NEW YORK – Janux Therapeutics is betting that its pipeline of biomarker-driven T-cell engagers will overcome limitations typically seen in this class of immunotherapies, such as cytokine release syndrome and a short duration of response.
Bispecific T-cell engager (BiTE) immunotherapies comprise two epitopes: one that binds a tumor-associated antigen expressed on the tumor cell and one that binds a T-cell receptor antigen. The purpose of the design is to recruit T cells directly to the tumor microenvironment and avoid mechanisms of tumor evasion and resistance to checkpoint inhibitors.
Amgen's Blincyto (blinatumomab), which binds CD19 on B-cell lymphoblasts and CD3 on T cells, was the first BiTE immunotherapy approved by the US Food and Drug Administration in a cancer indication. The agency granted accelerated approval to the drug in 2014 as a treatment for patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) and for CD19-positive B-cell precursor ALL in 2018. Those accelerated approvals have since been converted to full approvals.
Other BiTE immunotherapies approved by the FDA include Janssen's BCMA/CD3 T-cell engager Tecvayli (teclistamab) in October 2022 and Roche's CD20/CD3-directed T-cell engager Lunsumio (mosunetuzumab) in December 2022 for multiple myeloma and follicular lymphoma, respectively.
However, success in solid tumors has been more elusive with BiTE immunotherapies due to mechanisms that suppress T cells within the tumor microenvironment and limit T-cell infiltration. Toxicities resulting from off-target effects on healthy tissue such as neurotoxicity and cytokine release syndrome have also challenged the use of this class of drugs in solid tumors.
San Diego-headquartered Janux was founded in 2017 to develop T-cell engagers with high tumor-specific activity. The central problem faced by drugmakers in this space, according to Janux President and CEO David Campbell, is that there are very few targetable antigens on a tumor cell that are truly cancer specific. "Invariably, they're also expressed in healthy tissue," said Campbell.
Janux is hoping to tackle the problem by designing molecules with a peptide "mask" covalently bound to the tumor antigen binding domain, either CD3 or CD28, via a tumor-specific cleavable peptide linker. The mask prevents the antibody from binding to a cell until it is removed by tumor-specific proteases, thereby avoiding healthy cells.
Janux is building two lines of products using this technology. The tumor-activated T-cell engager (TRACTr) platform produces T-cell engagers with a tumor antigen-binding domain and a CD3 T-cell binding domain. In contrast, the tumor-activated immunomodulator (TRACIr) platform produces bispecifics with a tumor antigen-binding domain and a costimulatory CD28 binding domain.
In preclinical studies, Janux's lead agent JANX007, which is a prostate-specific membrane antigen (PSMA)- and CD3-directed T-cell engager, showed enhanced safety and pharmacokinetic properties and activated T cells at 500-fold lower potency compared to a non-masked PSMA-directed T-cell engager. PSMA is overexpressed in more than 80 percent of prostate cancers.
Based on these preclinical insights, the company is conducting a Phase Ia trial in which metastatic castration-resistant prostate cancer (mCRPC) patients will receive JANX007 by intravenous infusion once a week in 21-day cycles. Investigators will increase the dose until a maximum-tolerated dose is identified, and then in the expansion stage, patients will receive doses at previously identified tolerable levels. Investigators are monitoring prostate-specific antigen (PSA) levels and PSMA expression in relation to patient response.
Initial data from eight patients in the dose-escalation portion of this trial showed that JANX007 was well tolerated; four out of five patients receiving flat doses saw PSA levels decrease by between 31 percent to 67 percent and three patients on step dosing had PSA reductions of less than 10 percent.
Some patients with PSA reductions also experienced grade 1 or 2 cytokine release syndrome, which Janux interpreted as being related to the treatment's anti-tumor properties rather than off-target effects on healthy tissue. No patients had grade 3 cytokine release syndrome.
"Our early safety data shows that we didn't have any adverse events reported in healthy tissues that also expressed PSMA," Campbell said. Healthy tissues that express PSMA include the salivary glands, gastrointestinal tract, kidney, and liver.
"If you trigger an immune response in those healthy tissues, you can have significant side effects," Campbell continued. "We look at the early clinical data as proof of principle that our technology was able to drive an anti-tumor response that spared healthy tissue that expresses PSMA."
In a note to investors in July about this data, analysts for the brokerage firm Wedbush Securities also recognized the promising safety profile of JANX007 compared to other T-cell engagers. "In contrast to other PSMA-TCE programs, no evidence of transaminitis or gastrointestinal effects were observed," wrote Wedbush analysts Sam Ravina, Ritika Das, and Robert Driscoll. "Together with the observation that cytokine release syndrome was limited to patients demonstrating PSA reductions, we believe this strongly supports the tumor-restricted mechanism of action of JANX007, which is designed to limit off-tumor toxicity."
Newly diagnosed patients with prostate cancer are typically treated with androgen deprivation therapy plus Janssen's CYP17 inhibitor Zytiga (abiraterone) or a similar therapy. The next line of treatment is Novartis' PSMA-targeted radiopharmaceutical Pluvicto (177Lu-PSMA-617). Beyond that, there are few treatment options. Wedbush analysts estimated that 36,640 patients with mCRPC in the US and 50,000 in the European Union will require treatment after progression on next-generation anti-androgen therapies.
Janux's second clinical stage program is an EGFR/CD3-directed T-cell engager, JANX008. In preclinical studies, JANX008 demonstrated improved safety and pharmacokinetics compared to a non-masked EGFR-directed T-cell engager and had potent activity in multiple ex vivo and in vivo colorectal cancer models.
Based on this, the firm began a Phase I trial of the drug in April in patients with advanced or metastatic solid tumors, focusing on colorectal cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and renal cell carcinoma. Campbell said the company chose those four tumor types because EGFR is overexpressed in anywhere from 50 percent to 95 percent of patients.
"We're collecting additional data using EGFR immunohistochemistry [testing]," Campbell said. "But we know the majority of patients in these four indications are going to overexpress EGFR, and therefore, be a candidate for our drug."
In the Phase I trial, Janux scientists will enroll up to 130 patients who will receive weekly JANX008 doses in 21-day cycles. The trial comprises a dose-escalation phase to determine the maximum-tolerated and recommended Phase II doses and a subsequent dose-expansion phase at the identified tolerable dose.
Campbell noted that the company is not selecting patients in the dose-escalation portion of the study using EGFR expression testing. "It's difficult to accrue patients if you have those sorts of entry criteria," Campbell said, noting that patients have multiple treatment options in this setting and that they often need to begin treatment immediately.
"We selected these [tumor types] because the vast majority of patients walking in the door are going to overexpress EGFR," Campbell said. He explained that while for now investigators are collecting data for informational purposes to figure out exactly how many and which patients are overexpressing EGFR, once the early Phase I results are in hand, the company would then be able to use EGFR expression as entry criteria in subsequent Phase Ib and Phase II studies.
For future marketing purposes, he envisions the patient selection strategy for JANX008 will likely be similar to Eli Lilly's EGFR inhibitor Erbitux (cetuximab), which is marketed for KRAS wild-type EGFR-expressing metastatic colorectal cancer as detected by an FDA-approved test.
Janux plans to provide a clinical update in 2024 after completing the dose-escalation and dose-optimization portion of this Phase I study.
According to Campbell, an EGFR-directed T-cell engager has the advantage over a small molecule EGFR inhibitor in that it can trigger the immune system to recognize and eliminate the tumor. "What we've all seen from the early checkpoint antibodies … is that when that immune system is triggered — and triggered well — some patients actually have such a long-lived response that you could almost use the word cure," he said.
Janux is hoping it can bring the long-lasting responses seen in some patients with Merck's Keytruda (pembrolizumab) and Bristol Myers Squibb's Opdivo (nivolumab) to those with EGFR-expressing solid tumors using its T-cell engager approach, though Campbell cautioned that its therapy programs are too early in development to demonstrate those types of enduring benefits. Additionally, Campbell said the resistance mechanisms associated with approved EGFR inhibitors are simply not relevant to EGFR-directed T-cell engagers because while mutations in EGFR can contribute to resistance to EGFR inhibitors, they do not affect T-cell engagers, which will recruit T cells when EGFR expression is present regardless of any mutations.
Among its other wholly owned assets, Janux has a TROP2/CD3-directed TRACTr program in development that is initially for triple-negative breast cancer, non-small cell lung cancer, and urothelial carcinoma, and a PD-L1/CD28-directed TRACIr program in solid tumors. Both are preclinical stage programs.
Janux is also developing two TRACTr programs under a 2020 collaboration agreement with Merck. In exchange for an exclusive worldwide license to products developed from the collaboration, Janux is eligible to earn up to $500.5 million per target in upfront and milestone payments, plus royalties on product sales. Merck is funding R&D efforts for these partnered programs.
According to Campbell, Janux is "in dialogue" with most of the major players in the pharmaceutical industry regarding further partnership opportunities for its programs. Concurrently with the clinical update on JANX007, Janux said it priced a $60 million stock offering, which Campbell said will allow Janux to advance another program into clinical stage and advance additional preclinical programs.