Closer to Approval for CLL? Ibrutinib Receives a Third Breakthrough Designation from the FDA for 17p deleted Patients

Here is the first part of the official press release on the third breakthrough designation for ibrutinib. This one is close to home.

The news is important, not only because it means there is another reason to believe the wonder pills will be in drug store near you next year some time, but because insurance, at least at first, will likely only pay for the designated indications, without putting up a fight.

The good news is however limited in its scope. It is only for CLL/SLL with 17p del. I don't know if the percentage of the cells that lack the short (think p for petit) arm of their 17th chromosome has been defined that will be needed to qualify. We know that 17p del tends to play more nicely at lower percentages. Not sure if the FDA gets down to that level of detail and I hope they leave that decision to a discussion between us and our doctors, as we do now when considering therapy.

What we do know is that this does not mean breakthrough designation for all of us with CLL. At least not yet.

Will it be used off label for others with CLL? Most cancer drugs are and one that in the studies so far appears to be as safe and efficacious as ibrutinib should be no exception. Who pays will be the bigger issues.

On a personal note, as one with small population of 17p deleted CLL cells, this is particularly good news, as I would have an option should my trial close or I need to leave it.

SUNNYVALE, Calif., April 8, 2013 /PRNewswire/ -- Pharmacyclics, Inc. (PCYC) announced today that the U.S. Food and Drug Administration(FDA) has granted an additional Breakthrough Therapy Designation for the investigational oral agent ibrutinib as monotherapy for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients with deletion of the short arm of chromosome 17 (deletion 17p). Patients harboring a deletion within chromosome 17 generally have poor response to chemoimmunotherapy and have limited treatment options. The presence of deletion 17p is one of the worst prognostic factors in patients with CLL.

In February 2013, FDA granted Breakthrough Therapy Designations for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) and as a monotherapy for the treatment of patients with Waldenstrom's macroglobulinemia (WM), both of which are also B-cell malignancies. Ibrutinib is jointly being developed by Pharmacyclics and Janssen for treatment of B-cell malignancies.

The Breakthrough Therapy Designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases where "preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development." The designation of a drug as a Breakthrough Therapy was enacted as part of the 2012 Food and Drug Administration Safety and Innovation Act. Pharmacyclics, together with Janssen, is working with the FDA to determine the implications of this Breakthrough Therapy Designation to the ongoing and planned development and the FDA filing requirements for the use of ibrutinib in CLL patients with deletion 17p.

The FDA Breakthrough Therapy Designation for ibrutinib in CLL patients with deletion 17p was based on data from pre-clinical and clinical studies where ibrutinib as a monotherapy was used to treat patients with this disease. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease which has a poor prognosis. In addition, Pharmacyclics and Janssen have recently initiated a Phase II study of ibrutinib in patients with CLL deletion 17p, RESONATE" -17, which is a single-arm, open-label, multi-center trial using ibrutinib as a monotherapy in patients who have deletion 17p and who did not respond to or relapsed after at least one prior CLL treatment (a high unmet need population). The primary endpoint of the study will be overall response rate. This global study opened this year and Pharmacyclics plans to enroll 111 patients worldwide.

What do Designer T cells mean to you and me?

The breakthrough in genetic engineering that lead to two of three patients with bad CLL getting a clean bill of health has generated world wide excitement, with good reason.

It's dramatic, it's a first, it's not chemo, it's mostly drug and big pharma money free , it's a doable technology for CLL that has possible applications for any cancer that can be recognized by its protein markers that protrude from their cell wall (in this case CD19), and it's still working a year later.

My bet is there will be a lot of money to move beyond this proof of concept to phase 1 trials, both at U Penn and other eager centers that can make the requisite designer genes.

That is mostly companies like Amgen and Genentech and a million start-ups, and universities, and big cancer centers such as MDACC, UCSD, Stanford, Dana-Faber, and others.

My bet is that these trials will not be hitting the local oncologists office anytime soon.

My bet is that the demand for this will outstrip the number of openings. It is a very personalized, hands on, and expensive therapy. My T cells won't work for you and vice versa.

My bet is that dosing will be critical as always in Phase 1 trials, but even more so here, where we know we have a very big bomb that can have quite a long fuse. Remember that the onset of the tumor lysis syndrome (TLS), the state where there is a very rapid and dangerous amount of cancer killed in a short time exceeding the kidneys' ability to handle all the debris, was quite delayed in the U Penn trial. Too high a cell dose, and the unpredictable TLS can kill you, too little, and the response is too feeble and the cancer continues to grow.

My bet is that choosing the right target is also critical. CD19, the target in the U Penn trial, is found on all B cells and its precursors, so this therapy wipes out nearly the entire immune army that produces antibodies. Does that mean you are cured of cancer, but may be at risk of dying from measles or chickenpox as the oldest soldiers (the memory cells) die off? We don't know, yet.

Are other targets better and more selective? Will they work as well without the immune risks? Again, that's what trials are all about- to answer these questions.

So what does this all mean to those of us with CLL?

Here's my best case scenario.

It means nothing today.

But I bet (when you have cancer you are always making bets with less than perfect knowledge), that in less than a year we will have limited opportunities to enter phase 1 trials on new iterations of the designer T cell therapies. This is too good a result and way too much fun for the MD/PHDs not to tinker with creating new cells to not work its way through the IRB committees quickly. Most trials will they likely be small and be restricted at first to those at the end of the present therapeutic rope, but as experience and safety data grows, in three years or so, bigger phase 1/11 trials now with pharma money may open for those looking at earlier or even front line therapy.

If all goes great, and and this is a big if, they can find a way to pay for this, we could have a new revolutionary treatment option in less than ten years. Maybe even seven or if a prominent senator is diagnosed with aggressive CLL, five.

That's the Cinderella story. The perfect fitting glass slipper and the lucky girl living happily thereafter.

But it won't be easy choosing what size or design is best, which virus is the safest to do the heavy lifting (the U Penn people used an HIV like virus with its reproduction genes disabled), what cancer center is best ready to handle possible TLS weeks out, what dose of T cells, what chemo if any is needed to clear the table before the gene therapy can begin, and a thousand other unknown unknowns.

So again for us patients, the trick is to stay alive, try to keep our powder dry by avoiding therapies that damage the marrow or immune system as long as possible, keep our ears to the ground for new research, assess whether we really need to do anything so don't get caught up in the hype and pressure and worry that we might miss the boat if we don't jump at this, and if we do need therapy, is what is available in a gene trial therapy the best choice?

The good news is that when we do need therapy, the choices are getting both better and tougher.

The devil we know such a FCR or Revlimid or Bendamustine or HSCT, or the devil that we are just getting to know such as the new small molecules such as CAL101, PCI 32765, ABT99 and more and more sharply focused cancer pathway blockades, or the completely unknown devil with his great promise, the new very sexy new kid in town - designer T cell therapy?

An exciting time for sure. I love these possibilities, but that is what they are possibilities. But so was Gleevec at one time.

For me, I am nervous about jumping too fast until I see more data, especially long term safety data. I am frightened that I will be, as Leonard Cohen said, "torn by what I have done and can't undo." Still the appeal is undeniable- the benefits of an allogenic transplant with much of the downside taken out of the equation.

So I plan to stay alive and follow my own advice given above.

But first I am going fishing in Missouri. And I don't even eat fish.

A major breakthrough in CLL therapy. There's a new serial killer in town.

They did it, they got the benefits of an allogenic transplant, namely a new population of T cells that alert the immune system in an ongoing way to search and destroy the cancerous B cells. A transplant sans transplant. The benefits without many of the most horrific risks.

Here's a link to a VIDEO that tells the story.

These T cells have been changed with the insertion of new genetic information by infection outside the body with an HIV type retrovirus that, when they are put back into the same patient, gives them the ability to recognize and attach to the CLL cells, to arouse a very robust inflammatory response (read that they initiate a killing frenzy of both cancerous and good B cells and its precursors), and most importantly to proliferate and stay around for at least a year.

Am I encouraged? You bet.

This has the potential to change everything. This has the real potential to cure CLL.

But at this point it all still potential and conjecture, and all therapies look great when they are brand new. There are may unknowns and concerns. Still, it is an exciting time to be a CLL patient.

More soon on what I think this means for anyone with CLL in general and for me in particular.

In the meantime, I am rooting for these new cops, this new "007" secret agents with their license to kill.

And all this was done with no pharma money!

Anyway you look at it, this is very good news.