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Generex to Meet with FDA about AE37 HER2 Peptide Vaccine; Companion Dx Path Still Unclear

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Originally published March 5.

By Turna Ray

Based on promising Phase II results, Generex Biotechnology is planning to meet with the US Food and Drug Administration about its investigational cancer immunotherapy for breast patients who have tumors that express low to intermediate levels of the HER2 protein, the company said this week.

Generex's HER-2/neu peptide vaccine, called AE37, is being developed as an adjuvant therapy for the 50 percent of breast cancer patients who express low to intermediate levels of HER2, and as a result, don't have HER2 expression levels high enough to be eligible for Roche/Genentech's Herceptin, according to the company.

However, although the AE37 immunotherapeutic is for a molecularly defined patient population, Generex is not currently planning to develop the drug with a new companion diagnostic to gauge HER2 expression in the intent-to-treat patient population.

"At the moment we are not working to set up a separate diagnostic test" for AE37, Eric von Hofe, CEO of Generex subsidiary Antigen Express, told PGx Reporter. AE37 is the first product Generex is developing using Antigen Express's Ii-Key Hybrid technology platform.

"There is currently the Dako HercepTest that can be used for scoring tumor tissue HER2 1+, 2+ or 3+; with low to intermediate expressing tissue being 1+ or 2+," Von Hofe said. "There are other tests, as well, that are available that claim to be more quantitative."

Patients who end up receiving AE37 will likely be those who were initially being considered for Herceptin treatment and, as such, were already tested with one of several FDA-cleared HER2 tests and found to have low to intermediate HER2 expression. This may be one reason why Generex expects it will not have to develop a companion test for its product.

The FDA has indicated that when a drug requires the aid of a molecular diagnostic to determine which patients should receive it, the test, in most cases, must be approved by the agency. "An IVD companion diagnostic device is an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product," the FDA states in its draft companion diagnostics guidance, released last year.

The FDA-approved labeling for HercepTest notes that it is indicated "as an aid in the assessment of patients for whom Herceptin treatment is being considered." Given the rationale for how a breast cancer patient might become eligible to receive AE37, it is unclear whether the agency will require a separate FDA-cleared companion diagnostic to market the drug for a subset of the HER2 population.

Meanwhile, Dako and other firms marketing FDA-cleared HER2 tests that are supporting an additional indication for Herceptin or that are intended to be used with a new HER2-targeted therapy have had to seek approval for their tests in these new settings (PGx Reporter 6/2/2010; 2/8/2012).

The agency notes in its companion diagnostic guidance that when a test has been cleared for use with one therapeutic product "and evidence becomes available that use of the same device is essential for the safe and effective use of a different therapeutic product, the IVD companion diagnostic device labeling should be expanded through approval or clearance of a new premarket submission (PMA or 510(k) as appropriate) or PMA supplement … to include the new therapeutic product."

At the San Antonio Breast Cancer Symposium in December, Generex announced interim results from a randomized, single-blinded Phase IIb trial comparing AE37 plus granulocyte-macrophage colony-stimulating factor or GM-CSF alone in 215 breast cancer patients who had completed standard therapy, were disease-free, had node-positive disease, or had high risk node-negative disease.

At the meeting, the company reported that at a median follow up of 17 months, breast cancer patients in the AE37 arm experienced 42 percent fewer disease recurrences than those in the control arm. When researchers analyzed only patients with low HER2 expression (with an score of 1+ or 2+ by immunohistochemistry testing), study participants experienced a 49 percent reduction in recurrence compared to controls. Meanwhile, HER2 over-expressing patients saw no reduction in cancer recurrence when treated with the vaccine.

Von Hofe told PGx Reporter that the breast cancer patients enrolled in the Phase IIb study had their IHC HER2 score determined on Dako's test.

At this point in the study, researcher reported no grade 4 or 5 toxicities and found no difference between toxicity profiles of patients in the vaccine and control groups. However, when the trial was presented at SABCS, the patient cohort size was too small to yield statistically significant results, according to a statement from Antigen Express. The company plans to enroll a total of 300 women in the Phase IIb study. The primary endpoint in the study is a reduction in cancer relapse after two years.

Last week, Generex provided an update from this same trial at the Cancer Immunotherapy Summit in Boston. At a median of 22 months follow up with more than 250 patients enrolled, 89 percent of low HER2 expressing patients treated with the AE37-containing regimen experienced disease-free survival compared to around 72 percent in the control arm.

Given these results, Generex is planning to hold an end of Phase II meeting with the FDA by the middle of the year. "Immediately following that meeting, the company will begin the process for submission of a Special Protocol Assessment for a Phase III trial," the firm said in a statement.

AE37 is derived from a peptide fragment of the HER2 oncoprotein. Antigen Express's Ii-Key Hybrid technology platform, upon which AE37 is based, modifies fragments of antigens to boost their ability to stimulate CD4+ T helper cells, which are key players in the body's immune system. "Incorporating the Ii-Key modification along with tumor-associated antigens can greatly enhance the immune system's ability to recognize and destroy cancer cells bearing any of the targeted antigens, as well as increasing immunological memory," Generex explained in a statement.

According to Generex, AE37 is the only HER2-based peptide vaccine being advanced in a randomized trial. AE37's use "is not restricted to patients with a particular type of human leukocyte antigen peptide," the company noted.


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