ONCS: OncoSec Medical Incorporated Analysis and Research Report

2018-03-06 - by Asif , Contributing Analyst - 292 views

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OncoSec Medical is a biotechnology company focused on designing, developing and commercializing innovative therapies and proprietary medical approaches to stimulate and guide an anti-tumor immune response for the treatment of cancer. The company's core platform technology, ImmunoPulse®, is a drug-device therapeutic modality comprised of a proprietary intratumoral electroporation delivery device. The ImmunoPulse® platform is designed to deliver DNA-encoded drugs directly into a solid tumor and promote an inflammatory response against cancer. The ImmunoPulse® device can be adapted to treat different tumor types, and consists of an electrical pulse generator, a reusable handle and disposable applicators. The company's lead product candidate, ImmunoPulse® IL-12, uses its electroporation device to deliver a DNA-encoded interleukin-12, or IL-12, called tavokinogene telseplasmid, or tavo, with the aim of reversing the immunosuppressive microenvironment in the tumor and engendering a systemic anti-tumor response against untreated tumors in other parts of the body.

The company's current focus is to pursue its registration-directed study of ImmunoPulse® IL-12 in combination with an approved therapy for melanoma in patients who have shown resistance to or relapse from certain other cancer therapies, which the company refer to as the PISCES study. Most of its present activities are directed toward advancing the PISCES study. The company also intend to continue to pursue other ongoing or potential new trials and studies related to ImmunoPulse® IL-12, all with the goal of obtaining requisite regulatory approvals from the U.S. Food and Drug Administration, or FDA, and comparable regulators in certain other jurisdictions to market and sell this product candidate.

In addition, OncoSec Medical is developing its next-generation electroporation devices, including advancements toward prototypes, pursuing discovery research to identify other product candidates that, like IL-12, can be encoded into DNA, delivered intratumorally using electroporation and used to reverse the immunosuppressive mechanisms of a tumor, and aiming to expand its ImmunoPulse® pipeline beyond the delivery of plasmid-DNA encoding for cytokines to include other molecules that may be critical to key pathways associated with tumor immune subversion.

Cancer Immunotherapy Treatments: Background

Many traditional modalities for treating cancer have limited clinical efficacy and are frequently associated with significant negative side effects. Immunotherapy, a relatively new therapeutic modality that has received significant attention in recent years, focuses on modulating the immune system to treat cancer rather than directly killing the cancer cells. Systemic delivery of immune-modulating proteins, such as interleukin-2, or IL-2, and IL-12, has shown early indications of efficacy, but with significant mechanism-based toxicity.

Recent attention has also focused on the development of monoclonal antibody drugs, which target critical “immune checkpoint” proteins and augment anti-tumor immunity. Therapies using monoclonal antibodies, such as anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4), anti-PD-1 (program cell-death-1) and anti-PD-L1 (programmed death-ligand-1), are being developed for the treatment of several cancers and have been approved for the treatment of some cancers, including metastatic melanoma and metastatic non-small cell lung cancer. Although these new immuno-oncology agents have shown clinical benefit for patients with late-stage cancer across multiple tumor types, only a small subset of the overall patient population responds to these therapies. Certain tumors are able to evade the immune system. The company believe that when tumors do not have any immune cells inside (immune desert) or surrounding the tumor (immune excluded), immune checkpoint therapies are less effective or ineffective. These tumors are sometimes referred to as “cold” tumors.

The company believe that if the company can convert an inactive, or “cold,” tumor with a low frequency of tumor infiltrating lymphocytes, or TILs, that limit the anti-tumor response and remove the interferon signature, into an active, or “hot,” tumor that can activate the anti-PD-1 or anti-PD-L1, then the company can increase the subset of patients who respond to these therapies. The company believe its ImmunoPulse® IL-12 platform addresses this objective, as it has the potential to reshape the tumor microenvironment in patients with an immunologically cold tumor into a highly-inflamed tumor with a fully engaged anti-PD-1 or anti-PD-L1 axis. The immunological components that enable this conversion relates to the intratumoral delivery of tavo, which increases the density of TILs, and in the presence of an anti-PD-1 antibody, a disabling of adaptive resistance and maximizing the cytotoxicity. The company believe intratumoral tavo can reshape the tumor through innate and adaptive immune mechanisms, which result in a brisk infiltration of TILs in a previously cold tumor.

The company believe there is a significant unmet medical need for patients who may not respond well to these therapies on their own. In particular, for patients who have “cold” tumors and would be unlikely to respond to an immune checkpoint therapy alone, its focus is to develop a therapeutic that has the ability to directly modulate the microenvironment of the tumor by stimulating a local immune reaction through the intratumroral delivery of IL-12 or other immune-modulating molecules. The company believe this would enable important immune cells to enter into the tumor and, in essence, turn the tumor “hot.” In doing so, the company believe intratumoral delivery of immune-modulating molecules, such as IL-12, could be used as a monotherapy, and importantly, could provide a strong biological rationale for treatment in combination with immune checkpoint inhibitors, such as anti-PD-1 or anti-CTLA-4.

Lead Product Candidate: ImmunoPulse® IL-12

The company's lead product candidate, ImmunoPulse® IL-12, is a drug-device combination. The drug consists of a plasmid construct called tavo, which encodes IL-12, which is delivered into a tumor using its proprietary electroporation device. A Phase I clinical trial in metastatic melanoma using electroporation to deliver plasmid-DNA encoding for IL-12 was completed in 2008. The data from this trial indicated that the in vivo gene transfer of IL-12 DNA using electroporation in metastatic melanoma was well-tolerated. In addition, anti-tumor activity was observed after a single cycle of treatment, including two complete responses. Importantly, regression in distant, non-injected/non-electroporated lesions was also observed, suggesting that local treatment with ImmunoPulse® IL-12 may lead to a systemic anti-tumor immune response.

In February 2017, the company received Fast Track designation from the FDA for ImmunoPulse® IL-12. The Fast Track program was established to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. Drugs that receive this designation benefit from more frequent communications and meetings with the FDA to review the drug’s development plan, including the design of proposed clinical trials and the extent of data needed for approval. Fast Track designated drugs may also qualify for expedited FDA review and a rolling Biologics License Application, or BLA, review, if certain criteria are met.

Clinical Programs

All of its ongoing and planned clinical programs relate to its lead product candidate, ImmunoPulse® IL-12. The company's current primary focus is to pursue its planned Phase II registration-directed study of ImmunoPulse® IL-12 in combination with Merck & Co., Inc.’s, or Merck’s, approved anti-PD-1 antibody KEYTRUDA® in patients with advanced, metastatic (stage 3-4) melanoma who have shown resistance to or relapse from an anti-PD-1 therapy (OMS-I103). The company refer to this study as PISCES.

In addition, OncoSec Medical has two ongoing clinical trials related to ImmunoPulse® IL-12, although OncoSec Medical is not currently actively pursuing these trials: A pilot trial of ImmunoPulse® IL-12 monotherapy in patients with triple negative breast cancer (OMS-I140); a Phase II investigator-sponsored trial with ImmunoPulse® IL-12 plus pembrolizumab in patients with advanced, metastatic melanoma (OMS-I102); and a Phase II trial of ImmunoPulse® IL-12 as a monotherapy in patients with metastatic melanoma (OMS-I100).

OMS-I103: The PISCES Study: An Open-Label Phase II Trial of Intratumoral pIL-12 plus Electroporation in Combination with Intravenous Pembrolizumab in Patients with Stage 3-4 Melanoma who are Progressing on either Pembrolizumab or Nivolumab Treatment

Melanoma is a deadly form of skin cancer with rapidly rising incidences both in the U.S. and internationally. The National Cancer Institute Surveillance, Epidemiology and End Results Program estimates that over 75,000 new melanoma cases were diagnosed in 2016, representing 4.5% of all new cancer cases in the U.S. Overall, the five-year survival rate for melanoma, regardless of disease stage, is over 90%; however, for patients who present with metastatic disease and receive systemic treatment, the five-year survival rate is considerably lower at less than 18%. Despite recent advances in therapy, advanced metastatic melanoma continues to present significant morbidity and mortality.

The PISCES study is a Phase II, 2-stage, open-label, single-arm, multi-center study of ImmunoPulse® IL-12 in combination with an intravenous anti-PD-1 antibody, Merck’s KEYTRUDA®, in patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as stage 3 or 4.

Patients in the study must be refractory to certain anti-PD-1 monoclonal antibodies, namely pembrolizumab (KEYTRUDA®) or nivolumab, as either monotherapy or in combination with other approved checkpoint inhibitors or targeted therapies according to their approved label, or relapsed as documented disease progression within 24 weeks of the last dose of anti-PD1 monoclonal antibodies. The primary endpoint of the study is to assess efficacy over 24 weeks of intratumoral pIL-12-EP in combination with pembrolizumab in patients with unresectable or metastatic melanoma who previously have progressed on certain approved anti-PD-1 antibodies (either as monotherapy or in combination with other approved checkpoint inhibitors).

In May 2017, the company submitted to the FDA an investigational new drug application, or IND, for the PISCES study, which, in general, must become accepted and effective before any human clinical trials may begin in the United States. Additionally, in May 2017, the company entered into a clinical trial collaboration and supply agreement with a subsidiary of Merck in connection with the PISCES study, in which OncoSec Medical has agreed to sponsor and fund the study and Merck has agreed to manufacture and supply KEYTRUDA® for use in the study. The PISCES study opened for enrollment in October 2017.

OMS-I140: Biomarker-Focused Pilot Study of ImmunoPulse® IL-12 in Patients with Triple Negative Breast Cancer

Worldwide, approximately 170,000 new cases of triple negative breast cancer, or TNBC, are diagnosed each year, accounting for approximately 15% of all breast cancer. TNBC frequently affects younger women (less than 40 years old) and is characterized by higher relapse rates than estrogen receptor positive breast cancers. TNBC is also associated with an increased risk of recurrence, both locally and in distant sites including the lungs and brain. Advanced TNBC remains a significant area of unmet medical need and there is no established standard-of-care. Treatment generally includes chemotherapy, with or without radiation and/or surgery, but no treatment regimen has demonstrated clear superiority.

In January 2017, the company amended the clinical protocol for its biomarker-focused pilot study of ImmunoPulse® IL-12 in patients with TNBC to improve the enrollment rate, as it had been slow to enroll, and in September 2017, the company enrolled half the patients needed for the study. The study is now open for enrollment and is ongoing. The primary objective of the study is to evaluate the potential of ImmunoPulse® IL-12 to promote a pro-inflammatory molecular and histological signature, and the secondary objectives include the evaluation of safety and tolerability; evaluation of local ablation effect (% of necrosis) and description of other evidence of anti-tumor activity. The study is being conducted at Stanford University and is designed to assess whether ImmunoPulse® IL-12 increases TNBC tumor immunogenicity by driving a pro-inflammatory cascade that leads to increases in cytotoxic TILs. The presence and number of TILs is thought to be a key requirement for promoting the anti-tumor activity of monoclonal antibodies, such as anti-PD-1. By driving cytotoxic immune cells into the tumor, ImmunoPulse® IL-12 could be used in combination with checkpoint blockade therapies, which have reported some, but limited, activity in TNBC.

OMS-I102: An Open-Label Phase II Trial of ImmunoPulse® IL-12 plus Pembrolizumab in Patients with Advanced, Metastatic Melanoma

In August 2015, the company enrolled the first patient in its Phase II investigator-sponsored clinical trial led by the clinicians at the University of California, San Francisco, or UCSF. The primary endpoint of this study is to assess the anti-tumor efficacy of the combination of intratumoral pIL-12 by electroporation and Merck’s KEYTRUDA® in patients with melanoma who are progressing or have progressed on anti-PD-1 therapy. The primary endpoint of the study is the best overall response rate of the combination regimen in patients whose tumors are characterized by low numbers of TILs. Recent data suggest that patients whose tumors are not associated with TILs or CD8+ T-cells at the tumor margin are unlikely to respond to anti-PD-1 therapies such as KEYTRUDA®, while those who are CTLA-4 and PD-L1 positive and have increased TILs are more likely to have a clinical benefit. Therefore, therapies that promote TIL generation and PD-L1 positivity may play an important role in augmenting the clinical efficacy of the anti-PD1/PD-L1 agents.

This hypothesis is being tested in this trial by enrolling a low-TIL metastatic melanoma patient population. Initial data was presented in February 2017 and the trial stopped enrolling patients in September 2017. The overall response rate in the 22-patient population was 43% at week 24 (best overall response rate was 48%), with one significant adverse Grade-3 event and one Grade-2 event, both of which were resolved with antibiotics or over-the-counter medicines. Based on these results, the company believe the combination therapy studied in the trial was well-tolerated. Ongoing analysis of days to best overall response, duration of response and progression free survival are underway as the existing patients are followed on a long-term basis.

OMS-I100: An Open-Label Phase II Trial of ImmunoPulse® IL-12 Monotherapy in Patients with Metastatic Melanoma

On December 5, 2014, the company released top-line six-month data from a Phase II repeat dose trial of tavo in patients with stage 3 and 4 metastatic melanoma. In this study, which was conducted at UCSF, 30 patients with stage 3 and 4 melanoma received up to four cycles of tavo delivered by electroporation on days one, five and eight of each 12-week cycle. Of the 29 patients in the study who were evaluable, an objective response rate of 31% (9/29) was observed, with 14% (4/29) of patients having a complete response and 17% (5/29) of patients having a partial response. Regression of distant lesions was seen in 50% (13/26) of patients with evaluable non-injected, non-electroporated lesions. Clinical endpoints included objective response rate, local and distant lesion regression, duration of response, overall survival and safety. The company believe the results of this study demonstrated that multiple treatment cycles of ImmunoPulse® IL-12 were well-tolerated, with no treatment-limiting toxicities. The majority of adverse events were localized to the treatment site and were Grade-1 or -2 in severity; however, five patients experienced at least one serious adverse event, four of which were not related to study treatment and one of which was assessed as definitely related to the combination of pIL-12 + electroporation but unlikely to be related to the individual components of the study treatment. No adverse events led to permanent discontinuation of study treatment, and no adverse events resulted in death.

In order to continue to acquire clinical and immune correlational data on melanoma patients treated with ImmunoPulse® IL-12, the protocol of the OMS-I100 study was amended in February 2014 to enroll up to 30 patients. Enrollment in OMS-I100 Addendum was completed in March 2016, the data base is locked and the clinical study report is pending.

Following participation in this trial, some patients participated in a separate study in which they received an anti-PD-1/PD-L1 therapy. Long-term, follow-up data regarding these patients suggest that ImmunoPulse® IL-12 may prime and enhance response rates to PD-1/PD-L1 blockade. Of the 29 patients who completed ImmunoPulse® IL-12, 14 subsequently received an anti-PD-1/PD-L1 treatment. Overall, five of these 14 patients (36%) experienced a complete response and four patients experienced a partial response (29%), for an overall response rate of 65%. Two patients experienced stable disease (14%) and three patients experienced progressive disease (21%). The company believe this retrospective sequential data could suggest combinatorial potential of an immune-priming effect with ImmunoPulse® IL-12 prior to anti-PD-1/PD-L1 therapy.

Other Trials and Studies

In addition to the trials and studies described above, OncoSec Medical has also pursued and closed Phase II clinical trials in patients with Merkel cell carcinoma, head and neck cancer and cutaneous T-cell lymphoma, although OncoSec Medical is no longer pursuing any of these clinical programs.

ImmunoPulse® Platform

The effectiveness of many drugs and DNA-based therapeutics is dependent upon their crossing the cell membrane. In the 1970s, it was discovered that the brief application of high-intensity, pulsed electric fields to the cell resulted in a temporary and reversible increase in the permeability of the cell membrane, a mechanism known as “electroporation.”

The transient, reversible nature of the electrical permeabilization of cell membranes and the resulting increase in intracellular delivery of therapeutic agents is the underlying basis of its ImmunoPulse® therapeutic approach. The company's electroporation delivery system consists of an electrical pulse generator, a reusable applicator handle and disposable applicators. While the extent of membrane permeabilization depends on various electrical, physical, chemical, and biological parameters, research with electroporation delivery has demonstrated an improvement in cellular uptake of chemical molecules such as chemotherapeutic agents (e.g., bleomycin and cisplatin), and nucleic acids (e.g., DNA and RNA).

Multiple viral and non-viral delivery modalities have been developed to deliver nucleic acids into cells, however, many of these methods have faced challenges related to the safe and efficient expression of the DNA-encoded biologic into the intended target cells. For example, viral mediated delivery technologies appear to be efficient at transfecting cells, but they have suffered from significant safety issues related to the immunogenicity of the viral vector, shedding of the virus, and potential integration of the viral DNA into the host genome. Other non-viral delivery methods have employed the use of nanotechnology to coat the DNA with fat molecules, called lipids. Although these lipid nanoparticle technologies have been used extensively in the clinic to deliver DNA-encoded biologic agents, few particles have been developed with the ability to specifically target cancer cells; instead, many of these particles naturally target the liver, which can lead to potential liver toxicities.

Like viral vectors and lipid nanoparticle technologies, electroporation has been used extensively in the clinic to deliver multiple therapeutic agents, including DNA. However, unlike these other technologies, electroporation has not seen the same safety concerns. In fact, the use of electroporation to deliver bleomycin intratumorally has been approved for use in Europe for cancers, such as basal cell carcinoma, and has been accepted across many European countries, including the United Kingdom.

The company's ImmunoPulse® platform employs an electroporation system designed to create favorable conditions to deliver plasmid DNA encoding immunotherapeutic cytokines directly into cells of the tumor microenvironment. The cytokine-encoding plasmid is first injected into the tumor. A needle-electrode array then delivers the electrical pulses produced in the pulse generator. In addition, OncoSec Medical is continuing to advance the field of electroporation by developing its tissue-based real-time adaptive control electroporation, or TRACE, technology. The TRACE technology uses electrochemical impedance spectroscopy, or EIS, to continuously evaluate the electrical properties of the tissue. By doing so, TRACE has the ability to modulate the electric field in real-time, thus optimizing the electroporation conditions and improving the transfection of the DNA into the cells.

The company's lead product candidate, ImmunoPulse® IL-12, consists of a plasmid construct encoding the proinflammatory cytokine IL-12 that is delivered into the tumor through in vivo electroporation using its ImmunoPulse® technology. OncoSec Medical is also researching other DNA-encoded, immunologically-active molecules, with an aim of developing additional immunotherapeutic drugs that, when delivered through electroporation using its ImmunoPulse® platform, may be capable of breaking the immune system’s tolerance to cancer.

Commercialization

Strategy

The company's primary focus is to continue its clinical development strategy for ImmunoPulse® IL-12, including its currently planned and ongoing Phase II clinical trials discussed under “Clinical Programs” above and potentially other Phase II or subsequent trials the company may pursue in the future, which may include trials focused on cancers that have demonstrated a response to anti-PD-1/PD-L1 checkpoint therapies, such as metastatic melanoma.

As a part of its commercialization strategy, the company also regularly investigate and evaluate potential collaboration opportunities, to identify rational combinations with existing and emerging monoclonal antibody therapies and other drugs. For instance, the company may seek to collaborate with pharmaceutical or biotechnology companies or government agencies to provide it with access to complementary technologies and/or greater resources. In addition, the company may seek to expand the applications of its technologies through strategic collaborations or other opportunities, such as in-licensing or strategic acquisitions, and the company may seek to out-license its intellectual property to other companies to leverage its technologies for applications that the company may not choose to internally and independently development.

Manufacturing and Supply

Currently, the company assemble certain components of its electroporation system, which is its proprietary delivery mechanism for its ImmunoPulse IL-12® product candidate, and the company utilize the services of contract manufacturers to manufacture the remaining components of these systems and for the manufacture, testing and storage of all of its supply of its plasmid product candidate for clinical trials or other studies. The manufacture of its systems and product supplies requires significant expertise and capital investment, including the use of advanced manufacturing techniques and process controls, and the company do not own and have no plans to build its own clinical or commercial manufacturing capabilities. The company expect to increase its reliance on third-party manufacturers if and when the company commercialize any of its product candidates and systems.

The company rely upon a small number of suppliers and manufacturers for its clinical activities, including distributors such as Cryosite, Sherpa, as well as manufacturers such as Richter Helm, VGXI and SGS, which collectively account for 100% of clinical materials; and Minnetronix, which accounts for 50% of electroporation systems support and materials. The company believe there are alternate sources of raw material supply and finished goods manufacturing to satisfy its requirements, although transitioning to other vendors, if necessary, could result in significant delay or material additional costs. In addition, for combination trials, the company typically rely exclusively on one supplier of the non-company-owned product used in the trial, such as its reliance upon Merck for the supply of KEYTRUDA® in the PISCES study.

OncoSec Medical is certified by all appropriate standards and authorities for the limited assembly and manufacture activities the company conduct, and the company and have established an audited quality management system for these activities. In addition, all contract manufacturers that the company use must comply with various requirements enforced by the FDA through its facilities inspection programs. See “Regulation” below for more information.

Performance Outlook

The company expect to use its available working capital in the near term primarily for the advancement of its existing and planned clinical programs, including primarily the initiation of the PISCES/KEYNOTE-695 study and, to a lesser extent, the continuation of its other clinical trials and studies described above. The company anticipate its spending on clinical programs and the development of its next-generation electroporation device for its ImmunoPulse® IL-12 platform will increase throughout its current fiscal year, primarily in support of the PISCES/KEYNOTE-695 study, while its spending on research and development programs will decrease due to its focus on the PISCES/KEYNOTE-695 study. The company expect its cash-based general and administrative expenses to remain relatively flat in the near term, as the company seek to continue to leverage internal resources and automate processes to decrease its outside services expenses. See “Results of Operations” below for more information.


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