On July 31, 2017 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new immunotherapies, reported its financial results for the second quarter ended June 30, 2017, and provided an update on the Company’s recent activities (Press release, Ziopharm, JUL 31, 2017, View Source [SID1234519976]).
"ZIOPHARM is unique in the breadth and stage of technologies delivering cell- and gene-based therapies that are impactful, controllable and, most critically, scalable," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM Oncology. "We have seen ongoing validation of RheoSwitch gene switch technology through the now expanded Ad-RTS-hIL-12 + veledimex study in recurrent glioblastoma. We are addressing the complexities of commercializing CAR-T, T-cell receptor, and other cell-based therapies with our rapid manufacture of patient-derived T cells under point-of-care and our off-the-shelf natural killer cells. The Sleeping Beauty system enables us to generate CAR-T cells co-expressing important biological effectors such as membrane bound IL-15 and uniquely positions us to express TCRs to efficiently target multiple neoantigens in solid tumors. This non-viral approach to gene therapy not only allows us to customize immunotherapies, but enables controllable and cost-effective T cells with curative potential in both solid and hematologic malignancies."
"During the quarter, we presented updated data at ASCO (Free ASCO Whitepaper) that linked immune response to overall survival in patients with recurrent glioblastoma when treated with Ad-RTS-hIL-12 + veledimex. Additionally, we initiated a stereotactic arm in this study as a lead-in to both the pediatric and immune checkpoint combination trials. We continue to make progress toward finalizing a registration path for Ad-RTS-hIL-12 + veledimex while evaluating partnership opportunities for the program," added Francois Lebel, M.D., Executive Vice President, Research and Development, Chief Medical Officer of ZIOPHARM Oncology. "In our cell therapy programs, we continue to progress towards clinical evaluation of Sleeping Beauty engineered peripheral blood lymphocytes to express TCRs targeting solid tumors, we are advancing our non-viral point-of-care approach for CAR-T therapies, and we also anticipate the imminent initiation of the Phase 1 trial to evaluate CD33 as a new target for CAR+ T cells in patients with relapsed or refractory acute myeloid leukemia (AML), a highly aggressive and underserved disease. Additionally, we look forward to the initiation of a Phase 1 trial evaluating our off-the-shelf primary NK Cells, which have demonstrated the ability to eliminate AML in preclinical models."
Adoptive Cell Therapies
ZIOPHARM is developing chimeric antigen receptor (CAR) T cell (CAR+ T), T-cell receptor (TCR) T cell (TCR+ T), and natural killer (NK) adoptive cell-based therapies. These programs are being advanced in collaboration with Intrexon Corporation (NYSE:XON) and selectively with MD Anderson Cancer Center, the National Cancer Institute (NCI) and/or Merck Serono, the biopharmaceutical business of Merck KGaA.
Announced FDA Acceptance of IND for CD33-Specific CAR-T Cell Therapy Targeting Relapsed/Refractory Acute Myeloid Leukemia. In May 2017, ZIOPHARM announced that an investigator-initiated Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for a Phase 1 trial infusing the Company’s CD33-specific CAR+ T cells for relapsed or refractory AML is active, with the first patient expected to begin treatment in the third quarter of 2017. The genetically modified T cells incorporate a kill switch to eliminate the infused product if there are serious adverse safety events.
Announced Advancement of Next-Generation Non-Viral CAR-T Cell Platform Empowered by Membrane-Bound IL-15 Under RTS Gene Switch Control. In April 2017, ZIOPHARM and its partners, Intrexon and Merck KGaA, Darmstadt, Germany, announced the advancement of a unique approach to develop therapeutic candidates for two CAR targets expressed on hematologic malignancies and solid tumors. The distinctive methodology centers on the proprietary RTS platform to regulate production of membrane-bound interleukin-15 (mbIL15) co-expressed with CARs and Sleeping Beauty, a non-viral genetic modification system to genetically modify clinical-grade T cells. The companies expect to advance this innovative approach towards the clinic in 2018.
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The IL-15 cytokine is increasingly recognized as a key driver of therapeutic effect in CAR+ T therapy, including in a recent Journal of Clinical Oncology publication which correlated lymphoma remissions in patients whose IL-15 levels were elevated after lymphodepleting chemotherapy.i Through the RTS gene switch, the expression of mbIL15 can be regulated to help CARs target cancers in a controlled manner, thus potentiating a new paradigm in T-cell therapy.
Additionally, the non-viral Sleeping Beauty transposon-transposase system is an exceptional therapeutic tool that holds multiple advantages over viral-based delivery systems for stably introducing genes encoding CARs and TCRs into T cells. It simplifies genetic modification, and when coupled with reduced ex vivo processing, offers a pathway to shortened manufacturing and personalized T-cell therapies.
Continued to Advance Research under the Cooperative Research and Development Agreement with the National Cancer Institute Utilizing the Sleeping Beauty System to Generate TCR-modified T cells Targeting Neoantigens. ZIOPHARM continued to advance research being carried out under the Cooperative Research and Development Agreement (CRADA) that the Company maintains with the NCI. Announced in January 2017 by ZIOPHARM and partner Intrexon, research conducted under the CRADA will be carried out under the direction of Steven A. Rosenberg, M.D., Ph.D., Chief of the Surgery Branch at the NCI’s Center for Cancer Research. Dr. Rosenberg and his team are advancing the Sleeping Beauty system into clinical trials to target neoantigens in solid tumors on a patient-by-patient basis. These efforts are based on published works in which the Sleeping Beauty system is described as the most clinically advanced non-viral gene transfer tool to reprogram T cells for personalized immunotherapy.ii,iii
Ad-RTS-hIL-12 + veledimex
Ad-RTS-hIL-12 + veledimex is ZIOPHARM’s gene therapy candidate for the controlled expression of interleukin-12 (IL-12), a critical protein for stimulating an anti-cancer immune response, using an RTS inducible gene switch that enables controlled in vivo expression of therapeutic proteins.
Announced Initiation of Stereotactic Treatment Cohort in Phase 1 Study of Ad-RTS-hIL-12 + Veledimex in Recurrent Glioblastoma. In June 2017, ZIOPHARM announced the initiation of enrollment in the stereotactic arm of its Phase 1 multicenter study of Ad-RTS-hIL-12 + veledimex, a gene therapy for controlled expression of IL-12, in patients with recurrent glioblastoma multiforme (rGBM). The stereotactic cohort will include rGBM patients, that are not scheduled to undergo surgical resection, to assess the safety and tolerability of a single dose of Ad-RTS-hIL-12 administered via injection and activated with orally-administered veledimex (20 mg QD, days 1-14). Stereotactic treatment will serve as a lead-in to the Company’s next phase of development for Ad-RTS-hIL-12 + veledimex in brain tumors, including planned anti‑PD‑1 combination therapy and pediatric studies.
Announced Positive Updated Results of Ad-RTS-hIL-12 + Veledimex in Recurrent Glioblastoma at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting. In June 2017, ZIOPHARM announced updated results from its Phase 1 multicenter study of Ad-RTS-hIL-12 + veledimex, including the 20 mg expansion cohort in patients with recurrent or progressive GBM at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting June 2-6 in Chicago. As of May 24, 2017, the median overall survival of all patients receiving intratumoral Ad-RTS-hIL-12 with 20 mg of orally-administered veledimex was 12.5 months, with a mean follow-up time of 9.2 months. The majority of the 15 patients in the 20 mg cohort had two or more recurrences prior to entry in the study, indicating very advanced disease.
Based on the increased ratio of CD8+/FOXP3+ (effector/suppressor) T cells measured in peripheral blood 14 to 28 days after viral injection, overall survival appears correlated with IL-12-mediated cellular immune activation. Furthermore, patients who received low dose or no steroids showed a much better survival rate than those who received elevated systemic steroids, as the latter presumably interferes with immune activation.
As previously reported, a strong, dose-dependent correlation between veledimex dose, veledimex blood-brain-barrier penetration, and IL-12 and IFN-gamma production was observed. Drug-related toxicities, which were primarily non-neurologic, showed a dose response to veledimex, were consistent with those previously reported, and importantly, continue to be reversed upon cessation of the activator ligand, with no drug-related deaths.
Anticipated and Achieved 2017 Milestones
Intra-tumoral IL-12 RheoSwitch programs:
– Updated clinical data from Phase 1 of Ad-RTS-hIL-12 + veledimex for rGBM presented at ASCO (Free ASCO Whitepaper)
– Initiate pivotal clinical trial for rGBM
– Initiate stereotactic administration of Ad-RTS-hIL-12 + veledimex for rGBM:
– Initiate combination study of Ad-RTS-hIL-12 + veledimex with anti-PD-1 for rGBM
– Initiate Phase 1 study in the treatment of brain tumors in children
– Update program at the Society of Neuro-Oncology Annual Meeting
CAR+ T programs:
– Continue CD19-specific CAR+ T 2nd-generation clinical study, enrolling patients under shortened manufacturing protocol
– Advance mbIL15 CD19-specific CAR+ T 3rd generation toward a Phase 1 clinical study evaluating point-of-care
– Initiate a CD33-specific CAR+ T clinical study in adults and children for relapsed or refractory AML
– Advance CAR+ T preclinical studies for at least one hematological malignancy under a shortened manufacturing process towards point-of-care
– Execute CRADA with NCI utilizing Sleeping Beauty to generate T cells targeting neoantigens for treatment of patients with solid tumor malignancies
– Advance development of process for delivering personalized gene-modified T-cell products against neoantigens
NK cell programs
– Initiate a Phase 1 study of off-the-shelf NK cells for elderly patients with AML not eligible for standard intensive chemotherapy
– Advance preclinical studies
Second-Quarter 2017 Financial Results
Net loss applicable to the common shareholders for the second quarter of 2017 was $17.7 million, or $(0.13) per share, compared to a net loss of $131.2 million, or $(1.01) per share, for the second quarter of 2016. The decrease is primarily due to the commitment to issue Series 1 preferred stock at fair value under the 2016 ECP Amendment and 2016 GvHD Amendment with Intrexon resulting in a $119.1 million non-cash charge during the three months ended June 30, 2016 that was not incurred during the three months ended June 30, 2017.
Research and development expenses were $10.8 million for the second quarter of 2017, compared to $129.2 million for the second quarter of 2016. The decrease in research and development expenses for the three months ended June 30, 2017 is primarily due to the Series 1 preferred stock issuance previously noted.
General and administrative expenses were $3.8 million for the second quarter of 2017, compared to $3.7 million for the second quarter of 2016.
The Company ended the quarter with unrestricted cash resources of approximately $97.2 million, plus approximately $27.3M in cash on hand at MD Anderson Cancer Center for programs to be conducted at MD Anderson Cancer Center under the current Research and Development Agreement. The Company believes its current resources will be sufficient to fund its currently planned operations into the fourth quarter of 2018.