It was old news presented at the American Society of Clinical Oncology meeting in Orlando, Fla. - PTK787, the vascular endothelial growth factor blocker from Novartis Pharma AG and Schering AG, fizzled in Phase III trials against metastatic colorectal cancer.
But Amgen Inc. and Abgenix Inc. brightened the party, offering favorable Phase II results against the same disease with their epidermal growth factor inhibitor panitumumab, and the drug's success as a second-line single agent in that study bodes well for pivotal Phase III data due in the second half of this year.
"Basically, from an efficacy standpoint, panitumumab and Erbitux are comparable," said Caroline Stewart, a senior analyst at IRG Research Inc. in New York, who is attending the ASCO meeting. However, panitumumab's much more convenient dosing regimen and cleaner side effect profile mean the drug - though late to market - likely will give main competitor Erbitux a run for its money, she said.
Abgenix's stock (NASDAQ:ABGX) closed Tuesday at $7.30, down 18 cents. Amgen's shares (NASDAQ:AMGN) ended the day at $62.90, down 9 cents.
Erbitux, from New York-based companies ImClone Systems Inc. and Bristol-Myers Squibb Co., won FDA approval in February 2004 for use in combination with irinotecan in metastatic colorectal cancer. Analysts have said the product could reach more than $1 billion in sales, and BMS reported $88 million in sales in the fourth quarter of last year.
"I think people are underestimating Amgen as a partner," Stewart added, pointing to the Epogen franchise established in the dialysis market. Epogen (epoetin alfa) is Amgen's blockbuster anemia drug.
"They created this whole section for reimbursement," she said. Now, committed to entering the oncology arena beyond supportive care, Amgen might boost panitumumab to greatness. Stewart has a "buy" rating on Abgenix, with a price target of $10.
In the pivotal trials, Thousand Oaks, Calif.-based Amgen and Abgenix, of Cambridge, Mass., are testing the drug as third-line monotherapy and a first-line combination agent. Amgen plans to file a biologics license application for panitumumab in the former setting first, and then ask the FDA to expand the label to include first-line combination treatment. (See BioWorld Today, April 28, 2005.)
"They just completed enrollment in the international pivotal trials in mid-March, and last night Amgen stated [the BLA] might be filed late this year or early next year," Stewart said Tuesday, noting that observers "kind of jumped onto" the news as a potential negative.
The pivotal trials' endpoint is progression-free survival, "so it's an event-driven trial, and you can't predict that with any certainty, but I still think it's most likely going to be filed by year's end."
Meanwhile, in the ASCO-reported Phase II study, patients expressing the EGFR protein showed a median survival time of 37.6 weeks and a median duration of tumor response of 18.1 weeks when given panitumumab. Twenty-nine percent of patients had their disease stabilize, and median progression-free survival (PFS) time topped out at 13.6 weeks.
Interestingly, the panitumumab combo trials involve Avastin (bevacizumab), the approved colorectal cancer wonder drug from South San Francisco-based Genentech Inc., which benefited handsomely from the disclosure in March by Novartis, of Basel, Switzerland, and Berlin-based Schering that their PTK787 missed statistical significance in terms of PFS. (See BioWorld Today, March 22, 2005.)
Details of that failure were offered at ASCO, along with further news about Avastin, which is labeled for use in combination with chemotherapy as a first-line treatment. ASCO data regarding Avastin as a second-line treatment in combination with the chemo regimen FOLFOX4 trumpeted significantly higher overall survival times, PFS and objective response rates than those seen in patients getting either mode of treatment by itself.
PTK787, though, "has lost," Stewart said. The drug is a multi-VEGF receptor tyrosine kinase inhibitor that blocks tumor angiogenesis and lymphangiogenesis by inhibiting all of the known VEGF receptors, while the monoclonal antibodies panatumimab and Avastin are specific.
The idea behind using the broad-spectrum "shotgun" approach is that drugs such as PTK787 might bring more efficacy and possibly better avoid the problem of resistance - even if the side effects prove less desirable than those with targeted agents. But the panatumimab and Avastin outcomes delivered at ASCO seem to show a win-win.
Avastin, though, changed the entire landscape and made PFS and overall survival somewhat trickier to measure as endpoints, Stewart said.
"It's a moving target," she said. "Patients all of a sudden are living longer [on Avastin]," and FOLFOX4 has moved into front-line therapy. As for PTK787, it "was supposed to be directly competitive to Avastin," since both are VEGF inhibitors - and the former, as an oral small molecule, offered a potential leg up, Stewart said.
"If patients could pop a pill, that would have been nicer," but PTK787 is "pretty much shot, for now," she said. Researchers believe the failure "might have something to do with the dosing regimen. It clears out of the system too quickly."
Often, Stewart acknowledged, "the biologics, if they're really safe, don't do anything." She pointed to the small-molecule EGFR inhibitors Tarceva (erlotinib), from Genentech and Melville, N.Y.-based OSI Pharmaceuticals Inc., and Iressa (gefitinib), from AstraZeneca plc, of London, both for non-small-cell lung cancer. Each boasts limited toxicity "but they work well only in a sub-group of patients." In general, the class has been "kind of a disappointment," she added.
So, for colorectal cancer - after Avastin and Erbitux - investors' eyes are on panitumumab. Amgen and Abgenix first collaborated six years ago when Abgenix agreed to use its XenoMouse technology to produce fully human monoclonal antibodies to an undisclosed Amgen target antigen, in return for up-front fees, milestone and potential royalties. At that time, ABX-EGF - later to be known as panitumumab - was part of an internal Abgenix program in preclinical studies. (See BioWorld Today, April 27, 1999.)
In July 2000, Abgenix partnered the product with Seattle-based Immunex Corp., which was bought by Amgen two years later. Several years after that, Abgenix and Amgen signed a revised agreement that gave Amgen authority over development and marketing and put manufacturing in Abgenix's hands. The firms will split costs and worldwide revenues. (See BioWorld Today, July 28, 2000; July 17, 2002; and Oct. 16, 2003.)
The meeting ended Tuesday. In other news from ASCO:
• Acadia Pharmaceuticals Inc., of San Diego, reported findings detailing its application of its assay technology known as R-SAT (Receptor Selection and Amplification Technology) to the development of high-throughput assays for the majority of known tyrosine kinase-linked receptors (RTKs). Also, at a recent Italian conference, the company highlighted its use of BRET (Bioluminescence Resonance Energy Transfer) technology to measure the interaction of RTKs with several signaling proteins, which allowed its scientists to define the biology of mutant forms of the epidermal growth factor receptor that have been associated with lung cancer.
• Agennix Inc., of Houston, said Phase II data showed, among other things, that oral talactoferrin alfa (talactoferrin) combined with standard chemotherapy for first-line treatment of advanced non-small-cell lung cancer enhanced the patients' response to chemotherapy on all the tumor-related endpoints including response rate, progression-free survival, time to response and duration of response. Talactoferrin appeared to be safe and well tolerated, with no drug-related significant adverse events.
• BioAlliance Pharma SA, of Paris, said a Phase III trial of its miconazole Lauriad 50-mg bioadhesive buccal tablets in head and neck cancer patients suffering from oropharyngeal candidiasis following radiotherapy demonstrated efficacy with 10 times less drug, and on a more convenient schedule, than the miconazole oral gel comparator. Of note, salivary secretion, which was dramatically reduced and even absent in 20 percent of patients, was statistically marginally more reduced and candidiasis lesions also were statistically marginally more extended in the miconazole Lauriad-treated patients than in the miconazole gel-treated patients (p=0.099 and p=0.069, respectively).
• Cell Genesys Inc., of South San Francisco, said additional results from its second Phase II trial of GVAX vaccine for prostate cancer, which include data on the 22 patients who received the highest dose, indicate that the median survival has not been reached for the group and that the final median survival will be no less than 24.1 months. Previously reported findings from the first Phase II study indicated an overall median survival of 26.2 months in a similar group of patients.
• CuraGen Corp., of New Haven, Conn., presented the final Phase I results for a single-dose of velafermin (CG53135) for the prevention of oral mucositis in patients receiving high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation, which suggest the drug is well tolerated following intravenous administration. Based on Phase I data, the 0.03-, 0.1- and 0.2-mg/kg doses of velafermin are being evaluated in an ongoing Phase II trial, expected to be complete during the first half of 2006. Also, after treatment with the drug, 22 of 30 patients in the study did not develop severe Grade III or IV oral mucositis.
• Genta Inc., of Berkely, N.J., reported data from various studies using Genasense (oblimersen sodium) Injection. In a pediatric solid-tumor study, escalating doses of Genasense and standard chemotherapy of doxorubicin and cyclophosphamide were administered to children who had received extensive prior therapy; biologically active plasma levels of Genasense relative to preclinical models were exceeded in patients, and authors concluded that the addition of Genasense to the chemotherapy program was well tolerated in children at doses that were comparable to adults. Other data include final Phase II data from a trial of Genasense plus docetaxel showed that 14 of 27 adults with advanced hormone-refractory prostate cancer achieved a major reduction in prostate-specific antigen, and median survival for all patients irrespective of response was 20 months.
• Guilford Pharmaceuticals Inc., of Baltimore, said findings from a study of Gliadel Wafer (polifeprosan 20 with carmustine) and temozolomide used in combination to treat high-grade malignant glioma determined the combination to be safe. During the trial, patients underwent surgical resection, followed with implantation of Gliadel, a localized chemotherapy inserted directly into the resection cavity, and then were treated with daily temozolomide and standard radiotherapy.
• Human Genome Sciences Inc., of Rockville, Md., said data from ongoing Phase I trials with HGS-ETR2 and HGS-ETR1 show the compounds were well tolerated in patients with advanced solid tumors, and support further evaluation in Phase II trials.
• Immunicon Corp., of Huntingdon Valley, Pa., offered more data from its trial in metastatic breast cancer and the significance of circulating tumor cells in the blood of such patients undergoing treatment. The original study data were published in The New England Journal of Medicine in August 2004 and showed the ability of CTC levels to predict patient outcomes in terms of progression-free survival and overall survival. New ASCO data indicated the significance of CTCs at monthly intervals after initiation of therapy, including time points beyond baseline and first follow-up visit to the physician.
• ImmunoGen Inc., of Cambridge, Mass., reported initial Phase II findings with its lead tumor-activated prodrug compound, huN901-DM1, in development for small-cell lung cancer and others that express the CD56 antigen. Thirteen patients had small-cell lung cancer and one had a CD56-positive small-cell carcinoma of the cervix. One patient had a durable, partial response (measured by RECIST criteria) to treatment. The cervical cancer patient also had a partial response in her first treatment cycle, but did not receive further treatment and her cancer progressed. Three patients had stable disease that was not durable.
• Introgen Therapeutics Inc., of Austin, Texas, provided an update of its ongoing clinical development of INGN 401, a nanoparticle formulation of the tumor suppressor gene FUS1. The data highlighted the potential of INGN 401 alone and in combination with Iressa (gefitinib), from London-based AstraZeneca plc, in the treatment of non-small-cell lung cancer.
• Kosan Biosciences Inc., of Hayward, Calif., presented preliminary data from a Phase II trial of KOS-862 used as a single agent in patients with non-small-cell lung cancer, including results from 50 evaluable patients, the majority of whom had advanced metastatic disease and had received previous treatment with taxanes. Thirty-four percent of the evaluable patients treated with KOS-862 were observed to have either partial responses (8 percent, or 4 patients) or disease stabilization (26 percent, or 13 patients). At the time of the analysis, median progression-free survival time for those patients was 26.6 weeks, and two of the patients continue on treatment.
• Ligand Pharmaceuticals Inc., of San Diego, offered results of new research in treatments for advanced non-small-cell lung cancer, including data from a Phase II trial of Targretin (bexarotene) capsules in patients with advanced NSCLC who have failed two or more prior systemic therapies; a Phase I trial of Tarceva (erlotinib) and Targretin as a targeted combination therapy for advanced aerodigestive tract cancers including NSCLC and head and neck cancer; and a Phase II trial of Ontak (denileukin diftitox) in previously treated patients with advanced NSCLC.
• MedImmune Inc., of Gaithersburg, Md., disclosed encouraging preliminary Phase I results with siplizumab indicating the antibody was safe and well tolerated in patients with certain T-cell lymphomas and leukemias. Siplizumab is a monoclonal antibody being evaluated in adults with CD2-positive lymphoma or leukemia. Partial remissions for some study participants were among the data presented by the National Cancer Institute.
• Millennium Pharmaceuticals Inc., of Cambridge, Mass., said clinical data in the front-line setting for the treatment of multiple myeloma underscore the potential benefit of Velcade in earlier lines of therapy. Data demonstrated a survival advantage in patients with poor prognostic factors, such as chromosome 13 deletion. In combination with standard therapy, dexamethasone prior to autologous stem cell transplant, an overall response rate of 67 percent was recorded, and stem cell harvest was successful in 100 percent of patients who proceeded to autologous stem cell collection. Overall response rate after single transplant was 90 percent.
• NeoPharm Inc., of Lake Forest, Ill., reported that data from four Phase I study databases of cintredekin besudotox (IL13-PE38QQR) in brain cancer patients showed a median survival rate of 44 weeks when administered by peritumoral infusion, while the median survival of 37.1 weeks was reported for patients who received the drug intratumorally. Prolonged survival of 190+ weeks (median 89+ weeks) also has been observed.
• OSI Pharmaceuticals Inc., of Melville, N.Y., reported data from two separate single-arm Phase II studies of monotherapy Tarceva in chemotherapy-na ve or front-line non-small-cell lung cancer patients that indicated antitumor activity. Data from another study showed that patients receiving Tarceva had slower deterioration of disease-related symptoms of cough, dyspnea and pain that was clinically and statistically significant. The company also reported encouraging results from studies evaluating Tarceva as a monotherapy or in combination therapy in head and neck cancer, renal-cell carcinoma, colorectal and hepatocelluar cancer.
• Point Therapeutics Inc., of Boston, presented positive results in the company's Phase II study of talabostat in combination with docetaxel in patients with advanced non-small-cell lung cancer in a second-line or third-line setting in a poster session. Thirty-six evaluable patients have completed the 18-week treatment period, with five showing a clinical response to treatment. Two had a complete response, defined as a complete disappearance of their tumor. Three patients had a partial response.
• Progen Industries Ltd., of Brisbane, Australia, presented results from a Phase II melanoma pilot trial with PI-88 delivered as a single agent. The safety profile proved acceptable with signs of benefit in some patients with advanced disease. Forty-four patients were enrolled, with 37 evaluable for efficacy. One had a partial response and 10 had stable disease, with a median survival rate of nine months.
• Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., said preliminary results from an ongoing Phase I study of the VEGF Trap administered intravenously to patients with advanced cancers have suggested that the product induces a tumor vascular response. Preliminary efficacy analysis showed evidence of tumor size reduction and prolonged stable disease in some patients after VEGF Trap treatment as a single agent. Regeneron is collaborating on VEGF Trap in oncology with Sanofi-Aventis Group, of Paris.
• Structural GenomiX Inc., of San Diego, reported preliminary data from its Phase I/II trial of Troxatyl in acute myelogenous leukemia, showing the drug was well tolerated and showed activity in adults with relapsed or refractory AML when administered by continuous infusion. The study has completed its target enrollment of 48 patients. There was no Grade III or IV toxicities observed in any of the 18 patients treated at the maximum tolerated dose of 60 mg/m(2) given over five days, and an overall response rate of 17 percent and response duration of at least six months.
• Synta Pharmaceuticals Corp., of Lexington, Mass., said preliminary data of an ongoing Phase II trial of STA-4783, administered in combination with paclitaxel, in patients with non-small-cell lung cancer showed a response rate in 44 percent of the patients, while an additional 38 percent experienced disease stabilization. Data from a Phase II study in soft-tissue sarcoma indicated that 47 percent of patients achieved non-progression of the disease at three months when treated with the drug.
• Telik Inc., of Palo Alto, Calif., reported positive interim data from a Phase I/IIa study evaluating Telcyta (TLK286) in combination with cisplatin in the first-line treatment of advanced non-small-cell lung cancer. Of the evaluable patients, researchers noted a 36 percent objective response rate and an 86 percent disease stabilization rate.
• Therion Biologics Corp., of Cambridge, Mass., said Phase II data showed that its Prostvac-VF prime/boost regimen resulted in a favorable clinical response with the majority of prostate cancer patients in all treatment arms remaining free of disease progression and exhibiting stable PSA scores at 50 months. Findings from a separate study of patients with metastatic androgen-insensitive prostate cancer showed treatment with Prostvac-VF to be associated with declines in PSA in several patients and a clear decrease in tumor size for one patient. Data from a National Cancer Institute-sponsored study showed that among patients who previously had received hormone therapy and subsequently developed rising PSA scores but did not have evidence of metastasis those who received Prostvac-VF appeared to respond better to the anti-androgen therapy nulutamide.
• Transgene SA, of Strasbourg, France, said a Phase II study of MVA-MUC1-IL2, administered with cisplatin and vinorelbine, in non-small-cell lung cancer patients showed a tumor response rate of 37 percent. Of the 35 evaluable patients, 13 showed partial responses, and about 71 percent showed disease control - partial response or stable disease - for more than 12 weeks. The company is estimating median time to progression and overall survival are 6.4 months and 13 months, respectively.
• ViroLogic Inc., of South San Francisco, presented data demonstrating the ability of its eTag assays to accurately predict treatment response for patients with breast cancer who receive Herceptin (trastuzumab). The company has developed a set of assays that enable broader analysis of the human epidermal growth factor receptor family.
• Xanthus Life Sciences Inc., of Cambridge, Mass., said data from a Phase I study of Amonafide (now called Xanafide) in combination with cytosine arabinoside demonstrated promising activity in patients with poor-risk acute myeloid leukemia. The company plans to start a Phase II study later this year.