Rexahn Pharmaceuticals
Overview
Rexahn Pharmaceuticals (RNN) is a clinical stage biopharmaceutical company dedicated to the discovery, development and commercialization of innovative treatments for cancer. The company's mission is to improve the lives of cancer patients by developing next-generation cancer therapies that are designed to maximize efficacy while minimizing the toxicity and side effects traditionally associated with cancer treatment. The company's clinical pipeline features three oncology product candidates in Phase II clinical development and additional compounds in pre-clinical development. The company's strategy is to continue building a significant pipeline of innovative oncology product candidates that the company intend to commercialize with partners. The company's three clinical stage drug candidates in active development are RX-3117, Supinoxin TM (RX-5902) and Archexin®.1
- RX-3117 is a small molecule nucleoside compound that the company believe has therapeutic potential in a broad range of cancers, including pancreatic, bladder, colon, and lung cancer. RX-3117 is being evaluated as monotherapy in a multi-center Phase IIa clinical trial in metastatic pancreatic cancer in patients who are refractory to, or have relapsed after, multiple prior rounds of chemotherapy. Rexahn is also planning to evaluate RX-3117 in combination with Abraxane® (nab-paclitaxel) as first line treatment in patients who are newly-diagnosed with metastatic pancreatic cancer and have not had prior cytotoxic treatment. In 2016, the company commenced enrollment in another Phase IIa trial in patients with locally advanced or metastatic bladder cancer. This Phase IIa clinical trial is a multi-center open label, single agent study of RX-3117 being conducted at 10 clinical centers in the United States. RX-3117 has received orphan drug designation from the U.S. Food and Drug Administration (the “FDA”) for pancreatic cancer. Orphan drug designation in the United States provides tax incentives for clinical research and a waiver from user fees under certain circumstances. In addition, an orphan drug generally receives seven years of exclusivity after approval for a designated use, during which period the FDA generally cannot approve another product with the same active moiety for the same indication. Rexahn has also received a positive opinion from the European Medicines Agency recommending orphan drug designation in pancreatic cancer.
- Supinoxin, or RX-5902, is a potential first-in-class small molecule inhibitor of phosphorylated-p68, a protein that the company believe plays a key role in cancer cell growth, progression and metastasis through its interaction with beta-catenin. In February, 2017 the company initiated a Phase IIa clinical study of Supinoxin in patients with metastatic triple negative breast cancer (“TNBC”).
- Archexin is a potential best-in-class, potent inhibitor of the protein kinase Akt-1, which the company believe plays a critical role in cancer cell proliferation, survival, angiogenesis, metastasis and drug resistance. Archexin has received orphan drug designation from the FDA for renal cell carcinoma (“RCC”), glioblastoma, ovarian cancer, stomach cancer and pancreatic cancer. Rexahn is currently conducting a Phase IIa proof-of-concept clinical trial of Archexin in patients with metastatic renal cell carcinoma to evaluate its safety and efficacy in combination with AFINITOR® (everolimus).
Since its inception, its efforts and resources have been focused primarily on developing its pharmaceutical technologies, raising capital and recruiting personnel. Rexahn has no product sales to date, and the company will not generate any product sales until the company receive approval from the FDA or equivalent foreign regulatory bodies to begin selling its pharmaceutical candidates. The company's major sources of working capital have been proceeds from various private and public financings, and licensing and collaboration agreements with its strategic investors and partners.
On May 5, 2017 the Company effected a one-for-ten reverse stock split of the outstanding shares of the Company’s common stock, together with a corresponding proportional reduction in the number of authorized shares of the Company’s capital stock.
The company's primary research and development focus is on oncology therapeutics. A key component of its strategy is to develop innovative drugs that are potential first-in-class or market-leading compounds for the treatment of cancer. According to the Centers for Disease Control and Prevention, cancer claims the lives of more than half a million Americans each year and is the second leading cause of death among Americans. In 2014, the World Economic Forum and the Harvard School of Public Health estimated that the 13.3 million new cases of cancer diagnosed worldwide in 2010 cost $290 billion, projected 21.5 million new cancer cases occurring in 2030 at a cost of $458 billion; and a 2016 American Cancer Society report projected that an estimated 1.7 million new cancer cases will be diagnosed in the United States in 2016. In 2015, Evaluate Pharma projected that global annual sales of cancer drugs would grow to $153 billion by 2020.
Current Cancer Treatments
Traditional cancer treatments involve surgery, radiation therapy and chemotherapy. Surgery is widely used to treat cancer, but may result in related or significant complications and may be ineffective if metastasis has occurred. Radiation therapy, or radiotherapy, can be highly effective in treating certain types of cancer. In radiation therapy, ionizing radiation deposits energy that injures or destroys cells in the area being treated by damaging their genetic material, making it impossible for these cells to continue to grow. Although radiation damages both cancer cells and normal cells, the normal cells are generally able to repair themselves and function properly. Chemotherapy involves the use of cytotoxic cancer drugs to destroy cancer cells by interfering with various stages of the cell division process. For certain cancers and in certain patients, these drugs have limited efficacy and debilitating adverse side effects. Administration of cytotoxic cancer drugs may also result in the development of multiple drug, or multi-drug, resistance, which is a condition that results when certain tumor cells that have survived treatment with cytotoxic drugs are no longer susceptible to treatment by those and other drugs.
Unmet Needs in Cancer
Despite significant advances in cancer research and treatments, many unmet needs still remain including:
- Long-term management of cancers: Surgery, radiation therapy or chemotherapy may not result in long-term remission, although surgery and radiation therapies are considered effective methods for some cancers. There is a need for more effective drugs and adjuvant therapies to treat relapsed and refractory cancers.
- Multi-drug resistance: Multi-drug resistance is a major obstacle to effectively treating various cancers with chemotherapy.
- Debilitating toxicity by chemotherapy: Chemotherapy as a mainstay of cancer treatment can induce severe adverse reactions and toxicities, adversely affecting quality of life or life itself.
Market Opportunity
There are several factors that are favorable for commercializing new cancer drugs that may be first-in-class or market leaders, including:
- Expedited Regulatory or Commercialization Pathways. Drugs for life-threatening diseases such as cancer are often candidates for fast track designation, breakthrough therapy designation, priority review and accelerated approval, each of which can lead to approval sooner than would otherwise be the case.
- Favorable Environment for Formulary Access and Reimbursement. The company believe cancer drugs with proven efficacy would gain rapid market uptake, formulary listing and third-party payor reimbursement. Drugs with orphan designations are generally reimbursed by third-party payors because there are few, if any, alternatives.
- Focus on Specialty Markets. The marketing of new drugs to specialty physicians can be accomplished with a specialty sales force that requires fewer personnel and lower related costs than a typical sales force that markets widely to primary care physicians and general practitioners.
Strategy
The company's strategy is to continue building a significant product pipeline of innovative drug candidates that the company intend to commercialize alone or with partners. This strategy has several key components.
Develop Innovative Therapeutics with the Potential to be First-in-Class or Market Leaders
The company plan to focus its research and development pipeline on potential first-in-class or market-leading compounds for the treatment of cancer. By expanding the breadth and depth of its oncology pipeline, the company aim to develop an industry-leading oncology therapeutics franchise. The company's pipeline spans several major classes of cancer drugs, including molecular targeted therapies, signal transduction and multi-kinase inhibitors, and nano-medicines for targeted delivery of compounds and small molecule cytotoxic compounds. Differentiated target product profiles and proprietary discovery and research technology platforms further support these strategic efforts.
Clinically Develop Drug Candidates as Orphan Drugs
The company intend to initially develop drug candidates for cancers that are orphan indications. Under the Orphan Drug Act, the FDA may grant orphan drug designation to new drugs developed to treat diseases generally affecting less than 200,000 patients. Incentives associated with orphan drug designation include tax incentives for research and development and an exemption from user fees under certain circumstances. Although the standards for orphan drug approval are not different than for non-orphan products, the path to approval may be faster because clinical trials may be smaller due to the smaller patient population. Further, a drug that is approved for its orphan-designated indication generally receives seven years of orphan drug exclusivity, during which the FDA generally may not approve any other application for a product containing the same active moiety and proposed for the same indication. An approved orphan drug also may qualify for an exemption from the branded prescription drug fee. The company plan to develop drug candidates for cancers that are orphan indications in order to take advantage of the benefits of orphan drug designation during development and the exclusivity available under the Orphan Drug Act for approved products, as well as the potential for reduced time to market. Drugs intended to treat rare diseases or conditions also may qualify for fast track designation, breakthrough therapy designation, accelerated approval and/or priority review, any or all of which can speed the approval process.
Target Signal Transduction Molecules with Multiple Drug Candidates
The company plan to expand its research and development pipeline to introduce new signal inhibitor drugs into clinical trials in the future. By identifying and characterizing the genes and proteins that control the signaling pathways and gene expression of cancer cells, the company seek to develop DNA/RNA-based and small-molecule drugs to treat a broad range of diseases caused by abnormal expression or functions of those genes and proteins.
Establish Partnerships with Large Pharmaceutical Companies
The company seek to establish strategic alliances and partnerships with large pharmaceutical companies for the development of its drug candidates.
In-License Unique Technology
The company continually review opportunities to in-license and advance compounds in oncology that have value creating potential and will strengthen its clinical development pipeline.
Capitalize on The company's Management Team’s Expertise for Drug Development
The company's management team possesses clinical development experience in oncology and several other therapeutic areas which facilitates strategic approaches to and competitive advantages in, the design, risk assessment and implementation of drug development programs. The company's management team also has prior experience in pharmaceutical alliances, product launches and marketing.
Pipeline Drug Candidates
Clinical Stage Pipeline
Archexin: Potential Best-in-class Anti-Cancer Akt-1 Inhibitor
Archexin is a potential best-in-class, potent inhibitor of the protein kinase Akt-1, which the company believe plays a critical role in cancer cell proliferation, survival, angiogenesis, metastasis and drug resistance. Archexin has received orphan drug designation from the FDA for RCC, glioblastoma, ovarian cancer, stomach cancer and pancreatic cancer. The company believe Archexin is differentiated from other Akt-1 inhibitors by its ability to inhibit both activated and inactivated forms of Akt-1, and as a result it is not expected to lead to drug resistance, which has been observed with other protein kinase inhibitors. Other targeted drugs may only inhibit inactivated Akt-1 and may also cause drug resistance. Akt-1 is over-activated in patients with many cancers, including breast, colorectal, gastric, pancreatic, prostate and melanoma cancers. Akt-1 activity may be inhibited by signaling molecules upstream of Akt-1 in cancer cells through the use of vascular endothelial growth factor and epidermal growth factor receptor inhibitors, but this treatment only indirectly affects the activity of native Akt-1. Because signal transmission for cancer progression and resistance occurs when Akt-1 is activated, the company believe it is also important to inhibit activated Akt-1. The company believe Archexin inhibits both activated and native Akt-1.
Archexin is an antisense oligonucleotide compound that is complementary to Akt-1 mRNA and highly selective for inhibiting mRNA expression, which leads to reduced production of Akt-1 protein. Archexin preliminarily appeared to be safe and well tolerated with minimal side effects in a Phase I study in patients with advanced cancers, where Grade 3 fatigue was the only dose-limiting toxicity and no significant hematological abnormalities were observed. The main objectives of the Phase I study were to determine the maximum tolerated dose, dose limiting toxicity and pharmacokinetic parameters for Archexin monotherapy. The Archexin Phase I study design was an open label, single arm ascending dose, safety and tolerability study.
Rexahn has completed an open label, two-stage Phase IIa clinical trial for Archexin that was designed to assess the safety and efficacy of Archexin in combination with gemcitabine. Gemcitabine is used to treat pancreatic, breast, ovarian, and lung cancers, and may be used for other cancers as well. Gemcitabine is a member of a group of chemotherapy drugs known as anti-metabolites, which prevent cells from making DNA and RNA, which in turn stops cell growth and causes cells to die. Stage 1 was the dose-finding portion of the study, and Stage 2 was the dose-expansion portion of the study using the dose identified in Stage 1 administered together with gemcitabine. The study enrolled 31 subjects aged 18 to 65 with metastatic pancreatic cancer at nine centers in the United States and India. The primary endpoint was overall survival following four cycles of therapy with a six month follow-up. For those evaluable patients, the study showed that treatment with Archexin in combination with gemcitabine provided a median survival rate of 9.1 months compared to the historical survival data of 5.7 months for standard single agent gemcitabine therapy. The most frequently reported adverse events were constipation, nausea, abdominal pain and pyrexia, regardless of relatedness.
Rexahn is conducting an ongoing Phase IIa proof-of-concept clinical trial of Archexin to study its safety and efficacy in patients with metastatic RCC. In this trial, Archexin is being administered in combination with Afinitor® (everolimus). The trial is being conducted in two stages. Stage 1 was a dose ranging study, with up to three dose groups with three RCC patients each, to determine its maximum tolerated dose (“MTD”) in combination with everolimus. In January 2016, the company completed Stage 1 of the study and commenced enrollment in Stage 2, which is a randomized, open-label, two-arm dose expansion study of everolimus versus Archexin in combination with everolimus to determine safety and efficacy of the combination. This phase of the trial (Stage 2) is anticipated to enroll up to 30 RCC patients who will be randomized to receive either Archexin in combination with everolimus, or everolimus alone, in a ratio of 2:1 The MTD was determined to be 250 mg/m 2/day of Archexin, which was identified in Stage 1 and will be administered in Stage 2 along with 10 mg of everolimus compared to 10 mg everolimus alone.
Rexahn has been issued a U.S. patent for Archexin that covers composition of matter and broad claims for the nucleotide sequences of the antisense compounds that target and inhibit the expression of Akt-1 in human tissues or cells, and for the method of using the compounds to induce cytotoxicity in cancer cells.
RX-3117: Oral Small Molecule Nucleoside
RX-3117 is a novel, investigational oral small molecule nucleoside compound. In pre-clinical models when activated (phosphorylated) by uridine-cytidine kinase 2 (“UCK2”), a protein that is overexpressed in various human cancer cells, RX-3117 is incorporated into DNA or RNA of cells and inhibits both DNA and RNA synthesis, which induces apoptotic cell death of tumor cells. The company believe RX-3117 has therapeutic potential in a broad range of cancers including pancreatic, bladder, lung, cervical, non-small cell lung cancer and colon cancer. RX-3117 has received orphan drug designation from the FDA for the treatment of patients with pancreatic cancer. RX-3117 has also been shown in animal models to inhibit the growth of gemcitabine-resistant human cancers and improve overall survival.
RX-3117 has demonstrated broad spectrum anti-tumor activity against over 100 different human cancer cell lines and efficacy in 17 different mouse xenograft models. Notably, the efficacy of RX-3117 in the mouse xenograft models was superior to that of gemcitabine. Further, RX-3117 still retains its full anti-tumor activity in human cancer cell lines made resistant to the anti-tumor effects of gemcitabine. In August 2012, Rexahn reported the completion of an exploratory Phase I clinical trial of RX-3117 in cancer patients conducted in Europe, to investigate the oral bioavailability, safety and tolerability of the compound. In this study, oral administration of a 50 mg dose of RX-3117 demonstrated an oral bioavailability of 56% and a plasma half-life (T 1/2) of 14 hours. In addition, RX-3117 appeared to be safe and well tolerated in all subjects throughout the dose range tested.
Rexahn is currently evaluating RX-3117 in a Phase Ib clinical trial to study the safety, tolerability, dose-limiting toxicities and MTD in patients with solid tumors. Secondary endpoints include pharmacokinetic analysis and an evaluation of the preliminary anti-tumor effects of RX-3117.
Preliminary results from the Phase Ib clinical trial of RX-3117 were presented in September 2015 at the 2015 European Cancer Congress. The results showed that, at the dose levels tested to date, RX-3117 administered orally appeared to be safe and well tolerated with a predictable pharmacokinetic profile. The most frequently reported treatment emergent adverse events were mild to moderate fatigue, gastrointestinal disturbances, anemia, pyrexia, decreased appetite and dehydration.
In addition, preliminary anti-tumor activity was seen in the Phase Ib clinical trial, with evidence of tumor reduction observed in one patient and stable disease observed in five patients persisting from between 112 and 276 days before disease progression occurred.
Patient enrollment has been completed in nine dose groups (30mg, 60mg, 100mg, 150mg, 200mg, 500mg, 1,000mg, 1,500mg and 2,000 mg). Based on the favorable safety and pharmacokinetic profile seen at the highest dose levels, the company initiated a dosing schedule modification to increase patients’ daily exposure of RX-3117 in the ongoing Phase Ib clinical trial. All newly enrolled patients are now receiving RX-3117 five times weekly. The company anticipate that the new dosing paradigm will increase drug exposure, maximizing potential therapeutic activity and enable more rapid determination of the MTD for further clinical study.
Based on the progress of the RX-3117 clinical development program and the level of interest expressed from a number of oncology-focused pharmaceutical companies, Rexahn is continuing discussions with multiple companies to explore collaborative business structures in an effort to maximize the potential value of the program.
Supinoxin: Potential First-in-Class p68 RNA Helicase Inhibitor
Supinoxin is a potential first-in-class small molecule inhibitor of phosphorylated-p68, a protein that the company believe plays a key role in cancer growth, progression and metastasis. Phosphorylated p68, which is highly expressed in cancer cells, but not in normal cells, results in up-regulation of cancer-related genes and a subsequent proliferation of cancer cells and tumor growth. Supinoxin selectively blocks phosphorylated p68, thereby decreasing the proliferation or growth of cancer cells. In pre-clinical tissue culture models and in-vivo xenograft models, Supinoxin has exhibited single-agent tumor growth inhibition, potential synergy with cytotoxic agents and activity against drug resistant cancer cells. In particular, in in-vivo xenograft models of human triple negative breast cancer and pancreatic cancer, treatment with Supinoxin on days one through 20 in mouse models produced a dose-dependent inhibition of tumor growth and a survival benefit.
Supinoxin is currently being evaluated in a Phase I dose-escalation clinical trial in cancer patients with solid tumors designed to evaluate the safety, tolerability, dose-limiting toxicities and MTD. Secondary endpoints include pharmacokinetic analyses and an evaluation of the preliminary anti-tumor effects of Supinoxin. Patients have received doses up to 25, 50, 100, 150, 225, 300, 425, 575, and 775 mg. Based on the favorable safety and pharmacokinetic profile seen at the highest dose levels (575 mg and 775 mg), Rexahn has initiated a dosing schedule modification to increase patients' daily exposure of Supinoxin. All newly enrolled patients are now receiving Supinoxin seven times weekly as opposed to once weekly. The company anticipate that the new dosing paradigm will increase drug exposure and enable more rapid determination of the MTD for further clinical study.
Preliminary results from the Phase I clinical trial of Supinoxin were presented in September 2015 at the 2015 European Cancer Congress.
The results showed that, at the dose levels tested to date, Supinoxin administered orally appeared to be safe and well tolerated with no Grade 3 or Grade 4 adverse events and several unrelated Grade 2 adverse events. The most frequently reported drug related adverse events were mild nausea, vomiting and fatigue. Pharmacokinetic analyses of the current data demonstrate both a predictable and desirable pharmacokinetic profile for an orally-administered route of therapy.
Clinical evidence of single-agent activity of Supinoxin was also observed in four patients who showed stable disease persisting from between 255 and 497 days as of September 14, 2015. At that time, three of the four patients exhibiting stable disease remained on active treatment. Those patients continue to be followed in the study.
Based on the progress of the Supinoxin clinical development program and the level of interest expressed from a number of oncology-focused pharmaceutical companies, Rexahn is continuing its discussions with multiple companies to explore collaborative business structures in an effort to maximize the potential commercial value of the program.
Pre-Clinical Pipeline
RX-21101: Nano-polymer Anti-cancer Drug
RX-21101 is an investigational anti-cancer nano-polymer drug that the company believe can mitigate some of the limitations of cytotoxic compounds, such as poor solubility and severe adverse reactions. Conjugating water-soluble and non-toxic N-(2-Hydroxypropyl)methacrylamide to conventional anti-cancer compounds may bolster efficacy while lowering toxicity by specific tumor targeting and increased stability in the body. In June 2015, RX-21101 was selected by the National Cancer Institute's Nanotechnology Characterization Laboratory for its pre-clinical characterization program to facilitate the advancement of RX-21101 towards human clinical trials.
Research and Development Process
Rexahn has engaged third-party contract research organizations and other investigators and collaborators, such as universities and medical institutions, to conduct its pre-clinical studies, toxicology studies and clinical trials. Engaging third-party contract research organizations is typical practice in its industry. However, relying on such organizations means that the clinical trials and other studies described above are being conducted at external locations and that the completion of these trials and studies is not within its direct control. Trials and studies may be delayed due to circumstances outside its control, and such delays may result in additional expenses for it.
