GTBP: GT Biopharma: Emerging Immunotherapies in Liquid Tumors

OTC:GTBP

Last summer the immuno-oncology world was elated with the FDA’s approval of the most exciting cancer therapy in years: Novartis’ (NVS) chimeric antigen receptor T-cell (CAR-T) therapy, Kymriah. The cell-based approach received approval for refractory or relapsed B-cell acute lymphoblastic leukemia. Just seven weeks later, Gillead’s (GILD) Yescarta was given the go-ahead by the agency for refractory or relapsed B-cell lymphoma.

This new cell therapy extracts T-cells from a cancer patient’s body, genetically alters them to recognize specific receptors on tumor cells, and then reintroduces them into the patient. While the therapy has shown impressive efficacy in patients who did not respond to other treatments, the price is prohibitive making it appropriate only as a last resort. The process is also time consuming, and in the long run vulnerable to analogous therapies that are cheaper and faster.

Hematological cancers were the first malignancies targeted by CAR-T due to proliferation of surface antigens on the target cells, the ease of measuring biomarkers and the natural movement of T-cells through blood, bone marrow and lymph nodes. Leveraging these same features, a protein-based alternative to CAR-T is now being developed that may be similarly effective.

GT Biopharma, Inc’s (GTBP) TriKE technology has shown superior NK cell cytotoxicity against hematologic tumors in preclinical work compared to earlier versions of the drug. TriKEs (Tri-specific Killer Engager) are an off the shelf option that employ a single chain, tri-specific fusion protein that binds to CD16 on natural killer (NK) cells and targets tumor antigens on cancer cells such CD33 in myeloid malignancies. It adds an IL-15 linker which enhances proliferation and activation of NK cells. TriKEs are particularly attractive due to their low cost of manufacture relative to CAR-T therapy and can be used off the shelf without any modifications of autologous cells in the lab. The company is currently in the process of submitting an investigational new drug application (IND) to the FDA for the TriKE in order to launch a Phase I/II trial in 2H:18.

GT Biopharma’s most advanced candidate is a bi-specific antibody drug conjugate (ADC) called OXS-1550 that is in Phase II clinical trials. Just three weeks ago, preliminary clinical results from the study showed that seven of thirteen evaluable patients with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) demonstrated a clinical benefit.

With two enviable immuno-oncology candidates leading the company’s development efforts in a therapeutic area dominated by first line treatments that have not dramatically changed in forty years, GT Biopharma merits a closer look. We provide a review of the company, highlighting its strategy, lead pipeline assets, potential for combination therapy and the therapeutic areas it plans to pursue with its OXS-3550 and OXS-1550 programs.

Company Strategy

GT Biopharma’s strategy is to acquire, develop and commercialize immuno-oncology platforms that present the ability to target multiple liquid and solid tumors. The company’s oncology portfolio consists of four drug candidates in preclinical and Phase II trials. Three of the assets are Killer Cell Engagers (TriKE and TetraKE) and the remaining compound is a bispecific antibody drug conjugate (ADC). GT Biopharma is developing its drug candidates as monotherapies; however, it is likely that the company will pursue combination approaches at some point adding chemotherapy, radiotherapy, checkpoint inhibitors or other immuno-oncology drugs to the mix.

View Exhibit I - GT Biopharma Pipeline

OXS-3550

OXS-3550 is a single chain, variable fragment (scFv), tri-specific recombinant fusion protein conjugate (TriKE). It targets the CD16 and CD33 receptors on NK and myeloid cancer cells respectively and incorporates a modified IL-15 linker. The anticipated Phase I/II study will focus on CD33-expressing high risk myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia or advanced systemic mastocytosis. The trial anticipates enrolling 60 patients and measurements of tolerated dose, response rate and overall survival will be taken at 28 days, 42 days and six months respectively.

OXS-3550 Mechanism of Action

Tri and Tetra-specific Natural Killer Cell Engagers (TriKE / TetraKE)

The TriKE and TetraKE engagers employ a single-chain variable fragment (scFv) that will bind with CD16 receptors on NK cells and with tumor antigens, such as CD33 receptors, on tumor cells. The connection creates an immunological synapse between the NK cell and the myeloid cell. The IL-15 linker promotes NK cell priming, survival and proliferation. The construct achieves three functions including directing NK cells to tumors via intracellular synapses, binding CD16 on NK cells to activate antibody-dependent cellular cytotoxicity (ADCC) and stimulating NK cell expansion.

OXS-3550 brings both antigen specificity and in vivo expansion to the NK cells. With each section playing its part, the TriKE anti-CD16 component attaches to the NK cell, priming its cytotoxic function, while the anti-CD33 component attaches to the malignant myeloid cell and the IL-15 linker enhances NK activity. CD16, also identified as FcγRIIIb is found on the surface of NK cells and is implicated in triggering lysis by NK cells and in ADCC. The CD33 transmembrane receptor is expressed on cells of myeloid lineage and can also be found on some lymphoid cells. IL-15 is located in the variable region and provides a self-sustaining signal that leads to the proliferation & activation of NK cells, giving them longer life to perform their cytotoxic duties. The connection made by OXS-3550 between the NK and myeloid cell forms a synapse which allows the NK cell to deliver granulysin, granzyme and perforin, which induce apoptosis or lysis in the cancer cell. The destruction of the cancer cell may release antigens that can be recognized by antigen presenting cells, and subsequently activate adaptive immune system processes.

TriKEs have several advantages compared to T-cell modification and stimulation. The immune approach is able to sidestep tumor evasion via downregulation of MHC molecules and does not require priming.

View Exhibit II - Schematic of Tri-specific Natural Killer Cell Engager

Preclinical work for OX-3550 was conducted in a mouse model and utilized three human tumor cell lines, including HL-60, Raji and HT29. Below we illustrate the cytotoxic NK activity in the various configurations of the killer engager. “161533” represents the TriKE which exhibited greater cytolytic activity throughout the series of target ratios. “No Ab” measures activity without an antibody which displayed the lowest level of activity. Cytolytic activity was measured at various ratios with 20:1 yielding the greatest level of success.

View Exhibit III - Cytotoxic NK Activity in Various Models
Ballera, Daniel; et al. IL-15 Trispecific Killer Engagers (TriKEs) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function. Clin Cancer Res. 2016 Jul 15; 22(14): 3440–3450.

OXS-3550 will address acute myeloid leukemia (AML) and other hematopoietic malignancies in its Phase I/II trial. The current first line treatment for AML is chemotherapy, usually administering cytarabine and anthracycline. Half of the patients under this regimen relapse, highlighting the need for new therapy. The current registrational pathway for OXS-3550 is for an investigational new drug (IND) application to be filed in the near term followed by the start of the in-human trial in the second half of 2018. We anticipate that if data is compelling, that GT may find a partner to develop the molecule further in Phase III trials.

OXS-1550

OXS-1550 is a bi-specific antibody drug conjugate (ADC) that is currently in a Phase I/II trial for B-cell leukemias and lymphomas. The ADC targets CD19 and CD22 on B-lymphocytes and has a cytotoxic drug payload of diphtheria toxin (DT390) attached. CD19 is a protein expressed on all B lineage cells and is a biomarker for B-lymphocyte development and lymphoma diagnosis. It can also be used as a biomarker on leukemia immunotherapies. CD22 is another protein found on the surface of B cells and is a regulatory molecule that prevents the overactivation of the immune system and development of autoimmune diseases.

The attractiveness of the platform is its flexibility to target other tumor antigens and carry a variety of payloads for delivery to the cell.

The first Phase I trial for OXS-1550 was launched in December 2013 and enrolled 25 participants. It determined the maximum tolerated dose and measured the therapeutic activity of the drug by percentage of blasts in the bone marrow and the change in lymph node size. Patients in the study had a minimum of three prior lines of treatment, and eight of them failed a hematopoietic stem cell transplant. The study found that nine patients had measurable drug levels, and adverse events were grade 1 or 2 and transient. Of the patients that had measurable drug levels, there were two durable responses and one of the patients who had failed multiple previous treatments has remained cancer free since the beginning of 2015.

In December 2015, a Phase I/II trial was launched targeting 44 patients examining OXS-1550 for treatment of relapsed or refractory B-lineage lymphoma and leukemia. Primary endpoints measured dose limiting toxicity and overall disease response. Secondary endpoints evaluated incidence of serious adverse events.

On June 11, GT Biopharma provided a preliminary look at the clinical results for the Phase I/II trial. The study included observations from 13 evaluable patients, and found a clinical benefit in in seven of them. Nine of the patients were relapsed/refractory B-cell lymphomas and four were acute lymphoblastic leukemia (ALL). Of the seven demonstrating a benefit, one achieved complete remission, one a partial response and five stable disease. For the ALL patients, three of the four exhibited a clinical benefit, with one complete response, one partial response and one presenting stable disease.

OXS-1550 Mechanism of Action

Bi-specific Antibody Drug Conjugates (ADCs)

Antibody drug conjugates use the antibody to deliver a toxic payload to cancer cells. ADCs are designed to selectively perform this function by using a receptor-specific portion of the monoclonal antibody to deliver the cytotoxic agent. The receptors, which for OXS-1550 are CD19 and CD22, must be specific to cancer cells with the cytotoxic molecule conjugated to the single chain fusion protein with a linker. This flexible platform can express multiple receptors and carry a variety of payloads that allow for targeting of both hematologic and solid tumors.

Below we provide an illustration of GT Biopharma’s bi-specific ADC. It includes the anti-CD19 moiety and anti-CD22 moiety which can individually or collectively bind the cancerous B-lineage cells. The toxic payload that is delivered is represented by DT390, a modified form of diphtheria toxin.

View Exhibit IV - Structure of Single Chain Fusion Protein OXS-1550

Indications

GT Biopharma is developing its NK enabling platform and bispecific ADC to address a variety of indications in myeloid malignancies and B-cell leukemias and lymphomas. Company research has identified approximately 30,000 CD33+ myeloid malignancy cases in the United States per year. B-cell leukemia and lymphoma cases are approximately 100,000 per year. While there are other first line therapies that will place these cancers in remission, from 10 to 50% will not respond favorably and will require further treatment. There is also the possibility that OXS-3550 and OXS-1550 could move ahead in the therapeutic pecking order, earning first shot at these patients. We highlight the success of Merck’s Keytruda, which was granted initial approval for second line treatment in patients with advanced or unresectable disease who no longer responded to other drugs. As Keytruda was better understood over time, it moved to first line treatment in NSCLC. While we are years away from this opportunity, there is a precedent for immunotherapies to displace older approaches with difficult side effect profiles.

Combination Therapies

One of the trends in immuno-oncology is the increasing focus on combination therapies. Checkpoint inhibitors are popular partners for other immuno-oncology agents because they take the brakes off of an attack on cancer cells. This class of immuno-oncology agent works well in conjunction with other approaches that release cancer cell antigens, which are able to activate T-cells for a further attack. Chemotherapy is another popular combination partner for immunotherapies given its ability to prime the immune system. Some of the combinations that have already been approved are between pembrolizumab and chemotherapies (pemetrexed and carboplatin) and between two types of checkpoint inhibitors (nivolumab and ipilimumab for first line treatment of kidney cancer). Numerous additional trials are also underway which combine checkpoint inhibitors with cancer vaccines, oncolytic viruses and agents that address other points in the cancer immunity cycle. A benefit of combination therapies is that they may reduce development of drug resistance, since a tumor is less likely to lose effectiveness when multiple compounds are administered together. The hope for combination therapy is that it will approach the cancer from two different directions creating a synergistic benefit. We anticipate that combination work will be in the future for both the NK cell engagers and the bi-specific ADCs.

Milestones

• Applied for NASDAQ uplisting
• OXS-3550 Activity
◦ IND filing - mid-2018
◦ First in-human clinical trials – 2H:18
• OXS-1550 data readout – 2H:18
• TetraKE pre-clinical work – 4Q18-1Q19

Summary

Immuno-oncology has emerged as a leading approach to address cancer over the last decade. New classes of drugs such as checkpoint inhibitors, CAR-T, oncolytic viruses and cancer vaccines have helped the body’s immune system precisely target cancer, and may replace the harsh treatments of yesteryear. New immunotherapies are advancing through clinical trials at a rapid clip including GT Biopharma’s TriKE and ADC candidates. The low cost and off the shelf availability of GT’s offerings may even displace other options such as CAR-T. While CAR-T has shown surprising efficacy, the cost is prohibitive and it only works in a minority of patients. This gap in treatment has highlighted the need for new immunotherapies and GT Biopharma’s NK cell engagers and ADCs may improve the stature of the cancer therapy formulary. The company has four immuno-oncology candidates that are in preclinical and Phase II studies. Based on company announcements and clinicaltrial.gov data, a Phase I/II trial for the TriKE platform’s OXS-1550 should begin in 2H:18. The lead program, OXS-3550 recently provided an interim update for its Phase II study showing durable responses for patients that did not benefit from prior therapy. The next stage for GT will likely be including their candidates in combination therapy where synergistic effects are expected to increase success rates. It is likely that at some point GT Biopharma will add checkpoint inhibitors or chemotherapy to a combination study. Right now, the company is focused on launching its in-man trials for OXS-3550 and completing its Phase II trial for OXS-1550. With the possibility of similar efficacy and improved safety relative to higher cost CAR-T therapy, we believe GT Biopharma merits a closer look.

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