Genprex’s Gene Therapy: Potential Breakthrough for Diabetes and Lung Cancer

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Summary:

• Genprex is developing novel therapies for diabetes and lung cancer.
• The company’s diabetes gene therapy exhibited encouraging preclinical results in both the diabetic mouse model and non-human primate [NHP] model, improving glucose tolerance and reducing insulin requirements by successfully converting alpha cells into beta-like cells.
• The GPX-002/003 gene therapy could be a long-lasting solution for diabetes, potentially benefiting many patients who require insulin replacement therapy.
• The company's lead therapy candidate, Reqorsa, has received FDA fast-track designation as a combination therapy with Keytruda and Tagrisso.
• Genprex has been granted a patent for the use of its Reqorsa therapy in combination with immune checkpoint inhibitors until 2037.
• The company has a strong financial position with zero debt and a cash balance of $29.52 million as of September 2022, inclusive of recent raise.

Genprex recently presented optimistic data on its diabetes gene therapy from its non-human primates study, followed by data from a previously concluded mouse model. In both studies, the diabetes gene therapy exhibited curative properties with the potential to change the course of the disease. Additionally, multiple preclinical trials and interim clinical results from ONC-001/2 provide evidence of Reqorsa’s safety and efficacy profile. The company’s Oncoprex technology and the applicability of the TUSC2 gene allow it to pursue additional indications besides non-small cell lung cancer [NSCLC]. Further, the success of its Acclaim 1/2 trials would provide enough headroom for Genprex to pursue other indications in addition to its diabetes gene therapy.

Company Overview:

Genprex Inc. (NASDAQ: GNPX) is a clinical-stage gene therapy company developing novel therapies for lung cancer and diabetes. The company was founded in 2009. The company’s therapy pipeline leverages its gene therapy platform, the Oncoprex Nanoparticle Delivery System, to deliver cancer-fighting genes systematically. Genprex’s lead therapy candidate, Reqorsa, is currently being researched under a Phase 1/2 clinical trial as a combination therapy with Tagrisso and Keytruda for the treatment of non-small cell lung cancer [NSCLC]. Reqorsa is also being evaluated in combination with Tecentriq for small-cell lung cancer [SCLC]. The company is pursuing various other oncological targets in addition to GPX-002/ 003, its gene therapies for diabetes.

Potentially Curative Diabetes Gene Therapy Addressing Diabetes at its Core

Genprex has licensed gene therapies for diabetes developed by researchers at the University of Pittsburgh. Both GPX-002 (for type 1 diabetes) and GPX-003 (for type 2 diabetes) aim to rejuvenate and replenish the pancreatic beta cells responsible for producing insulin. Both therapies use similar approaches wherein the Pdx1 and MafA transcription factors, which control the expression of insulin in the pancreatic beta cells, are delivered directly to the pancreas via an endoscope and an adeno-associated virus [AAV] vector. Infusing the viral construct directly into the pancreatic duct is likely to improve safety and drastically minimize the risks of toxicities or inflammation arising from the use of viral therapy/ viral vector.

The difference in the two therapies lies in targeting the primary hallmarks of type 1 and type 2 diabetes. Both type 1 and type 2 diabetes are recognized by the inability of the pancreatic beta cells to meet the body’s insulin-secretion needs. In type 1 diabetes, the immune system mistakenly destroys beta cells, restricting or blocking insulin production. GPX-002, for type 1 diabetes, employs a glucagon promoter that converts alpha cells into beta-like cells within the pancreas. These new cells not only enhance insulin production but also may evade immune system attacks. In type 2 diabetes, beta cells may become exhausted and dysfunctional, leading to reduced insulin production. GPX-003, licensed for type 2 diabetes, uses an insulin promoter to target and activate beta cells in the pancreas, thus promoting insulin production.

Preclinical Trial Results

The preclinical studies included in vivo tests in non-obese diabetic mice and non-human primates. GPX-002 was found to restore normal blood sugar levels for an extended time. In the T1D mouse model, GPX-002 successfully restored normal blood glucose levels for four months, potentially translating into decades for humans.

The company recently presented the preclinical trial results evaluating GPX-002’s ability to treat toxin-induced diabetes in non-human primates [NHP]. Like the studies in mice, the study in NHPs involved introducing specific transcription factors, Pdx1 and mafA, to the pancreas in an effort to create insulin-producing beta-like cells. The results showed that gene therapy increased the production of insulin, thereby improving blood sugar levels and reducing the need for insulin injections. Immunohistochemistry revealed the formation of insulin-producing cells. This not only confirms the previous encouraging results obtained in the mouse model but also suggests that gene therapy may be a promising treatment for diabetes that could provide long-term benefits by replacing the beta-cells and eliminating the need for insulin injections.

GPX-002/ 003 could prove to be transformational treatments for 37 million American adults, both diagnosed and undiagnosed, and 537 million people globally who are affected by this rapidly growing chronic disease.

Oncoprex - A Novel Drug Delivery System

Oncoprex, a novel systemic gene therapy delivery platform, is at the core of Genprex’s therapy pipeline utilizing a unique, proprietary non-viral delivery system. With the Oncoprex nanoparticle delivery system, plasmids containing tumor-suppressing genes are encapsulated within lipid nanoparticles. This resulting solution is then delivered intravenously and taken up by the tumor cells, potentially leading to therapeutic benefits. By using non-viral vectors, the risk of immunogenicity and cytotoxicity is significantly reduced, allowing for repeated therapeutic doses.

In gene therapy development, an inverse relationship between transfection efficiency (the level of expression of foreign genetic material, such as DNA or RNA) and toxicology profiles have been recorded. Although viral vectors have high transfection efficiency, they trigger a strong immune response, while non-viral vectors struggle with lower transfection efficiency but are much safer. Liposome formulation has been used widely as a non-viral delivery vehicle, with a number of drugs using liposomes as non-viral vectors having been approved. However, with the evolving and advancing landscape, new versions of liposomes or alternative lipid-based non-viral carriers known as lipid nanoparticles have gained prominence in the past two decades. Lipid nanoparticles [LNPs] have recently gained more attention due to their role in the COVID-19 mRNA vaccines. LNPs are an upgraded version of liposomes with improved stability, better target delivery, and higher drug-loading capacity, making them a promising vehicle for delivering various therapeutics. Oncoprex's use of LNPs and the subsequent development of Reqorsa have demonstrated positive results in clinical trials [ONC-001 and ONC-002].

Understanding Gene Therapy and the Selection of an Active Ingredient

While the root cause of cancer is complex and multifactorial, genetic abnormalities have been identified as a significant contributing factor. This can be attributed to the intricate processes of cell division and DNA replication, which are critical for tissue growth and regeneration. However, genetic mutations can occur, leading to alterations in genes that regulate cell growth, cell division, and repair, which in turn result in uncontrolled cell proliferation and tumor formation. Genetic mutations in tumor suppressor genes and oncogenes, which respectively regulate cell growth and facilitate cell division, are highly researched due to their importance in cancer development. Deletions of these genes can lead to a lack of tumor suppressor gene expression, or mutations in these genes can lead to the deactivation of tumor suppressor genes, resulting in uncontrolled cell growth or the activation of oncogenes, promoting tumor growth and progression.

The TUSC2 (tumor suppressor candidate 2) gene is one such tumor suppressor gene, the absence of which has been found to correlate with cancer cell proliferation. While the TUSC2 gene is present in normal cells, it is downregulated or deleted during early cancer development. Research has shown that approximately 80% of lung tumors exhibit a reduction or loss of TUSC2 mRNA expression. The loss or reduction of TUSC2 protein expression has been observed in 82% of non-small cell lung cancers [NSCLCs] and in all cases of small cell lung carcinomas [SCLC]. In NSCLCs, a lower level of TUSC2 protein is associated with poor overall survival. Genprex has hypothesized that reintroducing the TUSC2 protein could exhibit anti-tumor properties due to multiple pathways and a cellular process that leads to tumor cell death. Multiple research studies have found that the multifactorial mechanism of the TUSC2 gene not only induces apoptosis (cell death) in cancer and decreases cell growth but might also play a key role in promoting an immune response.

REQORSA™ - Lead Therapy Candidate

Genprex’s lead therapy candidate, the Reqorsa immunogene therapy, utilizes the Oncoprex nanoparticle delivery system to develop gene therapy targeting non-small cell lung cancer [NSCLC]. The company has piloted two clinical trials and is currently testing the drug as a combination therapy for underlying cancer.

The active ingredient within Reqorsa is the TUSC2 gene-expressing plasmid encapsulated within positively charged lipid nano-particles, which is then injected intravenously, targeting cancer cells. The way Reqorsa works involves a combination of gene therapy and immunotherapy characteristics, which creates a multi-modal mechanism of action. The treatment has been shown to inhibit the cell signaling pathways that promote cancer growth, enabling programmed cell death and regulating the immune system's anti-cancer response. It has also been shown to have overcome various mechanisms leading to drug resistance.

Preclinical and Clinical Results

Genprex had previously piloted two clinical trials: ONC-001 (monotherapy) and ONC-002 (combination therapy with Tarceva). The company also produced a number of preclinical trials exhibiting the synergistic effects of combination therapy: Reqorsa + anti-PD1/TKI.

1. Reqorsa + Tagrisso: Robust anti-tumor activity in NSG mice with H1975 Tagrisso-resistant human NSCLC xenografts.
2. Reqorsa + Keytruda: Strong anti-tumor immune responses were found against human NSCLC xenografts developed in humanized mice with metastatic lung cancer.

ONC-001 - A dose-escalation study was conducted by MD Anderson researchers in 2012 to assess the toxicity of Reqorsa and determine the maximum tolerated dose [MTD]. Thirty-one subjects with advanced NSCLC were treated with six dose levels, of which 23 subjects were administered two or more doses and were thus evaluable. The therapy was well-tolerated, and the only dose-limiting toxicities were two episodes of transient grade 3 hypophosphatemia. Cancer growth was found to be halted in five out of 23 patients, while the highest dosage was 0.09mg/kg. Furthermore, high levels of TUSC2 expression were detected in the tumors after Reqorsa administration, with evidence of tumor growth suppression. Overall, the trial was found to be well-tolerated, with tumor regression recorded in multiple cases (No response CR or PR were obtained). Reading too much into the efficacy data from the trial would not be appropriate, as the primary aims of the study were to assess the safety and toxicity of the therapy and determine the MTD for potential use in further phases of clinical trials, both of which were successfully met.

ONC-002 - Based on the results from the monotherapy and preclinical studies illustrating the synergistic benefits of combination therapy, Genprex enrolled 18 patients in the Phase 1 combination Tarceva trial and 10 patients out of 39 planned (3 of those 10 patients were previously part of the ONC-002, phase 1 trial) in the Phase 2 trial. The company halted the Tarvcea trial in favor of the Reqorsa + Tagrisso (combination therapy)/ Acclaim 1 clinical trial, possibly due to the receipt of FDA fast-track designation in January 2020.

Interim Results

The Phase 1 part of the ONC-002 trial was a dose-escalation study aiming to determine the maximum tolerated dose. The primary goal of Phase 2 open-label clinical trial was to measure response rate, and secondary endpoints included stable disease and survival rate criteria. Of the 10 patients enrolled in the Phase 2 trial, nine received two or more cycles of treatment and were thus evaluable based on trial protocol. No dose-limiting toxicities were reported among the 10 patients that were administered the treatment. The efficacy data, as indicated by disease control rate [DCR], was measured at 78%, with one subject achieving a complete response.

Preclinical trials and the ONC-001/2 clinical trials provided optimistic results in terms of the potential synergistic benefits of combination therapy and well-toleration of treatment as a monotherapy, with 78% DCR observed in the interim ONC-002 Phase 2 results. Even though the number of patients evaluated is small, it still provides a comprehensive idea of the therapy's overall efficacy and safety profile. Additionally, a 78% DCR seems like a decent endpoint to measure the trial's overall success.

Acclaim Clinical Trials

Moving Forward with Reqorsa’s possible path to approval, Genprex is undertaking two combination therapy clinical trials: Acclaim 1 (Reqorsa + TKI Tagrisso) and Acclaim 2 (Reqorsa + Keytruda). The company has received FDA fast-track designation for both these clinical trials for the treatment of non-small cell lung cancer [NSCLC].

Acclaim 1 - Genprex has initiated a Phase 1/2 dose-escalation and clinical response study evaluating Reqorsa in combination with AstraZeneca’s Tagrisso in patients who have progressed on Tagrisso. The Phase 1 portion of the trial will have a dose-escalation phase to determine the maximum tolerated dose (n=18) and a dose-expansion phase to evaluate toxicity profiles and efficacy in different patient groups (n=66). This will be followed by a randomized 1:1 Phase 2 trial to compare the combination therapy with Tagrisso monotherapy, with the primary endpoint being progression-free survival (n=74). The clinical trial includes subjects with EGFR-mutant metastatic NSCLC who have seen their cancer progress after treatment with Tagrisso. Genprex recently announced receipt of approval from the safety review committee to proceed toward the third and final cohort in the Phase 1 dose-escalation study.

Acclaim 2 - The company was granted fast-track designation by the FDA in January 2022 for another combination therapy: Reqorsa and Keytruda in patients who have progressed on Keytruda. Multiple pre-clinical trials have already demonstrated the synergistic effects of TUSC2 with that of Keytruda, allowing Genprex to progress with further clinical trials. The Acclaim 2 trial is expected to enroll 30 patients in the Phase 1 dose-escalation study, and the randomized 2:1 Phase 2 portion of the trial will enroll 126 patients. The study aims to enroll patients with late-stage NSCLC who were previously treated but progressed on Keytruda. The primary endpoint of the Acclaim 2 - Phase 2 trial is progression-free survival.

Genprex expects to complete the Acclaim 1 & 2 Phase 1 trials by the end of Q1 2023 and Q4 2023, respectively. Additionally, the fast-track designation paves the way for priority review and accelerated approval.

Acclaim 3 - The company is expected to initiate another clinical trial that aims to evaluate the safety and efficacy of Reqorsa with the Tecentriq combination as a maintenance therapy. The trial will enroll small-cell lung cancer patients who did not develop tumor progression after receiving induction therapy. The trial design will have a Phase 1 portion (n=12) as a dose-escalation phase to determine the recommended Phase 2 dosage and a Phase 2 portion (n=50) to evaluate toxicity profiles and efficacy in different patient groups.

Overcoming Drug Resistance - The Need For Reqorsa

Therapeutics advancement within the NSCLC landscape has led to the creation of multiple systemic therapies that include immunotherapies and targeted therapies for early-stage and metastatic NSCLC. Even though the use of targeted therapies and immunotherapies has shown clinical improvements, drug resistance remains a major obstacle in effectively treating NSCLC, thus impeding the progress of successful treatment options. NSCLC patients who initially respond to EGFR inhibitors such as Tarceva or Iressa often develop resistance due to secondary mutations in the EGFR gene, such as the T790M mutation. The third-generation TKI Tagrisso is the only EGFR inhibitor approved for patients with the T790 mutation. The success of Tagrisso has also been hindered, with patients eventually progressing on the treatment with a proliferation of multiple other resistance mechanisms. Tagrisso resistance has been found in some cases to result from other EGFR-dependent pathways, such as the emergence of EGFR C797S mutations and several others. Similar is the case with other targeted therapies, such as ALK inhibitors and ROS1 inhibitors, where mutations in the ALK gene (L1196M mutation) and ROS1 gene limit the efficacy of therapies. Resistance to immunotherapy or PD-1/PD-L1 inhibitors such as Keytruda or Opdivo can develop through various mechanisms, including loss of PD-L1 expression or upregulation of alternative immune checkpoints.

Multiple research papers have discussed the resistance mechanism of currently approved FDA therapies limiting their efficacy. Genprex believes drug-resistant patients can benefit from its therapy Reqorsa. Multiple preclinical studies have shown that Reqorsa can re-sensitize drug-resistant tumors and overcome drug-resistance mechanisms in TKI-resistant tumors. Furthermore, the superior efficacy arising from combination therapy (Reqorsa + TKI/IO) compared to either of the treatments alone was also exhibited by preclinical studies.

Large Total Addressable Market [TAM] with Unmet Needs

Non-small cell lung cancer [NSCLC] accounts for 82% of the total lung cancer cases diagnosed (236k cases) globally. Lung cancer accounts for 25% of total cancer deaths in the United States and has a five-year survival rate of just 22%. Additionally, the EGFR gene is overexpressed in 15% of patients diagnosed with NSCLC in the US, and the overexpression is often associated with poor prognosis. Treatment of lung cancer depends on the progression, type, and stage of cancer, among several other factors. The major treatments include surgery, radiation therapy, targeted therapy, chemotherapy, and immunotherapy. Multiple immunotherapies and targeted therapies have been approved by the FDA for the treatment of NSCLC.

Financial Positioning

The company has reported a cash balance of $25.52 million as of September 2022 and recently concluded a $4 million financing round. Additionally, the company does not carry any interest-bearing liabilities on its balance sheet, as per the latest filings. The company’s average operating cash burn in the recent past four quarters was $4.10 million, and the most recent quarterly operating cash burn was $4.57 million. As the company progresses in its clinical pipeline, the quarterly operating cash burn is expected to increase to over $5 million. The current cash balance, in my opinion, will support the company’s operating and research activities for the next 5-6 quarters. However, the company will likely require multiple rounds of financing in the coming quarters, with the impact of dilution tied to the company's future stock price, which in turn is dependent on clinical trial results and progress within its clinical pipeline.

Valuation, Assumption, and Views

Genprex’s preclinical and clinical trials provide a decent ability to predict the overall success of Reqorsa and estimate future cash flows. I have assumed a 15% probability of success, given the company has already provided reasonable interim Phase 1 clinical trial data through its ONC-002 trial. Additionally, to the best of my knowledge, I have modeled out the company’s future cash flows through 2038 and calculated the value derived from the combination therapy using an rNPV methodology.

Keytruda is believed to have three times the market share as Opdivo in lung cancer. In 2019, 18,383 lung cancer patients were treated with Keytruda, compared to 6,291 for Opdivo. Combining the Keytruda numbers with Tagrisso, I assume it to be well above the 20,000-patient mark (conservative estimates). Assuming Genprex could cater to 1/2 of the total patients treated with Tagrisso and Keytruda, the total number of patients to be treated with combination therapy can be expected to be well above 10,000.

The above calculations are just preliminary and do not specifically highlight the prerequisites, such as patient populations that are EGFR-mutated (for Tagrisso) or any other conditions limiting Reqorsa’s application. Based on the above assumptions, I have calculated the current value of Genprex’s combination therapies at ~$111 million, just considering the U.S. market. The company’s intrinsic value at the current moment (reflecting just the value derived only from its NSCLC combination therapy) is estimated to be $2.15 per share. Additionally, the company’s GPX-002/ 003 therapy candidates and Reqorsa’s SCLC indication provide further upside optionality.

Risk Profile

Please note that this article discusses one or more microcap stocks. It is important to be aware of the risks associated with investing in such stocks. These risks include volatility, low liquidity, and the potential for large price fluctuations. Investors should exercise caution and do their own research before investing in microcap stocks. Some of the company/industry-specific risks include:

• Execution Risk: Genprex’s current market value is contingent on its ability to successfully execute clinical trials and produce favorable clinical and efficacy results. Delays in enrollment, completion of clinical trials, and the approval process can increase the cash burn, affecting the company’s equity value.
• Capital & Dilution Risk: Genprex is a pre-revenue company and depends on external financing to carry out its operational and research activities. Additional stock issuance leading to dilution or failure to raise funds will negatively affect the company’s value.
• Technological Risk: With an evolving biotech industry, the development of a superior treatment or Genprex’s inability to adapt to any superior technology can render its treatment obsolete or less competitive in the market.

Concluding Remarks

Reqorsa, developed via the Oncoprex drug delivery system, potentially balances toxicology and transfection efficiency. The preclinical findings and initial clinical outcomes demonstrated the Reqorsa/ TUSC2 mechanism of action to be inhibition of cancer growth and stimulation of immune responses. Additionally, when used in combination with targeted or immunotherapeutic treatments, it exhibits synergistic properties and can overcome drug resistance. I believe these features are likely to reflect in the Acclaim 1 and Acclaim 2 clinical trial results, thus positioning Reqorsa in a large yet competitive market.

Furthermore, GPX-002/003 holds immense potential and might be the first-ever gene therapy evaluated in individuals with diabetes.

I remain bullish on the company’s long-term outlook, given the differentiated gene therapy approaches of Oncoprex and GPX-002/ 003, combined with a high addressable market and unmet needs.

Disclaimer: Genprex is a client of Quantum Media Group, LLC

Contact Details

Quantum Media Group, LLC

Ari Zoldan

ari@arizoldan.com

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