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After Setbacks, Innate Pharma on Track to Advance NK Cell-based Immunotherapy Pipeline

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NEW YORK – After a difficult 2020, Innate Pharma has started this year with a string of positive news about drugs in its pipeline and is aiming to prove that its technology has promising potential in treating cancer patients.

In the multi-cohort Phase II TELLOMAK trial, Innate's lead drug lacutamab yielded a prespecified number of responses in a biomarker-defined cohort of cutaneous T-cell lymphoma (CTCL) patients, based on which the company said it would advance the drug into the next stage of the study. Innate said it would also evaluate lacutamab in clinical trials for the more common peripheral T-cell lymphoma (PTCL).

Meanwhile, Innate's NKp46-based natural killer cell engager (NKCE), IPH6101, which it is developing in collaboration with Sanofi, is heading into investigational new drug application-enabling studies. Based on the terms of Innate's licensing deal with Sanofi, this milestone, announced in January, triggered a €7 million ($8.4 million) payment to Innate.

The string of good news was a welcome change for Innate, a biopharma firm founded in France nearly two decades ago that, as the name of the company suggests, is focused on advancing immunotherapies that take advantage of the innate immune system.

The firm, which incorporated a wholly owned US subsidiary in 2008 and was listed on the NASDAQ in 2019, had a challenging 2020.  

Early last year, Innate paused enrollment in the TELLOMAK trial after the vendor that handled lacutamab's fill and finish operations such as filling vials and packaging the drug for distribution went bankrupt. Several months later after Innate hired a new vendor, regulators gave the company permission to resume enrollment.

But that bit of good news was tempered in September when the company announced it would receive $50 million in milestone payments — not the originally announced $100 million — from its collaborator, AstraZeneca, after the first patient was dosed in a Phase III trial of monalizumab, which the companies are developing for squamous cell carcinoma of the head and neck, among other solid cancers. Even though Innate would be eligible to receive an additional $50 million contingent on the study results, the firm's shares dropped 27 percent and many of its investors were angry enough to pursue a class action lawsuit.

Innate finished the year by relinquishing its commercialization rights for moxetumomab pasudotox-tdfk (Lumoxiti) — the only commercialized asset in Innate's portfolio, which has regulatory approval for relapsed or refractory hairy cell leukemia — to its original developer, AstraZeneca.

Despite the series of setbacks last year, Innate CEO Mondher Mahjoubi is optimistic that the company is again on track to prove that the innate immune system has untapped potential when it comes to treating cancer. Most of the focus in immunotherapy development to date, Mahjoubi said, has been on the adaptive immune system, namely T cells, but these approaches have limits.

"The company was created on the very basic but fundamental belief that … in order to pique the cascade of reactions that lead to the immune response against cancer, it is paramount to boost and unleash NK cells," Mahjoubi said. "We are quite unique in that we are trying to tackle the NK cells instead of going after T cells, which of course everyone is doing."

While advances in immunotherapy have dramatically improved cancer care over the past decade, Mahjoubi sees a great deal of unmet need and opportunity to improve patient outcomes. In his view, a new generation of immune-oncology drugs can address that need by marshalling the power of NK cells and innate immunity.

Advancing lacutamab

The cohort in the TELLOMAK trial that Innate recently announced would progress to the next stage comprises patients with a subtype of CTCL called mycosis fungoides, which express the protein KIR3DL2. Innate will share details on how many patients responded to lacutamab in this trial at an upcoming medical conference. So far, the company has described patients' responses as encouraging and pointed out that since a prespecified number of patients have responded, it can now advance the drug to the next stage of the trial much sooner than anticipated.

Mahjoubi said the company is eager to expand accrual in the study and share data with health regulators and discuss further development plans for lacutamab.

Lacutamab is already on health regulators' radar; the agent has received fast track status from the US Food and Drug Administration and PRIME designations from the European Medicines Agency as a treatment for relapsed or refractory Sézary syndrome, another type of CTCL being evaluated in a cohort of the TELLOMAK trial. Sézary syndrome has some overlap with mycosis fungoides as a CTCL subtype but affects the blood in addition to the skin and has a far lower survival rate. Innate chose to conduct its initial Phase I lacutamab trial in Sézary syndrome, which yielded a 43 percent overall response rate and a favorable safety profile when combined with initial safety data from the TELLOMAK trial.

Roughly 90 percent of patients with Sézary syndrome have cancers that express the KIR3DL2 target (defined as having immunohistochemistry staining in at least one percent of cells), which is only true for half of patients with mycosis fungoides. This explains why the larger Phase II TELLOMAK trial has two mycosis fungoides cohorts — one with KIR3DL2-expressing cancers and one with KIR3DL2 non-expressing cancers — but only one, all-comer Sézary syndrome cohort.

Based on what is known about the mechanism of the drug so far, Mahjoubi and others involved in lacutamab's development expect the agent is not going to perform as well, if at all, in the non-biomarker-expressing mycosis fungoides cohort. According to Mahjoubi, including that cohort in the TELLOMAK trial is necessary to prove to regulators that the drug is truly working in a targeted fashion.

The antibody lacutamab works by binding to cancer cells that express KIR3DL2 and then linking to CD16 on NK cells via the antibody's FC region. "Then the NK cells come into play and they destroy the cancer cells," said Mahjoubi.

"If you believe the mechanism of action [of lacutamab], it should not work in the non-expressing cohort," Mahjoubi said. Still, the cohort of patients who don't express the biomarker is necessary, he said, not only to satisfy regulators, but because it will also help Innate determine if a companion diagnostic is needed to identify best responders to the drug.

Beyond the TELLOMAK trial, Innate recently announced a Phase Ib trial investigating lacutamab's activity in KIR3DL2-expressing PTCL. The Lymphoma Study Association is also conducting a randomized, Phase II trial comparing lacutamab plus chemotherapy against chemo in KIR3DL2-expressing PTCL.

Progress on NK-cell engagers

While lacutamab is the most advanced proprietary agent that Innate has in its pipeline, the company believes monalizumab, which targets NKG2A receptors expressed on CD8-positive T cells and NK cells, has the potential to be a first-in-class immune checkpoint inhibitor. The drug, which Innate partnered with AstraZeneca to develop and was the focus of the milestone payment controversy, is currently being evaluated in combination with cetuximab (Eli Lilly's Erbitux) in a Phase III clinical trial for head and neck cancers, as well as in combination with several other agents for various solid tumors.

Despite the recent progress in the company's more advanced programs, Mahjoubi was most excited about the NK-cell engagers that the company has in preclinical development, including IPH6101, the agent licensed to Sanofi that is now moving into IND-enabling trials. These NK-cell engagers are the product of a multi-specific antibody generation platform that Innate has "built from scratch" over the last five or six years, according to Mahjoubi.

"We started developing multi-specific antibodies that target multiple receptors on the innate lymphoid cells, and in particular on NK cells … and at the same time target tumor antigens," he said, describing a three-armed antibody, with one arm linking with the tumor antigen, and the other two arms targeting two receptors expressed on the NK cells.

Mahjoubi described the tri-specific antibody as a way to "ignite the immune response" by summoning the NK cells into the tumor bed so they can simultaneously attack cancer cells while releasing cytokines that also attract T cells to the tumor. "You have this sort of translation from innate to adaptive natural immunity," he said. "That's the name of the game."