Cancer

According to the National Cancer Institute, men have a 46% chance and woman have a 38% chance, of developing cancer in their lifetime. Talactoferrin alfa (talactoferrin) is a promising anti-cancer agent.

Animal Data

There have been many studies in mice and rats in which oral talactoferrin demonstrated a statistically significant anti-cancer effect. Talactoferrin caused tumor shrinkage or a substantial reduction in tumor growth in several different animal models and was effective against a broad range of cancers including some of the most common, such as breast, lung and kidney. Talactoferrin was as effective in animal experiments as approved chemotherapy and radiotherapy. Talactoferrin was also effective when given in combination with standard cancer therapies, enhancing the effect of chemotherapy and radiotherapy.

Talactoferrin anticancer activity, which is primarily mediated through its immunostimulatory properties, was abolished in mice lacking key immune components. Oral talactoferrin stimulated the production of the immunostimulatory cytokine IL-18 in mice, increasing IL-18 levels both in the gut and in systemic circulation. Oral talactoferrin was also shown to stimulate the activity of NK cells and to increase the production and activity of key circulating immune cells, the latter in both mice and humans.

Clinical Trials

Phase II Trial of Talactoferrin in First-Line NSCLC
Talactoferrin was evaluated in a 110-patient, randomized, double-blind, placebo-controlled, multi-center Phase II clinical trial. Patients with advanced NSCLC (stage IIIB or IV) received standard first-line chemotherapy, carboplatin/paclitaxel (C/P), plus either oral talactoferrin or placebo. The trial was prospectively powered (75% power) with a one-sided alpha of 0.05 to show an improvement in the primary endpoint of best overall response rate by CT scan, according to the Response Evaluation Criteria in Solid Tumors (RECIST), in the pre-specified evaluable population. The evaluable population was defined as patients who had received at least one dose of talactoferrin or placebo in combination with C/P and had CT scans available at baseline and at one time point after receiving the study drugs. The study met its primary endpoint with a substantial improvement in response rate. Results were presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2006.

The addition of oral talactoferrin to C/P improved the results on pre-specified endpoints, including confirmed response rate (the primary endpoint), progression free survival (PFS), and overall survival (OS).

There was also improvement in the secondary endpoint data, though the trial was not designed (in terms of treatment duration) or powered (in terms of number of patients) for these endpoints:

The median PFS in the ITT and evaluable patients increased by 2.8 months (67% improvement), from 4.2 months (C/P+placebo) to 7.0 months (C/P+talactoferrin).
The median duration of response in the patients with a confirmed response increased by 2.1 months (39%) from 5.5 months (C/P+placebo) to 7.6 months (C/P+talactoferrin).
The median overall survival in the ITT population increased by 1.9 months (22% improvement), from 8.5 months (C/P+placebo) to 10.4 months (C/P+talactoferrin), and in the prospectively defined evaluable population by 2.8 months (33% improvement) from 8.5 months to 11.3 months.

Talactoferrin was well tolerated without any talactoferrin-related Serious Adverse Events (SAEs). The incidence and severity of Adverse Events (AEs) was no higher in the talactoferrin arm than in the placebo arm. In fact, patients in the talactoferrin arm reported fewer AEs (p<0.01) and fewer severe (grade 3 or 4) AEs (p=0.01) than the patients receiving chemotherapy and placebo. In contrast, administration of Avastin was associated with significant side effects. For example, Avastin was found to have a 30% incidence of life-threatening pulmonary bleeding in patients with squamous cell carcinoma enrolled in its Phase II NSCLC trial. Consequently, the Avastin pivotal trial program excluded a variety of patients for whom Avastin was believed to be unsuitable. These excluded patients comprise approximately 50% of the advanced and metastatic NSCLC population.

Results from the talactoferrin Phase II first-line NSCLC trial, which was conducted at eleven of the top cancer centers in India, were submitted to and reviewed by the FDA prior to the Company’s End-of-Phase II meeting. At the meeting, the FDA confirmed that the Phase II trial provided the basis for moving forward with a large, pivotal Phase III trial in NSCLC and that the Phase II trial could provide supporting data for a Biologics Licensing Application (BLA). The FDA also provided Fast Track designation for the development of talactoferrin as a first-line treatment in NSCLC. Regarding the Phase III NSCLC trial design, the FDA agreed that (i) the trial can be global without a requirement for any minimum number of patients from the U.S., provided that the standard of care is uniform across countries and that patients are appropriately stratified by region; (ii) it is appropriate to use carboplatin + paclitaxel (the chemotherapy used in Phase II) as the comparator arm even with the approval of Avastin, since Avastin’s approval only applies to about 50% of patients with locally advanced or metastatic NSCLC and is associated with significant toxicities; (iii) PFS can be the primary endpoint for accelerated approval with the trial also powered to eventually look at overall survival for full approval; and (iv) a single pivotal trial powered for a high degree of statistical significance (p=0.01) for the PFS primary endpoint is acceptable.

The FDA also approved an SPA submitted by Agennix (including the final drafts of the Phase III protocol, statistical analysis plan, case report forms, data and safety monitoring board charter, independent radiology review charter, and site reference manual). The Phase II results and the draft Phase III protocol were also discussed with the EMEA, and EMEA Scientific Advice has been obtained. The EMEA confirmed that the single pivotal trial planned for this indication could serve as the basis for European marketing approval. Agennix is also in the process of exploring regulatory options for Japan.

According to the American Cancer Society, approximately 150,000 people are diagnosed with NSCLC each year in the U.S. According to the World Health Organization, another 300,000 are diagnosed annually in Europe, and 520,000 are diagnosed annually in the rest of the world. Agennix estimates that the potential annual sales opportunity for first-line treatment of NSCLC in the U.S. alone exceeds $4 billion.

Phase II Trial of TLF in Refractory NSCLC.
Talactoferrin monotherapy was recently evaluated in a randomized, double-blind, placebo-controlled, multi-center Phase II clinical trial in 100 refractory (2nd or 3rd line) NSCLC patients. Patients with advanced NSCLC (stage IIIB or IV) whose disease had previously progressed on one or two lines of chemotherapy received standard supportive care plus either oral talactoferrin or placebo. The trial met its prospectively defined primary endpoint of improvement in overall survival (OS). In the ITT population, median OS increased from 3.7 months in the placebo arm to 6.1 months in the talactoferrin arm, a 2.4 month (65%) increase in median survival (p=0.0404; Hazard Ratio: 0.68). The 6-month survival rate in the ITT population increased from 28% to 49% (p=0.0276). The median OS in the prospectively defined evaluable population (patients who had received at least one dose of talactoferrin or placebo and had CT scans at baseline and at one time point after receiving the study drug) increased from 4.4 months to 7.9 months (p=0.0171; HR: 0.59). Apparent activity was also observed in prognostically important patient subsets, including patients with ECOG performance status 0 or 1, patients with stage IIIB or IV disease, and patients receiving second- or third-line therapy. Talactoferrin appeared to be well tolerated in this study. The occurrence of total AEs and severe (Grade 3/4/5) AEs was lower in the talactoferrin arm, p=0.0037 and p=0.0024, respectively. Results were presented at the annual ASCO meeting in 2007.

Based on the monotherapy results in refractory NSCLC, the Company plans to initiate a pivotal Phase III trial in this indication. The company has finalized the protocol for the Phase III trial after obtaining and incorporating feedback on the trial design and protocol from key opinion leaders, and from the FDA (through the Fast Track review process that resulted in a Fast Track designation). The Company has also obtained favorable Scientific Advice on the Phase III monotherapy trial from EMEA.

The refractory NSCLC market is attractive. U.S. sales of Tarceva, the leading drug in the third-line setting, were $402 million in 2006, and Agennix believes the total third-line NSCLC market in the U.S. could approach $1 billion by 2010.

Other Clinical Studies of Talactoferrin in Cancer
In a previous Phase Ib clinical trial, patients with advanced or metastatic cancers whose disease had progressed on prior standard chemotherapies received oral talactoferrin as a second or third-line single-agent therapy. Talactoferrin appeared to be well tolerated, without a single drug-related SAE reported. The study included 36 patients with different tumor types, including twelve patients with NSCLC and seven patients with RCC. Responses (either partial or minor) were observed in patients with NSCLC, RCC and prostate cancer. (Minor responses were also observed in patients with breast cancer, ovarian cancer and melanoma in a separate Phase Ib trial.) Based on the encouraging results from this trial and since the largest numbers of enrolled patients were those with NSCLC and RCC, Agennix focused initial Phase II development of talactoferrin in NSCLC and RCC.

Phase II RCC Trial. A Phase II, open label, multi-center, 44-patient, single arm, talactoferrin monotherapy RCC trial was conducted at sites including M.D. Anderson, Stanford, University of Chicago, Cleveland Clinic, UCLA and Baylor. This trial evaluated the effects of single agent talactoferrin on patients with advanced RCC whose disease had progressed after being treated with at least one prior regimen of systemic therapy. This trial provided further indications of anti-cancer activity of talactoferrin, including partial responses, a median PFS of 6.4 months, a median OS of 21.1 months, and a 1-year survival rate of 77%. These results compare favorably to outcomes expected in this patient population based on published results with patients in this population who received placebo or were untreated. Results from this trial were presented at the annual ASCO meeting in 2006. Agennix also recently received Orphan Drug designation from the FDA and the EMEA for talactoferrin for the treatment of RCC.

Subsequent to the initiation of the talactoferrin RCC trial, Sutent (sunitinib) and Nexavar (sorafenib) were approved by the FDA as first-line treatments for patients with locally advanced or metastatic RCC, and Sutent appears to be emerging as the standard of care. Based on the talactoferrin results from the Phase II RCC trial and preclinical data with talactoferrin in combination with other therapies including Sutent, Agennix intends to conduct a combination-therapy Phase IIb trial in RCC. The trial will compare oral talactoferrin plus Sutent to placebo plus Sutent in first-line patients with locally advanced or metastatic RCC.

Phase Ib Data in RCC. The Phase Ib trial enrolled seven patients with RCC whose disease had progressed on previous therapy. Apparent anti-cancer activity was also observed in this study, with all seven patients demonstrating tumor shrinkage or a reduction in tumor growth rate (p<0.05), a biologically relevant endpoint in RCC. Four patients remained progression-free for over six months, with two patients receiving talactoferrin for over two years. In addition, one patient had a confirmed durable partial response with 71% tumor shrinkage by RECIST (about 92% shrinkage by WHO). This patient’s disease had previously progressed on a 4-drug chemotherapy/immunotherapy regimen consisting of capecitabine, gemcitabine, interferon and thalidomide. The patient also reported a dramatic improvement in clinical symptoms and quality of life. His “before” and “after” CT scans were featured on the cover of the International Journal of Cancer.

The median PFS in the seven RCC patients was 7.3 months, which compares favorably to the expected PFS of 2.4-2.8 months reported in the literature for untreated or placebo-treated patients.

Phase Ib Data in NSCLC. The median overall survival in the twelve NSCLC patients enrolled in the Phase Ib trial was 8.8 months, which compares favorably to the 4.7 months reported in second- and third-line patients receiving Best Supportive Care (BSC) or the 6.7 months reported in second- and third-line patients receiving Tarceva. Ten out of twelve (83%) and five out of twelve (42%) patients were alive at six and twelve months, respectively. These six- and twelve-month survival rates also compare favorably to the reported rates for BSC (43% and 22%) and Tarceva (53% and 31%).