Why does it take so long to get new drugs approved?

It has been several years since I first wrote about Humax-CD20 (technical name “ofatumumab“) - the next generation anti-CD20 monoclonal antibody that we hope will give Rituxan a run for its money.  We are still waiting for this new drug to become commercially available.  With a little luck, Humax-CD20 will get FDA approval sometime in 2009.

I probably know more about how this drug works in CLL patients than just about any other layperson.  My husband PC got compassionate use access to this drug when he developed significant allergic reaction to Rituxan.  He got Humax-CD20 by the boatload.  But for his fortunate access to Humax-CD20 therapy I expect PC would have had to face transplant decisions a couple of years earlier - a prospect that I dreaded since cord blood transplants for adults were in their infancy back then.

Will the FDA approve Humax-CD20 for CLL?

What is holding up the FDA approval process for Humax-CD20?  How is it that the company has yet to file for approval?  The answers are both simple and complex.  So much money rides on new drug development that companies have to take a very cautious approach to not blowing their chances, not getting in front of the FDA too soon, before they have their ducks in a row.

What impresses the FDA? The short answer is development of a drug that works better than presently available options in the really tough nut cases.  Especially in indolent cancers such as CLL this makes a lot of sense.  Early stage CLL patients with good prognostics hardly need any treatment at all, hence the recommendation to Watch & Worry.  Even when they do need a little something to kick the CLL back a couple of notches, these early stage and “smoldering” types have many therapy choices available to them.  It is hard to demonstrate the cojones of a new candidate drug in a such a crowded field.

How about the other end of the spectrum, the guys who have been around the chemo block more than a couple of times, patients who no longer respond to fludarabine or even Campath?  What about the cases where the lymph nodes and / or spleen are so enlarged that they have no chance of getting a good clearance with Campath? Remember, conventional wisdom says Campath is not likely to work on nodes that are “bulky”, larger than 5cm across.  As we wrote about in an earlier article, these “double refractory” patients have few options. None of the available “salvage therapy” options (barring a stem cell transplant) hold much hope of producing long term remissions.  I strongly urge you to re-read our review of Refractory CLL if you are not familiar with the study.  But you may want to get a stiff drink to help you with the bleak statistics, especially if you tend to have weak knees and don’t deal well with bad news.  Don’t say I did not warn you!

A strategy that might work with the FDA (I hope!)

Genmab has been very smart in their choice of patient cohort for testing the efficacy of Humax-CD20 as a single agent. Their inclusion criteria mandated that the patients (1) must have had several cycles of prior chemotherapy under their belts (2) they must be refractory to fludarabine (3) they must also be refractory to Campath orthey must be ineligible for Campath therapy because their bulky nodes are larger than the 5cm cutoff.

Presently these patients do not have many good options.  Majority of them are in late Rai stages and I expect over their CLL journey many of them have acquired more than their share of high risk chromosomal (FISH) defects. As we know by now, single agent Rituxan works - sort of - in chemo naïve patients.  It gets no respect at all in patients with high risk profiles or those who have had multiple rounds of chemotherapy.  As for double refractory patients, attempting Rituxan therapy as a single agent would be a waste of time in the vast majority of cases.

Genmab’s strategy is to see if Humax-CD20 can give these folks a better therapy choice.  If the clinical trial demonstrates improved overall response rates, longer remissions and longer survival times using Humax-CD20 with fewer adverse effects in this group of people, the company stands good chance of getting the coveted FDA approval.

Breaking news at ASH 2008 Conference

The results of the single agent Humax-CD20 trial in refractory CLL patients is published in this year’s ASH abstracts (abstract # 328).  You can read the full abstract by clicking on the link.  The long author list  has some of the best CLL experts in this country and Europe.  The trial was conducted at several centers.  While it is not a double arm or randomized study (there was no defined control group), the large cohort size (138 patients), expert panel and the multiple centers give credibility to the results.

Did Humax-CD20 hit it out of the ballpark?

OK, I hope at least some of you dutifully clicked on the link, got a little cross-eyed sorting out the statistics and now you are ready for my far more readable cheat-sheet analysis.  I thought so. I will break down the results into four sections:

  • Profile of patients recruited for this study
  • Their response to Humax-CD20 single agent therapy
  • How does this compare with other choices available to such patients?
  • What was the “cost” of Humax-CD20 therapy?

Last but not least, I will give you my two cent editorial opinion - cheap at the price, as they say.  You will have to draw your own conclusions, make up your own mind whether you agree with me or not. That is both your right and your obligation to yourself.

Yep, Genmab recruited a tough bunch of patients for their Humax-CD20 single agent study, just as advertised.  If you see yourself matching this profile (as my husband PC did), you too would have a certain sense of urgency in getting better therapy choices approved in real time.

I wish I can give you a straight thumbs-up or down on the evaluation of the results, but the devil is in the details. For starters, I would have liked to see many more Complete Responses (there was a single patient with a CR in the “BFR” group).  On the positive side of the equation, between 86 - 90% of the patients got some level of response or at least managed to keep their disease stable - no mean task for this crowd.  Single agent Rituxan would not have seen even single digit overall response rates in this patient cohort.

The remission duration was also short, of the order of 8-9 months, before treatment was needed again. Bummer.However, as most of us know, even early stage and chemo-naïve patients on single agent Rituxan therapy need repeat cycles of Rituxan every 6-12 months.  The million dollar question is whether Humax-CD20 therapy is repeatable in refractory patients.  The official word on this is not available.  But from a strictly anecdotal perspective, PC repeated his Humax-CD20 treatments for a total of 3 cycles, starting April 2006.  While he did not get the coveted CR, each time he got a good partial response with squeaky clean blood counts and significantly smaller lymph nodes. Each time the nodes started acting up again in 6-8 months.

So much for the duration of the remission, but even more important to us chickens, how long did the patients live? The median survival was roughly the same for both DR and BFR groups, about 14-15 months. This is tough news to swallow, especially if you identify with the profile of these patients. I think it is fair to say Humax-CD20 is no magic bullet capable of CURING late stage CLL patients. We still have to look to stem cell transplants to achieve that goal, at least for now.

Comparing apples to apples

Actually, the following is not exactly kosher comparison, it is more like comparing granny smith apples with golden delicious apples.  More or less the same, but not quite - someting to remember as you look at the comparison below.

Facing reality head on, how did the Humax-CD20 survival statistics compare with presently available therapy options for this patient cohort?  I am willing to bet that would be one of the criteria the FDA will be looking at as they make their decision.  Unfortunately, while this was a large scale study with a goodly size patient cohort conducted at multiple reputable centers in the USA and Europe, its design is not the gold standard of clinical trials - it is not a double arm randomized study with a well defined and tightly matched patient control group.  Since we do not have a defined control group to use for comparison, I will do the next best thing: compare these results with prior studies with similar patients - more or less.

The graph above comes from a very recent article (2007) and a credible research team (M. D. Anderson).  The abstract is given below, and you can find the full length review we did of it on our flagship CLL Topics website.

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 and Stem Cell Transplantation, MD Anderson Cancer Center.

The natural history and outcome of salvage treatment for patients with fludarabine-refractory chronic lymphocytic leukemia who are either refractory to alemtuzumab (“double-refractory”) or ineligible for alemtuzumab due to bulky lymphadenopathy (“bulky fludarabine-refractory”) have not been described. We present the outcomes of 99 such patients (double-refractory n = 58, bulky fludarabine-refractory n = 41)undergoing their first salvage treatment at our center. Patients received a variety of salvage regimens including monoclonal antibodies (n = 15), single-agent cytotoxic drugs (n = 14), purine analogue combination regimens (n = 21), intensive combination chemotherapy (n = 36), allogeneic stem cell transplantation (SCT; n = 4), or other therapies (n = 9). Overall response to first salvage therapy other than SCT was 23%, with no complete responses. All four patients who underwent SCT as first salvage achieved complete remission. 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 survival was 9 months, with hemoglobin < 11 g/dL (hazard ratio 2.3), hepatomegaly (hazard ratio 2.4), and performance status >/= 2 (hazard ratio 1.9) being significant independent predictors of inferior survival.

PMID: 17917961

Since the patients in the Humax-CD20 trial and the salvage therapy results reported in the M. D. Anderson are not exactly matched, you must take the comparison with a grain of salt.  However, the patients in the M. D. Anderson trial are also double refractory (or Campath ineligible because of bulky nodes), and therefore folks facing the same thorny therapy decisions.

The MDA reports overall response rate of 23%, significantly lower than the 51-44% reported for the Humax-CD20 trial. The survival statistics in the MDA study are broken out into the various therapy options open to the patients.  I expect in their case the “Monoclonal Ab” refers mostly to Campath therapy - no one would realistically expect single agent Rituxan to do much for these guys.  Like you I was stunned to see how steep the drop-off was for the “Monoclonal Ab” group.  Fully 12 out of the 15 patients were dead by 10 months.  Ouch. That hurts.

Now for the half full glass perspective: Except for “PA Combination” (purine analog combinations such as FCR, PCR, CFAR and similar alphabet soup drug combinations) with 16 month median survival in the MDA study, Humax-CD20 single agent therapy beat all of the other much more aggressive therapy options with its 14-15 month median survival. As I said above, this is not a strictly legit comparison since the groups were not exactly matched and computer randomized. You will have to make your own call whether the comparison is valid on this absolutely crucial point.

Risks and rewards

What was the price tag in terms of adverse effects?  I hope by now I have got you thinking of the balance between risks and rewards whenever you evaluate therapy options.  So, what is the cost of Humax-CD20 in terms of adverse effects? Did patients get enough of a bang for their buck?

As a comparison point, let us see how the refractory CLL patient group did in the M. D. Anderson study referenced above, using presently available therapy options.  Here is a quote from the abstract: “Early death (within 8 weeks of commencing first salvage) occurred in 13% of patients, and 54% of patients experienced a major infection during therapy.” Wow. Sounds pretty grim to me.

What did the Humax-CD20 trail have to say on the subject of adverse effects?

The infusion related side effects are something we have all come to expect with any monoclonal antibody therapy.  Likewise, the anemia and neutropenia are within acceptable levels.

But the Grade 3-4 infection rate for Humax-CD20 is more like Campath than Rituxan. In fact, this was a point of discomfort for me right from the beginning and during the course of a long conference call we tried (more or less unsuccessfully) to convince the company to include robust guidance for prophylactic medications in their clinical trial.  Last but by no means least I am deeply concerned about the 5 patients (4%) that died within 8 weeks of initiating Humax-CD20 therapy.  Sure, 4% early death is better than 13% reported in the MDA study, but it is still too high for comfort. Hopefully as we learn more about how best to administer Humax-CD20 and protect patients while we are doing it, these numbers will come down. There was a similar learning curve for Campath, early users faced a host of high risk opportunistic infections until we learned how to protect patients with prophylactic antiviral drugs.

Given the Humax-CD20 cohort and the MDA patient group are not exactly matched, it is hard to draw solid conclusions.  At first blush Humax-CD20 seems associated with fewer adverse effects, but this has to be confirmed in additional clinical trials with matched control groups. I would also like to see if the adverse effects reported for Humax-CD20 single agent use can be improved with appropriate protection of patients with antiviral and antibacterial drugs.

Editorial

I am glad to see how many top rated CLL experts were on the author list of this important paper. Just about each of the authors has been quoted at one time or the other on CLL Topics, each of them represents the best of the bunch. Too bad I was unable to attend the ASH conference this year - I would have liked to listen to the full presentation.  Perhaps I will be able to get hold of the presentation slides.

What is the bottom line?  Does Humax-CD20 represent an improvement over Rituxan?  I think the answer is YES.  Single agent Humax-CD20 did far better than we can expect from single agent Rituxan in a refractory CLL patient population. Will this be enough to get FDA approval? I hope so.They may have a problem with the fact that this was not a double arm study with well matched control group.  Will the company be sent back to the drawing board to conduct another long clinical trial with the necessary bells and whistles? Would the company’s more recent combination of Humax + fludarabine + cyclophosphamide (compared to the presently available FCR combo) in chemo naive patients fill in the blanks? If the FDA thinks there are too many unanswered questions that may delay commercial availability of the drug for several more years. That is a delay we can ill afford.  All the more reason why the patient community may need to get involved, see if we can get the FDA to listen to our perspective on things.  I will let you know when /if it is time for you guys to get into an activist mode.  Heck, the new boys in Washington DC say they want our input, perhaps we should take them at their word.

Looking over the patient profile in the Humax-CD20 study I was struck by the fact more than half of them had prior exposure to Rituxan.  It has been suggested that multiple infusions of Rituxan gradually leads to selection of CLL cells that no longer respond to the drug.  The mechanism is thought to be development of traits that block the killing power of complement. Now, as we described in our review article on what might make Humax-CD20 a smarter monoclonal than Rituxan, we highlighted the importance of complement mediated cell death in Humax-CD20 therapy. That raises an interesting question:  will patients who have not been previously treated by Rituxan and therefore had not developed resistance to complement mediated cell kill respond better to Humax-CD20 therapy?  My husband PC had pretty good response to Humax-CD20, but would he have had even better response if he had not had multiple cycles of Rituxan prior to trying Humax-CD20? Does prior flirting with Rituxan spoil patients for Humax-CD20?

Here is another little something to look forward to.  Remember that bit of excitement about “beta-glucan“, derived from baker’s yeast?  There were several excellent articles on the subject of how beta-glucan may get around complement inhibitory proteins that cancer cells develop as a way of defending themselves from complement’s killling power.  My friend the late Gordon Ross of the University of Louisville died of stomach cancer before he saw his research bear fruit.  But I am happy to tell you that two other high powered researchers have picked up the trail - Dr. Clive Zent of Mayo and Dr. George Weiner of University of Iowa. And here is the icing on the cake: CLL Topics is providing the seed money to the tune of $20K to get this important project off the ground.  Down the road I hope we will have better answers to the question whether monoclonals such as Rituxan and Humax-CD20 will work better in combination with beta-glucan, because the combination may prevent CLL cells from avoiding death by complement.

All in all, interesting developments on the Humax-CD20 front.  Now we have to be patient some more and keep our fingers crossed this important drug is soon approved by the FDA for general use in CLL. What do you think?  I look forward to your comments, questions and suggestions.