With its many setbacks due to systemic toxicities and side effects, chemotherapy remains the standard of care treatment for many cancers either as a first-line treatment or as an adjuvant. As medical technology evolves, hope may be coming in the form of immunotherapy, hormone therapy and resection improvements to displace the cytotoxic chemotherapy drugs on the market. In many cases there have been successes, in others dismal failures. Systemic poisoning is typically the reason for the poor safety profile of many chemotherapy drugs and is also the reason dosages have to be kept low for many in order to keep the safety profile acceptable. The safety of the lower dosages and the efficacy of the higher dosages is a never-ending balancing act as a minimal dosage of the drugs gives a better safety profile while the higher dosages typically give better efficacy.
In the last decade some pharmaceutical companies have modified their approaches of using chemotherapy drugs via targeted approaches rather than systemically poisoning the patients' bodies. While other technologies advance and begin to mature, the chemotherapy treatment regimen could be ready to step up to the next level also as the targeted treatment methodologies of some biotechs advance through clinicals and begin the final steps toward hopeful trial data and perhaps ultimate marketing approvals. Following are biotech companies with novel cancer tumor and tissue targeting technologies that use already-approved chemotherapy drugs. These companies are in various stages of development and give a good representation of what could be the next step in the evolution of chemotherapy treatment for many cancers.
Delcath Systems, Inc. (DCTH) is one of the most storied of the targeted chemotherapy drug biotechs. Its hepatic (liver) chemosaturation system, termed "percutaneous hepatic perfusion" (PHP), is a novel means of attacking liver cancer by isolating the patient's primary blood vessels supplying blood to and from the liver from the rest of the patient's body. A high dose of the anticancer drug, melphalan hydrochloride, is fed into the inferior vena cava via the patient's femoral vein. The melphalan hydrochloride is fed directly into the liver and its associated tumor(s) where it is allowed to work for 30 minutes at a very concentrated dose. The isolation-aspiration catheter then collects the drug-saturated blood as it exits the liver between two inflated balloons (in the blood vessels) and then filters most of the melphalan from the blood via an external filtration device. The blood is then returned to the patient's bloodstream via a third catheter in the jugular vein. The isolation balloons are then deflated, catheters removed and the patient is allowed to recover from the treatment before going home.
The company has been successful in obtaining the CE Mark approval for the system in April of 2011 for percutaneous intra-arterial administration of the chemotherapeutic agent melphalan hydrochloride to the liver. In April of 2012, the company announced additional CE Mark approval for its second generation filter to be part of the PHP system for the same indication but with much greater filtering efficiency of the chemotherapy agent from the bloodstream. With a small recent order of the system announced, the device appears to have had a slow start in Europe, but that may change if the system proves its worth in treating liver cancers. The U.S. regulatory process has been less friendly with the company after handing them a "refusal to file" response to their NDA for metastatic melanoma in February of 2011 citing safety and sterilization problems as well as statistical issues. The company continued to tout its technology with data being presented at several venues with varying levels of successes and failures for not only its initial indication of metastatic melanoma in the liver but also other secondary liver cancers. The company announced in its 2011 update that the company is making progress in its NDA for the FDA and expects resubmission by the end of 2Q 2012.
OncoSec Medical, Inc. (OTC:ONCS) is a relatively under-the-radar biotech with a novel means of assuring cancer tumors get well-saturated with either chemotherapy or immunotherapy agents. Through a technique called electroporation, a brief electrical current can be applied to a tumor which causes a temporary increase in the permeability or porosity of a tumor's outer membrane. This permeability allows a previously-injected agent to penetrate the tumor, greatly adding to the compound's efficacy. The pores then begin sealing back up within a few minutes of the current being removed. While in the hyper-porous phase, the injected drug can permeate into the targeted tumor by an increase of a factor of 1000 or more. Logic applied, the safety factor of an administered drug could be greatly enhanced by requiring much less agent in order to maintain the same efficacy or a drug's efficacy could be greatly enhanced without increasing the dosage relative to traditionally-injected agents. OncoSec has a patent portfolio protecting its systems it calls OMS ElectroChemotherapy and OMS ElectroImmunotherapy for its chemotherapy and immunotherapy applications, respectively.
At the "Future of Ablation Therapies" conference in September of 2011, OncoSec presented data for breast cancer as well as head and neck cancer early-stage trials. The phase I breast cancer trial data presented indicated that the treatment was safe, well-tolerated and achieved a complete response rate in 77% of its patient set (13 treated). Preliminary data for the head and neck cancer trial using Bleomycin as the chemotherapy agent also indicated the treatment was safe and well-tolerated with pain, infection, edema and dysphagia (difficulty swallowing) as the primary side effects. In the 92-patient trial, survival at 8 months was 95% and 86% at 24 months. Preliminary data analysis of the trial indicated that the primary endpoint of "local control of the tumor at 8 months" was achieved.
An April 23rd update of the head and neck cancer trial gave additional preliminary data with the patient set being broken down into two groups, primary tumors and recurrent tumors. Interim analysis in these patient sets had a primary endpoint of local tumor control in 94% of the primary tumor set and 57% in the recurrent tumor set (the latter typically being a much more difficult tumor to treat). The data set was comparable to the standard of care treatment of surgery. In order to analyze the quality of life for patients receiving the electroporation treatment, the company allowed a quality of life assessment via the European Organization for Research and Treatment of Cancer Core QOL questionnaire (EORTC QLQ). The treated patient set showed a mean overall score of 264 at baseline relative to 249 at eight months, indicating no significant difference in quality of life. An additional quality of life analysis by functional outcome analysis evaluated the patients' ability to swallow, normalcy of diet, and ability to eat in public as assessed by the Performance Status Scale for Head and Neck cancer (PSSHN). Although a numerical value wasn't given for the standard of care surgical procedure often used for this type of cancer, the company stated "if the patient had been treated with surgery, the expectation and historical experience would result in a greater degradation of function and quality of life for these patients as determined by the PSSHN and EORTC QLQ scores."
Celsion Corporation (CLSN) is another heavily-watched biotech using a targeted chemotherapy technique by which to fight cancer tumors. Their proprietary ThermoDox technology utilizes the already-approved doxorubicin drug that is prepared in a heat-activated liposomal encapsulation. When injected into a patient's body, the liposome accumulates in the liver and spleen. The company has been targeting primary liver cancer, so this accumulation is key. Adding to this natural accumulation of the nonpolar (fatty) liposome, tumors typically have higher microvascular permeability than normal tissue. This allows further accumulation of the drug-containing liposome in the liver cancer tumor. In the encapsulated form, the doxorubicin is fairly well shielded from the polar/aqueous blood stream and its efficacy is fairly limited. However, when a Radio Frequency Ablation (RFA) treatment targets the area with radio waves to locally heat the area to 39.5-42.0 degrees Celsius, the concentrated encapsulations are also heated which releases the doxorubicin drug to attack the cancer locally with a high dosage in the targeted area and little effect throughout the rest of the body.
Celsion's ThermoDox is well into a phase III trial termed the HEAT study that is under the FDA's SPA guidance for primary liver cancer (hepatocellular carcinoma). The primary endpoint of the trial is progression free survival with the secondary endpoints being time to local recurrence, overall survival, and Patient Reported Outcome score. The 652 patient set is a large group with enrollment set to complete in Q2 2012. A total of 380 events of progression are required per the SPA before the planned final analysis of the study. In April, the independent Data Monitoring Committee (DCM) for the trial unanimously recommended that the trial continue per its protocol. Celsion reaffirmed in the press release that the 380 events should come to fruition sometime late in 2012. This should be a huge catalyst for the company as not only is U.S. marketing approval dependent on the outcome, but the European Medicines Agency (EMA) has confirmed that the HEAT study is acceptable for submission for marketing authorization application (MAA).
Delcath's PHP, OncoSec's OMS ElectroChemotherapy and Celsion's ThermoDox technologies are dramatically different approaches to targeting cancer tumors with high doses of cytotoxic compounds to increase efficacy. At the same time, the technologies spare the patients from many systemic side effects associated with having toxic chemicals circulating at harmful levels in the patients' bloodstreams. Each of these three approaches has a huge upside for marketing as approval for their current indications would legitimize their technologies and offer a look at other possible indications targeting other cancer tumors with other chemotherapy agents. OncoSec has a larger upside potential due to its low market capitalization of $9.1 million versus Delcath's $131 million or Celsion's $63.1. However it is also in much earlier stages of development in its clinicals. As far as diversity of use, OncoSec does have its OMS ElectroImmunotherapy program also underway. In February the company initiated a phase II trial using OMS ElectroImmunotherapy for the treatment of Merkel cell carcinoma (MCC). DNA IL-12 is administered to the tumor area and a subsequent current is applied to increase the uptake of the protein into the tumor. The trial hopes to prove that the increased local expression of IL-12 at the tumor site will stimulate an immunologic response from the body "teaching" it to see the tumor as "foreign" and attack it to give the patient clinical benefit. The obvious implications of a safer profile and longer-term benefit from the body possibly targeting any future IL-12 over-expressed tumors that may try to recur could be of huge clinical significance. As the immunotherapy approach to fighting cancer further progresses, OncoSec's OMS ElectroImmunotherapy could generate much more interest if the right application comes along due to clinical success in immunotherapy companies. A partnership with another biotech with complementary immunotherapy agents could benefit both entities. Although an earlier stage biotech, the phase II trials planned and underway show substantial progress for OncoSec and will likely be catching the attention of investors and large pharmaceuticals as their technology advances and clinicals support the concepts, the earlier trials and the preliminary results.
Most chemotherapy agents will likely never be construed as "safe", but they can be made safer and have more efficacy as these three players and others more fully perfect their respective technologies and applications. Targeted chemotherapy is not a perfect science, but it could likely be the best balance between safety and efficacy for those patients needing aggressive cancer treatment and the best technology available. 2012 and beyond will prove to be exciting times for these biotechs. Please see the respective company websites for more information about these companies, their management, their intellectual property and their novel technologies.