Pretty please, cherry on top..

We really, really need this drug.  I hope the FDA approves it in short order.  If not, I will be coming back to you for getting mobilized and pull off a massive letter writing campaign.  Below are the comments I intend to make before the FDA panel on May 29th.  Sorry if I sound a little stuffy and pompous - my audience this time is different than the usual rag-tag CLL patient crowd I hang out with.

I do not know if they will ask me any questions, I hope they do.  Trust me, I am loaded for bear!  If you have any drop dead comments or suggestions for changes do let me know.  Otherwise, keep your fingers, eyes and toes crossed for all of us.  I will report on how things went after I get back home.


Good morning ladies and gentlemen. Please allow me to introduce myself.

My name is Chaya Venkat.  I am the Founder and President of CLL Topics Inc, an internet based organization dedicated to education and advocacy of CLL patients.  With all humility but no exaggeration I can say there are very few CLL patients who have access to the internet and who can read English that have not heard of CLL Topics. 

Today I speak before you on behalf of thousands of our members in this country and around the world who are anxiously following your deliberations.  For the record, neither I nor my organization has any financial ties to any drug company. I have paid out of my own pocket for the opportunity to speak before you.

An unmet need

The day of targeted monoclonal therapy is tantalizingly close - but not quite there yet for CLL patients.  Both Rituxan and Campath have major weaknesses when used as single agents.  Ofatumumab represents a valuable option for patients stricken with this incurable cancer. I would like to share with you how patients see this drug fitting into their therapy options. 

The FDA has recently approved Campath as a frontline drug in the treatment of CLL.  Campath is undeniably powerful - except in patients with bulky disease, when it is contraindicated.

There is another very good reason why patients are leery about initiating Campath therapy early in the ball game.  In addition to killing B-cells, Campath is also very good at demolishing T-cell counts.  As researchers at the Karolinska  Institute have demonstrated 1, many T-cell subsets remain a small fraction of their pre-therapy levels for many months.  During this period of T-cell deficiency and long lasting neutropenia, patients are only too aware that they are dangerously vulnerable to opportunistic infections and even secondary cancers. 

I realize Rituxan has not formally been approved as frontline or single agent therapy in CLL.  But I am sure this panel is aware that many patients and their physicians currently use it in that setting - for lack of a better monoclonal antibody.

Unfortunately, as shown in an important paper out of M. D. Anderson 2, single agent Rituxan has very limited activity even in chemo naïve patients and at massive doses.  In patients who have been around the chemo block more than once, single agent Rituxan is next to useless.  Response rates are often in the single digits, and most of them are a partial response at best.

The Goldilocks scenario

Bottom line, looking at it from a Goldilocks perspective, Rituxan does not have enough oomph as a single agent, and Campath has almost too much killing power - or should I say too much poorly targeted killing power.  We desperately need a new monoclonal antibody drug that has the admirable lineage specificity of an anti-CD20 monoclonal such as Rituxan, but one with increased killing power of a Campath - without unacceptable collateral damage of multiple bystander cell lines getting killed.  Results of the clinical trial under discussion here suggest ofatumumab represent the golden mean we need badly.

Fludarabine refractory patients

The situation is bleak for patients who have relapsed after fludarabine containing therapy.  The words “fludarabine refractory” are ominous indeed, reflecting as they do fewer therapy options, poorer response and scary survival statistics.  CLL is definitely not a “good cancer” for these folks.

A recent M. D. Anderson paper 3 reported on the outcome of salvage treatment for patients who are fludarabine-refractory and are either refractory to alemtuzumab or ineligible for alemtuzumab due to bulky disease. Early death (within 8 weeks of commencing first salvage) occurred in 13% of patients, and 54% of patients experienced a major infection during therapy. Overall median survival was 9 months. Gentlemen, these are grim statistics.

Ofatumumab in fludarabine and Campath refractory patients

The new drug application before you looks at exactly this tough to treat patient population.  While this ofatumumab study 4 is a single arm study, there is little doubt how poorly this patient cohort would have fared with, say, single agent Rituxan as control arm.

In stark contrast to all other salvage therapy options reported in the MDA paper 3, roughly 50% of these patients treated with single agent ofatumumab managed to get a decent response. Early death occurred in 3 to 4% of the patients, much smaller than the 13% quoted in the MDA study. 

These are not just dry statistics, each percentage point represents living breathing patients. Median survival of 14-15 months after ofatumumab (compared to 6 months reported in the MDA paper for other monoclonal salvage options) means a beloved spouse or parent who is around for another 9 months - a very big thing for the families involved. I know what this means at a very personal level:  my husband gained a precious couple of years of life due to ofatumumab therapy, giving cord blood stem cell transplants a chance to come up the learning curve. Two years earlier his chances of surviving a cord blood transplant would have been that much poorer.

I will not venture into why ofatumumab seems to work better, I will leave it to the experts among you. Whatever the reason, it is clear to our members that ofatumumab represents a next generation breakthrough anti-CD20 monoclonal drug that is desperately needed by CLL patients.  Its performance as a single agent is impressive, even in tough salvage cases, but even more important will be its contribution to chemoimmunotherapy combinations down the road.  For patients like my husband that develop serious hyper-sensitivity to chimeric Rituxan, this fully humanized monoclonal antibody is a godsend.

I would like to leave you with one additional thought.  As consumers of healthcare all of us are aware of the cost of modern drugs.  Rituxan costs an arm and a leg — and other body parts if the patient has no health insurance.  Common sense tells me that having two anti-CD20 monoclonal drugs in the market place is a good thing.  Competition has a salutary effect on pricing and product improvements. It is time we got a little competition going here. 

On behalf of thousands of CLL patients I urge you to approve this new drug application.  Please give our members access to ofatumumab.  Our very lives depend on it.

Thank you for your time. I will be happy to answer any questions.

References:

1. Leukemia. 2004 Mar;18(3):484-90.

Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia.

Lundin J, Porwit-MacDonald A, Rossmann ED, Karlsson C, Edman P, Rezvany MR, Kimby E, Osterborg A, Mellstedt H.

Department of Haematology, Karolinska Hospital, Stockholm, Sweden.

 

2. J Clin Oncol. 2001 Apr 15;19(8):2165-70.

Rituximab dose-escalation trial in chronic lymphocytic leukemia.

O’Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, Lerner S, Keating MJ.

Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston 77030-4009, USA.

 

3. Leuk Lymphoma. 2007 Oct;48(10):1931-9.

The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy.

Tam CS, O’brien S, Lerner S, Khouri I, Ferrajoli A, Faderl S, Browning M, Tsimberidou AM, Kantarjian H, Wierda WG

Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston 77030-4009, USA.

 

4. ASH 2008, Paper 328

Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of An International Pivotal Trial

Anders Osterborg, MD, PhD1, Thomas J. Kipps, MD, PhD2, Jiri Mayer, MD3, Stephan Stilgenbauer, Prof., Dr., med4, Catherine D Williams, MBBS, MRCP, FRCPath5*, Andrzej Hellmen, MD, PhD6*, Tadeusz Robak, MD, PhD7, Richard R Furman, MD8, Peter Hillmen, MBChB, PhD9, Marek Trneny, MD, PhD10, Martin J.S. Dyer, MA, DPhil, FRCP11, Swaminathan Padmanabhan, MD, MBBS12, Tomas Kozak, MD, PhD13*, Geoffrey Chan, MD14*, Randy L Davis, DrPH15*, Nedjad Losic, MSc16*, Charlotte A. Russell, MD, DMSC16, Magdalena Piotrowska, MD17*, Joris Wilms, MSc., Pharm16* and William G. Wierda, MD, PhD18*