If/when Cabo gets approval in differentiated thyroid cancer, it will be in post I-131 ablation setting. When you ablate the thyroid you will eventually need thyroid hormone replacement such as synthroid. Some endocrinologists will try to get the I-131 dose just right to avoid as long as possible, but in the end, patients inevitably become hypothyroid. Hypothyroid not an issue in post RIA therapy setting.
"The AE's make that unlikely in my mind. "
I agree, my interest in this topic comes from a scientific MOA point of view, not commercialization point of view. Even if a revelation that Cabo were to help with bone remodeling in Paget's, 70% of that population is asymptomatic.
"A search for "EFFECT OF CABOZANTINIB ON BONE METASTASIS" in quotes gives the IUPUI paper with quote:"
Thanks, I was looking for that paper. One also cannot r/o the possibility that higher bone mineral density may be a result of Cabo effect on osteoclasts rather than bone formation through osteoblasts.--- but I'm still having trouble fathoming benefit of Cabo in non tumor xenograph model.(I still believe any bone density benefit comes from resumption of normal bone growth upon tumor necrosis) Also pretty inconsistent from standpoint of weight loss. Another cabo xenograph paper had mice that were treated with Cabo looking unhealthy with weight loss over time. This breast cancer xenograph seems to contradict that other paper I'm thinking of.
"if you haven't yet seen them...the 3 Eva Corey (Univ of Wash) presentations are worthwhile, particularly the Abi, Enzalutamide, and Docetaxel preclinical combo work ups."
What struck me was that Abiraterone+Cabo in those Xenograph models didn't do so well with regards to OS in comparison to Enzalutamide and Docetaxel combinations with Cabo. Also, long term Cabo was equal to Cabo + combinations regarding OS. I'm thinking the later would not extrapolate to human studies.
Bone data in xenograph multiple myeloma looked interesting.
"The rise in serum IgG2b started earlier than vehicle control in both cabo-treated groups, but a significant difference was not observed in relative IgG2b at sacrifice. Cabozantinib dose dependently increased the necrotic tumor area in bone, indicating the possibility that the rise in IgG2b may have been due to lysis of plasma cells. Both cabozantinib doses decreased the frequency of soft tissue lesions. In summary, cabozantinib showed both bone-protective and anti-tumor effects in this murine model of MM. Based on these promising results, further investigation of cabozantinib in multiple myeloma is warranted. "
I'm wondering if lab work in Cabo MM is confounding. I'm hoping good or bad, we finally see some human MM workup at ASCO this year.
Below is breast cancer xenograph. I am a little surprised by the non-tumor bearing mice conclusions.(I seem to recall an exchange I had with wildbiftek) This particular study makes a clear distinction imho, that increased bone density occurred in non-tumor bearing cabo treated mice. Regardless of whether these results were to extrapolate to humans, I wouldn't get my hopes up on Cabo becoming an osteoporosis drug.
" In non-tumor bearing mice, bone mineral density (BMD) increased at the tibia with cabo 60 mg/kg (p
"It's unclear to me at present from the document you posted how close to the O'Brien-Fleming boundary Jevtana was"
Not clear to me either, but lets take a step back for a second.
Jevtana is a toxic drug in which IDMC required the trial to proceed to final analysis. Look at the first 3 months of Jevtana KM curves. Despite .70 HR at final, the first 3 months show a placebo benefit over control arm. Now look at Abby,Enzalutamide, and Xofigo safety profiles----all are not very toxic. Also look at Cabo EXAM experience in which the first OS interim displayed near 1 HR and the second interim displayed near .82 HR. Granted that was a higher dose in EXAM, but remember that COMET 1 is a much sicker population than that of EXAM or Jevtana TROPIC trial for that matter. Since Cabo is a toxic drug much like Jevtana, I suspect the HR may improve over time simulating both TROPIC and EXAM experience.-------Just thinking out loud---The committee probably was concerned with first 3 month OS placebo benefit in Jevtana TROPIC trial.
Here is the quote from APPLICATION NUMBER:
201023 on page 8
"The IDMC reviewed the OS interim analysis of 365 deaths in June 2009, did not express any
concerns regarding the safety on the 2 study treatment arms, and recommended that the trial
should continue to the final analysis. The study team remained blinded to the treatment allocation
and outcome throughout the trial."
Final HR was .7 in that study
"The pre specified interim analysis for Cabozantinib was only 387. Important to keep that in mind. For comparison Alpharadin 800+, Jevtana 1000+, Abiraterone 750+ etc."
Abiraterone interim was 500+ and I got the others wrong too. I am not so sure about the interim's for most of these drugs. I am really curious about Jevtana. I recall Ernie mentioning Jevtana. missing at interim.
"...although we have a much tougher population."
The pre specified interim analysis for Cabozantinib was only 387. Important to keep that in mind. For comparison Alpharadin 800+, Jevtana 1000+, Abiraterone 750+ etc.
" You look up any large platform company and Exelixis will likely have the larger cash burn"
meant to say small company large platform.
"The most legitimate claim those who question Morrissey have was the overcommit/underdeliver on getting an SPA for the Comet trials."
I am giving Morrissey the benefit of the doubt on this one. First of all, his predecessor was notorious for overpromise/underdeliver. I think the Morrissey mistake here was an extension of Scangos culture. (The only time I ever remember Scangos delivering on a commitment was the XL-184 partnership timeline with BMY) Being fairly new to new CEO positiion didn't help matters either. I think Morrissey learned a tough lesson here. You can tell he has learned his lesson of not overpromising/underdelivering. Especially when stakes much higher now than Scangos early stage development days. I am just wondering if we will get some underpromise/ overdeliver news eventually with Morrissey?
Morrissey takes the brunt of Exelixis's financial mess and I think some/most is unfair. Scangos didn't exactly leave him with a nice balance sheet. The financial woes of Exelixis under Scangos certainly differ from the likes of Regeneron for example. Regeneron and even Array pharma had large platforms and didn't bleed money like a stuffed pig in the way Exelixis always had. Under Morrissey, at least some of that was cleaned up. You look up any large platform company and Exelixis will likely have the larger cash burn.
Exelixis is one of the few to take on a large drug development program such as Cabozantinib without a partner, despite prior balance sheet issues. I commend Morrissey for what he has accomplished despite inheriting the unpleasantries from past culture. Granted Morrissey was part of that prior culture without being (the man) per say, but still.
Wasn't Scangos known more for deal making prowess? That said, Fran Heller may have had something to do with the larger XL184 and XL281 collaboration with Bristol and the PI3K collaboration with Sanofi. We can probably thank Scangos for favorable cobimetinib deal with Genentech.
If Scangos was at the helm, I think Cabo would have been partnered. Scangos always said that Exelixis could never develop XL184 on it's own. It wouldn't surprise me that there was some internal conflict on which direction to go with XL184 at some point before Scangos left.
" Is progression AR axis mediated. That thought takes us back to the rationale for Abi/Cabo and MDV/Cabo treatment."
Wilderguide had posted results of 18F-FDHT PET in cabo treated CRPC from ASCO 2013 awhile back. Very interesting to me that cabo interferes at the AR binding site.---I am perplexed that it doesn't correlate with serum PSA. (antiandrogen activity with FDHT doesn't either for that matter)----------Let me put this quote up again---"18F-FDHT, a ligand that targets the ligand-binding domain of AR, assesses receptor occupancy but not downstream activity."
The interesting thing is that FDHT uptake appears to correlate more directly with OS than other biomarkers. What I have seen with antiandrogens and cabo is that FDHT happens to be one of the more sensitive imaging biomarkers for demonstrating therapeutic benefit. Again, why is cabo and antiandrogen therapy have similar therapeutic affect on FDHT binding and such different effects on other imaging/lab biomarkers such as bone scan or PSA?
So with that I happen to agree with Wilderguide's quote "the hybridized multi-modality image work up of Cabo profiling makes sense." from a science perspective. Wilderguide loses me with how it makes sense from a regulatory perspective in Europe.---Only because I have no clue about regulatory impact of these imaging workups.
"No doubt in my mind that Cabo demineralizes bone in xenographs and human models."
should read demineralizes sclerotic bone met lesions
"Hbomb, have you any knowledge of this work-up?"
I haven't seen anything new of late. Who needs xenograph models for results in anatomical and diffusion weighted magnetic resonance imaging? The clinic has already demonstrated positive treatment effects in anatomical and diffusion weighted MRI for humans treated with Cabozantinib. The xenograph cabo treated models have already translated to humans in this regard.------------consistent data across the board pointing in the same direction. We know that Cabozantinib demineralizes metastatic bone lesions. Seems rather intuitive that necrotic tumor in bone would spur the return of blood flow and subsequent resumption of normal trabecular bone growth.-------I want to see what what confers Cabo resistance, and if the duration of benefit is good enough to produce stat sig positive COMET 1 results? No doubt in my mind that Cabo demineralizes bone in xenographs and human models. Who can really deny that at this point?
For example, volume and last price on different sites for YONG January 2016 $7 strike
48 and $.70 on yahoo options site
12 and $.65 on Nasdaq options site
The volume on my optionshouse option chain displays 0 volume, but I imagine it resets to 0 at market close. Under my account holdings section, it displays price at $.55.
So 3 different quotes on three different option chain sites. I was so happy with morningstar options chain because it appeared accurate. I didn't even mind that the quotes were delayed 20 minutes as long as they were accurate. That said, I would prefer real time quotes.
Anyone here no of a good place to get good free quotes on options. Morningstar used to have a good one, but for some reason took it away. I have an Optionshouse account, but it doesn't give me the last trade quote. I get the ask and bid on the tree, and am pretty annoyed that I can't get the last trade. I'm not too impressed with Optionshouse functionality in that regard. I own some long Jan 2016 calls on a security and I get some discrepancies between different sites on quoted prices and daily volumes.
Here is OncoGenex CEO quote
"Cormack says as many as 50 percent of men eligible for chemotherapy end up getting it, which he says translates to an addressable market of about 34,000 men in the U.S." This is for prechemo population that is due to read out any day now. Twitter talk from David Miller describes clinicians are very confident in positive results.
Here is the context from Luke Timmerman "OncoGenex Waits, and Waits, For Data on Prostate Cancer Drug" article that lead to CEO statement above
"One of the big risks for OncoGenex is that the other companies will make so much progress in the “pre-chemo” population, that there may not be that many patients left to sell to in the chemo population. Dendreon and Johnson & Johnson have shown in company-sponsored clinical trials that they both can extend lives by a median of about four months, and Medivation is positioning itself to possibly upstage both of those companies in that patient group. Plus, since many men with advanced prostate cancer either choose to forgo chemotherapy because of the side effects, or can’t take it because they’re too frail, it’s an open question how many patients would opt for the OncoGenex treatment in tandem with chemotherapy. Cormack says as many as 50 percent of men eligible for chemotherapy end up getting it, which he says translates to an addressable market of about 34,000 men in the U.S."
"The OncoGenex CEO happens to agree with me, despite having a phase 3 drug trial with docetaxel combination in prostate cancer."
Oddly enough, custirsen, SYNERGY prostate trial comparing custirsen+docetaxel vs docetaxel due any day now as well.
" I am only disappointed that Exel didn't do a trial vs Docetaxel.(possibly an Abiraterone/Enzalutamide arm included"
The Xofigo phase 3 Prostate design was brilliant. They allowed patients who refused Chemo and stratified. The brilliancy in this design is that Xofigo label isn't restricted to post chemo space. Unfortunately Exel had some bad advice on designing the trial post chemo for a drug that has obvious impact on bone metastasis.