HS-110 Interim Data
Heat Biologics, Inc. (NASDAQ:HTBX) announced positive interim survival data for its Phase II trial of HS-110 (viagenpumatucel-L), a cell-based therapy, in combination with leading checkpoint blockade inhibitors (CBIs). The trial was not a comparator trial; however, similarities in design with past trials enable some reference to the performance of HS-110. We review Heat’s pipeline, its HS-110 candidate, the Phase II trial, and comparable historical data.
Heat’s HS-110 candidate is one of four candidates currently being pursued by the company.
Exhibit I – Heat Product Pipeline (1)
HS-110 is a combination of Heat’s gp96 technology and cancer/testis antigens (CTAs) where the gp96 platform activates the immune system. gp96 is a naturally occurring, ‘heat shock’ protein that acts as an immune signaling agent. It is responsible for antigen presentation and immune stimulation, including inducing mucosal immune memory and activating B and T cell response. Heat has engineered gp96 to leverage this natural immune signaling protein and uses it to present specific, engineered antigens, namely CTAs, to train and activate the immune system. The therapy involves injection of cells that manufacture and excrete the antigen-presenting gp96.
Exhibit II – gp96 Platform Mechanism (2)
Heat has evaluated gp96 in conjunction with a PD-1 inhibitor in a murine model (B16F10) with a very aggressive, PD-1 resistant melanoma. Neither the mouse HS-110 nor the anti-PD1 significantly inhibited tumor growth, but a combination approach was effective.
Exhibit III – Murine Melanoma Model (3)
Heat is investigating HS-110 in non-small cell lung cancer (NSCLC) and is currently conducting a Phase II trial. The Phase II DURGA trial (NCT02439450) features two treatment settings, as first line maintenance and second line or greater therapy.
Exhibit IV – HS-110 Phase II Structure (4)
The treatment setting in first line maintenance is divided into two arms, HS-110 and pembrolizumab (KEYTRUDA) with and without pemetrexed (ALIMTA), a chemotherapy agent. The second arm features HS-110 and nivolumab (Opdivo). Pembrolizumab and nivolumab are mAb targeting programmed death receptor-1 (PD-1) and are known as checkpoint inhibitors. Checkpoint inhibitors interfere with the ability of tumor cells to defy immune response, allowing the body to attack the tumors. Finally, the cohorts within the nivolumab arm, cohorts A and B, evaluate the combination of HS-110 and nivolumab in both checkpoint inhibitor naïve and checkpoint inhibitor progressor subjects. The study is intended as proof of concept in a defined patient population.
Interim data was positive and compared favorably to historical data. The CheckMate 057 study was conducted in 2015 by Bristol Myers Squibb to evaluate Opdivo in non-squamous NSCLC. CheckMate 057 was a Phase III trial evaluating nivolumab versus docetaxel in patients with previously-treated non-squamous NSCLC. Patients were randomized 1:1 to nivolumab and docetaxel, with primary endpoint of overall survival (OS). Secondary endpoints included progression-free survival (PFS) and safety. Results showed that median OS was 12.2 months in the nivolumab only group versus docetaxel at 9.4 months (5). Median PFS was 2.3 months and 4.2 months for nivolumab and docetaxel, respectively. This compares to cohort A of Heat’s HS-110 trial in an almost completely non-squamous population (94%) that had median OS of 24.6 months and median PFS of 1.84 months. The interim data supports trial objective as clinical proof-of-concept and interim data compared favorably to historic data.
Exhibit V – Cohort A Versus Historical Data (6)
Results from Cohort B, checkpoint inhibitor progressors, were also comparable to historical data. Constantini et al. 2018 (7) and Schvartsman et al. 2017 investigated third-line or greater chemotherapy in CBI-failed subjects. Median OS ranged between 6.8 months and 9 months and median PFS ranged from 2.7 to 4.7 months in the studies. This compared to cohort B data with median OS of 11.9 and median PFS of 2.76, exceeding the upper end of median OS in the chemotherapies studied by almost three months. Heat’s Phase II DURGA trial lacks a control arm and there are limitations to comparing it with other trials; however, Heat’s interim results cast a favorable light on its candidate.
Exhibit VI – Cohort B Versus Historical Data (8)
Publication of Additional Preclinical COVID-19 Vaccine Results
Heat’s gp96 platform is not only being used for HS-110, but also in Heat’s COVID-19 vaccine candidate. On January 27, 2021, Heat issued a press release disclosing additional results regarding Heat’s COVID-19 vaccine. The additional results were published in Frontiers in Immunology. The publication highlighted data regarding memory T cells that demonstrated polyfunctional, anti-viral cytokine releasing, spike-protein specific CD8+ and CD4+ T cell memory response in lung and spleen of immunized animal models. Response was observed 30 days after a single vaccination. Memory CD8+ T cell responses were also observed at 60 days after injection in the lungs of the mouse model. T cell memory in the lungs is key in defense against COVID-19 as the T cells are responsible for managing infected cells.
Heat Biologics’ interim data reflects results from a combination approach of HS-110 with CBIs. They compare favorably to historical data with CBIs alone. This is an early confirmation of the opportunity for Heat’s gp96/CTA technology. The interim data shows HS-110’s potential as a second line or later therapy, in conjunction with an anti-PD-1, in either checkpoint inhibitor naïve or progressor patients. Based on this interim data, it appears that HS-110 and nivolumab could be superior to CBI or chemotherapy alone. As Heat completes the Phase II trial, we look forward to topline and final analysis from the study, which is expected to be presented at a major oncology conference yet to be disclosed. Heat management is in the process of arranging an End-of-Phase II meeting with the FDA where trial design for the anticipated Phase III will be a primary point of discussion. Management is also in talks with key opinion leaders (KOLs) regarding the optimal regulatory path to pursue for the candidate. Management is currently considering pursuit of regulatory approval for HS-110 as a frontline treatment for NSCLC or as second line in checkpoint inhibitor progressed patients.
In addition to HS-110, Heat has also leveraged its immunomodulating gp96 platform for its COVID-19 vaccine. The gp96-based vaccine is now being produced with clinical trials anticipated to start later this year in 2021. Management cautions that the recent discovery of mutated SARS-CoV-2 strains represents a moving target; however, Heat has utilized the full-length spike protein, providing the highest chance of capturing any variable regions to activate the host immune response.
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5. Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., … & Brahmer, J. R. (2015). Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. New England Journal of Medicine, 373(17), 1627-1639.
7. Costantini, A., Corny, J., Fallet, V., Renet, S., Friard, S., Chouaid, C., … & Cadranel, J. (2018). Hyper-progressive disease in patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab (nivo).