Medicenna takes on deadly brain cancer in clinical trial

Patients diagnosed with recurrent glioblastoma (rGBM) typically do not have a rosy prognosis. What’s more, the aggressive, fatal brain cancer has not seen any significant progress in treatment in many years.

Toronto-based company Medicenna is working on a novel treatment for the insidious disease using interleukins, a class of proteins that has been gaining attention from drug developers and researchers. CEO Fahar Merchant spoke with Outsourcing-Pharma about the research, and what it might mean for patients living with the cancer.

OSP: Could you please tell us about Medicenna—who you are, what you do, key capabilities and specialties, and what sets you apart from others in the field?​

FM: Medicenna is a clinical-stage immunotherapy company that develops highly selective engineered cytokines that we call Superkines. The Superkine platform comprises of various interleukins that can be designed to function as super-agonists, super-antagonists, or partial agonists, allowing us to incorporate novel but selective functionality that can modulate, fine-tune or amplify the immune system to tackle the most challenging immune based diseases, including a broad range of cancers with significant unmet needs.

For the past three decades, the interleukin field had not seen many meaningful advancements. Of course, recombinant human interleukin (IL)-2 was the first immunotherapy agent approved in the 1990s and marketed as Proleukin, but it is highly toxic and reserved as a last resort when all else fails. However, as the industry shifted towards finding more innovative immunotherapies to treat cancer, interleukins – once again – resurfaced, only this time, with new ways of harnessing their benefits without causing undue toxicities.

Medicenna’s Superkine platform was created with the purpose of realizing the full potential of interleukins, not just for cancer, but also in other disease areas such as auto-immune diseases, inflammation, fibrosis, and neurological disorders.

Based on our work and others, we firmly believe that interleukins, particularly Superkines can form the backbone of a new class of immunotherapies with the ability to address significant unmet needs. With Superkines, we have a tremendous amount of flexibility in how these molecules act, how great the effect is, and even how many functions they possess.

Our Superkines are highly versatile and can be designed to efficiently leverage the immune system in order to thwart aggressive forms of cancer to address significant unmet needs of patients. We’ve already made significant progress on this front with MDNA11, a novel IL-2 therapeutic that has demonstrated its potential to overcome Proleukin’s shortcomings.

Furthermore, in the case of recurrent glioblastoma (rGBM), the most aggressive and uniformly fatal form of brain cancer, we have seen remarkable improvements in patient outcomes and survival with our IL-4 Empowered Superkine, MDNA55.

OSP: Please describe rGBM, including how the condition impacts patients, how it differs from initial glioblastoma, and what prognosis is likely for someone diagnosed with it.​

FM: The current standard of care for glioblastoma (GBM) is surgical removal of the tumor, followed by a combination of radiation therapy and chemotherapy with Temozolomide (TMZ) for six weeks, followed by further treatment with multiple cycles of high dose of TMZ. Despite this harsh treatment regimen, use of TMZ improved the survival of newly diagnosed GBM patients by only 10 weeks.

Despite the best efforts of doctors and researchers over the past two decades, patients diagnosed with GBM typically survive less than 15 months after first diagnosis, and 5-year survival is less than 10% with surgery plus radiation and TMZ combo still being the only option.

Unfortunately, GBM is a highly invasive cancer and the vast majority of patients will experience a more aggressive recurrence of their tumor. Recurrent GBM patients have even fewer options — only a quarter of them are eligible for a repeat surgical resection, while the remaining three-quarters do not have any good second-line treatment options.

Since the approval of TMZ over 20 years ago there has been no new standard therapy for GBM demonstrating how incredibly difficult it is to treat. A major part of this difficulty is that GBM effectively co-opts the immune system to protect itself.

Because of this, our body cannot recognize that a tumor is there or use the immune system to attack it. In fact, GBM recruits non-cancer cells to create a tumor microenvironment (TME), which increases pro-tumoral growth factors such as interleukin-4 (IL-4), which in turn helps the tumor to thrive and also hide it from our immune system.

MDNA55 takes advantage of these changes by exploiting the selective overexpression of the IL-4 receptor on the tumor surface and non-malignant cells in the TME. By using an IL-4 Superkine as a highly selective targeting agent, MDNA55 delivers a potent cancer-killing payload to both, the tumor cells as well as the TME.

Because of its unique ability for dual-targeting, MDNA55 has shown for the first time, its ability to improve survival by several months in patients with the most aggressive forms of rGBM when compared to the standard of care.

To date, we have studied MDNA55 in 112 patients with rGBM and reported compelling data demonstrating its superior efficacy. Median survival after just one treatment with MDNA55 was 14 months, with 20 percent of patients surviving more than 24 months, versus a six-to-nine-month median survival, and only 2 percent of patients surviving past 24 months with the current standard of care.

MDNA55 has Fast-Track and Orphan Drug status from the FDA, and in September 2020, the FDA agreed that Medicenna could conduct an innovative open-label hybrid Phase III trial that allows the use of a substantial number of patients (two-thirds) from a matched External Control Arm to support regulatory approval of MDNA55 for rGBM. This hybrid trial design will reduce the overall number of subjects needed to enroll in the study to achieve the primary endpoint, as well as reduce costs and timelines associated with the study.

We are currently in active discussions regarding a strategic partnership to assist with clinical development and commercialization of MDNA55.

OSP: Please share the history of treatment for the disease and progress (or, as you mention, lack thereof) in discovering and developing therapies.​

MF: Drug development for brain tumors, such as glioblastomas, is difficult due to the blood-brain barrier (BBB). The BBB blocks transport of large molecules such as biologics, meaning that immunotherapies injected into the bloodstream will not reach the tumor.

MDNA55 circumvents this problem by being delivered directly to the tumor site using convection-enhanced delivery — a one-time procedure that is minimally invasive and similar to a biopsy procedure routinely performed by neurosurgeons.

The research space for GBM is especially active, with many groups applying for, and receiving, orphan drug designation from the FDA. Yet, there is still a dearth of newly approved therapies. However, our strong clinical data set indicates that MDNA55 could change the treatment paradigm for GBM and provide new hope for GBM patients and their families.

OSP: What are interleukins, and how are you engineering these proteins to put them to work as a therapeutic?​

FM: Interleukins are a subset of a larger group of cellular messenger molecules called cytokines. They are used to regulate immune responses by performing a range of functions, such as helping to locate foreign pathogens, driving the maturation of immune cells, and mediating cellular communications. As more research on these molecules is being released, it’s increasingly clear that interleukins have value beyond the human immune system.

On a high level, Medicenna’s platform enables the transformation of natural interleukins into Superkines, which are enhanced compared to their natural counterparts. For example, Superkines can be designed to stimulate the immune system, reverse immunosuppressive tumor microenvironments, deliver cell-killing agents without harming healthy cells, or turn off destructive autoimmune processes.

To enable their transformation, interleukins are engineered through a process known as directed evolution, where subtle changes are made to enhance their desired properties. This allows us to create a library of tunable Superkines, which are engineered to address the underlying mechanisms of the particular disease by selectively binding to certain receptor subtypes while avoiding others.

From this initial library, we then further design the selected Superkines via protein fusion, to enhance certain characteristics — such as improving pharmacodynamics and safety or optimizing their half-life to limit dosing issues — or to add new functions, such as the ability to deliver a payload of a cell-killing toxin specifically to cancer cells.

The Superkine platform gives us a lot of versatility with which to work, whether it is through picking an agonist or antagonist or eliciting a particular response when the molecule binds to its corresponding receptor, or avoiding receptor sub-types to improve safety.

Medicenna focuses on creating its Superkines from three major families of interleukins: IL-2, IL-4, and IL-13. These three families are known to modulate immune activity in 2000 different diseases.

OSP: You mention interleukins may have potential beyond treatment of this specific cancer—could you please share additional information about their potential?​

FM: We have an active pipeline beyond MDNA55, demonstrating the versatility of Medicenna’s Superkine platform for a variety of tumor types and autoimmune diseases.

Our co-lead candidate, MDNA11, is an IL-2 Superkine that is designed to overcome the shortcomings of Proleukin as well as improve upon competing IL-2 programs in development. What differentiates MDNA11 is its impressive ability to selectively target the CD122 receptor to preferentially activate anti-cancer effector immune cells rather than toxic and pro-tumor regulatory T cells (Tregs).

Additionally, this Superkine has been fused with recombinant human albumin, which facilitates further improvements over the currently approved IL-2 therapy, such as extending the half-life of the molecule and allowing it to accumulate at the tumor site for effective localization. MDNA11 is well suited for a wide range of solid tumors, and we will have more information to share following the initiation of the Phase I/IIa clinical trial, which is expected to commence in Q3 2021.

Turning to our preclinical pipeline, MDNA209 is similar to our MDNA11 molecule, except that it is a super-antagonist designed to calm the immune system, whereas MDNA11 is a super-agonist that activates the immune system. This molecule has potential applications for autoimmune diseases in which the body has an overactive immune system and produces aberrant T-cell responses. MDNA209 is currently in preclinical development.

Our other preclinical asset, MDNA19-MDNA413, is from our Bifunctional Superkine Immunotherapy (BiSKIT) platform and was the subject of our recent AACR data. This dual-function molecule has two objectives: block the pro-tumoral action of IL-4 and IL-13 on cells of the TME and, at the same time, activate CD8+ T cells and natural killer cells to attack the tumor.

The MDNA413 portion binds to the dual IL4R⍺/IL-13R⍺1 receptor on TME cells, which inhibits the phosphorylation of STAT6. This disrupts downstream signaling and, ultimately, inhibits the M2a polarization of tumor-associated macrophages (TAMs) and prevents the myeloid-derived suppressor cells (MDSCs) from suppressing T cell function. This effectively turns the tumor hot.

The MDNA19 portion is highly specific to CD122, similar to MDNA11, which activates the anti-cancer effector immune cells. Since the MDNA413 end of the molecule has blocked the immunosuppressive effects of the TME, the activated T cells and natural killer cells are better able to act on the tumor.

The variety of protein therapies with which we can fuse our Superkines to create novel BiSKITs opens up the possibility of developing a deep pipeline of fusion molecules either internally or in collaboration with other pharma companies. In addition to generating antibody-Superkine fusions or tri-functional Superkines, we can also potentially arm cell-based therapies and tumor-killing viruses with Superkines.

OSP: I imagine conducting a trial and treating study patients during a pandemic has been challenging. Could you please talk about some of the obstacles in conducting a trial—particularly one involving an insidious cancer—and how your team dealt with these issues?​

FM: Fortunately, the pandemic hasn’t impacted our clinical development very much. Medicenna has been a semi-virtual company since its inception, so, we already had processes in place for our team to conduct research and collaborate remotely.

We successfully completed enrolment in the IIb clinical trial for MDNA55 prior to the COVID-19 pandemic and have been moving forward with the Phase III plans without any delay.

The MDNA11 clinical trial is expected to initiate in Q3 2021 and in order to mitigate the potential impact of the ongoing pandemic we will be treating patients in multiple geographic locations including Australia, Canada, the UK, and the US. We are hopeful that increasing vaccination rates in these locations will help to prevent future negative impacts from the pandemic.

OSP: Do you have anything to add?​

FM: I would like to add more detail about the external control arm (ECA) that we will be using for the Phase III study for MDNA55. This is truly a landmark moment because it will be the first time a design of this nature has been supported and encouraged by the FDA for a registrational study.

With this design, two-thirds of the patients in the control arm will be matched into the trial through GBM patient registries going back five years. The prognostic factors for these patients will be well-balanced with those enrolling in the actual trial.

Medicenna demonstrated promising results for MDNA55 in the Phase IIb clinical trial when compared to a retrospective and a well-balanced ECA, which ultimately led the FDA to agree to incorporate a larger ECA population in the Phase III study using the same principles.

The ECA provides significant advantages for the Phase III trial:

• It allows us to conduct the Phase III trial with a much smaller “internal” control group, which helps save on resources and conduct the study more efficiently overall
• Fewer patients will be required in order to meet the primary endpoint, which could help shorten timelines
• It also helps in patient recruitment, since many of the patients are more willing to participate, knowing that they are more likely to receive a potentially more effective investigational drug rather than the standard of care.