N1177-inh Lung Cancer Staging

Typically, the staging of cancers involves assessing the size and location of the primary tumor(s), cancerous extension into the lymphatics as well as the presence or absence of distant metastases.  This approach is often referred to as the ¡°T-N-M staging scheme.¡±  N1177-inh is delivered as an aerosol formulation for use with Computed Tomography (¡°CT¡±) in staging lung cancer and monitoring patients¡¯ response to therapy.   In clinical practice a patient would inhale the product several hours prior to a CT scan. Having a mean particle size of ~270nm, the N1177 particles are then taken up by macrophages and cleared from the lungs into the lymphatics. Regions within lymph nodes that do not show uptake of N1177 may be suspected of harboring cancer cells. When used with high resolution CT, N1177-inh should allow for a more detailed and accurate assessment of the lymph node.

The Lung Cancer Market

Lung cancer kills more Americans than breast cancer, prostate cancer, and colon cancer combined.  Evidence shows that 85 % of lung cancer is linked to tobacco use [Source: MSN Healthcare / Mayo Clinic ¨C Report: More than half of U.S. Cancer Deaths Could Be Prevented ¨C 3/31/2005]. Accordingly, the potential market for staging lung cancer candidates with NSI¡¯s technology is large and has the potential to become much larger.  There are an estimated 46.2 million adult US smokers, and 44.7 million former smokers.  There are 1.2 billion smokers worldwide, with an estimated 1.04 million new lung cancer cases each year.  The American Cancer Society estimates there were 173,770 new lung and bronchus cancer cases in the US in 2004, and 160,440 deaths attributable to lung cancer that year.  Unlike cardiovascular disease, the risk of developing lung cancer remains after smoking cessation.  The net result is that lung cancer has superseded coronary heart disease as the leading cause of death among current and former smokers. [Mulshine, J. L. and Sullivan, D. C.  Lung Cancer Screening.  N. Engl. J. Med. 2005; 352:26:2714 ¨C 2720]

With a projection of more than 160,000 deaths from lung cancer this year, the disease now accounts for 30 percent of deaths from cancer in the United States.  Metastatic spread to regional or distant sites is evident in at least three-quarters of patients with lung cancer at the time of first diagnosis, so the five-year survival rate for lung cancer is only about 15%.  By contrast, if the cancer is detected early, in Stage 1, the five-year survival rate exceeds 60%.   

Of the approximately 170,000 patients diagnosed this year with lung cancer, about one-third will be thought to be operable at the time of initial diagnosis.  This is an important distinction since surgery is generally restricted to patients with early stage lung cancer.  The evaluation of regional involvement for metastatic spread is an important staging procedure in guiding the surgical approach.  Today this is usually done with a positron emission tomography (PET) scan or an operative evaluation or both.  Both PET and surgical evaluation of the mediastinal lymph nodes are expensive (typically over $2000 for PET and over $10,000 for surgical evaluation).  The surgical evaluation also involves considerable morbidity and even occasional death.

In the last decade there have been significant improvements in the speed (temporal resolution) and quality (spatial resolution) of CT imaging.  Recent reports suggest that the use of high resolution multi-slice or volume CT is associated with detection of Stage 1 lung cancer in over 70% of cases vs. 15% when using conventional equipment.  CT is now routinely performed along with PET to give a more complete assessment in which the structural information provided by CT and the functional information provided by PET are integrated.

Rationale for N1177-inh

The currently available methods for assessing extension of lung cancers into the lymphatics are inadequate.  N1177-inh was developed specifically to address these limitations.  It is inhaled as an aerosol and the particles distribute throughout the lung due to their small size.  The particles then clear the lung through the lymphatics and are retained within lymph nodes just as are cancer cells.  High resolution CT is able to visualize the nodes and characteristic patterns of enhancement indicate the presence or absence of metastatic deposits.

The literature has many citations describing the limitations encountered during lung cancer staging using CT.  For example:  ¡°CT can, in some cases, very accurately show tumour extent within and predict spread beyond the lung.  However, the question of whether the tumour has invaded the chest wall or the mediastinum and, if so, whether it is still potentially surgically curable, often remains unanswered.  In addition, the only sign for predicting lymph node involvement using CT is enlargement.  Many studies have shown that this sign is not very reliable.¡± [Verschakelen, J. A., Bogaert, J. and W. De Wever W., Computed tomography in staging for lung cancer. Eur Respir J 2002; 19:40S-48S].  Recent pilot reports from New York and Tokyo have suggested that the improved sensitivity of state-of-the-art spiral CT scans can detect lung cancer at a much earlier stage.  This has rekindled interest in finding an effective way to routinely detect early lung cancer. 

The medicinal chemists who created N1177 and the pharmaceutical scientists who formulated and tested N1177 spent thousands of man-hours optimizing its properties (composition, size, formulation) to assist in targeting.  First, the small size improves the efficiency of getting the drug from the delivery device and dispersed throughout the lungs.  Second, the small size combats the ability of the airway cilia to clear the N1177-inh out of the body.  Third, the particles are capable of crossing the lung epithelium and being taken up by macrophages. Finally, the surface of the NanoCrystal CT contrast agent is coated with materials to enhance epithelial and endothelial retention. 

Investigators from Battelle showed that aerosolized delivery of chemotherapeutics resulted in a greater than 30-fold enhancement of drug delivery to mediastinal lymph node tissue compared to measured drug levels in venous blood.

The use of an aerosolized contrast agent has several potential ways to enhance detection.  The fine aerosol deposition of concentrated iodinated nanoparticle is thought to enhance the definition of the mucosal surface.  In addition, such material could assist in discriminating between clinically significant space-occupying lesions and extraneous material such as insuspated respiratory secretions overlying normal respiratory structures.  The aerosolized contrast agents are expected to be cleared into pulmonary lymph nodes.  This may identify filling defects, perhaps indicating the presence of tumor cells, and could allow for the detection of early dissemination of lung cancer to regional lymph nodes.  This strategy may have additional benefits, since rescanning this area may permit more efficient staging of a suspected cancer patient as well as disease monitoring.

Competitive Landscape for N1177-inh

The single most significant barrier to adoption that this or any product must overcome is inertia.  Patients, physicians, and payors will all need to be shown convincing data that compels them to request, prescribe and pay for N1177-inh.  Those convincing data will be generated in the course of clinical development as the safety and efficacy of the product are determined.

Staging of Lung Cancer and Other Malignancies of the Thorax

At present there is a single product, Combidex (ferumoxtran-10), that could be considered to be a direct competitor to N1177-inh.  Combidex is a colloidal suspension of superparamagnetic iron oxide particles (¡Ü 50 nm) covered with low molecular weight dextran that appears as a signal void on certain MR images.  When it is injected intravenously it is taken up by macrophages and has a distribution very similar to that of N1177.  The product has been evaluated in some 150 cancer patients with suspected extension into lymph nodes of the head and neck, abdomen, pelvis, breast and lung regions.  Use of Combidex was helpful in reducing the number of false diagnoses and demonstrated sensitivity, specificity, positive predictive value and negative predictive value of around 85%.  The NDA for Combidex has been under review by FDA since 2000 and a recent Advisory Committee recommended against approval for the product.  The sponsor is currently in discussions with FDA to resolve outstanding issues.

We believe that N1177-inh will prove to be superior to Combidex for the staging of lung cancers, because it is administered as an aerosol into the lungs whereas Combidex is administered as a peripheral intravenous infusion.  In addition, CT is felt to be a more appropriate examination to perform for staging of lung cancers than is MR.

Inhalation ¨C N1177-inh:  Assessment of pulmonary infections

There are few products in development for imaging infections and fewer still that might have direct relevance to imaging pulmonary infections.  One radiopharmaceutical that appears to be promising is Infecton (Tc-99m labeled Ciprofloxacin). In a clinical trial involving over 573 patients, Infecton was shown to have sensitivity of 88.3%, specificity of 86.5% and an accuracy of 87.6%.  Indications that are envisioned for the product include: fever of unknown origin, osteomyelitis, wound infection, abdominal abscess, pneumonia, equivocal appendicitis, tuberculosis and opportunistic infections in immune compromised patients. The Phase 2 clinical trial is being conducted in Canada and the United States.

We believe that N1177-inh enhanced CT will prove to be superior to Infecton imaging with SPECT due to CT¡¯s having superior contrast resolution and spatial resolution. As mentioned previously, images from the CT and nuclear medicine studies, either SPECT or PET, can be fused to provide a complementary evaluation of anatomy and pathophysiology.