Inovio Pharmaceuticals Stock

Inovio Pharmaceuticals, Inc. operates as a biotechnology company. The company focuses on developing and commercializing DNA medicines to help treat and protect people from diseases associated with human papillomavirus (HPV), cancer, and infectious diseases.

In clinical trials, the company’s DNA medicine candidates have shown the ability to generate immune responses, especially CD4+, CD8+, and memory T-cell responses against targeted pathogens and cancers, via its precisely designed plasmids. These plasmids are delivered into cells using the company’s investigational proprietary smart device, CELLECTRA.

Many of the company’s lead candidates are focused on diseases associated with HPV. In 2022, the company announced data from a Phase 1/2 clinical trial with INO-3107 for the treatment of HPV-6 and HPV-11 associated Recurrent Respiratory Papillomatosis (RRP). In this trial, treatment with INO-3107 resulted in a statistically significant reduction of the median number of surgeries, a result that reinforces the company’s belief that DNA medicines (product candidates in development for diseases associated with human papillomavirus (HPV), cancer, and infectious diseases) may play a key role in the treatment of HPV-related diseases.

DNA Medicines Platform

The company’s DNA medicines platform consists of DNA plasmids and its investigational proprietary smart device, CELLECTRA, which is used to deliver the DNA plasmids into the cell. These two components combine to create a versatile platform that has the potential to target any disease or condition that is associated with a specific antigen or protein.

SynCon - DNA Plasmid Design Technology

The company’s precisely designed DNA plasmids are circular double-stranded DNA that have been optimized using its proprietary SynCon technology to express the target antigen or protein. In the areas of HPV-related diseases, cancer, and infectious diseases, the expressed proteins are the antigens that are strongly associated with the target disease. The company first identifies one or more antigens that are the best targets for directing the immune system toward a particular tumor or infectious disease. The company then applies its SynCon design process, which analyzes the genetic make-up of the selected antigens from multiple variants of a tumor or strains of a virus.

For each antigen, SynCon technology creates a new genetic sequence that represents a nucleotide consensus sequence of the targeted antigen. The company has generated immune responses, including CD4+, CD8+, and memory T cells, with SynCon-designed DNA medicines against various tumor-associated antigens, as well as against different strains of certain infectious diseases in human clinical trials. Because the engineered SynCon sequences are substantially similar to the original sequences, without matching them exactly. The company has developed a high-yield manufacturing process which it anticipates using to manufacture its DNA medicines.

CELLECTRA Delivery Technology

Large molecules, like DNA plasmids, tend to be hindered by the cell membrane from entering the cell. To overcome this hurdle and allow for an efficient cellular uptake of its DNA plasmids, the company has developed the CELLECTRA delivery technology, which delivers the DNA medicines directly into cells either intramuscularly (IM) or intradermally (ID). CELLECTRA devices use brief electrical pulses to reversibly open small pores in the cell membrane, allowing DNA plasmids to enter. Through this process, the cellular uptake of the DNA plasmids can be substantially increased compared to the injection of DNA plasmids alone. This improved cellular uptake has enabled the immune responses and efficacy results observed in the company’s clinical trials to date.

The company’s CELLECTRA device portfolio consists of three models. CELLECTRA 2000 can perform both IM and ID injections and has been used in numerous clinical trials to date. CELLECTRA 5PSP is the company’s new IM device utilizing a prefilled drug cartridge. CELLECTRA 5PSP has been used in the company’s Phase 3 trials (REVEAL1/REVEAL2) for cervical high-grade squamous intraepithelial lesions (HSIL). The company is also planning to use CELLECTRA 5PSP for the planned Phase 3 trial for INO-3107, its DNA medicines candidate for RRP. Finally, CELLECTRA 3PSP is its next-generation ID delivery device developed with support from the U.S. Department of Defense, which is ready for large volume production and application submission to regulatory agencies for review and approval.

CELLECTRA devices are validated and manufactured under Current Good Manufacturing Practices (cGMP). The company has filed device master files with the U.S. Food and Drug Administration (FDA) covering the use of CELLECTRA smart devices in human clinical trials. CELLECTRA 2000 and 5PSP models have received CE mark certification in the EU.

In October 2022, the company announced preliminary results from an open-label, multicenter Phase 1/2 trial evaluating the efficacy, safety, tolerability and immunogenicity of INO-3107, a DNA medicine candidate targeting HPV-6 and HPV-11 associated RRP. For this trial, adult patients first underwent surgical removal of their papilloma(s) and then received up to four doses of INO-3107, once every three weeks. The study protocol also included the administration of INO-9112, which encodes for human interleukin-12 (IL-12) to help enhance the immune response. The primary endpoint of this trial was safety and tolerability. Interim results from the trial showed INO-3107 to be well-tolerated with all patients completing the trial follow-up.

INO-3107 was granted Orphan Drug Designation (ODD) by the FDA in July 2020.

In February 2023, the company announced positive preliminary results from the second cohort of its Phase 1/2 clinical trial evaluating INO-3107 for the treatment of HPV 6 and HPV 11-associated RRP in adults. In the second cohort of 11 patients who were administered INO-3107 via the exploratory side port needle, 10 of the 11 patients (91%) had a reduction in surgical interventions in the year following initial treatment, with measurement beginning at Day 0, the start of trial therapy. Of these 10 patients, four did not require surgery.

VGX-3100 is designed to generate T cell immune responses against the E6 and E7 oncogenic proteins of high-risk HPV types 16 and 18 that can be present in both precancerous and cancerous cells transformed by these HPV types. E6 and E7 are oncogenes that play an integral role in transforming HPV-infected cells into precancerous and cancerous cells, thus making them appealing targets for T cell-directed immunotherapy.

The company has completed randomized, blinded, placebo-controlled Phase 2b and Phase 3 clinical trials of VGX-3100 compared to placebo, in women with HPV-16 and HPV-18 cervical HSIL. In the Phase 2b trial, women treated with VGX-3100 were more likely to demonstrate resolution of cervical HSIL and HPV clearance from cervical lesions than those women receiving placebo. In addition, antigen-specific T cell levels in women treated with VGX-3100 were greater than those treated with placebo.

The company is pursuing a biomarker signature for its VGX-3100 program. In May 2019, the company entered into a collaboration with QIAGEN N.V. to co-develop a liquid biopsy-based diagnostic for this biomarker signature to identify women with HPV-16/18 cervical HSIL most likely to respond to VGX-3100. In February 2021, the company announced an extension of its partnership with QIAGEN with a new master collaboration agreement to develop liquid biopsy-based companion diagnostic products based on next-generation sequencing technology to complement its therapies. QIAGEN is utilizing the Illumina NextSeq 550Dx platform for this biomarker, the first development based on a partnership QIAGEN and Illumina entered into in October 2019.

In December 2021, the company announced that it and QIAGEN had identified candidate biomarker signatures for VGX-3100 with the intent of selecting a final signature of a pre-treatment in vitro diagnostic to meet the specific characteristics desired to identify women with HPV-16/18 cervical HSIL most likely to respond to VGX-3100.

The company’s Phase 3 program, named REVEAL, consists of a primary trial (REVEAL1; HPV-301) and confirmatory trial (REVEAL2; HPV-303). The REVEAL trials are prospective, randomized (2:1), double-blind, placebo-controlled trials evaluating adult women with HPV 16/18 positive biopsy-proven cervical HSIL (CIN 2/3). The primary endpoint is regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 in the cervix, which was a secondary endpoint that was achieved in the company’s Phase 2b trial. Overall, the Phase 3 trials are evaluating cervical tissue changes at approximately 9 months after beginning a three-dose regimen of VGX-3100 administered at months 0, 1 and 3.

In March 2021, the company announced the results of the REVEAL1 trial of VGX-3100. The trial protocol-defined intention to treat (ITT) population (N=201) included all randomized participants regardless of availability of endpoint data and defines those without endpoint data as non-responders. There were eight such participants (seven in the treatment group, one in the placebo group) in the ITT population. Including participants with missing endpoint data, the percentage of participants meeting the primary endpoint was 22.5% (31/138) in the treatment group, versus 11.1% (7/63) in the placebo group (p=0.029; 95%CI: -0.4,21.2), which was not statistically significant. All secondary endpoints were achieved except for regression of cervical HSIL alone (95%CI: -0.6,24.5).

The company completed the 52-week safety follow-up of participants in REVEAL1 and showed that VGX-3100 remained well-tolerated through Week 88. In addition, participants treated with VGX-3100 who met the primary endpoint at Week 36 remained clear of HPV-16 and/or HPV-18 at Week 88.

REVEAL2 is the company’s second Phase 3 trial with VGX-3100. In April 2022, the trial protocol was amended to utilize a biomarker-selected population as the primary population, based on prior analysis of REVEAL1 results suggesting that this investigational biomarker had the potential to identify women more likely to respond to treatment with VGX-3100. The company announced that this trial would no longer be considered to be a pivotal trial and would not lead to a BLA filing for a biomarker-selected population, as the FDA advised it that the biomarker-positive population would not be sufficient to support approval of a potential marketing application for VGX-3100.

In March 2023, the company announced data from its REVEAL2 trial. Statistical significance was not achieved in the investigational biomarker-selected population for the endpoint of lesion regression and viral clearance. However, statistical significance was achieved in the all-participants population for the endpoint of lesion regression and viral clearance.

The company has completed a Phase 2 clinical trial (HPV-203) to evaluate VGX-3100 in participants who are HIV-negative with histologically confirmed anal or perianal HSIL, or anal intraepithelial neoplasia (AIN), associated with HPV-16 and/or HPV-18. This open-label trial enrolled 24 participants who received three doses of VGX-3100 delivered by its CELLECTRA-5PSP device. The primary endpoint of the trial was histologic clearance of the high-grade lesions and virologic clearance of the HPV-16/18 virus in anal/perianal tissue samples. In December 2020, the company announced Phase 2 efficacy results from this trial. One-half of participants treated with VGX-3100 (11/22) showed resolution of HPV-16/18-associated anal HSIL at six months following the start of treatment. VGX-3100 was well-tolerated in the trial.

The company has completed a Phase 2 trial (HPV-201) to evaluate the efficacy of VGX-3100 in participants with vulvar HSIL. This randomized, open-label Phase 2 clinical trial assessed the efficacy of VGX-3100 in 33 women with vulvar HSIL. VGX-3100 was administered with its CELLECTRA -5PSP smart device. The primary endpoint of the trial was histologic clearance of high-grade lesions and virologic clearance of the HPV virus in vulvar tissue samples. The trial also evaluated the safety and tolerability of VGX-3100. In January 2021, the company announced efficacy results from this trial. A 25% or more reduction in HPV-16/18-associated vulvar HSIL was observed for 63% of trial participants (12 of 19) treated with VGX-3100 at six months post-treatment.

The company’s product candidate INO-5401 is an immunotherapy consisting of three DNA plasmids encoding for three tumor-associated antigens: human Telomerase Reverse Transcriptase (hTERT), Wilms Tumor gene-1 (WT1) and Prostate-Specific Membrane Antigen (PSMA).

The company has completed a Phase 1/2 immuno-oncology trial of INO-5401 and INO-9012 (IL-12 plasmid) in participants with newly diagnosed GBM, in combination with cemiplimab (Libtayo), a PD-1 inhibitor developed by Regeneron Pharmaceuticals. This open-label trial began in 2018 and enrolled 52 newly diagnosed GBM participants. The primary endpoint was safety and tolerability, and the trial also evaluated immunogenicity and efficacy (Overall Survival, or OS).

In May 2022, the company presented OS data at the 2022 American Society of Clinical Oncology (ASCO) from GBM-001 Phase 2 trial. Median OS duration in patients with an unmethylated MGMT promoter (Cohort A) was 17.9 months, which compares favorably to historical comparisons (14.6-16 months). Median OS data in patients with a MGMT methylated promoter (Cohort B), was 32.5 months, which compares favorably to historical comparisons (23.2-25 months).

INO-5151 consists of DNA plasmids targeting Prostate Specific Antigen (PSA) and Prostate Specific Membrane Antigen (PSMA), combined with INO-9112, the IL-12 plasmid, for the treatment of prostate cancer.

In 2019, the company announced a clinical collaboration with Parker Institute for Cancer Immunotherapy (PICI) and the Cancer Research Institute (CRI) as part of which INO-5151 is being combined with an immune modulator (CDX-301, FLT3 ligand, a dendritic cell mobilizer) and a PD-1 immune checkpoint inhibitor (nivolumab) in participants with metastatic castration-resistant prostate cancer (mCRPC), in a PICI-sponsored platform trial (PORTER).

In 2022, the company announced the discontinuance of all internally funded COVID-19 vaccine programs for INO-4800. The decision followed a comprehensive review of market conditions and global demand for COVID-19 vaccines. In May 2022, the company announced the discontinuance of its INNOVATE program, which was focused on developing INO-4800 as a primary vaccine candidate against COVID-19. In October 2022, the company announced the discontinuance of these heterologous booster vaccine efforts for INO-4800 as market conditions continued to shift.

INO-4800 is one of two initial COVID-19 vaccine candidates included in the World Health Organization (WHO) sponsored Solidarity Trial Vaccines, which is designed to evaluate the efficacy and safety of promising new candidate vaccines selected by an independent vaccine prioritization advisory group composed of leading scientists and experts.

The company’s collaborator Advaccine has completed enrollment of its 200-participant homologous and 267-participant heterologous booster vaccine trials in China.

Using its SynCon technology, the company is able to create a precisely designed DNA plasmid that encodes for a specific monoclonal antibody (mAb). The company refers to these DNA plasmids as its dMAb product candidates. The company delivers the plasmid directly into cells of the body using its CELLECTRA smart delivery system, enabling the electroporated cells to manufacture those mAbs in vivo (i.e. by the body itself), unlike conventional mAb technology that requires manufacture outside of the body.

In December 2021, the company announced complete enrollment of a 46-participant Phase 1b trial in which its DNA medicine candidate INO-4201 was assessed as a heterologous booster in healthy volunteers previously vaccinated with rVSV-ZEBOV (ERVEBO), an FDA- and EMA- approved viral vector-based Ebola vaccine (NCT04906629).

In February 2022, the company announced results from the Phase 1b trial. INO-4201 was well-tolerated and boosted humoral responses in 100% (36 of 36) of treated participants. The company and its collaborators plan to publish the data in a peer-reviewed journal and provide updates on the next steps for INO-4201.

In 2018, the company announced a collaboration with CEPI under which CEPI would costs to support its pre-clinical and clinical advancement through Phase 2 of its vaccine candidate INO-4700.

The company dosed and completed enrollment for the first part (dose finding stage) of the Phase 2 trial (192 participants) of INO-4700. The multi-center Phase 2 trial was a randomized, double-blinded, placebo-controlled trial designed to evaluate the safety, tolerability, and immunogenicity of INO-4700 administered with CELLECTRA 2000 in approximately 500 healthy adult participants (NCT04588428). The trial was conducted at sites in Jordan, Lebanon, and Kenya.

Based on initial analysis of data from the studies, the company and CEPI agreed to discontinue development of INO-4700 for MERS in November 2022. Although INO-4700 was well-tolerated by participants in its clinical trials and generated immune responses, the two-dose regimen did not meet CEPI's selection criteria for further development.

In October 2021, the company completed enrollment of a 220 participant Phase 1b trial for its vaccine candidate INO-4500 in Accra, Ghana, which was the first vaccine clinical trial for Lassa Fever conducted in West Africa, where the viral illness is endemic. The trial was funded by CEPI. The dosing regimen involved two intradermal vaccinations at 0 and 28 days with either 1.0 mg or 2.0 mg doses.

In November 2022, the company announced that it and CEPI agreed to discontinue development of INO-4500 for Lassa Fever, following initial analyses of data from studies. Although INO-4500 was well tolerated by participants in the company’s clinical trials and generated immune responses, the two-dose regimen did not meet CEPI's selection criteria for further development.

Collaboration and Alliances

The company’s partners and collaborators include Advaccine Biopharmaceuticals Suzhou Co, ApolloBio Corporation, AstraZeneca, The Bill & Melinda Gates Foundation (Gates), Coalition for Epidemic Preparedness Innovations (CEPI), Defense Advanced Research Projects Agency (DARPA), The U.S. Department of Defense (DoD), HIV Vaccines Trial Network, International Vaccine Institute (IVI), Kaneka Eurogentec, National Cancer Institute (NCI), National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), the Parker Institute for Cancer Immunotherapy, Plumbline Life Sciences, Regeneron Pharmaceuticals, Richter-Helm BioLogics, Thermo Fisher Scientific, the University of Pennsylvania, the Walter Reed Army Institute of Research, and The Wistar Institute.

Advaccine

On December 31, 2020, the company entered into a Collaboration and License Agreement with Advaccine Biopharmaceuticals Suzhou Co., Ltd. (Advaccine), which was amended and restated on June 7, 2021 (as amended and restated, the Advaccine Agreement). Under the terms of the Advaccine Agreement, the company granted to Advaccine the exclusive right to develop, manufacture and commercialize its vaccine candidate INO-4800 within the territories of China, Taiwan, Hong Kong and Macau (referred to collectively as Greater China) and 33 additional countries in Asia.

ApolloBio

In December 2017, the company entered into an Amended and Restated License and Collaboration Agreement with Beijing Apollo Saturn Biological Technology Limited, a corporation organized under the laws of China, or ApolloBio. Under the terms of this License and Collaboration Agreement, which became effective in March 2018, the company granted to ApolloBio the exclusive right to develop and commercialize VGX-3100, its DNA immunotherapy product candidate designed to treat pre-cancers caused by HPV, within the agreed upon territories - Greater China (defined as China, Hong Kong, Macao and Taiwan).

Competition

The company’s competitors and potential competitors include large pharmaceutical companies broadly engaged in vaccine/immunotherapy research and development, such as Janssen Pharmaceuticals (part of J&J), Sanofi-Aventis, GlaxoSmithKline plc, Merck, Pfizer, Roche, AbbVie, Novartis, Bristol-Myers Squibb, and AstraZeneca, as well as various development-stage biotechnology companies involved in different vaccine and immunotherapy technologies, such as CureVac, Dynavax, Genexine, Hookipa, Iovance, Nektar, Nykode, Precigen, Translate Bio, Zydus, and Vir Biotechnology.

Significant Customers

During the year ended December 31, 2022, the company derived 94% of its revenue from the procurement contract with the DoD that it entered into in June 2020.

Research and Development

The company’s research and development expense included $187.7 million in 2022.

Intellectual Property

As of December 31, 2022, the company’s patent portfolio included approximately 100 issued U.S. patents and approximately 80 U.S. patent applications as well as approximately 800 issued foreign counterpart patents and approximately 700 counterpart foreign patent applications. These are comprised, in part, of two U.S. patent applications and approximately 40 counterpart foreign patent applications, directed to treatment of RRP; seven issued U.S. patents and five U.S. patent applications, as well as approximately 80 issued foreign counterpart patents and approximately 50 counterpart foreign patent applications, directed to treatment of GBM; approximately 70 issued U.S. patents and approximately 50 U.S. patent applications, as well as approximately 400 issued foreign counterpart patents and approximately 500 counterpart foreign patent applications, directed to its other earlier-stage product candidates; and approximately 30 issued U.S. patents and approximately 20 U.S. patent applications, as well as approximately 30 issued foreign counterpart patents and approximately 125 counterpart foreign patent applications, directed to its device delivery systems.

The company’s pending patent applications directed to treatment of RRP, if issued, would expire between about 2040 and 2043. The company’s issued patents directed to treatment of GBM expire between about 2027 and 2037 and its pending patent applications, if issued, would expire between about 2027 and 2040. The company’s issued patents directed to its other product candidates expire between about 2023 and 2036 and its pending patent applications, if issued, would expire between about 2027 and 2042. The company’s issued patents directed to its device delivery systems expire between about 2023 and 2036 and its pending patent applications, if issued, would expire between about 2023 and 2042.

Government Regulation

The company’s product candidates must be approved by the FDA through the Biologics License Application, or BLA, process before they may be legally marketed in the United States.

The company relies and expects to continue to rely, on third parties for the production of clinical and commercial quantities of its products in accordance with cGMP regulations. cGMP regulations require, among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

History

The company was incorporated in 1983. The company was formerly known as Biotechnologies & Experimental Research, Inc. and changed its name to BTX, Inc. in 1991 and to Genetronics, Inc. in 1994. Further, the company changed its name to Genetronics Biomedical Corporation in 2001; to Inovio Biomedical Corporation in 2005; and to Inovio Pharmaceuticals, Inc. in 2010.