High-dose systemic steroid administration has limited durability for patients who develop acute graft-vs-host disease (aGVHD). Novel agents seek to improve and expand the efficacy of the current standard of care for patients, specifically those with high-risk disease.

“We all want to find new agents that are more effective as frontline therapy for [patients with] aGVHD,” said Corey S. Cutler, MD, MPH, FRCPC, in an interview with 

. “Even with a very potent anti-inflammatory [such as] steroids, only 50% of our patients are getting a real benefit. Anything that we could use in the frontline setting that will help improve those response rates certainly seems like it will be a very welcome addition to our armamentarium.”

A complication of allogeneic hematopoietic stem cell transplant, aGVHD occurs in approximately 50% of patients who undergo this procedure. Onset of aGVHD usually occurs within 100 days of transplant and involves the skin, liver, and gastrointestinal (GI) tracts. Initiation of high-dose corticosteroids is the current standard of care; however, nearly half of patients become refractory to treatment.

Efficacy data for high-dose corticosteroids alone have demonstrated inferior response rates among individuals with high-risk aGVHD vs those with standard aGVHD. For example, a retrospective analysis stratified patients by risk status and reported that the overall response rate at day 28 after treatment was 44% (95% CI, 38%-50%) among 269 patients with high-risk aGVHD vs 68% (95% CI, 66%-70%) among 1454 patients with standard-risk aGVHD.2 The complete response rates (CR) were 27% (95% CI, 22%-33%) and 48% (95% CI, 45%-51%), respectively with partial response (PR) of 16% (95% CI, 12%-21%) and 21% (95% CI, 19%-23%).

To address this unmet need, investigators have initiated the phase 3 pivotal EQUATOR trial (NCT05263999), which will evaluate the novel monoclonal antibody, itolizumab (Alzumab), in combination with standard-of-care corticosteroids vs placebo in patients with aGVHD.

“We know that CD6 is a costimulatory receptor found on activated CD4 and CD8 T cells. We also know that the ligand called ALCAM, is expressed on antigen-presenting cells, as well as the inflamed tissues in the skin and GI tract. Since those [receptors] are [present in] the target organs of aGVHD, preventing these T cells from getting to their target makes a lot of sense [and] itolizumab is a promising compound,” said Cutler, who is medical director of the Adult Stem Cell Transplantation Program, director of clinical research, stem cell transplantation, and director of the Stem Cell Transplantation Survivorship Program at Dana-Farber Cancer Institute in Boston, Massachusetts.

Itolizumab, a first-in-class anti-CD6 monoclonal antibody targets the CD6–activated leukocyte cell adhesion molecule (ALCAM) pathway, which modulates the activity of T cells that drive immunoinflammatory diseases, and has demonstrated early activity as a first-line therapy for patients with high-risk aGVHD in the phase 1/2 EQUATE trial (NCT03763318).

“Itolizumab is a monoclonal antibody that binds to the CD6 [protein], which is expressed on immune effector, or proinflammatory T cells; it is part of the costimulation pathway,” John Koreth, MBBS, DPhil, said in an interview with 

. “Interestingly, [itolizumab] is slightly different [from other agents] in that it does not delete or kill the cells that it binds to, but results [in the] shedding of CD6 from the surface of the cells, and switches [these cells] from a CD6-high to a -low state. By doing so, it appears to switch them from a proinflammatory immune effector cell to a less inflammatory, regulatory T-cell phenotype. That is part of the mechanism [of action of the agent,] and interfering with the CD6 costimulation is another way of blunting the inappropriate immune activity that we believe is part of the underlying pathology in GVHD,” explained Koreth, who is the director of Translation Research and Stem Cell Transplantation and professor of medicine at Harvard Medical School.

The EQUATE trial comprised 2 parts: a 3 + 3 dose-escalation portion and a randomized double-blind phase.

 “The phase 1b/2 trial tested 3 dose levels—0.4, 0.8, and 1.6 mg/kg,” Cutler said. “According to our pharmacokinetic and pharmacodynamic studies, the 0.4-mg/kg dose was probably insufficient, but there was really no advantage of the 1.6-mg/kg dose [compared with] 0.8 mg/kg.”

 Meeting of the European Society for Blood and Marrow Transplantation, investigators reported updated data from the EQUATE study. At day 15 of treatment, the complete response rate was 52% among the 20 patients who received itolizumab and was maintained through day 29. The overall response rate was also assessed at days 15 and 29 and was reported at 74% and 65%, respectively. At day 29, 72% of patients were still receiving treatment with corticosteroids.

End of treatment was considered day 57, at which time 50% of patients had durable response. In a follow-up analysis, 45% of patients had an ongoing response at day 169 and the nonrelapse mortality rate was 35% with an estimated overall survival rate of 65%.

An observational end point of the EQUATE study was the reduction of corticosteroid use, which investigators reported that patients either maintained steroid reduction from day 29 and/or continued tapering through day 169. “These are the patients who we are concerned would not be likely to achieve a good response to the standard of care, which is corticosteroids alone,” Koreth said. “No FDA-approved therapies [are available] for this indication, but we do have patients who are routinely treated with steroids across the world.”

In terms of safety, at the interim analysis investigators reported that all participants experienced at least 1 adverse effect (AE), with serious AEs reported among 65% of patients. A concern for this patient population is infection, which was reported among 43% of participants.5 “I want to underscore that this is a sick population; these are patients with acute involvement, typically of the lower intestinal tract,” Koreth said noting that individuals often present with ulceration of the intestinal epithelium, risk of bleeding, and diarrhea. “

“We expect high rates of severe adverse effects [AEs] based on the nature of this illness. [That being said, we] did see infections [with the agent, although] the rates were not dramatically different than what we would have expected. Although there were rates of significant AEs, including a significant rate of infections, that did not differ from what we would have expected a priori going into the study, given the illness of these patients,” Koreth said.

EQUATOR Explores Benefit of First-Line Treatment

Building on the data from EQUATE, Koreth highlighted the data used to inform the protocol for the phase 3 design. “When [investigators] looked the specific subset of patients who were treated within 3 days of the onset of steroids, which is the trial design for the [phase 3] study, the CR rate was [61%] and the ORR was [67%]—again, this is across all dose levels,” Koreth said. “[These findings] did suggest a response rate that was substantial. [It is important to remember, however, that this] was an uncontrolled analysis, which is why the follow-up [phase 3] study is so critical.”

EQUATOR will enroll approximately 200 patients with grade 3/4 aGVHD, or grade 2 aGVHD with lower GI involvement, a population of patients at a higher risk to develop steroid refractory disease, Cutler said. “The randomized trial is an extension of the phase 1b/2 study [and] is the proof phase [in which] that we will [use] the preliminary data that we’ve gathered [to meet] the main objective [of the study]: to determine whether the addition of itolizumab to corticosteroids is in fact better than steroids alone for the initial therapy of aGVHD,” Cutler said.

EQUATOR will enroll approximately 200 patients with grade 3/4 aGVHD, or grade 2 aGVHD with lower GI involvement, a population of patients at a higher risk to develop steroid refractory disease, Cutler said. Staging will be determined using the Mount Sinai Acute GVHD International Consortium (MAGIC) grading criteria.3 Grade 3 disease is defined as stage II/III liver and/or stage II/III lower GI involvement with stage 0-III skin and/or stage 0/I upper GI involvement. Grade 4 disease is defined as stage IV skin, liver, or lower GI involvement with stage 0/I upper GI involvement.7 Additionally, patients must be 12 years or older and have undergone initial allogenic hematopoietic stem cell transplant, have evidenced of myeloid engraftment.3

Patients will be randomly assigned to receive itolizumab within 3 days of the first administration of high-dose corticosteroids or placebo. Based on the data from EQUATE, itolizumab administered at 0.8 mg/kg once every 2 weeks for 6 doses will be used in EQUATOR following an initial dose of 1.6 mg/kg.3 Steroid tapering is recommended.

“We’re [evaluating] to itolizumab in the frontline setting for [patients with] aGVHD [in an attempt to] both increase the response rate to initial therapy with corticosteroids, as well as prevent patients from having early relapses when we start tapering their corticosteroids,” Cutler said. “Steroids are very toxic in the acute setting and anything we can do to minimize our patients’ exposure to this class of drugs will be beneficial in the long term, as long as response rates are not compromised by giving lower doses of steroids.”

The primary end point is early disease response evaluated at 29 days after initiation of treatment. The secondary objectives include durability of response, corticosteroid use, survival outcomes, and chronic GVHD incidence.

“[Itolizumab] could be a potential game changer,” Koreth said. “If patients have a therapy that can rapidly induce a CR that is durable, allows us to taper steroids, and improves survival, then that would be the new standard of care for these patients, who, at this point, have a very significant unmet medical need. [This] is a rigorous trial design, and I hope, if successful, there will be a straight path to approval of the medication so that patients in need can receive it.”

Malard F, Huang XJ, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. 

. 2020;34(5):1229-1240. doi:10.1038/s41375-020-0804-2

MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. 

. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001

A study of itolizumab in combination with corticosteroids for the first-line treatment of acute graft versus host disease (EQUATOR). ClinicalTrials.gov. Updated April 14, 2022. Accessed May 24, 2022. https://clinicaltrials.gov/ct2/show/NCT05263999

Ng C, Chinn L, Acevedo LM, et al. Itolizumab, a novel targeted anti-CD6 therapy, induces cleavage of cell surface CD6 and rapid onset of efficacy in subjects with newly diagnosed acute graft-versus-host disease. Presented at: 

 Meeting of the European Society for Blood and Marrow Transplantation. March 19-23, 2022; Prague, Czech Republic. Accessed May 25, 2022. 

https://ebmt2022.abstractserver.com/program/#/details/presentations/638

Koreth J, Waller E, Nakamura R, et al. Updated interim results from the EQUATE study: preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed acute graft-versus-host disease. Presented at: 

https://ebmt2022.abstractserver.com/program/#/details/presentations/637

A study to evaluate the safety, tolerability, PK, PD, and clinical activity of EQ001 in subjects with aGVHD (EQUATE). ClinicalTrials.gov. Updated October 8, 2021. Accessed May 25, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03763318

Harris HC, Young R, Devine S, et al. International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium. 

. 2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001

Articles

Novel agents seek to improve and expand the efficacy of the current standard of care for patients with acute graft-vs-host disease, specifically those with high-risk disease.

Investigators Seek to Push Combination Therapy to the Front-line Treatment of aGVHD

The first-in-class antibody therapeutic, itolizumab, decreased levels of cell-surface CD6 and increased soluble CD6 (sCD6) in serum in patients with acute graft-vs-host disease (aGVHD), according to data from the phase 1b EQUATE trial (NCT03763318) presented at the 2022 Transplantation & Cellular Therapy Meetings.

Across 3 dose levels of 0.4 mg/kg, 0.8 mg/kg, and 1.6 mg/kg of itolizumab, surface CD6 levels on T cells rapidly decreased, and surface CD6 levels remained below baseline throughout treatment (

 < .001). Furthermore, levels of sCD6 in serum increased as cell surface CD6 decreased, indicating that itolizumab induced the release of cell-surface CD6.

“The observed association between itolizumab serum concentrations and clinical response highlights the importance of achieving high concentrations early in the treatment period to maximize pharmacodynamic effects and clinical efficacy,” lead study author, Cherie T. Ng, senior director of research at Equillium, Inc., wrote in the poster presentation.

CD6 is a co-stimulatory receptor expressed on CD4 and CD8 T-effector cells, which control T-cell activity and trafficking.

 Additionally, the CD6 ligand, activated leukocyte cell adhesion molecule (ALCAM), is expressed on antigen-presenting cells and tissues. Both CD6 and ALCAM are overexpressed during gastrointestinal inflammation, and prior clinical studies have pointed to CD6 relevant target for the pathogenesis of aGVHD.

Itolizumab targets the CD6-ALCAM pathway by binding to domain-1 of CD6. This causes CD6 shedding and the production of CD6

 T cells are hyporesponsive to stimulation, and they exhibit decreased activation, proliferation, and cytokine production.

Data presented at the Transplantation & Cellular Therapy Meetings were from 23 patients with grade III or IV aGVHD who were enrolled on EQUATE and had pharmacokinetic and pharmacodynamic data available as of September 2021. Moreover, patients were required to receive an allogeneic hematopoietic stem cell transplant (ASCT) using myeloablative or non-myeloablative conditioning regimens and to have a clinical diagnosis of aGVHD requiring systemic immune suppressive therapy.

Patients were excluded from the trial if they had the presence of morphologic relapsed primary malignancy, were treated for relapse after ASCT was performed, or required rapid immunosuppressive treatment withdrawal for early malignancy relapse. Other exclusion criteria included evidence of graft failure based on cytopenia, evidence of post-transplant lymphoproliferative disease, or any prior therapy for aGVHD, except for ASCT prophylaxis regimens or systemically administered corticosteroids.

All patients initiated intravenous (IV) steroids within 7 days prior to the first dose of IV itolizumab, which administered at doses of 0.4 mg/kg (n = 4), 0.8 mg/kg (n = 10), or 1.6 mg/kg (n = 9) every 2 weeks. Notably, all patients on the trial received at least 1 dose of itolizumab, while 70% of patients (n= 16) received at least 2 doses.

To determine cell surface CD6 levels on T cells, flow cytometry on fresh whole blood was performed, and a custom electrochemiluminescent assay was used to measure sCD6.

Additionally, ST2 and REG3α were quantified by ELISA, and the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm was used to calculate the MAGIC algorithm probability (MAP) score.

The primary end points of the trial were to assess the safety and tolerability of itolizumab and determine the optimal IV dose level. Secondary end points included the characterization of the pharmacokinetics and pharmacodynamics of itolizumab, and to assess the drug’s clinical activity by overall response rate, non-relapse mortality, chronic GVHD, and durability.

Additional data showed that by day 15 following the first dose, itolizumab doses of 0.8 mg/kg and 1.6 mg/kg increased the ratio of T-regulatory cells to T-effector cells. Furthermore, a decrease in PD-1 expression on T-effector cells was observed at all 3 dose levels at day 15.

Notably, 94% of patients who achieved a clinical response did so following the first dose of itolizumab. Therefore, investigators examined the relationship between itolizumab concentrations and efficacy at day 15. Higher concentrations of itolizumab corresponded to higher rates of complete responses (CRs).

At baseline, 8 patients had low MAP scores (no more than 0.290), vs 10 patients with high MAP scores (greater than 0.290). At day 15, patients who had low MAP scores at baseline achieved a CR rate of 67%, compared with 50% in patients with high MAP scores. Notably, these  trends did not result in a statistical significance, possibly because of the small population size.

The results from EQUTE informed the doses that will be evaluated in the phase 3 EQUATOR trial (NCT05263999), which will evaluate itolizumab vs placebo in combination with corticosteroids as a first-line treatment in patients with aGVHD.

Ng CT, Chinn L, Acevedo LM, et al. Itolizumab, a novel targeted anti-CD6 therapy, induces cleavage of cell surface CD6 and rapid onset of efficacy in subjects with newly diagnosed acute graft-versus-host disease. Presented at: the 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022. Abstract 371.

Consuegra-Fernandez M, Lin F, Fox DA, Lozano F. Clinical and experimental evidence for targeting CD6 in immune-based disorders. 

. 2018;17(5):493-503. doi:10.1016/j.autrev.2017.12.004

Soiffer RJ, Murray C, Mauch P, et al. Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow. 

. 1992;10(7):1191-200. doi:10.1200/JCO.1992.10.7.1191.

A study to evaluate the safety, tolerability, PK, PD, and clinical activity of EQ001 in subjects with aGVHD (EQUATE). ClinicalTrials.gov. Updated October 8, 2021. Accessed April 25, 2022. 

Itolizumab decreased levels of cell surface CD6 and increased soluble CD6 in serum in patients with acute graft-vs-host-disease.

Itolizumab Generates Rapid Responses, Lowers Surface CD6 Levels in aGVHD

Corey S. Cutler, MD, MPH, FRCPC, director, Adult Stem Cell Transplantation Program, director, Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, physician, Dana-Farber Cancer Institute, associate professor of Medicine, Harvard Medical School, discusses the exploration of itolizumab (Alzumab) in acute graft-versus-host disease (aGVHD).

The monoclonal antibody itolizumab targets the CD6 receptor. Patients with aGVHD typically present with high levels of CD6 on activated T cells, Cutler says. CD6 also assists in trafficking lymphocytes to areas of inflammation, Cutler adds. By targeting a CD6 activation marker on T-cells, itolizumab could attack the cells that might be pathologic in aGVHD, Cutler explains.

Researchers hope the addition itolizumab in the frontline setting of aGVHD can improve response rates of standard-of-care corticosteroids, Cutler notes. Furthermore, the addition of itolizumab could help prevent early relapses patients when corticosteroids are tapered, since steroids can be toxic in the acute setting, Cutler says. Minimizing exposure for patients to corticosteroids could benefit long-term survival, Cutler concludes.

Videos

Corey S. Cutler, MD, MPH, FRCPC, discusses the exploration of itolizumab in acute graft-versus-host disease.


Dr. Cutler on the Examination of Itolizumab in aGVHD

The development of graft-vs-host disease (GVHD) in is a major contributing factor to morbidity among transplant recipients. For those who develop severe cases (grade 3 or 4), options to improve up front treatment are necessary, and investigators are seeking to improve on standard treatments which typically involve corticosteroids administered at 2 mg/kg per day. One avenue of exploration is the use of combination therapies up front to induce more rapid, durable outcomes.

One such approach is using the first-in-class CD6-targeted therapy, itolizumab.

“We know that CD6 is a costimulatory receptor found on activated CD4 and CD8 T cells,” Corey S. Cutler, MD, MPH, FRCPC, said in an interview with 

.“We also know that the ligand called ALCAM [activated leukocyte cell adhesion molecule], is expressed on antigen-presenting cells, as well as the inflamed tissues in the skin and gastrointestinal tract. Since those [receptors] are [present in] the target organs of aGVHD, preventing these T cells from getting to their target makes a lot of sense.”

Cutler, an investigator on the phase 1/2 EQUATE trial (NCT03763318) which evaluated itolizumab, noted that the agent has demonstrated efficacy for the treatment of psoriasis and its utility as a treatment for severe aGVHD has the potential to change the standard of care. “Itolizumab is a monoclonal antibody directed against the CD6 receptor, which is commonly found on activated T cells. CD6 is a receptor found on lymphocytes, which helps them traffic to areas of inflammation. Targeting a marker of activation and proliferation helps us specifically target the T cells we think might be pathologic in aGVHD.”

Investigators of EQUATE evaluated the safety and efficacy of itolizumab at 3 dose levels: 0.4 mg/kg, 0.8 mg/kg, and 1.6 mg/kg once every 2 weeks. At the 48th Annual Meeting of the European Society for Blood and Marrow Transplantation, investigators reported updated data that demonstrated among 25 patients who received itolizumab, the overall response rate was 71% at day 15 and 64% at day 29 with a complete response rate of 50% at day 15 that was maintained through day 29. Responses at day 29 were durable, with most patients maintaining a response off-treatment (79% through day 169 and 50% through day 337).

Further, investigators reported that a 73% reduction in median corticosteroid dose was seen at day 29 (for the 16 responders). Finally, at month 12 among day 29 responders, the progression-free survival rate was estimated at 50% with an overall survival probability of 72% (compared with 14% for day 29 nonresponders).

, Cutler, who is medical director of the Adult Stem Cell Transplantation Program, director of clinical research, stem cell transplantation, and director of the Stem Cell Transplantation Survivorship Program at Dana-Farber Cancer Institute in Boston, Massachusetts, noted the clinical benefit observed with itolizumab in EQUATE and the observations that informed the design of the phase 3 EQUATOR trial (NCT05263999).

Please explain the outcomes investigators are attempting to improve on with the addition of itolizumab with the current standard of care corticosteroids.

We treat [patients with] aGVHD that involves the visceral organs with intravenous steroids and that response rate is approximately 50% in terms of [eliciting a] durable response. An additional 25% [of patients] will have GVHD that initially responds but recurs rather quickly [and] then the final 25% will have primary resistant aGVHD.

Even with a very potent anti-inflammatory [such as] steroids, only 50% of our patients are getting a real benefit. Anything that we could use in the frontline setting that will help improve those response rates certainly seems like it will be a very welcome addition to our armamentarium.

What was the rationale for combining itolizumab in combination with corticosteroids and what were the highlights of the study?

We don’t have enough data to suggest that using itolizumab alone is a good enough approach. We rely on the very potent and very rapid anti-inflammatory activity of corticosteroids for the initial management of aGVHD. That might change in the coming years but at the moment, the strategy is to add agents to the initial therapy for aGVHD. [However, if] the disease is very mild and restricted to the skin, in which case we can sometimes [use alternative agents such as monotherapy with sirolumus [Rapamune].

We’re [evaluating] to itolizumab in the frontline setting for [patients with] aGVHD [in an attempt to] both increase the response rate to initial therapy with corticosteroids, as well as prevent patients from having early relapses when we start tapering their corticosteroids. Steroids are very toxic in the acute setting and anything we can do to minimize our patients’ exposure to this class of drugs will be beneficial in the long term, as long as response rates are not compromised by giving lower doses of steroids.

The key takeaway [from EQUATE] was that there was a very reasonable response rate. Approximately half of patients had a complete response by 4 weeks from the initiation of therapy and the overall response rate was a little bit higher at approximately two-thirds, 64% to be exact.

We know that the earlier we start novel agents, the more likely they are to work, so using an agent [such as] itolizumab up front is the best place to [start]. The promising response rates are driving us to do this randomized trial. Response rates seen in a phase 1 or phase 2 trial are generally not reliable enough for us to make this a standard of care. [Investigators of] the phase 3 trial will [evaluate] the active compound itolizumab or placebo given in conjunction with corticosteroids, which are the mainstay of therapy still.

Were there any safety concerns noted with itolizumab?

Safety as reported in the phase 1b/2 trial was actually quite good. We have to understand that these are investigator-reported and investigator-attributed safety events. But there were very few dose-limiting adverse events [AEs]. In fact, there was only 1 dose-limiting AE that was reported in the EQUATE trial. These are [ill] patients and there are lots of AEs on study [and] that is not unexpected. As we can tell, at the moment, the drug appears to be safe when administered with corticosteroids.

Turning to the phase 3 EQUATOR trial, which is about to be initiated, what are the key objectives and what findings from EQUATE influenced the design of the EQUATOR trial?

The randomized trial is really an extension of the phase 1b/2 study [and] is the proof phase [in which] that we will [use] the preliminary data that we’ve gathered [to meet] the main objective [of the study]: to determine whether the addition of itolizumab to corticosteroids is in fact better than steroids alone for the initial therapy of aGVHD.

The phase 1b/2 trial tested 3 dose levels—0.4, 0.8, and 1.6 mg/kg. According to our pharmacokinetic and pharmacodynamic studies, the 0.4-mg/kg dose was probably insufficient, but there was really no advantage of the 1.6-mg/kg dose [compared with] 0.8 mg/kg. The 0.8-mg/kg dose [was determined to] be pursued in the randomized phase 3 trial.

The patients who will be enrolled in the phase 3 trial are those with either grade 3 or 4 aGVHD, or those with grade 2 aGVHD who have lower gastrointestinal involvement, which signals a higher risk group of patients. [Enrolled patients will receive] an induction dose [of 1.6 mg/kg] followed by maintenance dosing [every 2 weeks], at the 0.8-mg/kg dose level.

What will itolizumab provide to the treatment landscape for aGVHD?

I think we all really want to find new agents that are more effective as frontline therapy for [patients with] aGVHD. This is a promising compound. We have explored CD6 depletion as a way of preventing GVHD as early as the 1990s at Dana-Farber [Cancer Institute]. This is coming full circle for with us testing an agent that targets CD6 in the treatment of aGVHD. We’re excited to participate in the trial [and] are hoping for positive results, [so] we will see how the drug performs in a formal blinded randomized clinical trial.

We certainly can consider whether this drug has a role in chronic GVHD as well as acute. However, we're focusing our efforts on aGVHD space.

Ng C, Chinn L, Acevedo LM, et al. Itolizumab, a novel targeted anti-CD6 therapy, induces cleavage of cell surface CD6 and rapid onset of efficacy in subjects with newly diagnosed acute graft-versus-host disease. Presented at: 48th Annual Meeting of the European Society for Blood and Marrow Transplantation. March 19-23, 2022; Prague, Czech Republic. Abstract OS10-04. Accessed March 29, 2022. 

Koreth J, Waller E, Nakamura R, et al. Updated interim results from the EQUATE study: preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed acute graft-versus-host disease. Presented at: 48th Annual Meeting of the European Society for Blood and Marrow Transplantation. March 19-23, 2022; Prague, Czech Republic. Abstract OS10-04. Accessed March 29, 2022. 

Corey S. Cutler, MD, MPH, FRCPC, notes the clinical benefit observed with itolizumab in EQUATE and the observations that informed the design of the phase 3 EQUATOR trial.

Investigators Seek to Expand Treatment Options for aGVHD with Novel Anti-CD6 Agent

The addition of itolizumab to standard-of-care (SOC) corticosteroids vs placebo will be evaluated in patients with acute graft-versus-host disease (aGVHD), as part of the phase 3 EQUATOR trial (NCT05263999), according to John Koreth, MBBS, DPhil, who added that if the data prove to be positive, this approach possesses the potential to become a fill an unmet need and move the needle forward for this population.

Previously, results from the phase 1/2 EQUATE trial (NCT03763318) showed that among 25 patients with high-risk aGVHD, itolizumab produced a complete response (CR) rate of 52% and an overall response rate (ORR) of 64% at day 29, across all dose cohorts examined. In a subset of patients (n = 18) who received itolizumab treatment within 3 days of their first corticosteroid administration, the CR rate and ORR were 61% and 67%, respectively.

The randomized, double-blind, phase 3 trial will evaluate the safety and efficacy of itolizumab compared with placebo in combination with corticosteroids in the first-line treatment of patients with aGVHD.

 The primary objectives of the trial are to achieve early disease response, to evaluate the durability of response, corticosteroid use, survival outcomes, and the incidence of chronic GVHD in these patients, according to Koreth.

“Patients with higher-risk grades of aGVHD are a population of patients in need. The SOC of corticosteroids alone has been around for multiple decades with very middling outcomes at best. I entirely endorse the idea that we should all, as transplanters, be looking to see what can be done to advance the SOC for these patients,” Koreth, a senior physician at Dana-Farber Cancer Institute, said. “[I believe the] answer to this is: clinical trial participation. I hope itolizumab is 1 of those agents that people are [considering to have potential] benefit [in these patients] and [to be] worthy of [further] evaluation in a robust trial such as [EQUATOR].”

, Koreth, who is also the director of Translation Research and Stem Cell Transplantation, as well as a professor of medicine at Harvard Medical School, discussed the potential of itolizumab in patients with high-risk aGVHD, prior findings from the EQUATE trial, the key objectives of the phase 3 EQUATOR trial, and the hope for this agent in this patient population.

: Could provide background on itolizumab and its mechanism of action? How may this agent fill an existing need for patients with aGVHD?

: For several decades, at the Dana-Farber Cancer Institute, we have been interested in molecules that can potentially target the CD6 protein on the surface of immune effector cells. In previous work, we had shown that when we could selectively deplete immune cells carrying CD6 from the donor graft [in transplant patients], we were able to reduce the rates of GVHD [and have] impressive survival.

However, that therapeutic [that we tested] has not gotten to the market for a variety of nonscientific and nonbiologic reasons. Therefore, when Equillium came to us and said they had a different, but similar monoclonal antibody called itolizumab, which also targets CD6 and could be considered for GVHD treatment, we were interested.

Itolizumab is a monoclonal antibody that binds to the CD6 [protein], which is expressed on immune effector, or proinflammatory T cells; it is part of the costimulation pathway. Interestingly, [itolizumab] is slightly different [from other agents] in that it does not delete or kill the cells that it binds to, but results [in the] shedding of CD6 from the surface of the cells, and switches [these cells] from a CD6-high to a -low state. By doing so, it appears to switch them from a proinflammatory immune effector cell to a less inflammatory, regulatory T-cell phenotype. That is part of the mechanism [of action of the agent,] and interfering with the CD6 costimulation is another way of blunting the inappropriate immune activity that we believe is part of the underlying pathology in GVHD, which is a serious deal for our transplant patients.

Could you speak to the phase 1/2 EQUATE trial? What was the design of the trial, and what were the lessons learned?

This was the initial study that [we had] partnered with Equillium [to conduct]; it was done in a multi-institutional setting, and it selected for patients [with] high-risk aGVHD. These are the patients who we are concerned would not be likely to achieve a good response to the SOC, which is corticosteroids alone. No FDA-approved therapies [are available] for this indication, but we do have patients who are routinely treated with steroids across the world.

In this study of 25 patients with high-risk aGVHD, itolizumab was added to corticosteroids [and was explored at] several different dose levels. Responses were impressive. First off, the drug did what we expected it to do in that the levels of CD6 on the surface of immune cells went down substantially, especially at the 2 higher dose levels [examined. CD6 levels] remained depressed for several weeks, which was the interval between [doses]. Indeed, those cells appeared to switch more to a regulatory [T-cell] phenotype. As such, the regulatory T-cell ratios appeared to go in the direction we wanted with the treatment.

Secondly, the CR rate and ORR by day 29 were [52%] and [64%], respectively, across every dose, [although we should recognize] that certain doses may be less optimal than others. When [investigators] looked the specific subset of patients who were treated within 3 days of the onset of steroids, which is the trial design for the [phase 3] study, the CR rate was [61%] and the ORR was [67%]—again, this is across all dose levels. [These findings] did suggest a response rate that was substantial. [It is important to remember, however, that this] was an uncontrolled analysis, which is why the follow-up [phase 3] study is so critical.

[It should also be noted that these] responses were very rapid, generally more rapid than I had expected. Many of these CRs were in patients who had responded within 15 days, or within 2 weeks, of the onset of treatment. Although the initial response readout was for day 29, seeing these early responses by day 15 was heartening, as were the fact that they were durable.

[Seventy-nine percent of day 29 responders maintained a response through day 169], recognizing that treatment did not continue for 6 months. Even coming off the treatment, there was a durable impact [with this agent]. This is coupled with the fact that we were able to significantly [reduce] doses of corticosteroids, which is another way to determine [whether patients] are deriving benefit. All of this was promising, and suggested that this should be explored further in a pivotal trial.

What was been observed so far regarding the agent’s safety profile?

First, I want to underscore that this is a sick population; these are inpatients with acute involvement, typically of the lower intestinal tract. They have ulceration of the intestinal epithelium, risk of bleeding, diarrhea, and cannot [receive] anything by mouth. The barrier to bacteria, particularly within the intestinal tract, is now reduced [in these patients]. As such, infections are a major complication, [and they stem from] this inflammatory process. When you add additional therapy, it becomes difficult at times to separate what is [happening] due to drug vs the disease. We expect high rates of severe adverse effects [AEs] based on the nature of this illness.

[That being said, we] did see infections [with the agent, although] the rates were not dramatically different than what we would have expected. Impressively, the patients who responded to treatment had better survival than those who did not, suggesting that it was not a case where we were winning the battle, but losing the war. You could imagine a scenario where you come in with an agent that is so immunosuppressive that it completely ablates the immune system, and thereby destroys GVHD. However, at the same time, it destroys the patient's ability to withstand infections. In that setting, [patients] could have no benefit from such therapy.

In this case, we did not see that. What we saw was that the patients who responded to treatment were also the ones who had a survival benefit vs those who did not respond. Although there were rates of significant AEs, including a significant rate of infections, that did not differ from what we would have expected a priori, going into the study, given the illness of these patients.

These data informed the phase 3 EQUATOR trial, which was recently announced. What are the key objectives of this research, and what does the design look like?

This is a trial that is very focused on the patients who are relatively high risk. We are looking at [those with] stage 3/4 aGVHD, [which are] the most severe types of aGVHD. We are also looking at patients who have milder involvement but still have lower intestinal tract involvement. We believe that is a relatively high-risk population.

This is a multi-institutional phase 3 trial, [where patients will receive] itolizumab vs placebo as first-line therapy [in combination with corticosteroids]. This is up front, [which means we are evaluating this approach as something we can give] before patients run into problems. [This is for] patients who are aged 12 years and above, have this complication, and are within 3 days of starting their steroids.

The idea is to achieve early disease response [with itolizumab]. The major primary end point [of the trial] is the rate of CR at day 29. The key secondary end points include confirmed ORR, to see how durable those responses are, and to see how much you can taper [treatment with] corticosteroids for patients who are or who are not on the study drug. [Additionally, the trial will look at] survival within that first year after the start of treatment for [rates of] chronic GVHD.

What do the timelines currently look like for this research?

The trial is [currently open to enrollment. This study follows patients for 1 year to evaluate long-term outcomes]. It is not enough, in my mind, to just have a day 29 readout, declare success at 1 month, and then [potentially] find in the long run that [this approach] failed to be beneficial [for the patients].

If the data prove to be positive down the line, what could this mean for this population?

This could be a potential game changer. If patients have a therapy that can rapidly induce a CR that is durable, allows us to taper steroids, and improves survival, then that would be the new SOC for these patients, who, at this point, have a very significant unmet medical need.

There is a lot of ‘ifs’ there, but this is the way to do it. You do a randomized pivotal trial in a multi-institutional setting and in a multi-regulatory environment across different countries. That is a rigorous trial design, and I hope, if successful, there will be a straight path to approval of the medication so that patients in need can receive it.

What is your key take-home message to colleagues regarding itolizumab?

Patients with intestinal involvement and higher grades of aGVHD are medically underserved by the current SOC, which is corticosteroids alone. Any clinical trial in this space, be it [EQUATOR] or another trial, should be prioritized by any transplant center that has an academic inclination or an inclination toward moving the SOC in a better direction.

We do have high-quality data in patients with high-risk aGVHD that were gathered prospectively in a multi-institutional setting and showed both tolerable safety and promising efficacy with this agent. It does sound like an interesting agent worthy of discussion.

Equillium announces initiation of the phase 3 EQUATOR study of itolizumab in first-line acute graft-versus-host disease. News release. Equillium, Inc.; March 4, 2022. Accessed March 28, 2022. 

A study of itolizumab in combination with corticosteroids for the first-line treatment of acute graft versus host disease (EQUATOR). ClinicalTrials.gov. Updated March 3, 2022. Accessed March 28, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05263999

The addition of itolizumab to standard-of-care corticosteroids vs placebo will be evaluated in patients with acute graft-versus-host disease, as part of the phase 3 EQUATOR trial.

Itolizumab Under Further Investigation in EQUATOR Trial as Frontline aGVHD Treatment

John Koreth, MBBS, DPhil, director, Translational Research, Stem Cell Transplantation, senior physician, Dana-Farber Cancer Institute, professor of Medicine, Harvard Medical School, discusses the key objectives of the phase 3 EQUATOR trial (NCT05263999) in acute graft-versus-host disease (aGVHD).

EQUATOR will randomize patients to receive the current standard of care, corticosteroids, in combination with itolizumab or placebo as a first-line therapy, Koreth explains. High-risk patients with stage 3/4 aGVHD, which ranks among the most severe types of GVHD, are the focus of EQUATOR, Koreth says. Additionally, patients with milder aGVHD who still have lower intestinal tract involvement will be included in the study, since this population is also considered high-risk, Koreth adds.

The goal of the trial is to achieve early disease response, and the primary end point will be the rate of complete response at day 29, Koreth continues. Patients who are within 3 days of starting treatment with corticosteroids will be eligible for the study, Koreth concludes.

John Koreth, MBBS, DPhil, discusses the key objectives of the phase 3 EQUATOR trial in acute graft-versus-host disease.


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