Cell Therapeutics’ recent acquisition of Systems Medicine will not only garner CTI worldwide rights to brostallicin, a DNA minor-groove binding agent that has shown anti-tumor activity in various types of cancer, but will also enable CTI to leverage SMi’s affiliation with the Translational Genomics Research Institute to personalize treatment for brostallicin and other oncology drugs in their pipeline using PGx tools.
CTI acquired privately held SMi on July 31 in a $20 million stock-for-stock merger. The financial terms of the acquisition may also net SMi stockholders as much as $15 million in cash or in shares of CTI common stock if certain milestones are met.
Under the terms of the deal, SMi will operate as a wholly owned subsidiary of CTI, “utilizing its genomic-based platform to guide development of CTI's oncology products, including brostallicin,” CTI said in a statement.
SMi and Phoenix, Ariz.-based non-profit TGen have a strategic relationship in which SMi uses TGen’s genetic tools to pinpoint through clinical trials the mechanisms and cancer types best suited for an investigational drug. TGen holds founders stock in SMi.
CTI said that it expects operating expenses for clinical development of brostallicin “to have minimal impact on burn rate.” Brostallicin is currently in Phase II clinical studies. CTI already has two other cancer drug candidates — Xyotax and pixantrone — in clinical trials and expects market approval for both drugs in 2009.
In an e-mail to Pharmacogenomics Reporter last week, a CTI spokesperson said that the company will gain a number of PGx tools from SMi via TGen to develop personalized oncology products, including high-throughput RNAi profiling, comparative genomic hybridization, and gene-expression profiling.
While “SMi’s business model does not involve commercialization of [diagnostics], we plan to partner with Dx companies if and when appropriate in the future,” the spokesperson said.
Although CTI’s aim to personalize cancer treatment leaves the opportunity open for the future development of a companion diagnostic, the research is still in early stages. Brostallicin is a second-generation minor-groove binder that is in Phase II clinical trials in the US and in Europe, and has shown anti-tumor activity in various cancers and a favorable safety profile in more than 200 patients.
“There appears to be at least one unique translocation that we believe correlates to clinical activity in subsets of sarcoma,” the CTI spokesperson said, adding that the drug appears to have antitumor activity in cancer cells with mismatch repair deficiencies in subsets of colon, ovarian, breast, and other cancers.
In a paper published in the April 2002 issue of Cancer Research by researchers at the Istituto di Ricerche Farmacologiche "Mario Negri," Università degli Studi di Milano, and the Pfizer spin-off Nerviano Medical Sciences, the investigational compound showed “broad antitumor activity in preclinical models and dramatically reduced in vitro myelotoxicity in human hematopoietic progenitor cells compared with that of other minor groove binders.”
Additionally, in a mouse study in ovarian cancer, “the antitumor activity of brostallicin was higher in the GST-π-overexpressing tumors without increased toxicity,” the authors reported.
Brostallicin has a novel mechanism of action for conferring antitumor activity, since it binds covalently to DNA within the DNA minor groove. Most other targeted cancer drugs, such as camptothecins and anthracyclines, bind to the major groove in DNA.
“By binding to the minor groove, brostallicin targets a new means to interfere with DNA division and leads to tumor cell death,” CTI said. “Brostallicin has demonstrated synergism in vitro in combination with standard cytotoxic agents as well as newer targeted therapies.”
Brostallicin has taken the long road to CTI’s pipeline. Originally developed by Pharmacia, rights to the drug were assigned to Italy’s Nerviano Medical Sciences following the Pfizer/Pharmacia merger in 2003. Eventually, Nerviano licensed worldwide rights to SMi. CTI said it will continue to leverage SMi’s close ties to the Italian research facility for the manufacture and development of brostallicin, as well as other products in CTI’s pipeline.
In addition to brostallicin, CTI plans to launch two oncologics, pixantrone and Xyotax (paclitaxel poliglumex) in early and late 2009, respectively. Pixantrone is an anthracycline derivative for the treatment of non-Hodgkin’s lymphoma and various other hematologic malignancies, solid tumors, and immunological disorders. Xyotax is a chemotherapeutic agent for non-small cell lung and ovarian cancers; the therapy is also being studied as a potential treatment for breast and prostate cancer. CTI is conducting the Xyotax program with Novartis.
With a potential launch for brostallicin slated for 2010, the drug “fills CTI’s clinical pipeline gap,” the company said.
“We expect brostallicin and SMi will fit perfectly with CTI’s effort to develop individualized cancer medicines where genomic targeting of specific populations of patients should increase the probability of clinical success and patient benefit, while at the same time offering us the potential to market an additional solid tumor indication product in the United States alongside our Xyotax program with partner Novartis,” James Bianco, president and CEO of CTI, said in a statement.
"We expect brostallicin and SMi will fit perfectly with CTI’s effort to develop individualized cancer medicines where genomic targeting of specific populations of patients should increase the probability of clinical success and patient benefit, while at the same time offering us the potential to market an additional solid tumor indication product in the United States.”
CTI currently has preclinical programs in src kinase inhibitors and is looking at novel approaches to IGF inhibition; once these programs advance they will also be studied using the PGx tools gained from SMi’s close ties with TGen, CTI said. Additionally, the company plans to use pharmacogenomics to help identify the clinical development program for a bisplatinum compound expected to enter preclinical studies in the first half of 2008.
By gaining access to SMi’s PGx tools, CTI said it can also conduct more efficient clinical trials.
The acquisition allows CTI to use SMi’s technology platform to “target a cancer drug’s ‘context of vulnerability’ guiding clinical trials toward patient populations where the highest likelihood of success should be observed, thereby potentially lowering risk and shortening time to market,” CTI said in a statement.
When asked to estimate the cost of a PGx-driven trial, CTI said it would be hard to gauge a priori “since it depends on biomarkers and clinical indications that will be defined by prospective pharmacogenomic preclinical work.
“If a previously undefined and large collection of genes … is required, it could be quite expensive; if a single protein bioassay is required, the costs would be nominal,” the CTI spokesperson wrote in an e-mail.
Whether a PGx-driven trial will be more or less expensive than a normal trial depends on the results of the preclinical hypothesis testing and initial Phase IIa clinical trial results, according to the spokesperson. “If we hit our end points 50 percent to 100 percent of the time, we’d expect greatly reduced trial timelines and costs. It will come down to properly defining the patient subgroups we want to pursue and then working with the FDA to move those forward.”
The acquisition also integrates some members of SMi’s team directly within CTI’s functions. Daniel Von Hoff, SMi founder and director of TGen, will head CTI’s strategic product portfolio committee. Richard Love, another SMi founder and CEO of ILEX Technology, will join CTI’s board of directors.
Meanwhile, Jeff Jacob will remain as CEO and president of SMi, but will take a more integral role in managing CTI’s portfolio. “We are excited to have Jeff and his team leading the Systems Medicine subsidiary guiding the development path of our current preclinical drug candidates and also providing CTI access to other potentially exciting cancer drugs for our portfolio or for out-licensing opportunities,” Bianco said.