The top 15 biopharma licensing deals of 2020

Licensor: Daiichi Sankyo
Licensee: AstraZeneca
Deal size: $6.0 billion
Upfront: $1.0 billion
Asset: TROP2-targeted antibody-drug conjugate datopotamab deruxtecan for lung, breast and other cancers

A licensing deal between AstraZeneca and Daiichi Sankyo has taken the number-one spot on the top 15 chart for the second year running, and once again the deal involves one of the Japanese drugmaker's antibody-drug conjugates (ADCs).

AZ agreed to pay $1 billion upfront over two years for ex-Japan rights to datopotamab deruxtecan (DS-1062), an ADC that targets tumor-associated protein TROP2, plus another $5 billion in milestones.

That makes the deal only a little smaller than the $6.9 billion headline figure for AZ's licensing of Enhertu (trastuzumab deruxtecan) from Daiichi in 2019. Within a few months of AZ coming on board, that drug was approved for patients with previously treated HER2-positive breast and gastric cancer.

Both those deals have hinged on the strength of limited clinical proof-of-concept data, which signals AZ's enthusiasm for the ADC category as a future pillar of its fast-growing oncology business.

TROP2, which is overexpressed on tumor cells, is also the target of Immunomedics’ ADC Trodelvy (sacituzumab govitecan), which was approved last year for previously treated triple negative breast cancer (TNBC).

DS-1062 is likely to be the next drug in the class to reach the market if clinical trials go as planned. AZ is planning to focus initially on the sizable population of non-small cell lung cancer (NSCLC) patients who fail immunotherapies like Merck & Co's PD-1 inhibitor Keytruda (pembrolizumab), with a TNBC program following shortly behind.

AZ has bought into the idea that Daiichi can come from behind to claim a big piece of the market, provided it can back up the notion that DS-1062 has a best-in-class profile.

The drug combines an antibody targeting TROP2 that's conjugated using a stable linker with a potent topoisomerase I inhibitor payload. It has a lower drug-to-antibody ratio that Daiichi suggests should both boost cell-killing activity and limit side effects.

Analysts at SVB Leerink believe that profile could give DS-1062 an edge if borne out in the clinic, although they have pointed to cases of interstitial lung disease in early human testing that could be a liability and will need to be monitored.

One of the concerns is that TROP2 is also found on cells in some normal tissues, and some TROP2-targeting drugs have stumbled on safety issues in the past. They include Pfizer's PF-06664178.

The TROP2 category is sparsely populated, with hardly any other candidates in the clinic other than a couple of drugs from Chinese firms Kelun Group and Bio-Thera Solutions. AZ has said DS-1062 is one of half a dozen oncology candidates in its mid- to late-stage pipeline with blockbuster sales potential.

Licensor: Seattle Genetics
Licensee: Merck & Co
Deal size: $4.5 billion
Upfront: $1.6 billion
Asset: LIV-1-targeting antibody-drug conjugate for breast cancer and other solid tumors

The second-largest licensing deal of 2020, like the first between AstraZeneca and Daiichi Sankyo, involved an antibody-drug conjugate (ADC) for cancer, reinforcing the value that is being attached to these assets by Big Pharma companies.

Merck & Co's investment in Seattle Genetics is somewhat unusual, however, because the New Jersey drug giant doesn't normally attach such sizable biobuck figures to its licensing deals. It put down $600 million in cash and made a $1 billion equity investment in Seattle Genetics, in return for rights to the phase 2 asset ladiratuzumab vedotin and some follow-up candidates, with another $2.6 billion on tap if the program fulfills its promise.

The ADC targets LIV-1, an antigen expressed on most advanced breast cancers and several other solid tumors including lung, head and neck, esophageal and gastric cancer. The antibody portion is connected to a microtubule-disrupting agent (monomethyl auristatin E) that causes cell-cycle arrest and apoptosis, or programmed cell death.

The ADC is being investigated in phase 2 trials for breast cancer and other solid tumors, and Merck and Seattle Genetics say they plan to test it both as a monotherapy and in combination with Merck's mega-blockbuster checkpoint inhibitor Keytruda (pembrolizumab). The first trials are planned in triple-negative breast cancer (TNBC), a particularly aggressive form of the disease. Keytruda claimed FDA approval for PD-1-positive TNBC last November.

The two companies began exploring the effect of combining the ADC and Keytruda in a phase 1b/2 TNBC trial a few years ago, and Merck must have liked what it saw from that study, reported at the 2019 San Antonio Breast Cancer Symposium: a 54% overall response rate for duo, with at 90% of the 26 evaluable patients seeing some degree of tumor shrinkage.

The scale of Merck's commitment stems from the view that in addition to having direct cancer-killing power, ladiratuzumab vedotin can create a more favorable microenvironment for Keytruda, as the cell deaths caused by the ADC should increase the tumor infiltration of white blood cells.

A side deal between Merck and Seattle Genetics covered tyrosine kinase inhibitor Tukysa (tucatinib) for metastatic HER2-positive breast cancer, with Merck paying $125 million upfront and committing to up to $65 million in milestones for the exclusive license to the drug in Asia, the Middle East and Latin America.

Licensor: Genmab
Licensee: AbbVie
Deal size: $3.9 billion
Upfront: $750 million
Assets: Multiple bispecific antibodies for cancer

Diversifying its pipeline to reduce its reliance on blockbuster immunology drug Humira (adalimumab) has been a priority for AbbVie's management for years, resulting in a series of pipeline-boosting deals as well as a mega-merger with Allergan as it prepares for patents to expire on the $20 billion product in 2023.

One of AbbVie's major focus areas is oncology, and 2020 saw the company put a hefty $3.9 billion on the table—including $750 million upfront—for up to seven bispecific antibody candidates for cancer from Danish biotech Genmab.

Topping the list of the bispecific antibodies is epcoritamab, an anti-CD3 and anti-CD20 drug. With that asset, AbbVie will compete directly with Roche's mosunetuzumab and follow-up glofitamab and Regeneron's REGN1979 in hematological cancers like lymphomas.

Last year, Genmab reported phase 1/2 results for epcoritamab in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL), setting up a phase 3 program that started last November.

Analysts at Jefferies said the results were roughly in line with Regeneron's data for REGN1979, but that epcoritamab might have an edge in terms of safety, specifically a lower risk of cytokine release syndrome (CRS).

Both Roche and Regeneron are considered to be further head in development, though, with pivotal trials already underway, so AbbVie and Genmab are playing catch-up. The partners point to their drug's subcutaneous route of administration as a key differentiator from other CD3xCD20 bispecifics, which have to be given by infusion.

AbbVie will share commercial epcoritamab responsibilities with its new partner in the U.S. and Japan, where Genmab will book sales. AbbVie will handle commercialization in the rest of the world, with Genmab in line for royalties of between 22% and 26%.

Also covered by the deal is a CD3x5T4 antibody and another bispecific targeting two different portions of the CD37 molecule, which along with epcoritamab are worth up to $1.2 billion in clinical and commercial milestones to Genmab.

The licensing deal bolsters AbbVie's pipeline in oncology and specifically blood cancers, where it is already a major player with drugs like Johnson & Johnson-partnered Imbruvica (ibrutinib) and Roche-partnered Venclexta (venetoclax).

That opens up the possibility of combination studies, of course, and the two partners have pledged a big and speedy phase 3 program for epcoritamab "across the entire spectrum of B-cell malignancies and lines of treatment." The first patients were enrolled in the program in January.

Licensor: Sage Therapeutics
Licensee: Biogen
Deal size: $3.1 billion
Upfront: $1.5 billion
Assets: Zuranolone for multiple depression types and SAGE-324 for essential tremor

Biogen is approaching a crunch FDA decision in June for its Alzheimer's drug aducanumab after a costly clinical development program, with a positive verdict far from assured. In the meantime, the biotech has been bulking up what has been regarded for some years as a somewhat thin late-stage pipeline, with three multibillion deals making it into our 2020 list.

The largest is its $3.1 billion deal with Sage Therapeutics for two drugs: GABA receptor positive allosteric modulator zuranolone (SAGE-217) for multiple types of depression and follow-up SAGE-324 for essential tremor and other neurological disorders.

The upfront portion of that totaled $1.5 billion, including $875 million in cash and a $650 million equity investment that gave Biogen a 10.7% stake in Sage. Another $1.6 billion was tied to milestones. In return for its investment, Biogen gets 50% of any profits generated in the U.S., while also sharing all costs and losses evenly with Sage.

The deal raised a few eyebrows, largely because zuranolone had already failed a phase 3 study in major depressive disorder (MDD) in 2019, thwarting Sage's initial filing timetable for the drug. Undeterred, Sage pressed on with new pivotal studies aimed at winning approval in either MDD or postpartum depression (PPD), with results due later this year.

Despite the risks, analysts at Jefferies said it was a savvy move, allowing Biogen to "get the milk without having to buy the whole cow," adding that there would be plenty of upside potential if those studies deliver as hoped. That would also soften the blow if aducanumab doesn’t get a green light from the FDA, given MDD and PPD are both sizable markets that could elevate zuranolone to blockbuster status.

The new LANDSCAPE trials program is testing a two-week course of 50mg of zuranolone—a higher dose of the drug than was used in the failed MOUNTAIN study in MDD. SAGE-324, meanwhile, is a next-generation asset with a similar mechanism of action that is being assessed in a phase 2a clinical trial. Essential tremor is thought to affect millions of people in the U.S. alone, making it one of the most common movement disorders.

The alliance comes as both Biogen and Sage are facing pressure to bring new products to market. Biogen is dealing with the loss of patent protection on its big-selling multiple sclerosis drug Tecfidera (dimethyl fumarate), as well as competition to spinal muscular atrophy therapy Spinraza (nusinersen). The company has also suffered pipeline setbacks, including toxicity issues with SMA gene therapy BIIB089.

As for Sage, it has just one product on the market, Zulresso (brexanolone) for PPD. But it has a burdensome 60-hour infusion regimen and has underperformed commercially, with sales of less than $7 million last year. Just a year ago, Sage was forced to lay off more than half its workforce as it cut spending back to focus on zuranolone.

Licensor: Sangamo
Licensee:  Biogen
Deal size: $2.72 billion
Upfront: $350 million
Assets: Up to 11 neurological disease programs, including ST-501 for Alzheimer’s and ST-502 for Parkinson’s

Biogen's second big licensing deal in 2020 was for the genome-editing technology zinc-finger nuclease (ZFN), which had been all but written off a few years ago when attention turned to fashionable rival platforms like CRISPR. Now that technology is experiencing something of a renaissance.

ZFNs are engineered DNA-binding proteins that allow targeted editing of the genome by creating double-stranded breaks in DNA at specific locations. Sangamo's lead ZFN drug disappointed in early-stage trials, wreaking havoc on its share price in 2019. A year later, Biogen stumped up $350 million upfront in cash and equity for a series of the company's preclinical assets in the neurology space, with a $2.37 billion biobucks stream to go with it.

The wide-ranging deal covers ST-501 for diseases linked to tau protein, including Alzheimer's, and ST-502 for conditions associated with alpha-synuclein, such as Parkinson's. It also includes an undisclosed neuromuscular target, as well as nine other programs based on various genetic targets.

Sangamo is responsible for early research activities, with costs split between the two companies, and Biogen will take over once they are ready for clinical testing. Trials will kick off in 2022 or 2023.

None of the licensed projects have advanced beyond the preclinical development stage yet, so the deal represents one of the largest ever signed for such early-stage assets. It's another big gamble for Biogen, particularly in light of the failure of Sangamo's SB-913 in the rare disease MPS II.

Analysts at Credit Suisse say the deal is a good one, though, because it was a low-cost way to bolt on a pipeline of compounds to back up Biogen's core focus on central nervous system disorders.

Biogen, meanwhile, is just the latest biopharma company to buy into Sangamo's ZFN pipeline. Others include Pfizer, which signed up in 2017 and has a hemophilia A candidate in phase 3, Sanofi with drugs for sickle cell disease and beta-thalassemia in midstage development, Gilead's Kite in oncology, and Novartis in autism.

Sangamo's chief executive Sandy Macrae has said that other platform-style alliances similar to the Biogen deal could be forthcoming as momentum builds behind the ZFN technology and it is matched to the right indications.

Licensor: Nurix Therapeutics
Licensee: Sanofi
Deal size: $2.55 billion
Upfront: $55 million
Asset: A pipeline of protein degradation therapies

Harnessing cell pathways that clear out damaged or excess proteins has become a hot pursuit in biotech, and one of the players in the field—Nurix Therapeutics—signed a sizable collaboration in that field with Sanofi.

Protein degradation therapies aim to harness the body’s natural machinery to remove rogue proteins associated with disease. Using Nurix’s approach, proteins are tagged with ubiquitin using E3 ligase enzymes, which marks them for destruction by protein-denaturing machinery in cells. The proteasome then unfolds and digests the proteins.

Tapping into this cellular garbage disposal system could open up some targets previously considered to be "undruggable," according to Nurix, while also producing more durable responses than drugs that simply block the function of harmful proteins.

In January 2020, Sanofi partnered with San Francisco-based Nurix, paying $55 million upfront to start working on three programs against undisclosed targets, with another $2.5 billion in milestones.

Sanofi is clearly happy with progress on the alliance so far, as it doubled down on the deal a year later, paying $22 million to take the total number of projects to five. Details are sketchy, with the partners saying only that the program covers small-molecule drugs for "challenging diseases in multiple therapeutic areas."

Sanofi has exclusive rights to the compounds and will handle clinical development and commercialization. and Nurix has retained an option to co-develop and co-promote up to two products in the U.S.

The Sanofi deal follows a $2.75 billion pact Nurix formed with Gilead in 2019 to develop five drugs for cancer and other diseases, as well as a 2015 program with Celgene (now part of Bristol-Myers Squibb) that was also in oncology.

Other companies are competing in the protein degradation field, including Arvinas, C4 Therapeutics and Kymera, producing a string of licensing deals that show strong interest among biopharma majors. Novartis and BMS are also working on their own projects in this arena, while other players include Amphista, Cullgen and Foghorn.

Nurix, meanwhile, pulled off a $120 million funding round last year that will help push its in-house projects into the clinic. They include an orally delivered BTK chimeric targeting molecule (CTM) for B-cell malignancies.

Licensor: Astex/Taiho
Licensee: Merck & Co.
Deal size: $2.5 billion
Upfront: $50 million
Assets: Small-molecule inhibitors against several drug targets, including the KRAS oncogene

Interest in the KRAS oncogene as a target for cancer drugs was running high in 2019 and continued into the early part of 2020 when Merck & Co. agreed to put as much as $2.5 billion into an alliance with Taiho and Astex on KRAS and other drug targets.

Just $50 million of that total was upfront, reflecting the fact that none of the small-molecule inhibitors covered by the deal have advanced beyond preclinical development. But Merck is also providing R&D funding to get the program underway.

KRAS is one of the most frequently mutated oncogenes in human cancers, accounting for approximately a third of mutations in all human cancers. It is estimated to occur in approximately 90% of pancreatic cancers and 20% of non-small cell lung cancers (NSCLC), both of which are challenging to treat. Tumors with KRAS mutations also tend to be more aggressive and portend a poor prognosis.

KRAS was considered an "undruggable" target for decades, as efforts to find inhibitors were stymied by its structure, which is marked by limited pockets where drug agents can bind. Amgen was the first to come up with a solution when it discovered that a specific KRAS mutation called G12C could be targeted with drug compounds, irreversibly forcing the abnormal KRAS into an inactive state.

Amgen's much-hyped lead KRAS candidate sotorasib is gunning for an FDA decision by August 16 in KRAS G12C-mutated non-small cell lung cancer (NSCLC), after showing it could stop tumor growth or shrink tumors in 90% of patients.

Following behind is Mirati's adagrasib, which is due to be filed for the same indication later this year. Both sotorasib and adagrasib are billed as future blockbusters, with EvaluatePharma penciling in 2026 sales of $1.5 billion and $1.74 billion respectively.

The Merck/Astex/Taiho trio are also trailing candidates from Boehringer Ingelheim, Johnson & Johnson/Wellspring, and AstraZeneca/Ionis. And it isn't Merck's first foray into KRAS.

In 2018, Merck extended a collaboration with Moderna that began in 2016 to develop mRNA-based vaccines for cancer, paying $125 million to bundle in mRNA-5671, Moderna’s mRNA KRAS cancer vaccine.

The goal for that alliance is to test the vaccine alone and alongside Merck's immuno-oncology drugs, including checkpoint inhibitor Keytruda (pembrolizumab). Moderna's vaccine started phase 1 testing last November in various KRAS-mutated cancers, including NSCLC, colorectal and pancreatic cancers.

All seems to be going well with the Merck/Astex/Taiho alliance, and in January of this year, Merck exercised its option to pick up global rights to a portfolio of small-molecule inhibitors of SHP2, another hot target in oncology. SHP2 regulates the RAS-MAP kinase pathway, which is frequently overactive in human cancers.

Licensor: Denali Therapeutics
Licensee: Biogen
Deal size: $2.15 billion
Upfront: $1.025 billion
Assets: Small molecules that inhibit LRRK2 to treat Parkinson's disease, headed by DNL151

Biogen's third-largest deal of 2020 was a $1 billion-plus buy into an experimental Parkinson's disease therapy developed by Denali Therapeutics. The alliance put further weight behind an emerging but still largely untested drug target.

The deal gives Biogen rights to co-develop and co-commercialize small-molecule drugs for Parkinson’s that target mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, including Denali's most advanced candidate DNL151 (also known as BIIB122), which has completed a phase 1b trial.

That data haven’t been revealed in detail yet, but they must be encouraging, as Biogen and Denali are now planning to start two late-stage studies of the drug, one in Parkinson's patients who carry LRRK2 mutations and the other in Parkinson's patients independent of mutation status. Both trials are expected to start before the end of this year.

Kinase-activating mutations in the LRRK2 gene are among the most common genetic causes of inherited Parkinson's disease. Scientists believe these mutations mess up the function of lysosomes—important garbage-disposal systems inside cells—causing neurons to degenerate.

This is not Biogen's first foray into the LRRK2 category, as the company already has an option agreement with Ionis on BIIB094, an antisense oligonucleotide that targets the mRNA coded by the LRRK2 gene. That drug is in a phase 1 clinical trial.

Biogen's alliance with Denali includes an exclusive option to license two more programs for neurodegenerative diseases, including one that targets amyloid-beta in Alzheimer's disease. Biogen also has rights to first negotiation for another pair of assets. All of those are in preclinical development.

If any drugs that come out of the collaboration are approved, Biogen and Denali will sell them together in the U.S. and China, with Biogen taking the rest of the world.

It's worth noting that the deal also gives Biogen a line on Denali's Transport Vehicle (TV) technology, which is designed to make it easier for large molecules to penetrate the blood-brain barrier. That is one of the main challenges in developing neurological drugs and could be a useful technology for a central nervous system specialist like Biogen.

Licensor: Roche
Licensee: Innovent Biologics
Deal size: $2.1 billion
Upfront: $140 million
Assets: Cell therapy and bispecific antibody technologies for immuno-oncology

Roche hasn't been at the leading edge of the cell therapy drive in oncology, spearheaded by CAR-T therapies, preferring instead to participate obliquely. For example, it tested its checkpoint inhibitor Tecentriq (atezolizumab) with Gilead's CAR-T Yescarta in lymphoma patients.

The Swiss drug major has been working on its own cell-based immuno-oncology platform though, thanks to in-house efforts as well as partnerships with companies like SQZ Biotechnologies, which has a platform that allows B cells to be engineered as therapeutics for a broad range of cancers. And it formed a $2 billion alliance with T cell receptor (TCR) specialist Adaptive Biotech.

Last year, that work resulted in a licensing deal with Chinese biotech Innovent Biologics, which claimed non-exclusive access to the Swiss major’s cell therapies, as well as certain bispecific antibodies for both blood and solid cancers.

Details were scant, but Innovent will "create, develop, manufacture, and commercialize the products," with Roche keeping option rights outside China. If it does so, Roche will pay $140 million upfront and $1.96 billion in follow-up payments based on clinical, regulatory and sales milestones. Innovent hasn’t revealed how much it paid Roche for access to the technologies.

Roche's work on cell therapy has resulted in what it describes as a "universal" or modular CAR-T cell technology, which doesn't directly recognize and bind to a target antigen on cancer cells, but achieves that targeting through the use of other "adaptor" molecules, such as Roche's bispecific antibodies.

In theory, that allows CAR-Ts to be developed that can target antigens on tumors without needing to re-engineer a patient's donated T cells. Down the line, there are hopes the universal CAR-T principle could also be deployed in "off-the-shelf" T cell therapies that would do away with the need to harvest cells from patients.

Licensor: uniQure
Licensee: CSL Behring
Deal size: $2.05 billion
Upfront: $450 million
Asset: Hemophilia B gene therapy etranacogene dezaparvovec

There was a lot of speculation last year that gene therapy specialist uniQure could be a takeover candidate. But the suitor that emerged, Australia's CSL Behring, opted instead to license uniQure's lead candidate etranacogene dezaparvovec (AMT-061) for clotting disorder hemophilia B.

The deal—which included $450 million upfront and $1.6 billion in milestones—propelled CSL to the forefront of a race to bring a hemophilia B therapy in front of regulators, with its main rival Pfizer and its fidanacogene elaparvovec in phase 3 testing.

Just a few months after the deal was signed, however, the FDA placed AMT-061 on a clinical hold after a case of liver cancer was seen in uniQure's phase 3 HOPE-B trial. That hold now looks set to be relaxed after an independent investigation found the case was "highly unlikely" to be linked to the therapy.

uniQure has said it doesn’t expect to have to delay its timeline for filing AMT-061 for approval, as dosing in HOPE-B had been completed before the hold was placed.

Now, uniQure is gathering data from the trial as it matures. Its last update at the American Society of Hematology (ASH) congress in November showed the one-shot therapy curbed bleeding episodes and all but eliminated the need for infusions of clotting factor IX in severe or moderately severe hemophilia B patients.

That data helped uniQure turn around perceptions of its gene therapy, which had suffered in comparison to Pfizer's candidate in early data readouts. The company switched from using wild-type factor IX to a gene variant known as Padua in its therapy and began posting stronger results. That led to speculation it could be snapped up amid a flurry of other gene therapy acquisitions like those of AveXis, Spark and Audentes.

Licensing AMT-061 to CSL likely takes a takeover of uniQure off the table, which could explain the dramatic fall in the biotech's share price after the deal was announced.

Under the terms of the deal, $300 million in milestones are tied to regulatory events and first commercial sales, and CSL is also on the hook for tiered royalties that top out a little above 20%. The agreement has cleared antitrust regulatory review in Australia and the U.K., but as of the end of March was still subject to an ongoing review in the U.S.

Assuming that comes through, CSL will have the task of developing the commercial strategy for AMT-061, which lies firmly in its wheelhouse. The company is a well-established global player in the hemophilia market. Its portfolio of clotting factor products includes long-acting hemophilia B product Idelvion (albutrepenonacog alfa), which is estimated to have a 30% share of the global market.

Licensor: Takeda
Licensee: Neurocrine Biosciences
Deal size: $2.02 billion
Upfront: $120 million
Assets: Seven psychiatry compounds including drugs for depression, schizophrenia and anhedonia

Our annual list of top licensing deals more often than not involves a big biopharma company buying into assets generated by a smaller counterpart, but not always. In 2020, little Neurocrine Biosciences put $120 million on the table to claim exclusive rights to seven psychiatric drug candidates from Japan's Takeda.

The batch of seven includes three already in clinical trials for treatment-resistant depression, schizophrenia, and depression-associated anhedonia, an inability to feel pleasure.

Neurocrine almost doubled its pipeline as a result of the deal, while Takeda offloaded some low-priority assets, but still retained options to buy them back in at a later date if any prove particularly compelling.

The clinical candidates include luvadaxistat (NBI-1065844, previously TAK-6831), a selective d-amino acid oxidase (DAAO) inhibitor in phase 2 trials for schizophrenia. Neurocrine is hoping that the drug could tackle the negative symptoms of schizophrenia, like apathy and social withdrawal, which don't respond to current antipsychotic drugs.

Those hopes have been dashed a bit, however, as luvadaxistat flunked the first readout from the phase 2 INTERACT trial, missing its objective of improving negative symptoms measured by the widely used PANSS NSFS scale.

Neurocrine isn’t giving up just yet, saying it saw a positive impact on cognitive symptoms of schizophrenia in the study that "warrants further investigation," while the safety profile looked clean.

Following behind luvadaxistat are NBI-1065845 (formerly TAK-653), an AMPA potentiator intended for the roughly one-third of patients whose depression doesn't respond to current drugs, and NBI-1065846 (TAK-041), a GPR139 agonist, both being prepped for phase 2 trials. For now, the other four candidates—all in preclinical development—are being kept under wraps.

Along with the upfront fee, Neurocrine has pledged to pay up to $495 million in development and $1.4 billion in commercialization milestones for the seven candidates, which have extended its R&D focus beyond neurology and endocrinology. Takeda can choose to forego milestones in any of the projects and switch to a 50:50 profit-sharing arrangement.

It's the second sizable deal for Neurocrine in the last two years, coming after the company handed over $165 million upfront to Voyager Therapeutics in 2019 for a clutch of four gene therapies, including one for Parkinson’s disease.

That deal has a similar structure to the tie-up with Takeda, as Neurocrine has promised up to $1.7 billion in milestones for the programs, and Voyager can also choose to share profits instead of booking milestone payments.

Neurocrine is funding its pipeline expansion from its stable of four approved drugs: AbbVie-partnered Orilissa (elagolix) and Oriahnn (elagolix/estradiol/norethindrone acetate), for the treatment of endometriosis and uterine fibroids, respectively, as well as Ingrezza (valbenazine) for tardive dyskinesia and Ongentys (opicapone) for Parkinson’s disease.

The star of the show at the moment is Ingrezza, which is knocking on the door of blockbuster status after posting sales of $993 million in 2020.

Licensor: Alnylam
Licensee: Blackstone
Deal size: $2 billion
Upfront: $2 billion
Asset: Royalties and milestones associated with Novartis' cholesterol-lowering drug inclisiran

Stretching the definition of a licensing deal a little, but worth a mention, is the $2 billion investment by private equity firm Blackstone in genetic medicines specialist Alnylam in exchange for a 50% cut of the royalties on its Novartis-partnered cholesterol fighter inclisiran.

The RNA interference drug—acquired by Novartis when it bought The Medicines Company for almost $10 billion in 2019—has been approved in Europe as Leqvio. It's approved for use as an add-on to statins, or an alternative to statins for patients who can't take or don’t respond to them.

But Alnylam got some bad news in December when the FDA rejected the U.S. marketing application for the drug due to unresolved issues relating to a manufacturing facility in Italy.

That could delay the program well into the second or third quarter of this year, especially as the pandemic raises difficulties in inspecting the plant, according to the Swiss drugs giant, which insists the issue has nothing to do with inclisiran’s efficacy, safety or manufacturing techniques.

The setback came a few months after Blackstone agreed to buy $100 million of stock in Alnylam—which originally developed the drug—and pony up $1 billion for 50% of the biotech's royalties and commercial milestones for inclisiran.

Under the terms of the deal, Alnylam is also in line for $150 million from Blackstone in return for a stake in its cardiometabolic programs vutrisiran or ATTR amyloidosis and ALN-AGT for high blood pressure, as well as a loan facility of up to $750 million.

Inclisiran targets PCSK9, making it a direct rival to Amgen's Repatha (evolocumab) and Regeneron and Sanofi’s Praluent (alirocumab), both of which are antibodies that require more frequent dosing. Novartis' RNAi drug can be given as an injection just once every six months, compared to once a month or every two weeks for the antibodies.

The antibodies have struggled to gain traction in the marketplace, even after pushback from payers prompted substantial price cuts. Evercore ISI analysts have suggested that inclisiran could do better, possibly reaching $2 billion in peak annual sales.

Novartis is no stranger to slow burners in the cardiovascular arena. Its heart failure drug Entresto (sacubitril/valsartan) was first launched in 2016 and after a sluggish start has grown into a blockbuster with sales of $2.5 billion last year.

While the Alnylam deal is anchored by the inclisiran program, Blackstone sees it as a broader strategic investment in the biotech and its RNAi platform, which has already generated three approved products. The platform "has the potential to transform the lives of patients suffering from a range of debilitating diseases," said the private equity firm.

Licensor: I-Mab
Licensee: AbbVie
Deal size: $1.94 billion
Upfront: $200 million
Asset: Anti-CD47 monoclonal antibody lemzoparlimab

CD47 is a hot target in immuno-oncology at the moment, on the back of research suggesting that inhibiting the protein seems to neutralize a key mechanism that tumors use to avoid being attacked by the immune system. This is sometimes described as a "don't eat me" signal.

Last year, Gilead forked out $4.9 billion to take over Forty Seven, which has been a pioneer in the CD47 arena. AbbVie took a less expensive route via its $1.94 billion licensing deal with I-Mab—including an upfront fee of $200 million—for lemzoparlimab, the Shanghai-based biotech's anti-CD47 antibody.

The move puts AbbVie in competition with not only Gilead, but also Pfizer/Trillium, ARCH Oncology, Innovent Biologics, Zai Lab and others in what is becoming an increasingly busy category.

There have been some early casualties in the CD47 field. Bristol-Myers Squibb picked up a candidate (CC-90002) as part of its Celgene merger, but it showed little activity in a phase 1 trial and now seems to be shelved.

AbbVie and I-Mab reckon that lemzoparlimab may have a safety and pharmacokinetic profile that will give it a leg-up over Gilead's magrolimab and other rivals if it hits the mark in clinical testing.

AbbVie has a slightly checkered history with its deal-making in cancer. Its $21 billion acquisition of Pharmacyclics in 2015 brought in a blockbuster blood cancer therapy Imbruvica (ibrutinib), a notable success, if a bit expensive. But the much-hyped drug at the heart of its near-$6 billion buyout of Stemcentrx in 2016 was officially abandoned in 2019.

The I-Mab deal is a much less risky way to dip a toe into CD47, and it offers AbbVie the potential to combine lemzoparlimab with its stable of oncology medicines, including Venclexta (venetoclax), which is used to treat chronic lymphocytic leukemia and acute myeloid leukemia.

There's also an option for AbbVie to take on two more bispecific versions of the drug with potential in solid tumors as well as blood cancers, paying out a minimum of $500 million each to bring the potential value of the deal up to $3 billion.

AbbVie gets exclusive rights to develop and commercialize lemzoparlimab in all areas of the world outside greater China and will pay I-Mab tiered royalties in the low- to mid-teen percentages if the drug reaches the market. Milestones are split $840 million for meeting clinical and regulatory objectives and $900 million for commercial achievements.

Licensor: Blueprint Medicines
Licensee: Roche
Deal size: $1.7 billion
Upfront: $775 million
Assets: RET inhibitor pralsetinib

Roche added to its targeted cancer portfolio with a $1.7 billion licensing deal for RET inhibitor pralsetinib from Blueprint Medicines, setting up a tussle with Eli Lilly's Retevmo in RET fusion-positive tumors.

The deal was one of the larger bolt-ons for the Swiss drugs giant, which tends to rely more on its in-house R&D. It paid $675 million upfront for the license and made a $100 million equity investment in Blueprint, with another $927 million at the back end in milestones.

Pralsetinib had been filed for approval at the time of the deal, while Retevmo (selpercatinib) was already on the market as a treatment for patients with advanced, RET-positive non-small cell lung cancer (NSCLC) and thyroid cancer.

Since then, Roche has gotten the regulatory decisions it was seeking for pralsetinib, which is now on the market as Gavreto. An FDA green light for the drug in the NSCLC indication in September, followed by an okay in thyroid cancer late last year, has put the product on a level footing with Retevmo, which became the first RET inhibitor to be approved for marketing last May.

Lilly secured Retevmo via its $8 billion acquisition of Loxo Oncology. Lilly booked just $37 million in Retevmo sales last year before it lost its lead, and now it has to contend with a rival therapy that offers similar efficacy and may have a safety advantage, according to analysts at SVB Leerink. Roche's formidable oncology marketing clout and diagnostics expertise will no doubt be a major boost to Gavreto.

On the safety side, Retevmo has warnings on its label that Gavreto does not, including an increased risk of a heart rhythm abnormality known as QT interval prolongation. That said, a clinical expert interviewed by SVB Leerink said he felt that wouldn’t dissuade prescribing decisions. Gavreto's label warns of interstitial lung disease/pneumonitis, which doesn't appear on Retevmo's label.

The deal gives Roche an exclusive license to sell pralsetinib outside of the U.S. and China. Roche will co-promoting Gavreto with Blueprint in the U.S. CStone Pharma has the rights to the drug in greater China.

Roche estimates that around 10% to 20% of people with papillary thyroid cancer—the most common type of thyroid cancer—have RET fusion-positive tumors, while almost all cases with the less common medullary form of the disease carry RET mutations. The genetic signature is seen in around 2% of NSCLC cases.

That's a relatively small target population for Retevmo and Gavreto to fight over, although EvaluatePharma predicted $1.2 billion in 2026 sales for Retevmo and $723 million for Gavreto—and that was before Roche came on board.

Roche and Blueprint, meanwhile, say they are already looking at new indications for their drugs, and working on a next-generation RET inhibitor candidate for which Roche has opt-in rights.

The deal also doused speculation that Blueprint might be a takeover candidate, given Gavreto is its most advanced project. The biotech also sells kinase inhibitor Ayvakit (avapritinib) for some patients with gastrointestinal stromal tumors (GIST), but it suffered a setback when the FDA rejected the drug for broader use in GIST last year, pegging back its sales potential.

With Roche on board, Blueprint now looks far more likely to remain independent.

Licensor: Innovent Biologics
Licensee: Eli Lilly
Deal size: $1.025 billion
Upfront: $200 million
Asset: Exclusive rights to PD-1 inhibitor Tyvyt outside China

Chinese biotech Innovent Biologics appears on our 2020 list as a licensee, but it also cut a deal in the other direction with longstanding partner Eli Lilly, handing over ex-China rights to PD-1 inhibitor Tyvyt (sintilimab).

The two companies have been working together on the checkpoint inhibitor since 2015, splitting rights to it in China where it is approved as a third-line treatment for classical Hodgkin lymphoma, and was the first PD-1 inhibitor to get reimbursement approval from the Chinese authorities. Last August, however, Lilly decided it wanted to take its involvement in the drug global.

The decision came fast on the heels of new data from the ORIENT-11 study showing that the combination of Tyvyt with Lilly's Alimta (pemetrexed) and chemotherapy helped previously untreated non-squamous non-small cell lung cancer (NSCLC) patients live longer without their tumors progressing.

That could unlock a big new indication for Tyvyt, although one that comes with potent competition in the form of Merck & Co's Keytruda (pembrolizumab), which continues to dominate first-line NSCLC immunotherapy thanks to compelling survival data and despite upstart therapies from Bristol-Myers Squibb, Roche and others trying to steal its crown.

Undeterred by its latecomer status in immuno-oncology, Lilly put down $200 million upfront and cued up another $825 million in milestones for expanded access to Tyvyt, as it tries to catch up with the leaders in immuno-oncology. It's a tough challenge, given there are six PD-1/PD-L1 agents already on the U.S. market.

The partners have submitted the ORIENT-11 results to the Chinese authorities to try to get a label expansion in NSCLC there, and that indication looks like it could be the frontrunner in the U.S. and other ex-China markets.

Lilly said at the time it expects to get FDA approval within the next two to three years, and there has been speculation that the company—along with other PD-1/PD-L1 aspirants like Novartis and GlaxoSmithKline—will try to compete with the more established checkpoint inhibitors on price.

Lilly and Innovent are also running upwards of 20 studies as they try to catch up with rivals. The drug is being tested in kidney, liver, colorectal, gastroesophageal and small cell lung cancers, as well as diffuse large B-cell lymphoma (DLBCL).

Lilly clearly has ambitions to build its own immuno-oncology franchise. Earlier this year the company formed a $1.6 billion R&D alliance with Dutch biotech Merus, tapping into its T-cell redirecting bispecific antibody expertise.