The Proof is in the Science..Is Bristol Myer Squibb missing the Boat?So why is Bristol Myer Squibb going to commercialize Ipilimumab at 3mg/Kg instead of 10 mg/kg?Could it be possible that BMS is looking to add a Maintenance phase to the therapy? Or is it because of the high 3-4 adverse effects at the higher dosage?
FindingsThe best overall response rate was 11•1% (95% CI 4•9—20•7) for 10 mg/kg, 4•2% (0•9—11•7) for 3 mg/kg, and 0% (0•0—4•9) for 0•3 mg/kg (p=0•0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0•3 mg/kg, respectively; the most common grade 3—4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0•3 mg/kg group) and diarrhea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0•3 mg/kg group).
InterpretationIpilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.
FundingBristol-Myers SquibbSource: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70334-1/abstract
Elliott Sigal said in the Bristol-Myers Squibb Q1 2010 Earnings Call “We do plan to commercialize the 3-milligram dose and the indication that I mentioned.”
So with that, there may be a problem with dose being to low. Based on the information that I have obtained, 3mg/ Kg may be to low to block all the CTLA-4/B-7 receptors on the T-cells. Cells known to express CTLA-4 include activated CD4+ and CD8+ T cells, and B cells.
So if you don’t activate the T-cells, the CTLA-4 receptor is not up-regulated and the Ipilimumab is not tied up. That is why we see excess Ipilimumab at low concentrations.
What we want to look at is the maximum delta (change between) time intervals. If the T-cells are activated, then the delta would be greater than the half-life of the Ipilimumab.
It has been noted that we need at least 10ug/ml in the serum Ipilimumab to block all the CTLA-4 receptors. With that in mind we need to take into account the drug’s half life and we must also take into account the T-cells expansion over time of the Activation.
So we need to start out with enough Ipilimumab to last through the T-cell expansion and activation.
With that in mind, we should start at 0 to 33 days. That is the time the CD4+ T-cells need to reach maximum propagation.
We should also look at the interval of 33 to 64 days. That is the time frame when the CD8+ T-cells are at their maximum expansion.
The 0.1 and 0.33 mg/kg are to low to complete the 33 day interval. This means those two points are substrate limited.
(Not enough Ipilimumab)The mean ± SD MDX-CTLA4-01 terminal elimination half-life was 299.4 ± 126.9 h (12.475 days).
12.5+/-5.3 days is the elimination Half Life of the Ipilimumab
Source: http://clincancerres.aacrjournals.org/content/13/6/1810.full
Adaptive from A. Bashey
At 1536 hours or 64 days at 3mg/kg, there is still some anti-CTLA-4 in the blood system, but it is far below 10 ug/ml level
According to the research, you need at least 10 ug/ml to saturate all the CTLA-4 receptors in host’s body. Base on the work research done by Bashey et al, 3 mg/kg dose of Ipilimumab will only get you to about 4ug/ml in the host’s serum. 3mg/kg of Ipilimumab falls short of blocking all the CTLA-4 receptors. This is why I believe that this is one of the reasons for such a low response rate.
By back calculating from day 64, and using the half-life of 12.5 days, one would need at least 9.6 mg/kg to block all the CTLA-4/B-7 pairs. But does this take into the account of the expanding and activated T-cells?
Dr. Jedd Wolchok did a dose concentration experiment and determined that 10mg/kg of Ipilimumab gave the best response rates.
But the new dose concentration 10 to 15 mg/kg used, so there is 3 to 4 times amount of Anti-CTLA-4 in the serum which means at 64 days into the activation of T-cells, there should be enough anti-CTLA-4 antibodies to block the newly upregulated CTLA-4 receptors of the expanded CD4 and CD8 T-cells and Tregs, not to mention the B-cells.
Elliott Sigal
“Yes, Jami. Let me address the comment. I would not call 020 not pivotal. It wasn't pivotal in our thinking years ago. And as a result of conversations with health authorities, and this is why we do this, we decide what is an appropriate indication on file for and do we have data to enable a review. Of Phase III study, that's survival with ipilimumab that does compare against an experimental vaccine in previously treated patients. We consider pivotal to the indication of metastatic melanoma in previously treated patients, where there is no standard of care and therefore we feel it's appropriate standard of care is often experimental regimen to compare with the well-characterized experimental treatment and we chose the vaccine. We have an adequate study to check the contribution of ipi alone as well as ipi in combination with the vaccine. We do not to commercialize the vaccine. We do plan to commercialize the 3-milligram dose and the indication that I mentioned. The old 24 first-line study is a different patient population and a different regiments. And when that data becomes available, we hope to provide enough information from that study to talk about an expanded indication for the drug.”
Source: http://seekingalpha.com/article/201918-bristol-myers-squibb-q1-2010-earnings-call-transcript?page=9
Conclusion: 3mg/kg of Ipilimumab is to low in my opinion to produce the response rates that the patients are looking for. We desperately need the dose range between 10 to 15 mg/kg to get more complete responses. We need to suppress the Treg function and keep the T-cells activated longer.
The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2
Take Care,
Jimmy B
