Nonconformity of NOV002 Used in Phase 3 NSCLC Trial Sponsored by Novelos Therapeutics, Inc to NOV002 (Glutoxim(R)), Used in Phase 1/2 NSCLC and all Previous Trials

Jun 29, 2010, 08:31 ET from Pharma Vam

SAINT PETERSBURG, June 29, 2010 /PRNewswire/ -- The Company VAM is the developer of product Glutoxim(R) registered in Russia in 1998, registration No. P N002010/01. We possess significant knowledge and experience in manufacturing of this product as well as in the clinical development application of Glutoxim(R). In accordance with an Agreement dated June 20, 2000, the company VAM diligently and successfully transferred all of the "know-how", manufacturing and quality assurance information on the active drug substance and finished injection forms of the product Glutoxim(R) to Novelos Therapeutics, Inc.

Up to October 2005, the active pharmaceutical ingredient used in Glutoxim(R) (US code name NOV002) was synthesized according to the original manufacturing process and technology transferred from the company VAM to Novelos. The original NOV002 (Glutoxim(R)) used in the Phase 1/2 NSCLC and all previous trials met predetermined clinical endpoints and yielded encouraging results.

After the completion of the Phase 3 NSCLC trial and learning that NOV002 had failed to meet clinical endpoints, VAM requested Novelos to provide samples of products used in the Phase 3 trial. At VAM's request, an independent chemical and biological analysis of the samples was performed in the State Technological Institute of Saint-Petersburg and State Research Trial Institute of Military Medicine.

Expert opinions - excerpts[1]

Technological Institute

"On the basis of data generated by the element analysis it is possible to make a conclusion, that all three presented dry samples considerably differ from each other on parity of Pt:Fe which varies from ~ 2 to 70 atoms of platinum on 1 atom of Iron. Such appreciable variance in comparability of concentrations of iron and platinum testifies that it is impossible to consider all products standardized.

In spite of the fact that according to IR and a nuclear magnetic resonance spectroscopy on kernels 1H and 13C supplied samples of NOV002 contain pure enough disodium salt of oxidized glutathione, they do not correspond to Glutoxim(R) due to the high concentration of iron (II) that destabilizes action of platinum complex, which proves to be true on the basis of quantum chemical DFT calculations"

Trial Institute of Military Medicine

"The comparative assessment of hemostimulating activity of 3 presented samples (Lots 05, 06, 07) of NOV002 and Glutoxim(R) was performed using a model of Cyclophosphamide induced hemodepression. Research results have shown:

    1. Essentially differing hemostimulating activity between 3 presented

    2. Target effect was reached in groups with Glutoxim(R) and Lot 05.

    3. In the groups receiving Lot 06 and Lot 07 physiologically incompatible
       stimulation of hematopoiesis, led to deterioration of rheological
       blood properties and, as consequence, death of study animals that
       raises requirements in an assessment of their safety."

On recently, in 2010, VAM became aware that in August of 2005, Novelos had modified manufacturing process and quality assurance specifications for the NOV002 that was used in the Phase 3 NSCLC trial. Novelos undertook these changes without the corresponding coordination with VAM, original developer.

To the best of our knowledge Novelos had not conducted any preclinical or clinical studies of the newly synthesized active pharmaceutical ingredient before initiating the Phase 3 clinical trial. As noted above, the Phase 3 NSCLC trial using the modified active pharmaceutical ingredient failed to meet clinical endpoints. The original NOV002 (Glutoxim(R)) used in the Phase 1/2 NSCLC and all previous trials met predetermined clinical endpoints and yielded encouraging results.

VAM firmly believes that it is our obligation and ethical duty to inform the oncology community regarding of the modification and nonconformity of the Novelos NOV002 product used in the Phase 3 NSCLC trial as compared to the NOV002 (VAM Glutoxim(R)) product used in the Phase 1/2 NSCLC trial and all preceding clinical and preclinical studies that served as the basis for the IND package compilation.


[1] Full reports are on file at VAM.

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