Soon after joining Innate Pharma more than four years ago, chairman and CEO Mondher Mahjoubi, MD, charted a course for the immuno-oncology drug developer based on a promising finding in the first patient administered in a Phase I trial of its first cytotoxicity-inducing antibody. The drug was an in-house candidate called lacutamab (IPH4102) that was being studied in patients with a rare cancer.
“The first patient enrolled in the Phase I trial responded to lacutamab at the first dose level” of 0.0001 mg/kg, Mahjoubi told GEN Edge. “We thought this was quite rare if not unique in Phase I, because Phase I was not meant to detect the activity of the drug. It was essentially for the durability.”
Mahjoubi told his team, “we have a medicine here. It should be our top priority, and our goal should be to bring this medicine to the patients who need it the most.” Mahjoubi previously led AstraZeneca’s oncology division before taking the helm of Innate on at the end of 2016.
Since then, Mahjoubi has made the development of lacutamab the top priority for the French biotech, as it builds out a pipeline of antibodies against cancer. The antibody has since progressed to the Phase II TELLOMAK trial (NCT03902184), which is assessing lacutamab’s efficacy and safety in patients with advanced cutaneous T-cell lymphoma (CTLC).
In February, Innate advanced the trial to its second stage, announcing that lacutamab showed a “positive early signal” in the study’s second cohort of patients with a subtype of CTCL, KIR3DL2-expressing mycosis fungoides, sooner than anticipated. The company won’t disclose that signal until it presents preliminary data at a scientific meeting later this year, Mahjoubi said.
“Beyond just response rates, we believe disease control rate could provide best read on treatment benefit,” Daina Graybosch, PhD, managing director, Immuno-Oncology and a senior research analyst with SVB Lerink, and two colleagues, reported in a February 24 research note.
“Management reiterated [to us] today that achieving stable disease is clinically meaningful in MF [mycosis fungoides], given how debilitating symptoms of MF (like pruritis) can be on patient’s quality of life (QoL). We note that QoL is a key secondary endpoint in TELLOMAK and an important one for regulators.”
Results from the Sézary cohort should be published next year, Mahjoubi said. Graybosch observed that those results would be “likely the first to file opportunity for lacutamab,” adding that “future data readouts will answer how broad lacutamab’s opportunity will be.”
That progress followed the resumption of recruitment in TELLOMAK in June 2020, after the FDA had imposed a partial clinical hold six months earlier, with several European countries temporarily halting the study.
The regulatory setbacks came after Innate’s fill-finish manufacturing subcontractor, Rentschler Fill Solutions (RFS), unilaterally withdrew the Certificate of Conformity it received from Austria’s drug regulator for batches of lacutamab that included one used in the trial. RFS declared bankruptcy at the end of 2019.
“We had to inform the health authority in Europe and in the U.S. about the facts and decided to put on hold the study ourselves for a very simple reason: We wanted to stop using that batch coming from the provider that went bankrupt,” Mahjoubi said.
“We had to pause the recruitment about six months, essentially in the U.S.,” by which time French and U.K. regulators allowed Innate to resume accruing patients, followed later by authorities in Germany, Italy, and Spain.
“The FDA decided to put the study on hold until we come with a new batch. So it cost six months in the process of bringing this new medicine to patients. But hopefully now we can catch up from that delay that we had at the beginning of the study, with the reopening of [clinical] sites as well as the opening of new sites to help catch up.”
Lacutamab is a first-in-class antibody under study in patients with mycosis fungoides and Sézary syndrome, both CTLC subtypes. Lacutamab targets KIR3DL2, a tumor marker expressed in most CTCL subtypes. Trials in peripheral T-cell lymphoma (PTCL) are expected to launch later this year.
KIR3DL2 is an inhibitory receptor of the KIR family, with only a restricted expression on normal tissues. However, KIR3DL2 is expressed by about 65% of patients across all CTCL subtypes and expressed by up to 90% of patients with more aggressive CTCL subtypes, especially Sézary syndrome, and up to 50% of patients with PTCL.
Two additional trials
Patients with relapsed/refractory PTCL will be the focus of two additional parallel trials set to start later this year. One is a company-sponsored Phase Ib study designed to assess lacutamab as a monotherapy in KIR3DL2-expressing patients with relapsed PTCL, set for the first half of 2021.
Set to start in the second half is the Phase II KILT (anti-KIR in T Cell Lymphoma) trial, in which the Lymphoma Study Association (LYSA) will launch an investigator-sponsored, randomized trial designed to compare lacutamab in combination with chemotherapy GEMOX (gemcitabine in combination with oxaliplatin) versus GEMOX alone in KIR3DL2-expressing relapsed/refractory patients.
Lacutamab generated positive results in its Phase I trial (NCT02593045) in relapsed/refractory CTLC, which dosed its first patient in December 2015. Data showed lacutamab generating a confirmed global overall response in 16 of 44 patients (36%), of which all but one response was seen within the 35 Sézary syndrome patients evaluated (43%). About 90% showed disease control—namely an improvement of their quality of life with significant reduction in their pruritus.
“IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome,” Prof. Martine Bagot, MD, PhD, of Hôpital Saint Louis in Paris, and colleagues conducting the Phase I wrote in a 2019 study published in The Lancet Oncology. “If confirmed in future trials, IPH4102 could become a novel treatment option for these patients.”
Lacutamab enjoys the European Medicines Agency’s PRIME designation as a treatment for relapsed or refractory Sézary syndrome (SS) in patients who have received at least two prior systemic therapies—the first time the EMA’s PRIME designation has been granted for a potential treatment of any sub-type of T-cell lymphoma. The FDA earlier granted lacutamab its Fast Track designation.
Engaging NK, tumor cells
Innate Pharma’s other development priority, Mahjoubi said, is its multi-specific NK cell engager (NKCE) antibody platform—the focus of an up-to-€400 million ($471 million) collaboration with Sanofi launched in 2016. In January, Innate gained a €7 million ($8.2 million) milestone payment from Sanofi after it agreed to advance their lead NKCE antibody candidate, IPH6101 (also called SAR443579) into IND-enabling studies. The companies began a GLP-tox study for IPH6101, with plans to launch a clinical study, possibly as soon as this year.
“Hopefully, by the end of the year, early next year—[Sanofi] did not disclose exactly the date, but the idea is to go fast and enter the clinic as soon as possible,” Mahjoubi said.
“We try to engage NK cells with tumor cells, so they can not only act in attacking and destroying these cancer cells, but also release all sorts of cytokines that boost the T cell response,” he said of the platform. “Depending on the tumor antigen that the company selects, we can use as many antibodies as possible.”
IPH6101 is a NKp46-based NKCE based on Innate’s proprietary multispecific antibody format. According to a 2019 study published in Cell by a team led by Laurent Gauthier, PhD, Innate’s director of research & drug development, NKCEs are multifunctional antibodies designed to trigger tumor-cell destruction by targeting two activating receptors, NKp46 and CD16, on NK cells, as well as a tumor antigen on cancer cells.
“Our multi-specific technology provides a versatile platform with different format options and the potential to co-engage up to three different activating receptors on NK cells and two different tumor antigens on cancer cells,” Laurent’s team wrote. “Together with the stronger anti-tumor activity of these molecules in preclinical models than of gold standard mAbs, such as rituximab, obinituzumab, and cetuximab, these results support the clinical development of NKCEs for cancer immunotherapy as a complement to existing immuno-oncology approaches.”
Innate Pharma is also partnering with Sanofi to develop another NKCE antibody using an undisclosed tumor antigen—and working separately with AstraZeneca to use the platform with a tumor antigen specific to that company.
“We will be presenting a new set of data this year about the level of activity with preclinical models that we have developed in-house that is quite impressive,” Mahjoubi said.
Furthest along in Innate’s pipeline is another candidate partnered with AstraZeneca under an up-to-$1.275 billion collaboration launched in 2015. Monalizumab (IPH2201) is a potentially first-in-class immune checkpoint inhibitor targeting receptors for NKG2A, an inhibitory checkpoint receptor for HLA-E, that is expressed on tumor infiltrating cytotoxic CD8+ T cells and NK cells.
In October, AstraZeneca dosed the first patient in the Phase III INTERLINK-1 trial (NCT04590963), a randomized, double-blind, multicenter, global study designed to compare the efficacy and safety of monalizumab and cetuximab compared to placebo and cetuximab, in an estimated up to 600 patients with recurrent or metastatic head and neck squamous cell cancer (R/M SCCHN) who have been previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.
The first-patient dosing triggered a $50 million milestone from AstraZeneca, with Innate eligible to receive another $50 million milestone payment should the interim analysis demonstrates the combination meets a pre-defined threshold of clinical activity. To date, Innate has received $400 million from AstraZeneca.
“There is an interim analysis that is planned after 18–24 months, when the pre-specified number of patients is accrued, so we could expect at least two years before we have the interim analysis,” Mahjoubi said.
Last year, Innate presented efficacy data at scientific conferences from a Phase II expansion cohort investigating the combination of monalizumab and cetuximab in R/M SCCHN patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors. The data showed an overall response rate in line with previously reported data and a manageable safety profile.
That cohort was doubled last year, from 20 to 40 patients, as part of a study assessing a combination of monalizumab, cetuximab and durvalumab in first-line immuno-oncology (I/O) naïve patients with R/M SCCHN. Recruitment for that cohort is complete, with data expected to be published later this year.
Among Innate’s other pipeline candidates are:
- Avdoralimab (IPH5401), a Phase II anti-C5aR1 antibody being developed to treat COVID-19 and bullous pemphigoid. Last year the company halted enrollment in the Phase I STELLAR-001 study (NCT03665129) in three oncology indications, based on data from cohort expansions in non-small cell lung cancer and I/O-naïve hepatocellular carcinoma.
- IPH5201, a Phase I blocking antibody targeting the CD39 immunosuppressive pathway, also partnered with AstraZeneca. The first patient was dosed last year in a Phase I trial (NCT04261075) evaluating IPH5201 alone or in combination with durvalumab (anti-PD-L1) with or without oleclumab (anti-CD73) in advanced solid tumors.
- IPH5301, a preclinical, proprietary CD73-blocking antibody that according to Innate could promote anti-tumor immune responses across a wide range of tumors.
- Two other preclinical candidates against undisclosed targets, both partnered: IPH6101 (with Sanofi), and IPH62 (with AstraZeneca)
Sanofi and AstraZeneca are among biopharma giants with which Innate has partnered since it was established in 1999 by four scientists focused on innate immunity and two biopharma executives: Hervé Brailly, PhD, chairman of the company’s Supervisory Board; Eric Vivier, DVM, PhD, chief scientific offer and a professor at Aix-Marseille University; Marc Bonneville, DVM, PhD, of Institut Mérieux; and the late Alessandro Moretta, MD, PhD, of Genoa University; Jean-Jacques Fournié, PhD, director of CRCT (The Cancer Research Center of Toulouse); and François Romagné, PhD, director of the immunotechnology platform aMi-mAbs at Aix-Marseille and Innate’s former CSO.
While Innate’s 2020 revenue—derived from collaborations, licensing agreements, and government research funding—fell 18% year over year, to €70.45 million (nearly $83 million), Innate finished 2020 with a net loss of €63.98 million (about $75.4 million), more than triple the €20.76 million (about $24.4 million) net loss reported for 2019.
Much of that difference reflects Innate’s taking a €43.53 million (about $51.3 million) charge for impairment of intangible assets related to its decision in December to return to AstraZeneca the U.S. and E.U. commercialization rights of Lumoxiti (moxetumomab pasudotox-tdfk) for relapsed or refractory hairy cell leukemia—rights that the company assumed in 2018. Innate concluded that sales of the CD22-directed cytotoxin would be lower than anticipated, a gap it said was aggravated by the COVID-19 pandemic.
Innate says it remains in good shape to weather 2021, having ended last year with cash, cash equivalents, short-term assets, and financial assets of €190.571 million (nearly $224 million) as of December 31, 2020, down from €255.869 million ($300 million) a year earlier.
Innate bases most of its approximately 220 full-time equivalent employees at its headquarters in Marseilles, France, with the rest based at its U.S. operations hub in Rockville, MD.
That headcount has dipped 6% from a year ago, when Innate reported a workforce of 235 FTEs. “Innate Pharma expects this number to evolve over time to support the business priorities as needed,” a company spokesman stated.