NorthWest Biotherapeutics Inc (NWBO)

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Cel-Sci’s head and neck cancer study testing Multikine is an interesting comparison to the DCVax-L GBM trial. This seeking alpha author compares Multikine to the delay in results that took place with BMY’s Ipilimumab, describing the “delayed clinical effect”. The author does a good job of explaining what that “effect” is, and I think it sounds a lot like what’s happened in the L trial. You’ll notice that the author writes that a DMC could look at the unblinded data they see (and the DMC sees unblinded data every time they meet - it’s not just seen in a scheduled formal interim analysis), and because this “delayed clinical effect” doesn’t happen with the old treatments (with chemo, the good and bad effects are usually fairly immediate), they may incorrectly and prematurely determine that the trial is futile (and this determination may be heightened if any of the DMC are invested in a competing product, lol).

The Delayed Clinical Effect
What has been consistent and is now acknowledged by researchers is that immunotherapy can cause an immediate response, like quick tumor shrinkage. We saw that demonstrated in the Phase II Multikine trial. However, what is important to note is that most immunotherapies produce what is referred to as a "delayed clinical effect". This is an observation that was not observed or understood by researchers ten years ago.

Immunotherapies can produce an immediate response and also a delayed beneficial effect which does not show up until years later. Researchers are now acknowledging that the OS data from immunotherapies must be looked at differently. If we just use the standard Time-Driven method, then we miss the real benefit of the immunotherapy which can happen "years" after a trial is designed to end.

For example, imagine a three-year Time-Driven trial that utilizes a traditional six-month IDMC review for efficacy and futility. The IDMC may review the trial's early two- to three-year data and determine that there is significant tumor reduction. However, at that time, the data does not show any significant differences in the deaths occurring between the treated and the standard of care group.

Thus, it is conceivable that an IDMC could conclude "prematurely" that the trial is futile and end the trial. However, with the understanding of the "delayed clinical effect", the IDMC allows the trial to continue. The patients are continued to be followed beyond the initial study time for an additional one to two years. Then, the gap between the deaths occurring between the treated and the standard of care group widens significantly in favor of the treated group.

Patients who survive past the "inflection point" on the Kaplan-Meier curve experience an extended survival benefit compared to the standard of care group and could potentially be cured.

I believe this is what we are seeing with Multikine. I also believe that the fact that the trial has been ongoing for almost nine years will actually be a statistical advantage. The staggered patient enrollment over the years might be a blessing in disguise. Informed oncologist, doctors, IDMC and researchers are all now fully aware of the "delayed clinical effect" of immunotherapy and will allow trials to continue when taking this "delay" phenomenon into consideration.

We are now nearing the end of the ninth year of the trial. We believe the described "delayed clinical effect" is occurring in this Multikine trial: a decreasing event rate due to the “delayed clinical effect”. After nearly 9 years, and based on our analysis, we should only be waiting for just a few more events.

The author also makes a REALLY good point in the second paragraph listed here when he states,

The IDMC could potential unblind the study early. However, the question is, should they unblind and stop the study early? No! I believe they should let the study continue until the appropriate number of 298 is reached.
Why?

Because the secondary study measure is Progression-Free Survival ("PFS"). PFS is the length of time that the patient does not get worse during and after treatment. If the last death occurs on a patient who was in the Multikine-treated sample for three years, the results are different than if that last death patient had been in the Multikine-treated sample for eight years. That difference in time for that one patient makes a significant statistical % difference in the numeric evaluation of the difference of the Multikine and SOC curves.

You get it, right? If one person lives 8 years instead of 3 years, it can make a difference in the curve comparison, so imagine what those DCVax-L top 100 people’s numbers are ultimately doing to the comparison of curves. I explained the importance of those comparisons in my post #23704.


Anyhow, I think this article presents an interesting comparison to illustrate what might be happening, not only to Ipi, but to DCVax-L as well.

https://seekingalpha.com/article/4291092-cel-scis-multikine-trial-learning-bristol-myers-ipilimumab