Pharma Strategy Blog

It’s easy to forget that oncologists (whether medical, radiation or surgical) and hematologists deal with death and dying every single day, it’s sadly an integral part of the daily job.  Sometimes though, something comes along that offers hope or perhaps a glimmer of possibilities that life might be significantly extended beyond what is considered usual.

As a marketeer, I was also lucky enough to be a small part of one of those moments in the brief history of time.

Much of the data we see in oncology is about small incremental improvements – a few weeks here, a few months there.  We rarely hear about the stunning improvements of a several years though, because they mostly belong to rarer diseases, but occasionally something bigger than the sum of the parts comes along.

Way back in 1999 when I arrived in the US, I found myself in an empty office with a huge book (De Vita’s Principles and Practice of Oncology) on the desk and a list of about a dozen compounds and people associated with each project team.  One of those was an early phase I compound called STI571, which later became known as imatinib (Gleevec), a breakthrough treatment for chronic myeloid leukemia (CML).

People often ask what it’s like to be involved with new product development. The short answer is it’s a bit like a roller coaster – you have to learn to terminate the also-rans early and reinvest resources in more promising projects and of course, picking the winners from the losers is never as easy as it looks, as well as drive and motivate a diverse bunch of people so that great teams are formed.   It’s about quiet leadership, inspiring others to go above and beyond rather than rah rah management, which tends to be more about politics and self interest than anything else.  Basically, it means getting everyone on board, move the project forward expeditiously and navigate the challenges along the way and have some fun together as well, because:

1. you spend 12 hours a day in their company
2. you really want this to end well for patients
3. be a meaningful experience for all involved.

On bad days, fire drills for someone else’s urgent licensing project/evaluation may well derail you from your focused efforts.

On good days, you get to meet the physicians involved in the clinical trials, hear their stories, you meet real patients in the clinics and hear their stories too…  about hope, endurance, fear, the funerals they planned and the genuine wide eyed wonder of various test results that show the drug is working and they’re actually on the long road to recovery and getting their life back.  At that point, everyone cries, even the cynical curmudgeonly ones.

This is ultimately what many of us really live for in the Pharma industry – an opportunity to make a real difference to people’s lives and help them beat the odds.

With that background, you may all be wondering where I’m going with this post.  The answer is simple.  Last night I was checking out the latest Blood Journal online and spotted a paper from Tim Hughes and the International Randomized Study of Interferon and STI571 (IRIS) investigators.  It describes the latest update from the trial, which opened to accrual in early 2000, ten years ago.  I had goosebumps waiting for the article (see reference below) to load – an update a decade on from initiation of  a cancer trial? How many times do you hear about that in the news?  You don’t, typically.

What was the article about?

“This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients”

One of the most important measurements in CML is Major Molecular Response or MMR, which refers to the level of transcripts in the blood ie BCR-ABL is less than 0.1%. The lower the levels the better, due to a lowered leukemic burden and risk of relapse.

What does the data now tell us?

“Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time.”

In short:

“Patients with BCR-ABL transcripts >10% at 6 months and >1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years.”

Broader impact of this data:

Prior to the approval of Gleevec, people newly diagnosed with CML had maybe a typical lifespan of 3-4 years with interferon, longer with stem cell transplants, but with a high cost in terms of long term side effect management and maybe a year or less if unfortunately diagnosed with accelerated or blast crisis CML.  These days, the outlook is much better.  According to some of the investigators I’ve spoken to recently, a  few of the original patients who entered the accelerated phase trials in 1998/1999 are still alive, which is amazing when you consider it’s over 10 years on.  They’ve not only beaten the odds  but for many, they were able to live a fairly normal life, something none of us imagined in those days.  For newly diagnosed patients, the TKIs now means that 10 years (not weeks or months) extra life is a reasonable and realistic goal to aspire to.  For most people, there are also 3 excellent choices whereas before the choice of interferon or stem cell transplant was much starker.

This is the first time I’ve really been convinced by the data that there is compelling evidence for a strong association between the degree to which BCR-ABL transcript numbers are reduced by kinase therapy and long-term clinical outcome. This is something Tim Hughes has been raising for several years, with the idea that people who achieve a deep molecular response are more likely to sustain better long term outcomes. Before, it very much a theory or even a hope, now it’s reality.

This data also has a major impact on the second generation TKI’s, because both nilotinib (Tasigna) and dasatinib (Sprycel) have both been shown to be superior to imatinib in frontline (newly diagnosed) CML in terms of earlier and deeper responses.   Now,  we don’t have any long term survival data beyond 18 months to two years for either of the 2nd generation TKIs compared to 7 or 8 years survival data for Gleevec, but this new evidence suggests that attaining a sustained MMR is ultimately best for the long term health of people with CML.

In general efficacy terms, it’s like going from a drug that offers 90% response rates to ones that incrementally improve it to say, 93 or 94%, but the real impact is at the molecular level because if you can achieve an MMR, ie reach what Tim Hughes called the ‘safe haven’ at ASCO, you are less likely to relapse.  For the first time I can see that being a real advantage for the 2nd generation TKI’s over Gleevec, since the MMR data with the second generation TKI’s is superior to Gleevec.  That said, for people who are doing well on Gleevec and have attained a good molecular response, there is no reason to change.

The future:

There are also several other TKIs in development, including bosutinib (Pfizer) and ponatinib (Ariad).  Ponatinib is particularly exciting because it inhibits the rare T315I mutation, which none of the others do and is currently in phase II clinical trials.  This is one to watch out for in the future.

Either way, they’re all good drugs and I’m personally delighted to have been a smart part in the early development of one of them; it’s a privilege to have worked with some great investigators and as well as learning from many wonderful people dealing with cancer.

With this new data and scientific evidence, I can see the mantle is finally passing on to a new generation of therapies.  To have one great drug approved for CML that made a genuine difference is truly amazing, to have 3 approved is incredible and there a few more still in development.  For people living with CML, there is indeed Hope.

References:

Hughes, T., Hochhaus, A., Branford, S., Muller, M., Kaeda, J., Foroni, L., Druker, B., Guilhot, F., Larson, R., O’Brien, S., Rudoltz, M., Mone, M., Wehrle, E., Modur, V., Goldman, J., Radich, J., & , . (2010). Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS) Blood, 116 (19), 3758-3765 DOI: 10.1182/blood-2010-03-273979

Disclosures:

I’m a former employee of Novartis and worked on the early development and original launch of Gleevec in CML and GIST.  My opinions are my own, but I’m clearly biased by the incredible experience 🙂  Novartis has also been a client, but was not involved in any way with this post.

Author owns no shares in any of the companies mentioned.