This week FDA gave their complete response to Merck-Serono’s Movectro (oral cladribine) registration application for relapsing remitting multiple sclerosis. The Agency is requiring more safety data, calling for additional analyses or new studies. Cladribine was recently approved in Russia and Australia but received a negative opinion from European regulators in September that was reiterated in January.
Merck-Serono obviously wants to meet the FDA concerns with completed and ongoing trial data. Top-line results from the CLARITY (CLAdRIbine Tablets Treating MS OrallY) extension study and ORACLE MS (Oral Cladribine in Early MS) study are expected by the end of 2011. Top-line results from the ONWARD (Oral Cladribine Added ON To Rebif [interferon beta-1a] New Formulation in Patients With Active Relapsing Disease) study are anticipated in the first half of 2012.
In December 2010 BOLT had an opportunity to speak with some of our multiple sclerosis Thought Leaders about the cladribine situation. We’ll be chatting again with the Panel in May 2011. But here are some of our bullet points, based on their comments from the last time around. As always, our questions are in italics, their responses are plain font.
Ø Merck-Serono has suggested that the delay in approval is due to a missing Ph-III trial. We think the issue is that FDA has extended the evaluation so that the Ph-III CLARITY data can mature to 4-years, and there can be a preliminary read on ONWARD and ORACLE. This will clarify what happens when patients are treated for the first two years with cladribine and then given two more years of follow-up. This data will be available in early 2012, and based on this we expect FDA to approve Mylinax for RRMS.
“Are you a supporter or non-supporter of EMEA or FDA approving cladribine and what is the key driver in favor or against? I don’t know what their problem is. In fact, I was so impressed with the results from cladribine that together with our hematologists here we are actually prescribing cladribine in the equivalent of the parenteral dosage to patients giving them the same regimen they would get with the cladribine tablets except we are giving it to them parenterally because that drug is available to us. Got it. So what is the scuttlebutt on what FDA’s problem is? I don’t know is the honest answer. If I knew I couldn’t tell you is the second honest answer because I am on their advisory and steering committee. But in fact, I really don’t know. If I was the person at FDA or Health Canada or wherever that is well aware of what studies are being done. First of all, the question is did the Scripps clinic study done more than a decade ago really qualify as a first phase III study? I think the answer is no. So in effect we only have one phase III study, which they knew in advance that was all they were going to have and I guess they got the notion from EMEA and FDA that is all they would need. Today, I can’t believe people would want you to do two phase III studies anymore. It is so onerous, each of these studies costing anywhere from 50 to 60 million dollars. It is a huge expenditure. If you have got a very good, properly controlled phase III study I don’t know why you need to do it twice, but that is another issue. One thing that I would probably be holding for is the four-year data because you are releasing a drug where you know two years of treatment is effective but nobody knows what to do after two years. You could say, well, why don’t you just approve the drug and once we have the four year data we can advise further as to what to do after two years. Or since the four-year data is going to be available in the early part of 2012 why wouldn’t I just wait for that? That is what I would be thinking if I were one of the FDA people, going look you are going to have that data in a couple of months why don’t you just give us that data and then we can make our final decision. That sounds like what is actually happening. That just makes sense because at this point we would say, aha the way the extension study was designed in CLARITY you have got patients who took two years of full high dose therapy who were then randomized to receive nothing. It would be really interesting to know if those patients over the subsequent two years did extremely well and could tell us that two years of treatment buys you two years of freedom. That would be excellent. Whereas some of the patients had to take cladribine for four full years. Is that going to be a problem? Is there going to be a safety issue with the four year treatment that we didn’t see with two years? Do they need to take cladribine every year for four years? How difficult was that? What happened in years three and four? There is going to be four-year data, why wouldn’t I want that information before we set a full approval. To me, that would be the reason why they are waiting.
“So I want to turn your attention to cladribine. Do you think FDA will ultimately approve it? From what I understand, the hold up is that the FDA requires two phase III trials and they only have one. Yeah, I had heard that there was just a really high concern at FDA about the rate of secondary malignancy. Yeah, I heard that rumor but when I asked people, and I think we even asked somebody at the company, and what is being said is that this is the issue is that they don’t have a second phase III. I don’t know what the truth is. They were not given approval in Europe”.
“I need you to comment on cladribine. EMEA turned them down. Correct. We will know theoretically in the next few days whether its fate is the same with the FDA, or whether the FDA is going to extend the review process, or whether the FDA is going to approve or recommend it as a two-year medication. We will know in a relatively short time horizon. How are you betting? I was personally surprised about the EMEA. I would think that the FDA is going to take a slightly different position if I was a betting man. From that point of view I would think they are going to approve it for a two-year treatment with the expectation that they need to submit long-term data for a longer term indication”.
“So why do you think FDA has put the kibosh on Merck Serono? Well, they gave it to them first and now they are of course back. The people who really gave them the kibosh were the European Medicines Agency committee. The FDA still has them in line. They just gave them another three months to put something together. There is nothing else as far as I know and since I am in the ONWARD study I am constrained. But the cancer issue is the issue as far as I know. So far what they have released is not something that I would imagine is sufficient to put the kibosh on a drug”.
Ø The EMEA has been more concerned about increased cancer risk than is FDA. Cladribine carries a very high risk of causing secondary malignancy (colon cancer, skin cancer, leukemia) when used in the hairy cell leukemia population. In those trials the total parenteral dose of cladribine was 0.7 mg/kg and the rate of secondary malignancy was 8%. In MS the drug is being studied at 3.5 mg/kg and 5.2 mg/kg, and the oral bioavailability is 60%. Thus (according to one panelist) the MS dose is at least 3-fold higher. Most of our panelists do NOT agree that the cancer rate should be higher in MS, and in fact with short follow-up in the MS program the cancer rate has not been as excessive as a straight extrapolation of the hairy cell frequency would predict. The first bureaucrat who evaluated the cladribine registration package for EMEA was overly concerned about this cancer risk. Merck-Serono has appealed his decision and is getting a different examiner. Ultimately we believe EMEA will also accept the 4-year data, moderate their cancer concern, and approve cladribine for the EU.
“They are sticklers about the malignancies in the EMEA. I don’t know why. The malignancy rate was actually lower than in any of the interferon trials. And there was no real ill signal from the malignancies that these are a common type of cancer that is being driven by the drug. I quite honestly don’t understand why they are having the issue. And is EMEA’s cancer concern something fixed in stone or do you get the sense that they too are basically just waiting for that four-year data as well? Word has it that it was one of the people who took the file who had this bee in his bonnet over it. They have appealed and I think they will get a different person. I don’t know what has happened with that. The issue really hasn’t arisen in any other country. I suspect the problems in the other countries are that they are waiting for four-year data. The malignancy date is so low and so scattered that it was all a low dose. The only malignancy in the high dose happened two years after the patient discontinued cladribine and in most of the other tumors were found within six months of treatment. So when you have something that comes up in six months it is pretty unlikely that it was the drug that you are giving them. It is more likely that they showed up with this cancer that only got discovered because you do such intense investigations in people when they are in clinical trials. Right. The cancer detection rate in every clinical trial is significantly higher than in the general population and the reason is because you look”.
“My theory is they have this very high rate of secondary malignancy and there is no way to get around that. Apparently, the European medicinal authorities were concerned about that. They haven’t seen that in their clinical trial as best I know, at least not that rate during the follow up. Although I don’t know how quickly those malignancies appear. Nor I. And of course people with cancer have a higher rate of cancer. Although I guess my ultimate thesis here is it just seemed like an insurmountable problem for Merck Serono. I think the European authorities may have used the same logic you are because they mentioned malignancy as their main cause for concern apparently, at least that is what was put out. The FDA, on the other hand, just hasn’t said. All I saw that they said was they want to extend the evaluation period for three months”.
“What is the future for cladribine? Cladribine, I don’t think has a future. I don’t think the FDA is going to approve it. The European Union refused to look at it further. They are appealing the European Union, but if you look at cladribine in Hairy cell leukemia it was used as a monotherapy; just one course and it was used at a dose of 0.1 mg/kg per day for seven days and it was curative. So that was a total dose of 0.7 mg/kg. Now in the MS studies they are looking at 3.5 mg/kg and 5.2 mg/kg. The bioavailability is 60 percent for the oral formulation. So in the follow-up study in the Hairy cell leukemia population the risk of secondary malignancy after cladribine treatment was 8 percent. So that is the long-term safety data that they are missing from the MS trials? Right. So basically one in ten patients treated with cladribine with get malignancy from cladribine. And so the FDA is going to be aware of that. Are these all AMLs? No, they are a variety of different cancers, many different organ systems. So there is colon cancer, skin cancers, some leukemias, but they are just across the board. Is the mechanism understood? The mechanism is, let me put it this way: cladribine is taken up into all cells initially, but it is broken down very quickly in most cells because they have a lot of deoxycytidine kinase. What kind of cells? It is taken up in most cells, but it only persists in lymphocytes and basically ovarian cells. The reason being is because lymphocytes and ovarian cells have a high ratio of nucleotidase to deoxycytidine kinase. They have low levels of nucleotidase and that that is the enzyme that breaks it down. So the active form of the drug persists only for a very short period of time in most cell types, but it doesn’t need to be there long because it is cross-linked to DNA and prevents DNA repair. So all it takes is one mutation to give you a cancer. Got it. And the other thing that is going on in the MS studies is that they are dosing it repeatedly, not just giving it one time as they did in hairy cell leukemia”.
“I will tell you my theory and you tell me if it sounds like it could be a Walt Disney Fantasy. I first look at the Hairy cell leukemia results. Those folks are getting total parenteral dose cladribine of 0.7 mg/kg. Right. Leustatin, yeah. They have a secondary malignancy rate of 8 percent. So then I look at the oral dosing for MS and it is either 3.5 mg/kg or 5.2 mg/kg and an oral bioavailability is 60 percent. When I do the math on that, and it sounds to me like the first MS dose is still three times higher than what they were giving these Hairy cell leukemia patients. We are not even talking about what you would possibly do for a second lifetime dose. This first dose is already three times higher. And in those leukemia patients there was a secondary malignancy of 8 percent. So my theory is that both FDA and EMEA are looking at this and going show us what the lifetime secondary malignancy rate is and Merck Serono can’t do that. What do you think of all that? I don’t know enough about it. I didn’t follow the math and the calculation of the dose. And part of the reason that I thought that we were ending up with lower doses that you continue to give the Leustatin maintenance in the lymphoma for longer. So their lifetime exposure is quite high. I thought they were a one shot deal. Oh if you are right then I am wrong about this. I just don’t know. Patients who have non-Hodgkin’s are getting other stuff and they are more likely to get immune suppression and they are more likely to get secondary cancers”.
Ø Some panelists would consider using cladribine in those who have found interferon and GA intolerable, rather than having failed on them outright. Other panelists say that they see cladribine as a rescue approach. They would administer one (or maybe two) course(s) of therapy and then switch to maintenance with IFN or GA.
“So in reality if it comes as a two year medication then I potentially will use this in the patients without have failed other medications predominantly because of side effects. I am going to be a little bit more hesitant in the patients who failed because of continued inflammatory disease activity because with cladribine I kind of give up the window for a period of time to, for example, move onto something else. When you talk about failed medications, what other therapies or regimens will the patient you are considering for cladribine use have been on? We may have moved through interferon and we may or may not have moved also to Copaxone or visa-versa. I am not sure that at this point how long this concept of that you move through both injectable categories before you consider an oral category. I would think that the oral category may potentially insert itself before the second injectable or instead of the second injectable”.
“Again, the way I like to see the use of some of these more toxic MS therapies is in short term. And what I was going on is I thought that if I gave cladribine once, twice and continued them on a maintenance drug with less toxicity that I would get benefit without the risk. I am still imagining cladribine can work into a paradigm of horizontal and vertical combination therapy with interferon or Copaxone. Okay. By the way, we give high dose steroid now to think like we cool someone off, or Cytoxan or something, I would be very happy giving cladribine.
“Cladribine is only present for a period of time in the patient as an agent. The biologic effect is there but the direct drug is only present for a period of time. At least to date there is no real indication that this is a drug that affects fertility. I understand that some of my colleagues view this differently. But from the mode of action and how cladribine is metabolized I do think that there is a potential window in the youngish female patient that would like to pursue pregnancy at some point in time, but couldn’t do this safely, for example, on Gilenya. So I is actually a group of patients where perhaps many people would not think of, but that is actually the group of patients that I may potentially use it. It is this middle body of patients. If in a year or two the ORACLE trial is going to be positive or show results it may also change the use of cladribine potentially as an induction therapy. So cladribine right now is an agent that had at least as good efficacy as Gilenya with the potential that you have interrupted dosing so that you have only annual courses or perhaps even after the second annual course that you have along a treatment window before you go to the next treatment cycle. The majority of patients that are on cladribine have only grade one lymphocyte reduction so they don’t have severe lymphocyte reduction. In addition, if the patient were to become pregnant after cladribine and outside of the drug elimination window then I do not have the consideration such as with Gilenya where the patient would transmit the drug through the placenta to the fetus”.