Many a biotechnology company can tell war stories of negative Phase III data, followed by analyst downgrades and a decline in stock price.
But Onyx Pharmaceuticals Inc. had what is arguably an even more frustrating tale to tell: positive Phase III data, followed by an analyst downgrade and a decline in stock price.
Emeryville, Calif.-based Onyx and partner Bayer AG announced Friday the opening of a randomized, double-blind Phase III trial of sorafenib (formerly BAY 43-9006) in combination with carboplatin and paclitaxel in patients with advanced metastatic melanoma. (See BioWorld Today, May 16, 2005).
On Saturday, the partners presented positive Phase III data at the annual meeting of the American Society of Clinical Oncology in Orlando, Fla. There, they reported that in advanced renal-cell carcinoma - that is, kidney cancer - sorafenib improved progression-free survival from a median value of 12 weeks up to 24 weeks.
Hollings Renton, president and CEO of Onyx Pharmaceuticals, called the doubling of progression-free survival time "a remarkable effect."
"Kidney cancer patients and their doctors haven't seen this kind of data in this type of large, well-controlled study," he told BioWorld Today. He also noted that though only 2 percent of patients demonstrated the 30 percent tumor shrinkage required by the formal criteria of the clinical trial protocol for a partial response, 75 percent of patients showed "some tumor shrinkage."
Renton said that the company remains blinded to overall survival rates, but intends to file a new drug application based on progression-free survival. In March, Onyx had announced that an independent data monitoring committee concluded that the trial met its surrogate endpoint of statistically significant longer progression-free survival. Based on those data, in April, Onyx recommended to the study investigators that all patients in the trial be offered access to sorafenib. On Saturday, Bayer and Onyx went one step further, announcing the availability of sorafenib through an FDA-approved treatment protocol, the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) study, for eligible individuals.
The data might be remarkable, but Wall Street remained underwhelmed. Wachovia Securities downgraded the stock Monday from "perform" to "underperform." Prudential Securities, while not officially giving a rating, essentially concurred, saying that the sorafenib data presented at ASCO "came short of The Street's expectations."
The reason for the response: potential competitor Sutent, from Pfizer Inc., might work even better.
Sutent data from a Phase II trial also were presented at ASCO over the weekend; the drug had a time to progression of 8.7 months. Additionally, though sorafenib had less severe side effects, partial response rates were much higher with Sutent: 40 percent vs. 2 percent for sorafenib.
Wachovia analyst George Farmer called Sorafenib's effect on progression-free survival "extremely impressive," but nevertheless concluded that "with likelihood of achieving future milestones already baked into the stock, in our view, our downgrade reflects strong data from sorafenib competitors and low potential for drug application in other cancer indications beyond renal-cell carcinoma and malignant melanoma." His firm lowered its 12-month guidance from $29 to $34 to $23 to $27.
The progression-free survival rate reported for sorafenib, at about 5.6 months, is essentially unchanged from what the drug achieved in its Phase II trial. The Prudential report stated that was below expectations; analysts wanted a better performance in Phase III because in Phase II patients were randomized to placebo for part of the trial.
When comparing Phase III sorafenib vs. Phase II Sutent data, Farmer cautioned that "Phase II uncontrolled data often present better than controlled, randomized Phase III data," leading to what he termed a "haircut" for Phase III results. Possibly, sorafenib's bad hair day is due to two opposing effects that ultimately cancelled each other - a decrease because of a switch from Phase II to Phase III trial design, and an increase because patients were no longer randomized to placebo in Phase III.
Data also were presented at ASCO on a third drug, Pfizer's AG013736, that showed promise for kidney cancer. In a Phase II trial, AG013736 achieved a 46 percent partial response rate with median time to progression not reached after 12 months of follow up. Prudential's analysts concluded that "although AG013736 may not be a near-term threat to sorafenib in [renal-cell carcinoma], the data suggested that more efficacious targeted therapies could be developed."
Monday, Onyx's shares (NASDAQ:ONXX) finished the day at $27.29, down $4.56, or 14.3 percent. Renton said that the decrease in stock price was a "short-term reaction." He said that the company is very optimistic about the drug's prospects in both renal-cell carcinoma and melanoma, as well as Onyx's ability to develop the drug more broadly. Sorafenib is in about a dozen other clinical trials in a variety of indications sponsored by Onyx and Bayer, as well as two dozen more that are sponsored by the National Cancer Institute.
In other news from the meeting:
• Adherex Technologies Inc., of Research Triangle Park, N.C., said Phase I data of ADH-1 (Exherin) showed it was well tolerated over a 20-fold dose range and has displayed evidence of antitumor activity in three patients with advanced chemotherapy-resistant cancer.
• Amgen Inc., of Thousand Oaks, Calif., said an initial report from a study of 701 older cancer patients with solid tumors demonstrated Neulasta (pegfilgrastim) administered in the first cycle of myelosuppressive chemotherapy resulted in reductions in febrile neutropenia and related complications, compared to those who received Neulasta in later chemotherapy cycles after developing a low white blood cell count. The company also reported final results of a Phase III study demonstrating that 200 mcg of Aranesp (darbepoetin alfa) administered every two weeks is as effective as 40,000 U of Epoetin alfa dosed once a week in boosting hemoglobin levels and reducing the need for red blood cell transfusions in cancer patients with chemotherapy-induced anemia. Finally, new interim data from a single-arm, open-label study of 1,225 cancer patients receiving chemotherapy demonstrated that Aranesp administered every three weeks was effective in increasing and maintaining patient hemoglobin levels to greater than or equal to 11 g/dL.
• Aphton Corp., of Philadelphia, said preliminary data from an ongoing open-label, multicenter Phase II trial with IGN101 in patients with several types of solid tumors showed that the median number of circulating tumor cells had been reduced by about 50 percent in the 17 patients enrolled.
• Ariad Pharmaceuticals Inc., of Cambridge, Mass., said its mTOR inhibitor, AP23573, administered as a single agent, provides striking clinical benefit and symptomatic improvement in advanced sarcoma patients across multiple sarcoma subtypes in an ongoing Phase II trial.
• ArQule Inc., of Woburn, Mass., presented interim results of ARQ 501 in an ongoing Phase I monotherapy trial, which has demonstrated clinical tolerability, favorable pharmacokinetics and evidence of antitumor activity in patients with advanced solid tumors who had failed chemotherapy.
• Biomira Inc., of Edmonton, Alberta, and Merck KGaA, of Darmstadt, Germany, updated annual survival results from the Phase IIb trial of liposomal MUC1 vaccine to treat non-small-cell lung cancer patients with Stage IIIB disease. In November, two years after the last patient was enrolled, the median survival of patients receiving best supportive care was 13.3 months and the median survival of those receiving vaccine had not yet been reached. The median survival of the vaccine arm will be no less than 23 months, and the companies plan to move forward with a Phase III trial.
• Celgene Corp., of San Diego, said clinical data from a Revlimid study in chronic lymphocytic leukemia showed that 12 out of 14 relapsed or refractory patients responded to treatment, experiencing a decrease in absolute lymphocyte count. Revlimid also provided evidence that it could be used to treat myelodysplastic syndrome patients with deletion 5q chromosomal abnormalities. And Phase III trials showed that when Revlimid plus dexamethasone was used to treat patients with relapsed or refractory multiple myeloma, it more than doubled the response rate compared with placebo plus dexamethasone.
• Cell Genesys Inc., of South San Francisco, reported follow-up Phase II data of GVAX vaccine for acute myelogenous leukemia, showing the vaccine therapy is generally well tolerated and might reduce residual leukemic cells that persist after chemotherapy.
• Cell Therapeutics Inc., of Seattle, reported preliminary Phase II data of Xyotax in combination with carboplatin for first-line induction and single-agent maintenance therapy of advanced Stage III/IV ovarian cancer, showing that 98 percent of 82 patients achieved a major tumor response. Phase I data of weekly Xyotax given in combination with radiation for patients with esophageal and gastric cancer demonstrated that 36 percent of patients achieved a complete disappearance of their tumor. And two Phase III studies of Xyotax for first-line treatment of non-small-cell lung cancer patients with poor performance status 2 showed a 40 percent improvement in overall survival compared with vinorelbine, and similar rates as the current standard regimen of paclitaxel/carboplatin.
• Coley Pharmaceutical Group Inc., of Wellesley, Mass., said Phase II data of CPG 7909 combined with standard chemotherapy in the first-line treatment of advanced non-small-cell lung cancer showed an objective response rate of 37 percent, compared with 19 percent in patients who received chemotherapy alone.
• Cytogen Corp., of Princeton, N.J., said Phase II data of Quadramet in combination with docetaxel demonstrated good palliative effect lasting five months after the first treatment cycle when used in 30 patients with progressive hormone-refractory prostate cancer. The company also said that further data demonstrated how Quadramet in conjunction with chemotherapy, such as gemcitabine, to treat osteosarcoma might enhance anticancer activity.
• Cytokinetics Inc., of South San Francisco, and London-based GlaxoSmithKline plc, said interim results from a Phase I trial of SB-743921 showed the compound appeared to have an acceptable tolerability profile on the once-every-21-days schedule.
• Dendreon Corp., of Seattle, said Provenge improved survival in men with asymptomatic, metastatic androgen-independent prostate cancer when compared to patients receiving placebo.
• Genentech Inc., of South San Francisco, reported data from a joint interim analysis of two Phase III studies of Herceptin (trastuzumab) in early stage breast cancer. The studies showed that human epidermal growth factor receptor 2-positive breast cancer patients receiving Herceptin plus chemotherapy had a 52 percent reduction in the risk of disease recurrence compared to patients receiving chemotherapy alone. Separately, Genentech and F. Hoffmann-La Roche Ltd., of Basel, Switzerland, announced data from a Phase III study of Avastin (bevacizumab) plus paclitaxel and carboplatin chemotherapies in first-line non-squamous, non-small-cell lung cancer. The trial met its primary endpoint, with treated patients having a 30 percent improvement in overall survival, compared to those receiving chemotherapy alone. The companies also said a Phase III study of Avastin plus paclitaxel in first-line metastatic breast cancer met its primary endpoint, showing a doubling of survival time without cancer progression in patients receiving Avastin plus paclitaxel, compared with those receiving paclitaxel alone. With partner OSI Pharmaceuticals Inc., of Melville, N.Y., Genentech presented additional data from a randomized Phase III trial of Tarceva (erlotinib) used in combination with gemcitabine in advanced pancreatic cancer, demonstrating a 23.5 percent improvement in overall survival, compared with gemcitabine plus placebo, when used as a first-line treatment. Based on those data, the company recently submitted a supplemental new drug application. Finally, Genentech presented Phase II results of Omnitarg (pertuzumab), showing the compound had limited activity as a single agent in ovarian, breast and prostate cancers. The company plans to pursue further study in the ovarian cancer indication.
• Genta Inc., of Berkeley Heights, N.J., said long-term follow-up Phase III data of Genasense injection in patients with advanced malignant melanoma showed a significant increase in durable response (p=0.02) and a near-significant trend toward increased overall survival (p=0.077).
• GenVec Inc., of Gaithersburg, Md., reported encouraging findings from the dose-escalation portion of the Phase II trial of TNFerade in patients with locally advanced pancreatic cancer showing dose-dependent improvements in tumor shrinkage and resectability and in patient survival, as well as a decrease in the levels of tumor marker CA 19-9.
• GTx Inc., of Memphis, Tenn., said Acapodene was well tolerated in a Phase IIb study and significantly reduced the risk of prostate cancer by about 48 percent among men treated for a full year, compared to placebo.
• Hybridon Inc., of Cambridge, Mass., said Phase I results showed Imoxine was well tolerated and had immunopharmacological activity. Imoxine is in a Phase II single-agent study in patients with renal-cell carcinoma, and Hybridon plans to start a new Phase I/II study in non-small-cell lung cancer patients. The company also presented preclinical data on a class of synthetic agonists of TLR9 that induce high levels of interferon-alpha in human cell-based assays and animal studies in monkeys.
• ImClone Systems Inc. and Bristol-Myers Squibb Co., both of New York, reported results of several studies of Erbitux. One showed a 37 percent partial response in irinotecan-refractory metastatic colorectal cancer patients when Erbitux was used with Avastin and irinotecan. Another showed a 10 percent complete response and a 71 percent partial response in patients with non-resectable, EGFR-expressing metastatic colorectal cancer when treated with Erbitux and Folfox-4. The company is developing Erbitux with other targeted therapies in colorectal, lung, pancreatic and ovarian cancers.
• Immunicon Corp., of Huntingdon Valley, Pa., presented further data from its clinical trial in metastatic breast cancer and the significance of circulating tumor cells in "non-measurable" disease. It also presented data on the significance of CTCs in the blood of metastatic breast cancer patients undergoing treatment.
• Introgen Therapeutics Inc., of Austin, Texas, reported interim results of its Phase II trial in patients with advanced small-cell lung cancer previously treated with chemotherapy, showing that 67 percent of evaluable patients had objective responses to chemotherapy following INGN 225 treatment.
• Keryx Biopharmaceuticals Inc., of New York, said Phase II data demonstrated the tolerability and potential efficacy of KRX-0401 (perifosine) in the treatment of patients with biochemically recurrent hormone-sensitive prostate cancer. Of the evaluable patients, 82 percent had stable disease.
• Kosan Biosciences Inc., of Hayward, Calif., presented preliminary data from a Phase I trial of KOS-953, showing early signs of anticancer activity and tolerability in heavily pre-treated patients with relapsed or refractory multiple myeloma. Phase Ib trials of KOS-862 in combination with carboplatin and gemcitabine in patients with advanced solid tumors confirmed preclinical studies suggesting a clinical benefit, low potential for drug interactions and no overlapping toxicities.
• Ligand Pharmaceuticals Inc., of San Diego, reported data from two pivotal Phase III studies of Targretin (bexarotene) capsules in front-line combination therapy with standard chemotherapy to treat advanced non-small-cell lung cancer. The trials did not meet their endpoints of improved overall survival and projected two-year survival.
• Lorus Therapeutics Inc., of Toronto, presented an abstract on how Virulizin induces production of IL-17E to enhance antitumor activity by recruitment of eosinophils into tumors. Results from the Phase III trial of Virulizin in pancreatic cancer should be available by the end of the year. The company also said preliminary results of a clinical trial of GTI-2040 in combination with docetaxel in patients with non-small-cell lung cancer showed no dose-limiting toxicities.
• MedImmune Inc., of Gaithersburg, Md., said Phase II data of 112 patients with Stage IV metastatic melanoma showed a 12.7-month median survival for patients treated with Vitaxin alone, and a 9.4-month median survival of patients treated with Vitaxin plus dacarbazine. The current standard of care had a median survival of 7.9 months.
• MethylGene Inc., of Montreal, said Phase I data demonstrated the safety, tolerability, pharmacokinetic and pharmacodynamic properties of MGCD0103 in patients with advanced solid tumors and non-Hodgkin's lymphoma. The company also presented clinical and preclinical data for MG98, demonstrating a reduction in DNA methyltransferase mRNA.
• MGI Pharma Inc., of Minneapolis, and SuperGen Inc., of Dublin, Calif., presented data on Dacogen (decitabine) injection from a trial of three different dosing regimens and a Phase III study in patients with myelodysplastic syndromes. Dacogen demonstrated a 44 percent overall response rate in the first trial, and a 17 percent overall response rate in the MDS trial.
• Millennium Pharmaceuticals Inc., of Cambridge, Mass., announced positive results from studies of Velcade in lymphoma and lung cancer. Median survival had not been reached at 10.5 months in mantle-cell lymphoma patients, who demonstrated an overall response rate of 42 percent. Non-small-cell lung cancer patients receiving Velcade with or without docetaxel showed a response rate and overall survival comparable to approved agents. The company also said that Phase I/II prostate cancer results of MLN2704 showed four of six patients receiving a high dose achieved a reduction in prostate-specific antigen.
• NeoPharm Inc., of Lake Forest, Ill., said final Phase I data of LE-SN38 to treat advanced colorectal cancer showed that enzyme made in the liver, UGT1A1, plays a major role in metabolizing SN-38. The company also reported Phase I data of LEP-ETU in patients with advanced cancer showing an encouraging safety profile.
• Novacea Inc., of South San Francicso, presented results from the ASCENT study of DN-101 in combination with Taxotere vs. weekly Taxotere plus placebo in 250 advanced prostate cancer patients. Data demonstrated that prostate-specific antigen response occurred more frequently in patients receiving DN-101 plus Taxotere than those in the control group, but the difference was not statistically significant.
• OSI Pharmaceuticals Inc., of Melville, N.Y., said an analysis from the Tarceva registration study in non-small-cell lung cancer showed a greater, but not significant, survival benefit from Tarceva therapy in all subsets of patients whose tumors expressed EGFR protein and for those whose tumors possessed an abnormally high copy number of the EGFR gene.
• Oxford Biomedica plc, of Oxford, UK, said Phase II data of TroVax in colorectal cancer show that the maximum antibody levels targeted against the 5T4 tumor antigen are significantly higher than in the Phase I/II trial in post-chemotherapy patients. In the earlier study, there was a highly significant correlation between antibody titer and time to disease progression among responders.
• OxiGene Inc., of Waltham, Mass., said Combretastatin A4 Prodrug was well tolerated when combined with radiotherapy thus far in the Phase Ib portion of a planned Phase Ib/II combination trial in patients with advanced cancer.
• Pharmacyclics Inc., of Sunnyvale, Calif., presented data that validated the time to neurologic progression endpoint, which has been used in clinical trials evaluating Xcytrin (motexafin gadolinium) injection to treat lung cancer patients with brain metastases. Data showed that the procedures used to evaluate neurologic outcomes produced results consistent with other clinical benefit outcomes.
• PharmaMar SA, of Madrid, Spain, presented results from five clinical studies of Yondelis, including data that suggest the compound is effective in reducing PSA and alleviating pain in about 12 percent of men with advanced prostate cancer. Phase I data of Kahalalide F in solid tumors showed that a complete response was found in a patient with melanoma, and stable disease lasting for more than three months was seen in lung, colon and unknown origin adenocarcinoma patients.
• Pharmexa A/S, of Hoersholm, Denmark, said Phase I/II data in non-small-cell lung cancer showed that 214 doses of the peptide vaccine GV1001 were administered without any serious side effects, and an immune response was seen in 13 out of 24 evaluable patients completing four weeks or more of treatment.
• Point Therapeutics Inc., of Boston, reported positive interim results from Phase II single-agent and combination studies of talabostat in patients with Stage IV melanoma. Two patients had at least a 30 percent reduction in tumor size in response to talabostat, with one achieving a complete response.
• Pro-Pharmaceuticals Inc., of Newton, Mass., said Phase I data showed that Davanat and Davanat/5-FU are well tolerated in cancer patients with advanced solid tumors. The company initiated a Phase II trial in refractory colorectal cancer patients.
• Sanofi-Aventis Group, of Paris, said final results showed that gastric cancer patients who received a Taxotere injection with cisplatin and 5-fluorouracil had significantly improved overall survival rates compared to patients who received a standard treatment.
• Seattle Genetics Inc., of Bothell, Wash., said SGN-30 was well tolerated and demonstrated objective antitumor activity in systemic anaplastic large-cell lymphoma, while SGN-40 has shown evidence of biological activity in multiple myeloma.
• Sonus Pharmaceuticals Inc., of Bothell, Wash., presented results that showed a single 175-mg/m2 dose of Tocosol paclitaxel administered over 15 minutes delivered 67 percent more active paclitaxel into the circulation over time compared to an identical dose of Taxol given over three hours.
• SuperGen Inc., of Dublin, Calif., said results from a Phase III study indicated that pancreatic cancer patients with progressive disease following treatment with gemcitabine can benefit from Orathecin (rubitecan capsules), which can be taken at home with manageable toxicity.
• Therion Biologics Corp., of Cambridge, Mass., said Phase I data from two Panvac-VF studies for the targeted treatment of pancreatic cancer suggested that treatment is well tolerated and resulted in prolonged overall survival.
• Transgene SA, of Strasbourg, France, said Phase II prostate cancer data showed that in 63 percent of patients MVA-MUC1-IL2 induced a significant increase in the time the prostate-specific antigen takes to double.
• Vical Inc., of San Diego, said Phase II data of high-dose Allovectin-7 showed patients appeared to benefit from having at least two cycles of treatment. The data have helped in designing a Phase III trial for chemo-na ve patients with metastatic melanoma, who will receive the full 2-mg dose in a single lesion.
• Vion Pharmaceuticals Inc., of New Haven, Conn., reported data of Cloretazine, showing significant single-agent activity in previously untreated elderly patients with high-risk acute myelogenous leukemia and high-risk myelodysplasia.
• ViroLogic Inc., of South San Francisco, said data demonstrated the ability of its eTag Assay System to provide a direct measure of activated vascular endothelial growth factor receptor Type 2, and its effects on downstream signal transduction pathways in an in vitro model system.
• Viventia Biotech Inc., of Toronto, disclosed updated clinical data for its cancer therapeutic, Proxinium, showing the compound has a good safety profile and can produce encouraging efficacy results including a demonstrable survival benefit in patients with refractory head and neck cancer.
• ZymoGenetics Inc., of Seattle, said interleukin-21, administered in an outpatient setting, showed evidence of antitumor activity and was reasonably well tolerated with reverse toxicities in a Phase I trial.