Karuppiah Kannan, PhD, Senior Director, Global Program Lead at Takeda, Boston, Massachusetts, highlights subasumstat in combination with rituximab for CD20+ relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

My name is Karuppiah Kannan. I am a global program leader for oncology therapeutic area unit at Takeda Pharmaceuticals here in Boston.

First of all, let me give a brief introduction about this molecule and asset. This molecule is known as TAK-981 previously. It's called subasumstat. It is a SUMOylation inhibitor. SUMOylation as a mechanism blocks the endogenous interferon signaling in normal cancer cell growth.

By inhibiting this process, you're basically activating endogenous interferon signaling and engaging innate immune mechanisms to fight against cancer cells.

Early data by the preclinical teams have demonstrated 981 or subasumstat's ability to actually activate the endogenous signaling that resulted in anti-tumor activities by engaging innate immune mechanism.

A lot of people talk about the novel immunotherapy modalities where people are activating adaptive immune mechanism. This molecule actually engages adaptive but through activating the innate immune mechanism. It's kind of a novel mechanism, but it is a first-in-class molecule and it is the first time this biology and this mechanism is being utilized in treating cancer.

We are excited about that data that we've had from the preclinical team, then we end up asking that question in the clinic, and that's what we are here to talk about today.

What we are encouraged by in the current phase I study, right now it is the dose escalation portion. We are escalating subasumstat dosage in combination with rituximab, which is an approved therapy for non-Hodgkin's lymphoma.

The study is actually enrolling patients in CD20-positive non-Hodgkin's lymphoma space that have failed prior rituximab-containing therapies. These are relapsed refractory lymphoma patients that are being enrolled in a dose escalation study with the primary objective of understanding safety and tolerability of this combination.

In this study, we have so far enrolled close to 27 patients. Among these 27 patients, 21 of them received a weekly dose of 981 and then the standard dose of rituximab, and 6 of the patients we're exploring can we give subasumstat twice weekly.

In all these 27 patients so far, we haven't observed any dose-limiting toxicity. We have observed some adverse events (AEs) in low grade, which are typical of what happens when you treat patients with interferon therapies. That include mild fever, diarrhea, and chills, and things like that, but no DLT so far.

Not only that, but this combination is very well tolerated. We have seen among these patients close to 30 percent of them show response. We observed 2 of the patients showed complete response, and then 4 patients showed partial responses. You're seeing responses and you are not seeing DLT, shows that you got a good therapeutic window. The study is still ongoing. We are so excited about the early encouraging data that we are seeing in the study so far.

At the completion of the escalation portion, we are planning to open the study, because it's a phase 1 study. We are looking forward to opening the phase 2 portion of the study in which we will expand in select subset of patients.

In the current study, it's almost like all-comer non-Hodgkin's lymphoma. Anybody with follicular, mantle cell, DLBCL, they can enroll.

We are looking forward to once we declare the recommended phase 2 dose, which we expect in a few months, then open it up into specific cohorts so that we can give appropriate recommended phase 2 dose treatment to those patients and check for efficacy in that patient population. We are looking forward to that. That's where this study is going.

Usually, when programs go into a phase 1 portion, your primary objective is just safety and tolerability, but when you see efficacy even at that stage, we are excited and so are the PIs excited about the expansion portion of the study.

Also, what this mechanism of action in combination with rituximab bring to this patient population when they actually relapse after (rituximab), they're looking for any option. This serves that niche of patients who are looking for novel treatment options.

In this ASH meeting, we're also presenting another trial in progress. We have another study that's open. That study is in combination with anti-CD38 antibodies. We have actually 2 different antibodies, mezagitumab, which is an investigational antibody that's homegrown from Takeda. Also, we have anti-CD38, daratumumab, which is an approved agent in multiple myeloma space.

We have another study ongoing and we are currently enrolling patients in the dose escalation portion for that study. That's open. That shows to the medical community that we are planning to explore this mechanism of action, this inhibition of SUMOylation as a mechanism of action in treating multiple hematologic malignancies.

In addition to that, we are also encouraged by the data seen by colleagues from MorphoSys. MorphoSys have tafasitamab, which is an anti-CD19 antibody. It's Fc-enhanced. It is approved with lenalidomide, an accelerated approval from FDA for second-line DLBCL.

Colleagues from MorphoSys worked with Takeda and then did some preclinical experiments with subasumstat and tafasitamab trying to see if this combination provides additive and synergistic benefits in preclinical model systems.

They were able to beautifully demonstrate that addition of 981 enhances the ADCC and the ADCP potential of antibodies that are Fc-enhanced, which tafasitamab is. They were able to not only show in in vitro model systems but also in animal model systems.

There is a poster being presented with that data as well. That's also another exciting avenue that as a company, we are interested in exploring even further.

Also, I want to open it up a little bit broader how much we are excited about what we are seeing, not only as a company at Takeda, but also with the PIs that are part of this program. Not only the heme space, even in solid tumor space. We have couple other studies that have opened already and enrolling, and we have generated some positive data.

One is a first-in-human, single-agent study in which we are exploring just subasumstat single-agent in solid tumors and the hematologic malignancies. Also, we have another combination study in solid tumors with subasumstat plus pembrolizumab in indications where pembro is approved and also indications where pembro is not approved, exploring these innate immune mechanism activation by subasumstat in multiple tumor and indications that we are actually excited about exploring this mechanism across the board.