Antibody–Drug Conjugate News: From BioProcess Insider

The following news items have appeared on the BioProcess Insider site over the past year. Together they indicate the direction in which the ADC sector is moving.

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BEYOND ADCETRIS — SEATTLE GENETICS AIMS FOR BIG BIOPHARMA STATUS
30 April 2018: Seattle Genetics is building toward a bigger future. For the first quarter 2018, the company’s total revenues grew to US$141 million (€116 million) compared with $109 million in the same period last year. This was attributed to a 36% increase in sales of the Adcetris (brentuximab vedotin) ADC, which pulled in $95 million. With increased R&D expenses and acquisition of Cascadian Therapeutics, total costs for the quarter jumped by almost 30% to $234 million, so the company ended with a net loss of $112 million.

Progress Over Profits… for Now: Profitability will come, said chief executive officer Clay Siegall. “We want to be profitable, we expect to be profitable, and we certainly could be profitable now based on our revenue if we skinny down everything and don’t do what we’re doing.” But the vision is to make Seattle Genetics “a much more powerful, big, expansive company,” he continued, invoking success stories of Biogen, Gilead, and Celgene — which have gone from having one lead molecule to big pharma status, with portfolios boasting several top-selling drugs.

“We aspire to becoming a really valuable, important company for cancer patients, and we think we have the nucleus to do it,” he said. “We have the pipeline to do it. So it doesn’t feel like it’s the right time to pull off the gas pedal and make being profitable our top priority, even though we want to be profitable at the earliest possible time.”

Partnerships and Licensing Deals: Developed with Takeda Pharmaceuticals, the Adcetris ADC uses Seattle Genetics linker technology to combine the brentuximab monoclonal antibody (MAb) with a cytotoxic small molecule. The product received approval from the US Food and Drug Administration (FDA) in 2011 to treat Hodgkin lymphoma (HL).

Since then, Seattle Genetics has expanded its proprietary and partnered pipeline: It is investigating a pyrrolobenzodiazepine (PBD) dimer as a highly potent cytotoxic agent while collaborating with companies including Genentech/Roche, GlaxoSmithKline, Genmab, and Pfizer. Seattle Genetics also has licensed its linker technology to AbbVie, Astellas, Bayer, Celldex, Genentech/Roche, GlaxoSmithKline, Pfizer, and Progenics.

“We’re no longer Adcetris and a bunch of early stage products,” said Siegall. “We’re now multiple late-stage products across oncology, and we’re really excited about this. I think we have a great future.”

IN-HOUSE INVESTMENTS HELP SYNTHON KEEP CONTROL OF ADC PRODUCTION
10 October 2018: Synthon Biopharmaceuticals has chosen to develop its ADC capabilities in-house to keep control of planning and product quality. Chief scientific officer Aad Van de Leur spoke at KNect365’s Bioproduction Congress in Dublin, Ireland, on the need to adapt biomanufacturing strategies and technologies for next-generation therapies, using his own company’s ADC capabilities as an example.

“With the introduction of innovative high-potent biopharmaceuticals like ADCs, the industry had to adapt and move to different strategies to produce these products,” he told BioProcess Insider before his talk. “Next to the standard CGMP [current good manufacturing practice] requirements, additional safety aspects need to be taken into account. In addition, the volumes of these products would be limited, resulting in smaller facilities and options to use single-use materials, but also the need to adapt certain equipment.” Solvents are needed in ADC manufacturing that can hamper the utility of single-use materials, he continued. “Therefore, Synthon put significant effort into leachables and extractables studies.” Results were presented in Dublin along with positive clinical outcomes from a phase 1 study in patient cohorts.

Homegrown Manufacturing: Based in Nijmegen, the Netherlands, Synthon Biopharmaceuticals is a relatively small company that has decided to invest in linker-drug, monoclonal antibody (MAb), and cytotoxic drug-substance manufacturing facilities.

“We believe manufacturing cost, planning, and product quality can be tackled best when under our own control,” Van de Leur said. “This is key to efficient and timely development of complex products like ADCs. However, working with high- potent products puts much emphasis on safety for both employees and environment, [requiring] complex cleanroom facilities including negative pressure, fume hoods, and isolators. Our facilities have been inspected by regulatory authorities and partners and meet the standards to produce for clinical and commercial needs.”

More than 600 biomanufacturing decision-makers and scientists convened in Dublin for KNect365’s Bioproduction Congress in 2018. But following the £3.9 billion ($5.1 billion) merger of Informa and UBM, the Bioproduction Congress will locate next year with CPhI Worldwide in Frankfurt, Germany.

NIIMBL AND BPOG PUBLISH ROADMAPS FOR ADCS, VACCINES, AND GENE THERAPIES
15 November 2018: In collaboration with the BioPhorum Operations Group (BPOG), the US National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) has published a series of technology “roadmaps” for the biopharmaceutical industry. These documents cover regulatory considerations and manufacturing issues for gene therapies, vaccines, ADCs and bispecific antibodies based on insight from biomanufacturers, equipment makers, suppliers, academic institutions, nonprofit organizations, and federal agencies. The roadmaps offer a clear vision of innovation for biomanufacturing processes and platforms, and address technology needs and opportunities for process optimization, analytics, and standards development.

NIIMBL is funded by the US Department of Commerce’s National Institute of Standards and Technology (NIST) with support from industry and academic institutions. It launched in March 2017 with a goal of accelerating innovation, supporting development of standards to enable more efficient and rapid biomanufacturing capabilities, and helping to educate and train a bioprocess workforce. In 2017, NIIMBL teamed with BPOG (an industry group of end users and suppliers) to help develop these roadmaps.

“We teamed with BioPhorum to leverage their expertise in facilitating the roadmap development process,” NIIMBL spokesperson Daniel Maiese told BioProcess Insider. “Our collaboration also enables NIIMBL to synergize its US roadmapping efforts with the BioPhorum’s global technology roadmap. The NIIMBL roadmaps will become part of that. As a public–private partnership, NIIMBL was able to convene subject matter experts from several stakeholders groups including manufacturers, suppliers, academic institutions, and federal government. This helped provide broad perspective and input into the technology gaps and areas of opportunities for each of these product classes.”

Download the ADC/bispecifics roadmap here: https://niimbl.force.com/s/ads-bispecifics-roadmap.

AJINOMOTO BIO-PHARMA ENTERS THE RAPIDLY GROWING ADC SPACE
29 November 2018: Contract development and manufacturing organization (CDMO) Ajinomoto Bio-Pharma Services has launched a bioconjugation technology that it says offers high productivity and short conjugation reaction times. AJICAP technology helps ADC developers control the location of payload conjugation to an antibody and fine-tune the quantity of payload attached.

“The technology deploys a proprietary affinity peptide to direct controlled conjugation to a specific site on the antibody in a relatively straightforward synthetic process,” senior director of business development Jason Brady told BioProcess Insider. Unlike other such technologies, it “does not require genetic modification of the antibody, nor does it require any esoteric chemistry to achieve a drug-to- antibody ratio (DAR) of two,” he continued. That is widely considered to be the optimal value.

“ADCs that are currently commercially available are produced as heterogeneous mixtures containing a randomly determined distribution of payloads decorating the antibody molecules,” Brady explained. “Controlling the DAR in the development of next- generation ADCs is believed to assist in increasing the therapeutic window of these targeted biologics, leading to overall better clinical efficacy and less toxicity.” So the technology can be transferred easily to production, he says, because “it shows high productivity and short conjugation reaction times, which all lead to an ease of manufacture.”

According to this year’s CPhI Annual Report, the ADC space is predicted to expand at nearly 20% until 2030, with 17 new drugs currently in late-stage development and double-digit approvals of ADCs expected over next three years. Outsourcing of ADC manufacturing is expected to top 70% of overall ADC manufacturing, driven by small companies in the pipeline needing specialist development expertise and facilities.

Brady told us his company has entered the space because “oncology continues to be the fastest growing segment of the biopharmaceutical market, and ADCs are a rapidly growing class of the oncology therapeutics.” He reiterated the report findings, adding that demand is coming primarily from emerging biotechnology as well as mid-sized to large pharmaceutical companies with a focus on oncology therapeutic development.

Although his company has not divulged its investment in this technology, Brady said that the platform emerged from Ajinomoto’s internal R&D organization in Kawasaki, Japan, and the company has trained and recruited staff capable of working with clients to test it.

ASTRAZENECA SIGNS $6.9 BILLION ADC DEAL WITH DAIICHI SANKYO
3 April 2019: AstraZeneca and Daiichi Sankyo will codevelop cancer ADC DS-8201 in a collaboration worth up to $6.9 billion. AstraZeneca will pay $1.35 billion (€1.2 billion) up front for rights to DS-8201 (trastuzumab deruxtecan). The UK company will pay a further $5.5 billion if this drug achieves regulatory and sales targets. Under the agreement, Daiichi will manufacture DS-8201. AstraZeneca will help develop and sell it worldwide except in Japan, where Daiichi has exclusive rights.

Spokesman Rob Skelding said that AstraZeneca’s background in commercial development of cancer drugs was key to the partnership. “AZ is the chosen partner due to its scientific heritage in developing and marketing some of the most transformative drugs for the treatment of breast cancer over the past several decades along with recent scientific leadership in lung cancer.”

Targeting Cancer: DS-8201 is produced using Daiichi’s DXd ADC technology based on a linking peptide that joins the antibody and drug components and breaks down after the drug binds to a target cell. The product has breakthrough therapy and fast-track status in the United States for breast cancer, and it has accelerated-review designation for gastric and gastroesophageal junction cancer in Japan. DS-8201 is in trials as a treatment for several types of HER2- expressing tumors, including cancers of the breast, lungs, and gastric system.

“A broad and comprehensive global development program with trastuzumab deruxtecan is under way in North America, Europe, and Asia including five pivotal studies,” Skelding said, adding that the partners will share all R&D costs 50/50. They will seek approval for breast-cancer treatment this year. “A first regulatory submission is scheduled for the second half of 2019 for patients in the advanced or refractory breast cancer setting.”

CELLTRION JUMPS INTO ADC SPACE THROUGH CANADIAN PARTNERSHIP
10 April 2019: Korean drugmaker Celltrion has signed a deal with Canadian company iProgen Biotech to develop an ADC pipeline. Although it is best known for a portfolio of marketed biosimilars, Celltrion has been investing in internal R&D and has five antibodies in development for diseases ranging from rabies to influenza. Now the company is planning to develop up to four ADCs through this partnership agreement.

Financial details were not divulged, but spokesperson Gunn Lee told BioProcess Insider that the deal forms part of his company’s strategy in “not just developing and commercializing MAb biosimilars, but also researching new drug candidates,” which will drive future growth. Celltrion will manufacture and supply four recombinant antibodies to iProgen (two of which will target HER2 and CD20) and provide support for the chemistry, manufacturing, and control (CMC) aspects of an investigational new drug (IND) application and phase 1 clinical trial conducted by iProgen.

ADCs show great promise in targeting cancer. But only a few are currently available on the market. In 2010, Pfizer voluntarily withdrew its ADC Mylotarg (gemtuzumab ozogamicin) after results from a postapproval clinical trial raised safety and efficacy concerns. But the product was reintroduced in 2017.

Meanwhile, the industry continues to invest in this sector, with companies such as Pfizer, Roche, Takeda, and Daiichi Sankyo investing in R&D and manufacturing over the past few years. Outsourcing technology and manufacturing companies also have invested in this space, including WuXi Biologics, Lonza, Piramal, ADC Bio, and Althea.

Dan Stanton is editor of BioProcess Insider, [email protected]. Gareth Macdonald is a freelance contributor. You can subscribe to receive the twice weekly BioProcess Insider newsletter and stay caught up with the latest ADC and biopharmaceutical manufacturing news.