Oncology R&D: Exploiting New Molecular Targets Is Challenge for 2003

The next wave of cancer drugs entering late-stage development reflects the improved understanding of cancer biology and oncogenesis made possible by sophisticated genomics and bioinformatics technologies.

Genomics and bioinformatics have uncovered a wealth of new molecular targets for drug development, helping to make oncology by far the most active area of pharmaceutical research in 2002. There are 1,026 oncology drug projects in Phase II or Phase III, compared with 440 for the next largest category, nervous system therapeutics, and 328 for anti-infectives, according to data contained in F-D-C Reports' NDA Pipeline. (Each indication for a drug counts as a different drug "project.")

The newer targeted therapies pose development challenges for both industry and FDA.

For example, because these agents target cells overexpressing a specific molecular target (such as the epidermal growth factor receptor), they may have an indicated patient population that does not easily fit within regulations first written for cancers defined by disease site (such as colorectal cancer).

Similarly, it is more difficult to evaluate the cytostatic activity of many targeted therapies under a paradigm designed for cytotoxics. Cytostatic therapy, if successful, would treat cancer as a chronic disease with chronically administered treatment, and research indicates that cytostatics may complement or even enhance cytotoxics. Endpoints for trials involving cytostatics thus may differ from chemotherapy endpoints and new or different surrogate endpoints must be validated.

Sponsors may address concerns about pivotal trial design, conduct and analysis in the emerging regulatory environment by requesting a Special Protocol Assessment from FDA. Celgene and Imclone are among several late-stage developers of targeted therapies that have used this program.

The two most advanced agents demonstrating cytostatic tumor growth inhibition, Bristol/ImClone's Erbitux and AstraZeneca's Iressa , target the epidermal growth factor receptor. Development of both has stumbled. After FDA refused to file the Erbitux BLA, Bristol took over a larger role in developing the monoclonal antibody. Bristol has submitted Phase III protocols for two second-line metastatic colorectal cancer trials to FDA, President-Americas Donald Hayden reported to analysts during the J.P. Morgan H&Q conference Jan. 8.

AstraZeneca is looking to sequential and neoadjuvant therapy after Iressa (geftinib) failed to show benefit in first-line treatment of non-small cell lung cancer ("The Pink Sheet" Aug. 26, 2002, p. 9). OSI and Genentech stated that Tarceva , the EGFr inhibitor they are developing with Roche, was "on track" in Phase III despite the Iressa results (¹ (Also see "Genentech Tarceva Trials “On Track” Despite INTACT: Response To Iressa" - Pink Sheet, 26 Aug, 2002.), p. 11).

The highest-profile class of targeted therapeutics was once angiogenesis inhibitors, the subject of a media and market frenzy following a 1998 front-page New York Times story on Entremed's angiostatin and endostatin (both now discontinued). In 2000, 12 anti-angiogenic agents were in Phase III.

Angiogenesis inhibitor research continues, albeit with a lower profile. Results to be reported over the next year or two could be pivotal not only to the specific drugs but also to the class. The NDA Pipeline lists five angiogenesis inhibitors in Phase III oncology trials as 2003 begins.

Novartis' vascular endothelial growth factor receptor inhibitor PTK-787 has the "potential to be the first oral VEGF inhibitor," Novartis Oncology President David Epstein predicted at the J.P. Morgan conference Jan. 9. The once-daily compound, co-developed with Schering AG, entered Phase III in December for treatment of colorectal cancer. Novartis' Gleevec (imatinib) is the one of the first targeted therapies approved by FDA.

Novartis continues to highlight PTK-787 to the investment community despite a rocky road for VEGF inhibitors in 2002. In September, Genentech announced that a Phase III study of its anti-VEGF monoclonal antibody Avastin (bevacizumab) combined with chemotherapy for relapsed metastatic breast cancer did not meet its primary endpoint.

However, that trial did not terminate Avastin's prospects. A 900-patient Phase III trial in metastatic colorectal cancer continues, as does enrollment in late-phase Eastern Cooperative Oncology Group NSCLC, breast cancer and colorectal cancer trials.

Sugen (Pharmacia) elected to discontinue all trials of its small molecule VEGF blocker semaxanib in early 2002, after interim analysis of a Phase III trial evaluating the drug with standard chemotherapy in advanced colorectal cancer did not find evidence of clinical benefit. Another angiogenesis inhibitor, SU-6668, an oral compound being co-developed with Taiho, is in Phase II oncology trials.

Aeterna's Neovastat , an oral liquid "multifunctional" angiogenesis inhibitor extracted from marine cartilage, is the subject of two Phase III trials. A renal cell cancer trial is evaluating Neovastat's ability to increase survival time in patients who failed to respond to standard immunotherapy. An NCI-sponsored study is evaluating non-small cell lung cancer patients who are also receiving standard chemotherapy and radiotherapy.

Results of the Neovastat kidney cancer trial are expected in the first half of 2003. The first-line therapy NSCLC trial has a longer timeframe, with results expected by the end of 2005.

While anti-angiogenic matrix metalloproteinase inhibitors have a spotted history (marimastat, BAY 12-9566 and prinomastat all showed no benefit in Phase III), Bristol has advanced the second-generation MMPI BMS-275291 to Phase III for NSCLC.

Thalidomide's anti-angiogenic effects are being tested in cancer as Celgene looks to expand labeling for the drug, returned to the market in 1998 for leprosy. A predicted sNDA filing for newly diagnosed multiple myeloma was delayed two years until 2004, based on discussions with FDA indicating that a fifth trial would be required before submission. The Phase III trial has been reviewed by FDA's Special Assessment Program.

A thalidomide analog with stronger TNF-alpha inhibition, Celgene's Revimid , is in concurrent pivotal trials for treatment of previously untreated multiple myeloma and refractory metastatic melanoma. FDA's Special Assessment Program also reviewed Revimid's Phase III protocols.

Abbott is making a public bet (an unusually bold move for an often reclusive company) that cytostatics are the key emerging area in oncology. On its corporate website, the company declares that it is "focused on developing exciting new classes of cytostatic drugs, which allow the treatment of cancer as a chronic disease with longer-term, non-toxic therapy."

The company specifically points to MMPIs, antimitotic agents (such as ABT-751, in Phase I for solid tumors), farnesyltransferase inhibitors (such as the preclinical ABT-100), and angiogenesis inhibitors (the lead anti-angiogenic, ABT-510, is in Phase I for solid tumors; in earlier development are ABT-567, ABT-828, a Tie-2 inhibitor and KDR/VEGFR inhibitors).

Abbott has one oncology agent in later-stage trials: the endothelin receptor antagonist atrasentan (ABT-627). The company has a fast-track designation for the lead indication, prostate cancer, currently in Phase III. The once-daily oral compound is in Phase II for brain, breast, ovarian and renal cell cancer.

Abbott had an interest in another Phase III agent, the radiolabelled anti-MUC-1 monoclonal antibody pemtumomab, through an alliance with Antisoma. The targeted MAb went to Roche in one of the Swiss company's five oncology transactions in 2002.

Roche gained exclusive worldwide rights to Antisoma's oncology portfolio (pemtumomab, in Phase III for ovarian cancer and Phase II for gastric cancer; the anti-MUC-1 MAb Therex , in Phase I; the antibody fragment Therafab , in Phase I to increase radiation doses in NSCLC; and DMXAA, a vascular targeting agent in Phase I). A late-2002 deal with Beaufour Ipsen also gives Roche worldwide rights, excluding Europe, to the topoisomerase inhibitors diflomotecan (Phase II) and BN-80927 (preclinical).

Roche used a licensing deal to gain entry to the novel cytotoxic class of epothilones, tubulin-inhibiting compounds with a mechanism similar to paclitaxel that have shown suggestions of activity in resistant tumors. Roche will co-develop and co-promote Kosan's KOS-862 (epothilone D), now in Phase I for solid tumors. Epothilone compounds are byproducts of a microorganism, Sorangium cellulosum, first isolated from mud taken from Africa's Zambezi River.

Bristol has made the largest commitment to epothilone research to date, with one epothilone B analog, BMS-247550, in Phase II for taxane-resistant cancers and NSCLC, and another, BMS-310705, in Phase I. Novartis' epothilone B EPO-906 is in Phase II.

Taxane resistance and toxicity has opened up a niche for smaller companies looking to improve existing compounds. Two enhanced formulations of paclitaxel are in Phase III, for example. American Pharmaceutical Partner's Capxol cremophor-free, nanoparticle formulation of paclitaxel completed Phase III enrollment in December 2002 and could be filed in 2003. Cell Therapeutics' Xyotax is in Phase III with a potential late-2004 submission. Xyotax is a water-soluble sugar molecule polymer-bound to paclitaxel that dissolves in the tumor, releasing otherwise bloodstream-inactive paclitaxel.

Antisense, another approach to targeted therapy that is indebted to genomics research, is on the verge of FDA review. The first antisense agent for oncology could be submitted to FDA in 2003.

Genta/Aventis' Genasense (augmerosen) targets the Bcl-2 protein to unblock the central apoptosis pathway, enhancing chemotherapy effectiveness. A 2003 filing is possible, Aventis COO Richard Markham told the J.P. Morgan analyst conference Jan. 7. Phase II/III trials are underway in chronic lymphocytic leukemia, malignant melanoma and multiple myeloma.

Lilly/Isis Affinitac , an antisense inhibitor of protein kinase C alpha expression, is in Phase III for NSCLC. Trial results, expected this year, could support a 2004 filing. Isis' Vitravene , for CMV retinitis, is the first antisense agent approved in the U.S. Lorus also has an antisense oligonucleotide in Phase III. GTI-2040 targets the R2 component of the ribonucleotide reductase enzyme for treatment of pancreatic cancer.

The single most active area of late-stage cancer research, according to the NDA Pipeline, is cancer vaccines: several are in Phase III in the U.S. (see ² chart: Harnessing The Immune System) [Editor's Note: Contributed by the editors of NDA Pipeline, an F-D-C Reports drug development and clinical trials database.]