Can someone walk me through the rationale for approval of Bexxar at this time. The following are some random thoughts. Coulter took a high risk non traditional path to seek approval by conducting a single arm uncontrolled study. Zevelin going after the exact same indication was approved based on the data of two studies one of which was controlled, monotherapy rituxan.
If one looks at the control arm of the zevelin study (monotherapy rituxan) it showed the same response rate as bexxar in the meta analysis to be presented at ASH with a higher complete response rate. Very small numbers in the complete response rate group.
The Bexxar pivotal study was completed in the 98-99 time frame. The standard of care for NHL has changed immensely since then rendering the data not relevant given todays tx paradigm.
The end point of the single arm 60 pt uncontrolled study was duration of response compared to response to prior chemotherapy. That is no longer relevant given the current use of rituxan as "maintenance therapy" where susequent response can be of longer duration than the prior duration of response.
In the composite meta analysis of 250 pts from 5 uncontrolled studies there are too few patients in too many groups. What i refer to here is the following. Pts were exposed to two diff doses (.3 or .4mCi/kg) based on two separate factors, bone marrow involvement (greater or less than 25%)and platelet counts (greater or less than 100/ul. The point is there are too few pts and too many variables to adequately inform physicians on the "best" patients for the drug and the safest use of the drug.
Intermediate and long term safety is a significant question question given the small number of pts that have been tx for the anticipated label. (remember alot of the clinical experience with Bexxar is from the front line setting, not the refractory indication they are seeking from the FDA)The specific concern in MDS (myelodysplastic syndrome) and secondary leukemias. There have been sevaral of these as a result of Bexxar exposure.
Least important but not irelevant is the history of this drug at the FDA. The FDA has had years to approve this drug if they felt it was an important addition to the care of the NHL patient.
any thoughts on the above?
If the safety data for 76 chemo naive patients is 100% clean, and for 600+ chemo teated patients it is identical for Bexxar and control group, what do you see as a safety issue here?
and if GSK had an opportunity to walk away scot-free since 05/02 but continued to participate, to me shows they'd like to have the product.
In reponse to the prior post, at the risk of being redundant, the data in 76 chemo naive pts is not relevant to the label that bexxar is going in front of ODAC for. They are seeking approval in the same pt population that Zevelin was approved for, tx refractory NHL or transformed histology. Safety or efficacy in the front line setting is not relevant.
Regarding the second paragraph this drug will never be meaningful to GSK economically. They inherited this in the SK acquisition. The term of the original contract "expired" around may of 02 as a result of the failure of Coulter, and now Corixa to get Bexxar approved. Now at any time glaxo can walk away from this drug with no financial tail. Much like they already chose to do in Europe.
<<Zevelin is an easier drug to administer and it is struggling in the market despite having a first mover advantage. >>
I did a double-take when I read that and then I realized that you must have meant zev vs. rit, not zev vs. bexx. The nice thing about bexx is the longer half-life of the isotope. Of course, it's a moot point unless the drug gets approved, but I think it will be a factor if bexx gets on the market.
<<Spoke to some additional physicians here at ASH regarding the comparison of secondary malignancies with Bexxar vs historic controls. Point was made that in the era of rituxan the historic control data is no longer relevant. Pts do not recieve the same total cumulative doses of alkylating agents now that they did in the past (prior to rituxan).>> True... and the experience of 76 chemo-untreated Bexxar patients shows it:
<<In contrast, there have been no reported cases of tMDS/tAML in 76 previously untreated pts with 2.7 yrs median follow-up.>>
<<I and many others here at ASH are of the opinion that they need to do a controlled study, using a fixed dose, likely .3mCi/kg, appropriate exclusion (>25% marrow involvement), and inclusion (plt ct >100k/ul)then the data could speak for itself.>> Many is - like 3? 4? I am of extremely high opinion of GSK oncology people, they would have sponsored a relatively small trial you are talking about if there ever would be a justified doubt about data quality.
Your right there is a new sheriff in town at the FDA and the first "action" from the FDA under the new sheriff was a rejection of the FRX drug Lercanidipine despite beeing approved and available in over 60 countries. Many of your prior posts (old abstracts) are not relevant becasue they are from a diff era in the mgmt of NHL. The one thing we do agree on is that Bexxar has activity, no question about it. We have known this since the trials were completed in 1999. I and many others here at ASH are of the opinion that they need to do a controlled study, using a fixed dose, likely .3mCi/kg, appropriate exclusion (>25% marrow involvement), and inclusion (plt ct >100k/ul)then the data could speak for itself. Spoke to some additional physicians here at ASH regarding the comparison of secondary malignancies with Bexxar vs historic controls. Point was made that in the era of rituxan the historic control data is no longer relevant. Pts do not recieve the same total cumulative doses of alkylating agents now that they did in the past (prior to rituxan). No need to get angry at me, and resort to name calling, debate the data.
Nope; There's a new sheriff in town. Bull
Go Billy Tauzin
I know who u r bitch.
You've yet to address the difference in CR following Rit/non-respond/refract. Rit is a great drug but only as good as it's "molecular claw" ie affinity for CD20. Sure Zev may be easier but is that what you'd want?
Show us some "harderdata2002" as to why I would rather have Zev when Rit fails. MDS/hypothyroidism (give me a break) this drug can save lives when noneother can.
You're full of
Bex 25%/Zev 0%
Results of Four ZEVALIN Clinical Studies Presented At ASH.
Issue: Dec 6, 1999
NEW ORLEANS--(BW HealthWire)--Dec. 6, 1999--
ZEVALIN in NHL Patients Previously Treated with Rituxan
Leo I. Gordon, M.D. of the Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL, authored a poster presentation of interim results of a non-randomized controlled, open-label Phase III trial evaluating the safety and efficacy of ZEVALIN in follicular NHL patients who are refractory to Rituxan, i.e., who did not achieve a response or had a time to progression (TTP) of less than six months with the most recent course of Rituxan.
The interim overall response rate was 46 percent with all responders achieving a partial response. Eighty percent of these patients had sizeable tumors (greater than 5cm in single diameter) and 76 percent were chemotherapy-resistant.
No mention of CR
If the FDA asks for additional studies it is likely that Glaxo will walk away from this drug, even if it gets approved there will be no meaningful market for it. Zevelin is an easier drug to administer and it is struggling in the market despite having a first mover advantage. CRXA has perhaps two years of cash assuming that they dont have to do additional studies.
I am very familiar with the abstracts posted by one of the optimists on the board. The problem is that most of those abstracts are not relevant to the pivotal trial or to the label that CRXA is seeking for Bexxar. Activity in the front line setting is not relevant, a data dredging to pull out the transformed pts from multiple studies is not directly relevant, etc.
The interesting abstract is the one that looks at the incidence of MDS and secondary leukemias in the tx refractory NHL pt and compares that with what has been seen with Bexxar. This was discussed in detail recently at the "International Society for Biological Therapy of Cancer" mtg. The "concern" is that the incidence of these secondary malignancies is shifted forward, sooner after completion of therapy, with Bexxar than has been seen after multiple exposures to cytotoxic chemotherapy. There appears to be a spike up about 1 year after Bexxar exposure, where in the historic controls looked at they would appear at a later time point. This is important because regardless of why a patient develops a secondary malignancy they are generally treatment refractory.
So to answer the question "do i think i am smarter than the authors", the answer is no, but i speak with them and their peers to better understand the data. It is also important to keep in mind that Dr. Kaminski has a large financial interest in the success of this drug.
crxa was going to panel against the wishes of the FDA regardless of the change to active status of the application. The change to active status is a "non event", the panel had been set weeks before the change. Likely nothing more than horse trading prior to the inevitable panel. Keep in mind there is no new data, no new trial, just more interpretation of an outdated trial design from the mid 90's that was completed in 98/99. If you read the "Guidelines for dispute resolution above the division level" it states clearly that no additional data can be provided. The drug has activity, it is just not clear that they adequately demonstrated the risk/benefit. keep in mind c225 from imclone had activity. MAXM's maxamine was sent to panel for a public execution, don't over interpret an FDA panel being scheduled.