisai disclosed on February 2. Naito added that his company would use proceeds from the collaboration to accelerate research and development of treatments for Alzheimer’s disease and cancer, Reuters reported.

  • #1. Merck & Co. and Ablynx

    Value: €5.78 billion ($7.139 billion)

    Date announced: July 22, 2015

    Summary: In an up-to-€4.08 billion (about $5 billion), four-year expansion of an up-to-€1.7 billion ($2.1 billion) immuno-oncology collaboration to address additional checkpoint modulator targets, announced February 3, 2014, the companies agreed to discover and develop up to 12 additional cancer drugs based on single-domain antibody fragments, or Nanobodies®, through preclinical proof-of-concept. After that, Merck & Co. will have the option to advance specific lead candidates. Merck will also oversee clinical development, manufacturing, and commercialization of any products resulting from the collaboration, which grew to 17 Nanobodies programs.

    Updates: On January 29, Ablynx joined Sanofi in announcing the pharma giant’s planned €3.9 billion ($4.8 billion) acquisition of Ablynx, a deal designed to expand the buyer’s R&D pipeline and rare blood disorders portfolio. Sanofi plans to acquire all outstanding ordinary shares of Ablynx—including shares represented by American Depositary Shares (ADSs), warrants, and convertible bonds of Ablynx—at €45 ($55.48) per share cash. The offers are expected to be launched by the beginning of the second quarter, when the deal is expected to close.

    In its March 2018 investor presentation, Ablynx disclosed that it expected to begin its first two clinical studies arising from the collaboration later this year. Last year, Ablynx started an IND-enabling toxicology study with a bi-specific Nanobody—triggering a €2.5 million ($3.1 million) milestone payment to Ablynx in June 2017—and completed a second in-vivo proof-of-concept study with a mono-specific Nanobody. Ablynx also said it has received €33 million ($40.7 million) upfront and €6 million ($7.4 million) in preclinical milestone payments to date from its partnership with Merck.

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