The CoVal™ technology is the platform upon which we intend to build a portfolio of CoVal™ fusion product candidates. Our lead candidate is HspE7, which we are currently developing to treat HPV-related diseases.  External collaborators are also investigating HspE7 as a treatment for HPV-related conditions in HIV-positive patients, LEEP failures in CIN patients and genital warts.  Our historical development programs with HspE7 are summarized in the following paragraphs:

In trials involving over 400 patients, HspE7 has been well tolerated.  The predominant adverse experience noted from HspE7 treatment at various doses and schedules has been injection site reaction, (mild to moderate in severity) clearing in hours to days without treatment.  Mild to moderate flu-like symptoms also have been observed in some patients.

Recurrent Respiratory Papillomatosis

In February 2004, we reported results from an open-label, single arm, multi-center RRP phase II trial in 27 patients ages two to 18 years old requiring frequent surgical debulking.  The dosing regimen was 500 mg HspE7 administered subcutaneously in three doses over 60 days.  Patients were followed for up to 60 weeks from the first dose to assess the frequency of required surgeries and the safety and tolerance of HspE7.  The trial met its targeted primary endpoint of lengthening the time between surgeries following treatment with HspE7.  The time between post-treatment surgeries, measured as the median post-treatment interval, increased by a mean of 95% compared to the pre-treatment period.  The mean of the first post-treatment interval after surgery increased to 106 days from an average of 55 days between surgeries before treatment with HspE7 (p<0.02).  The average annual surgery rate after treatment with HspE7 decreased from approximately 8.7 to 6.5 (p<0.003).  Of the 27 patients in the study, two patients required no surgery in the 48-week follow-up period compared to a pre-treatment median of 63 days and 101 days respectively. The median interval of all surgeries reported following treatment suggests that the 27-child patient population experienced an aggregate of 87 fewer surgeries during the first year after treatment.  Overall, these results were internally consistent and statistically significant.

Genital Warts

We have completed a six month phase II, multi-center, randomized, double-blind, placebo-controlled study in 54 male and female patients with anogenital (external genital or peri-anal) warts.  The dosing regimen was 500 mg HspE7 administered subcutaneously in three doses over 60 days. The primary objective of the study was to determine whether this regimen was more effective than placebo in reducing the total area of anogenital warts. A secondary objective of the study was to compare the safety of HspE7 to placebo in these patients.  Results from this trial showed that, at six months, genital warts decreased in size by a median of 53% compared to a median of 16% in patients treated with placebo.  At six months, 35% of patients treated with HspE7 had complete clearance of warts compared with 25% of patients treated with placebo.  The complete response rate for patients with genital warts varied depending on the gender of the patient and location of the warts.  The treatment met expectations, but the variance in size reduction was much greater than expected. As a result, we concluded that the study did not include sufficient patients for the trial results to be statistically significant.

During a study of AIN patients who received 500 mg HspE7 administered subcutaneously in three doses over 60 days, one of our investigators identified an improvement in genital warts.  In a retrospective review of the data, 23 patients were identified for continuing follow-up for up to 24 months.  Within the cohort, 11 of 23 patients reaching the 12 month evaluation point, 11 of 17 patients reaching the 18 month evaluation point and eight of ten patients reaching the 24 month evaluation point had complete clearance of internal and external warts.

Cervical Intraepithelial Neoplasia / LEEP Failures

The NCI and a research collaborator have sponsored or are sponsoring three separate phase II CIN trials using different dosing regimens.  These studies, which target the accrual of 249 patients in the aggregate, include:

• an initial single arm trial in 21 HIV-negative females with high-grade CIN to assess pathological and clinical response, HPV status and immunological markers, followed by a single arm trial in an expected 12 additional patients;

• a single arm, open-label trial in up to 66 HIV-negative females with high-grade CIN; and
• a randomized, double-blind placebo-controlled trial in 150 HIV-negative females with low-grade CIN to assess pathological and clinical response, HPV status and immunological markers.

In November 2004, we announced the results of a trial of HspE7 in 21 high grade cervical dysplasia patients that was sponsored by the Norris Comprehensive Cancer Center of USC in Los Angeles, California.  Patients in the trial received HspE7, and then were scheduled to undergo LEEP two months following the last dose. In the trial, 40% of the patients were considered responders at the time of the scheduled surgery, based upon a downgrading of disease from high grade to low grade or no dysplasia. After vaccination 64% (nine of fourteen) of patients tested developed a specific immune response to viral antigens related to the cause of the disease. This result is an early response rate for HspE7, since LEEP was performed only two months following the last dose of the drug.

In March 2005, we announced that data from a Phase II study in high grade cervical dysplasia using HspE7 was presented by Mark Einstein, M.D., of Albert Einstein College of Medicine on behalf of the New York Phase II Consortium and under the sponsorship of the National Cancer Institute (NCI) at the Society of Gynecologic Oncologists Annual Meeting on Women’s Cancer TM.  The Cancer Therapy Evaluation Program of the NCI and Nventa Biopharmaceuticals Corporation are collaborating on the development of HspE7 under a Clinical Trials Agreement.

This NCI Phase II trial was designed to evaluate the efficacy and safety of HspE7 against CIN III.  There were 31 women who completed the trial.  Each patient received three subcutaneous injections with 500 mg of HspE7 over a sixty-day period.  Sixty days after the last injection, the women underwent a Loop Electrocautery Excision Procedure (LEEP) or Cone biopsy of the cervix, which are standard surgical procedures for patients with high grade dysplasia, to remove the affected area. To evaluate the effect of HspE7, a complete pathologic response was defined as no evidence of high grade cervical dysplasia.  A partial response was defined as colposcopic regression of the lesion by greater than 50 percent.

Of the 31 patients, 10/31 (32 percent) had a complete pathologic response; 12/31 (39 percent) had a partial response and 9/31 (29 percent) had stable disease.  No patient had progressive disease.  The overall response rate was 22/31 (71 percent).  Further studies will need to be done to determine if women with complete responses may safely avoid the surgical procedures that are now standard treatments for high grade cervical dysplasia.  The most common adverse events were injection site reactions; other adverse events were headache and flu-like symptoms.  No patient had a serious drug-related adverse event during the observation period.

Nine women in this trial had a prior history of LEEP and subsequent recurrence.  The response rate with HspE7 was 5/9 (56 percent) in these patients.  This observation is important because it suggests that the patients who are difficult to treat because they have relapsed after LEEP may respond very well to HspE7.

Dysplasias in HIV+ Patients

The U.S. National Cancer Institute (“NCI”) is sponsoring a phase I/II trial with HspE7 to treat AIN in 15 HIV-positive patients.  The trial will evaluate clinical and immunological response of escalating doses of HspE7 and viral load at six months.  We have conducted preclinical studies that demonstrate Hsp fusions induce killer T cell responses in animals that are deficient in CD4+ T helper cells, which are regulatory cells in the immune system that are best known for their ability to promote antibody production.  In HIV-positive patients the number and function of T helper cells is substantially impaired. Because HspE7 activity apparently does not require T helper cells, we believe it has the potential to treat patients immunocompromised by HIV infections.

Anal Intraepithelial Neoplasia

In February 2004 we reported the results of a randomized, double-blind, placebo-controlled, multicenter non-pivotal phase III trial in AIN in 133 patients, 110 of whom continued into a blinded cross-over study.  The original HspE7 dosing regimen was 500 mg HspE7 administered subcutaneously in three doses over 60 days.  In the cross-over study, patients who received placebo were given HspE7.  Patients that had received HspE7 were given one booster from six to 12 months after the initial dose.  The phase III trial did not meet its primary endpoint of demonstrating that the patients’ dysplasia downgraded from high grade to low grade or no dysplasia at six months. The results were difficult to interpret due in part to a high level of disagreement among the pathologists as to whether the samples should be classified as high-grade, low-grade or no dysplasia.  In addition, the placebo effect that we had anticipated based on a previous phase II trial and studies of the natural history of the disease was double the estimate used to power the study.  Certain secondary endpoints, such as downgrades assessed through the physician’s observations of manifestations of the disease, did achieve statistical significance at certain observational time points.

In an earlier open-label phase II trial in 82 patients using three 500 mg subcutaneous doses of HspE7, 82.9% of previously untreated patients with high-grade AIN demonstrated a partial response 24 weeks after receiving HspE7, compared with a placebo response rate estimated from an earlier trial to be 18.6%.  That trial supported the possibility that HspE7 is effective.  Based on the data in AIN in the aggregate and taking into account the normal variability in the reading of biopsies, we believe that HspE7 may be active in AIN. 

HPV-Related Cancers

Based on investigator feedback that the patients' carcinomas were so advanced that a meaningful clinical response could not reasonably be expected in a population of the targeted size,  we suspended a 2001 study in Brazil in patients with advanced cancer after only seven of 23 projected patients received the planned five doses of HspE7.  The treatment regimen itself was judged to be well tolerated in the dosed patients. 

Preclinical studies conducted in animal models have provided some evidence to suggest that HspE7 may stimulate cell-mediated immunity to fight cervical cancer.  In vivo studies of tumor implantation and rejection in a murine model of cervical cancer (TC-1 tumor cells) showed:

• treatment with HspE7 promotes regression of established TC-1 tumors;
• treatment with HspE7 that leads to tumor regression also provides protection against a subsequent challenge with TC-1 tumor cells; and
• treatment with E7 alone or an admixture of Hsp and E7 does not cause regression of TC-1 tumors.