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AVEO Pharmaceuticals, Inc. Message Board

  • biwinning63 biwinning63 May 21, 2013 8:54 PM Flag

    FDA approved Pazopanib with no US patients, crossover, and no positive OS...(repost)

    The reason the FDA recommendation is material, even though it was made at a point where there was incomplete data (percentage survival versus a longer OS on both arms), is that there is a risk when dealing with the FDA that when they make a recommendation, they expect you to comply even if it doesn’t make practical sense or they are proven wrong with additional data. In this case, outside of not disclosing the FDA recommendation, it is the FDA’s behavior, and not the company’s behavior that is questionable. If you go back and look at the FDA’s ODAC brief for Pazopanib approved in 2009, it was a single phase III done primarily in Eastern Europe with no US patients, it was compared against a PLACEBO, and its OS wasn’t significantly different than the PLACEBO arm, the PFS data has always been the standard to base approval not OS, that study and 6 out of the 8 RCC trials have cross over and if not, subsequent treatment. All the points the FDA or the ODAC panel raised at the Tivozanib meeting have been previously discounted to accept the other drugs. Tivozanib is as good or better than Pazopanib and the other VEGF inhibitors, it is an incremental improvement on the other VEGF inhibitors - thus there is next to no risk, and it is easier for the patient to take (the benefits clearly outweigh the risks) so the company had no rational reason to expect denial. This, along with the fact that the FDA accepted the NDA, and didn’t reject it within 60 days (which is what they are supposed to do if there is an issue with the trial) points to the FDA making an exception to the way it is treating AVEO and Tivozanib. My conclusion is that they are biased due to making the recommendation and can’t objectively analyze the data and the risk /reward. However, like good bureaucrats, they are technically correct that a second phase III trial is a standard for other drug approvals, they had made exceptions for the other 7 RCC drugs to only have one phase III trial, and it is within their sco

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    • You might mention that the OS for Paz was HR=.73, P=.02, yes that was not stat sig due to the fact it was just an interim peek, but still a sound trend. A hell of a lot better than trending the wrong way.

      If you are so enamored with formal trial stats that this does not count, why do you try and pull out the "censor x-overs" complete nonsense in another thread?

      Finally your argument that the accepted (not RTF'd) the NDA means they agree with it is childish. We here this all the time, "how can the FDA not approve if they ....". Easy, the standards for approval are far more stringent than accepting a submission.

      • 1 Reply to fib1_1_2_3_5
      • Do you guys not understand that it is not hard for a working drug to be statistically different from a sugar pill placebo or that its not a great accomplishment that you trend better than the sugar pill placebo but it is much harder to be different than an active drug, especially when your drug and the active drug are combined in the comparator arm, and there is a positive effect to combining them. Keep it simple and just compare the raw data in months, as the patient populations are similar. Tivozanib has better PFS and OS than pazopanib. If you approve pazonanib then, the risk benefit of Tivozanib is better, and it should have been a slam dunk. Either you made a mistake approving pazopanib, or you are making a mistake denying Tivozanib, its just that simple,(unless there is some fraud with the FDA)

    • From the ODAC on pazopanib in 2009-Background Summary: The randomized, placebo-controlled Phase 3 trial of pazopanib in advanced RCC showed a 5 month improvement in median PFS (HR 0.46 (0.34-0.62), without a statistically significant improvement in OS. The safety results showed an excess incidence of hepatotoxicity in addition to the occurrence of important adverse reactions known to VEGF inhibitors, including hypertension, hemorrhage, arterial thrombo- embolic events, and gastrointestinal perforation. It is also associated with torsades de pointes and a prolonged QTc interval. VOTE: Is the benefit-to-risk profile demonstrated for pazopanib acceptable for the treatment of patients with advanced RCC?
      Keep in mind that there are no US patients in this trial, it is being compared to a placebo so the PFS is only 9.2 months -less than sunitinabs 10.8 month (Tivozanib has 11.9 moths) and it has terrible toxic side effects not noted for Tivozanib. The only thing its got going for it is compared to placebo the HR is less than 1 for OS. Guess which one was approved? Go figure.

      • 1 Reply to biwinning63
      • And look ast the wonderful press release- only have to have EKGs on the drug...FDA NEWS RELEASE
        For Immediate Release: Oct. 19, 2009
        FDA Approves New Treatment for Advanced Form of Kidney Cancer
        The U.S. Food and Drug Administration today approved Votrient (pazopanib), the sixth drug to be approved for kidney cancer since 2005.

        Votrient is an oral medication that interferes with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.
        Votrient is intended for people with advanced renal cell carcinoma, a type of kidney cancer in which the cancerous cells are found in the lining of very small tubes (tubules) in the kidney. In 2009, approximately 49,000 people were diagnosed with renal cell carcinoma and 11,000 people died from the disease.
        “The last five years have seen dramatic improvements in treatment options for patients with kidney cancer. Before 2005, the options available offered only limited effectiveness,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.
        The five other drugs approved for kidney cancer and their approval dates are: Sorafenib (December 2005), Sunitinib (January 2006), Temsirolimus (May 2007), Everolimus (March 2009), and Bevacizumab (July 2009).
        The safety and effectiveness of Votrient was evaluated in a 435-patient study that examined a patient’s progression-free survival – the length of time, following enrollment in the study, before the tumor began growing again or before the patient died. Progression-free survival averaged 9.2 months for patients receiving Votrient compared to 4.2 months for patients who did not receive the drug.The most common adverse reactions (≥20%) were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. Grade 3/4 adverse reactions that differed by ≥2% between arms were abnormal hepatic The most common adverse reactions (≥20%) were diarrhea, hypertension, hair color changes, nausea,

    • My conclusion is that they are biased due to making the recommendation and can’t objectively analyze the data and the risk /reward. However, like good bureaucrats, they are technically correct that a second phase III trial is a standard for other drug approvals, they had made exceptions for the other 7 RCC drugs to only have one phase III trial, and it is within their scope of power to not grant the exception for Tivozanib. It all boils down to a bureaucrat wanting to prove he has authority at the expense of the patients’ interests.
      However, there may be an out to all this, if the FDA considers a label change/warning about OS sufficient and thinks it shows they still are in control. This is also why I think AVEO is floating the patient naïve data –which is what the typical US patient would be, and may be willing to change the label to include the naïve patient OS- which should favor Tivozanib over Sorafenib. The data that is unfavorable to Tivozanib is the poor prognosis and previously treated patients. If you are in the 15% that has low HIF, and based on current treatment, you are going to die quickly, you may do better by a few weeks on the other drugs. If you are in the other 85%, Tivozanib is your best shot -although rotating through other VEFG inhibitors or mTorrs after 12 months improves outcomes as does switching from them to Tivozanib as there is a resistance phase that is mitigated by subsequent therapies..

      • 1 Reply to biwinning63
      • regulatoryexpert@att.net regulatoryexpert May 22, 2013 12:26 PM Flag

        You are absolutely wrong!! You are trying to mislead the investors. When Pazopanib was approved in 2008, the RCC had very limited treatment options. Sutent was approved initially based on conditional approval (accelearted approval due to limited treatment options) and Sorafanib with full approval because they did randomized trial Vs placebo i.e. not single arm trial like Sutent (later Sutent converted to full approval based on randomized trial). Pazopanib already was conducting the trial then after submitting SPA (special protocol assessment) to FDA and after obtaining their feedback (which Aveo DID NOT DO).
        Tivo NDA was submitted when the market was saturated with 6 products available in the RCC market plus all the 6 products have already demonstrated clinical benefit with their Full approvals.
        Here is the accurate details below:
        • The approval of VOTRIENT was supported by a unanimous decision by the FDA's Oncology Drugs Advisory Committee (ODAC) that the benefit-to-risk profile for VOTRIENT is acceptable for patients with advanced kidney cancer. The ODAC reviewed data from a Phase III clinical trial showing that VOTRIENT reduced the risk of tumor progression or death by 54 percent compared to placebo, regardless of prior treatment.
        • In this Phase III trial, the overall median PFS was 9.2 months with pazopanib and 4.2 months with placebo. Treatment-naive patients who received VOTRIENT experienced 11.1 months of median progression-free survival (PFS) versus 2.8 months with placebo. Additionally, patients who had previously received cytokine-based treatment achieved 7.4 months of median PFS with VOTRIENT versus 4.2 months with placebo
        • The most common adverse events occurring in greater than or equal to 20% of subjects treated with VOTRIENT included diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. Grade 3/4 adverse events among these toxicities that differed by greater than or equal to 2% included abnormal liver function, hypertension

 
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