Fred Aslan, MD, Artiva Biotherapeutics President and CEO

From its inception two years ago, Artiva Biotherapeutics focused on producing natural killer (NK) cell therapies, with help from a South Korean seed investor, as the cornerstone of its business model even before turning its attention to researching them and developing them into cancer treatments.

“Our differentiation is that we really started with a manufacturing-first approach, based on ten years of work performed by our partners Green Cross Holdings Corp (GC) and its GC LabCell,” Artiva President and CEO Fred Aslan, MD, told GEN.

Apparently Artiva’s manufacturing-first approach has paid off. The San Diego startup inked an up-to-$1.88 billion exclusive global collaboration and license agreement with Merck & Co. to develop novel chimeric antigen receptor (CAR)-NK cell therapies targeting solid tumor-associated antigens.

Merck and Artiva have agreed to partner on an initial two CAR-NK programs, with the pharma giant retaining an option for a third. Merck has already selected the first target, and the companies have a short list of preferred targets for the other programs, said Peter Flynn, PhD, Artiva’s Chief Operating Officer.

“It will be several years, I’d guide, before an IND for the first program,” Flynn said. “This year will be about identifying the best binding element for the extracellular part of the CAR, which is usually an antibody-like motif.” Merck’s biologics expertise will assist in identifying good binders. “This year will then be construction and optimization of structures within the cellular product,” Flynn said.

For each program under their collaboration, Merck will provide funding to Artiva — $30 million upfront for the first two programs, and $15 million more if it exercises its option for the third.

Merck also agreed to pay Artiva up to $612 million per program in payments tied to achieving development and commercial milestones, plus royalties on sales of any product derived from the collaboration.

On the Way

“The overarching goal for Artiva was to basically create a traditional biologics business model for cell therapy,” Flynn said. “We are well on the way.”

Merck and Artiva will not disclose the targets for their planned NK cell therapies, but they are not in Artiva’s current or planned pipelines.

Artiva’s pipeline is led by AB-101, an allogeneic NK cell therapy. The company is enrolling patients into a Phase I/II trial (NCT04673617) designed to assess the safety and clinical activity of AB-101 alone and in combination with the anti-CD20 monoclonal antibody rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) who have progressed beyond two or more prior lines of therapy.

“We anticipate probably having some data to show maybe later this year,” Flynn said, adding that the company aims to present that data at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition in December.

Also in Artiva’s pipeline are two preclinical CAR-NK cell therapy candidates: AB-201, which targets HER2-positive solid tumors; and AB-202, which targets CD19 positive B-cell malignancies. “We anticipate INDs for those over the next 18 months,” Flynn said.

Artiva says its collaboration with Merck will apply its novel NK-specific CAR costimulatory structures and proprietary NK cell manufacturing platform, which is designed to generate allogeneic NK cells from healthy donor umbilical cord blood (UCB) units selected for key characteristics. The company says its proprietary, large-scale, campaign-based manufacturing process can produce enough pure and highly active NK cells to treat hundreds to thousands of patients, with the opportunity for repeat dosing, from each UCB.

The NK cells are engineered to express proprietary CARs that are optimized for use in those cells, and/or can be combined with antibodies to further enhance their therapeutic activity and specificity against tumor cells. The NK cells are cryopreserved and ready for off-the-shelf therapeutic use, without needing manipulation upon arrival at clinical sites.

Artiva was incorporated in 2019 and formally launched in June 2020 when it emerged from stealth mode with $78 million in Series A financing. 5AM Ventures, venBio Partners, and RA Capital Management co-led the financing, joined by Medivate Partners and seed investors and strategic partners GC and GC LabCell.

Platform Pivot

Seoul-based GC LabCell developed the NK cell manufacturing platform used by Artiva, based on work that started around 2008-2009, with a clinical study launched in 2010.

Artiva credits its manufacturing success to more than a decade of work by seed investor and partner GC LabCell, which has a research and GMP manufacturing facility in Seoul. [Artiva]
GC started out its platform with peripheral blood derived NKs, then pivoted to cord blood after seeing improved scalability and consistency from donor to donor. Over that time, GC also developed a proprietary engineered feeder cell.

Artiva sources cord blood units in the U.S., and ships them to GC LabCell in South Korea, where the NK cells are manufactured and cryopreserved before being shipped back to the U.S., where they are then distributed to clinical sites, thawed, and infused into patients.

“We take the NKs from that cord blood unit. They’re exposed to this engineered feeder cell, which drives activation of the NK cells, which in turn drives expansion of the NK cells,” Flynn explained. This happens in two steps. “We derive the NK cell master cell bank from every cord blood unit that we purchase, which is then cryopreserved. We then take a vial of that master cell bank, and that goes through a subsequent two-week bioreactor process, where again they’re exposed to this engineered feeder cell. That results in the massive expansion of the NK cells.”

For its lead candidate AB-101, Artiva estimates, it can derive from every UCB between 4,000 and 8,000 vials, at 1 billion cells per vial of pure NK product over the course of a few weeks.

“Huge Level of Interest”

Artiva’s focus on manufacturing, plus growing interest from drug developers in NK cell-based therapies, helped the company attract interest from several biopharmas when it started some business development outreach last year at the J.P. Morgan 38th Healthcare Conference.

Peter Flynn, PhD, Artiva’s Chief Operating Officer.

“There was a huge level of interest,” Flynn said, for several reasons.

One was the success of CAR-T therapies starting with Novartis’ Kymriah® (tisagenlecleucel), approved in August 2017, and Kite, a Gilead Company’s  Yescarta® (axicabtagene ciloleucel), approved two months later. Kymriah sales grew each quarter in 2020, rising to $141 million in fourth-quarter sales and $474 million for all of last year. Yescarta’s 2020 sales stood at $563 million up 23.5% from $456 million in 2019, including $129 million in Q4, up about 6% from $122 million a year ago.

Flynn also cited the acquisition of Kite by Gilead for $11.9 billion in 2017, and of Juno Therapeutics by Celgene for $9 billion the following year. Celgene has since been bought by Bristol-Myers Squibb for $74 billion.

Last year, several positive announcements stoked more biopharma enthusiasm for NK cell therapies. In results published February 6, 2020 in The New England Journal of Medicine, researchers from MD Anderson reported success with umbilical and cord blood-derived CAR-engineered NK cells in a first-in-human Phase I/II trial (NCT03056339) of CAR-NK cell therapy for patients with relapsed or refractory B-cell hematologic malignancies. Of 11 patients who received the therapy at three different dose levels, eight responded (73% overall response rate), with seven patients (64%) achieving complete remission (64%). None showed major toxic effects.

Also at ASH, Fate Therapeutics presented results from a Phase I study (NCT04023071) showing 3 of 4 heavily pretreated patients with relapsed / refractory B-cell lymphoma achieved an objective response, including two complete responses (CR), following treatment with FT516, Fate’s universal, off-the-shelf natural killer (NK) cell product candidate, in combination with rituximab. FT516 is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor.

Also, Gamida Cell presented positive results from a Phase I trial (NCT03019666) showing that its NK cell-based cancer immunotherapy GDA-201 used with monoclonal antibodies showed positive clinical activity in heavily pretreated patients with advanced non-Hodgkin lymphoma (NHL). Of 19 patients with NHL, 14 responded to treatment (74% ORR) with 13 of the 14 showing complete responses (68%).

Looking Beyond Blockbuster

Of the biopharmas with which Artiva engaged, Merck emerged as the most attractive to the NK cell therapy startup.

“We did find in Merck, being a top-5 pharma company with a leading immune-oncology franchise, a very knowledgeable partner that will help pursue these potentially transformational opportunities,” Aslan said. “And very important for Artiva, it’s an important source of external validation for the maturity and potential of our process development and manufacturing capabilities.”

For Merck, NK cell therapies represent a potential broadening of the company’s anti-cancer pipeline, now anchored by Keytruda® (pembrolizumab). The checkpoint inhibitor blockbuster immunotherapy racked up $14.380 billion in sales last year, up 30% from $11.084 billion in 2019–including $3.993 billion during the fourth quarter, up 28% from $3.111 billion in Q4 2019.

Nicholas Haining, BM, BCh, Vice President, Head of Discovery Oncology and Immunology, Merck Research Laboratories, added in a statement: “At Merck, we continue to explore new ways to transform the most innovative science into better therapies for patients who need them most. We look forward to working with the team at Artiva with the hope of developing new NK cell-based treatments for cancer.”

The COVID-19 pandemic forced the companies to combine virtual with face-to-face meetings. Artiva and Merck were able to do both since South Korea was able, during the pandemic’s initial months, to contain SARS-CoV-2 effectively enough to avoid the lengthy lockdowns carried out in Europe and the U.S.

“They were very interested in the manufacturing facilities, and can we really achieve what we say we can achieve?” Flynn recalled. “We had first person tours of the manufacturing facility we shared with them initially, so they could actually physically see the equipment and the facility,” Flynn recalled. “The facility always stayed open [with people wearing masks], the facility and our research facility, and that’s been a huge benefit to us. We haven’t had any down time in R&D, because it’s all in South Korea.”

As a result, he added, groups from Merck’s South Korean entity MSD Korea could travel to GC LabCell’s research and GMP manufacturing facility in Seoul, and tour the facility.

“They actually had boots on the ground due diligence as well as virtual due diligence,” Flynn said. “Hopefully what they saw in us, I think, was this ability to deliver on this manufacturing capability, which really fits the pharma business mode.”

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