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Years After Genetic Finding, Drugs Targeting CALR-Mutant Myeloproliferative Neoplasms Enter Trials


NEW YORK – More than a decade after mutations in the CALR gene were first linked to the development of myeloproliferative neoplasms, CALR-targeted drug candidates are advancing to Phase I clinical trials.

If these drugs reach the market, they could provide a treatment option for a group of patients with myelofibrosis and essential thrombocythemia who typically must wait until their condition turns serious to attempt a risky stem cell transplant.

About 300,000 patients in the US have myeloproliferative neoplasms. Kapila Viges, CEO of the MPN Research Foundation, said patients can have very different presentations of the disease, and it can take "years or decades" to get a diagnosis. Although myeloproliferative neoplasms are classified as chronic cancers that patients can live with for many years with blood count monitoring, Vigas said some patients can abruptly progress, and their condition can become serious.

"That uncertainty is really concerning to patients," Viges said. "We think from a psychosocial perspective, it's worse than an acute cancer because while cancer may be more serious, it's predictable, and there's a plan and a protocol, whereas when you're diagnosed with [a myeloproliferative neoplasm] watch and wait is almost a first-line approach. It just adds to the anxiety."

Currently available treatments include JAK1/2 inhibitors and allogeneic stem cell transplantation. If myeloproliferative disorders are untreated or if patients fail first-line therapy, that can lead to a poor prognosis and progression to more aggressive disease, including acute myeloid leukemia.

Roughly 50 percent to 60 percent of patients with myeloproliferative disorders carry a mutation in JAK2, and about 5 percent to 10 percent have a mutation in the thrombopoietin receptor gene MPL. In December 2013, a pair of papers published in the New England Journal of Medicine proposed that mutations in CALR could be a third category for classifying myeloproliferative disorders, accounting for 25 percent to 35 percent of patients.

Following these reports, many patients who had not tested positive for JAK2 and MPL finally had the chance for a concrete diagnosis, and a genetic driver to connect to their disorder, even if they did not yet have a treatment.

Translating that insight into a therapy required more research to pin down the mechanisms underlying the role of the CALR gene and the protein it encodes, called calreticulin, in myeloproliferative disorders, according to Patrick Mayes, head of biology at the biopharmaceutical company Incyte.

Because calreticulin is a highly conserved chaperone protein located in the endoplasmic reticulum, it was initially unclear how it could lead to the myeloproliferative neoplasm phenotype. But in a study published in Cancer Discovery in 2016, researchers showed that mutations in CALR gave the protein an abnormal, positively charged C-terminal tail, resulting in a "kind of rogue chaperone function," according to Mayes. The complex is then transported to the cell surface where, like JAK2, it activates the JAK-STAT pathway, leading to oncogenic transformation of the cells.

That discovery, plus subsequent studies clarifying the interaction of mutant CALR and MPL, allowed drugmakers to begin targeting CALR therapeutically.

At Incyte, researchers reasoned that inhibition of mutant CALR signaling should lead to reversion of the phenotype in patients with myeloproliferative disorders. "We started campaigns to look for molecules that specifically inhibit mutant calreticulin function about five years ago," Mayes said. "And because this is occurring at the cell surface, we believed that antibodies were the best way to modulate this."

Incyte markets the JAK1/2 inhibitor Jakafi (ruxolitinib) and is advancing a pipeline of investigational therapies for blood disorders, including INCA33989, a mutant CALR-targeted monoclonal antibody. In preclinical studies, treatment with INCA033989 reduced levels of mutant CALR and showed signs of activity against the disease.

Incyte filed an investigational new drug application for INCA033989 in 2023 and is now advancing it in the LIMBER Phase I dose-escalation trial. In the trial, Incyte researchers will evaluate the safety, tolerability, and dose-limiting toxicity of INCA033989. They will also determine a recommended dose for expansion and a maximum-tolerated dose in patients with myelofibrosis or essential thrombocytopenia with a documented CALR exon-9 mutation.

In a separate Phase I study within the LIMBER trial, researchers will also test INCA033989 alone or in combination with Jakafi in the same setting. Secondary endpoints for both studies will include measures of disease response including anemia, change in symptoms, and changes in mutant CALR burden.

"We're aiming to modify the disease in a meaningful way. We want to eliminate the mutant [CALR] clone, if at all possible," Mayes said, explaining that by the time patients with myelofibrosis enter clinical studies, they typically have advanced disease and a high variable allelic frequency (VAF) for CALR. The investigators will track that number in patients, looking for an elimination or reduction of the mutant CALR clone.

"We believe this is a drug that has the potential to target the stem cell, which drives the disease and is hopefully going to modify the disease or potentially [result in] a cure for these patients in the long term," Mayes added. Incyte is hoping to share this initial Phase I data in late 2024 or early 2025.

Johnson & Johnson is also advancing a CALR-directed drug in a Phase I clinical trial. JNJ-88549968 comprises a bispecific antibody designed to bridge mutant CALR and a T cell with subsequent T-cell mediated cytotoxicity against the cancer cell. The drug was discovered by the Austrian biotech company MyeloPro, which partnered with J&J subsidiary Janssen to codevelop the drug.

In preclinical studies, JNJ-88549968 showed selective binding to CALR-mutated cell lines, did not bind to wild-type cells, and demonstrated cytotoxicity toward patient-derived CALR-mutated CD43-positive cells. The drug also had activity in xenograft murine leukemia models.

In the trial, J&J researchers will determine the recommended Phase II dose and an optimal dosing schedule for the drug in patients with myelofibrosis or essential thrombocytopenia who test positive for CALR driver mutations. As secondary outcome measures, they'll be tracking the number of participants with anti-drug antibodies, overall response rate, complete response rate, time to response, and duration of response.

The drugmaker believes that JNJ-88549968 has curative potential in CALR-mutant disease. Robert Kralovics, MyeloPro cofounder and one of the researchers who originally identified disease-causing mutations in CALR, said the drug could potentially eliminate disease-causing, CALR-mutated stem cells. "Resolution of symptoms would follow once the pathologic cells are removed," he added, but cautioned that resistance mechanisms could develop, as has been seen with other antibody-based cancer treatments. However, he said the most common resistance mechanism, loss of surface antigen expression, is not possible because the complex must be membrane expressed to function as an oncogene.

J&J did not respond to a request for an interview about JNJ-88549968.

The MPN Research Foundation, meanwhile, is expanding its support for research into myeloproliferative neoplasms in 2024 by launching a large-scale patient registry including data from electronic medical records and information about the natural history of the disease. Viges said the foundation will allow researchers to learn more about the origins of myeloproliferative disorders and how progression-related events take place. They will also partner with industry to provide support for clinical trials and identify new biomarkers that can be used as endpoints.

Viges said the new registry will include input from all stakeholders, especially patients, "to make sure their voices, unmet needs, and symptom burdens are considered."