Posted by Jeff Berk, BOLT International;
Here’s your cactus flower of the day; cereus aethiops. One of the “queen of the night” cacti, named because the flowers bloom at night and wither by mid morning. Thus, the best photos are taken about 3am.
So a quick review of my life: Last week I was hoping and praying that somebody would send me to Paris this summer for ICAD. That prayer remains open, but thanks to an interesting twist of fate, yours truly will be blogging to you next week from the 13th Annual International Myeloma Workshop in … Drumroll… Paris. Be careful what you wish for, right?! Now, as for ICAD, seriously, pharma peeps, if there’s one thing I know pretty well, it’s Alzheimer’s. So let’s shake those budgets loose, shall we?
Before I turn to multiple sclerosis, I received a follow up from a reader, with a request to link back to Pfizer’s press release dated April 15th, and share the following “rebuttal” to my Thought Leaders not being satisfied with the available data set on joint space narrowing with tofacitinib. Interestingly, said reader also asked if they were really Thought Leaders; to which I’ll reply, cryptically, “Yes, and they’re YOUR Thought Leaders!” (People tell me things that they won’t say when they’re serving on Advisory Boards. I think the reason’s because I serve better vodka than Pharma companies). But anyway, here’s the relevant paragraph from the press release: The ORAL Scan study met all primary endpoints at the 10 mg BID dose, showing statistically significant changes versus placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates at six months; in reducing the progression of structural damage, as measured by change from baseline in modified Total Sharp Score (mTSS) at six months; in improving physical function, as measured by mean change in HAQ DI at three months; and in reaching DAS28-4(ESR) <2.6 at six months.
If anybody else wants to add their 2¢ on whether they think tofacitinib will match anti-TNF or other biologics on reduction of joint space narrowing, please either post directly or email me if you want to remain anonymous.
This will be my last multiple sclerosis blog for a month. I just completed the interviews for BOLT’s 13th Multiple Sclerosis Thought Leader panel. We’ll publish that in early May, and for the paying clients, we’ll talk about BG-12, fingolimod, teriflunomide, and a ton of other stuff. After a while some of that will make it to this blog. But since it’s on everybody’s mind now, and since I’m NOT going to talk about the whys and wherefores tonight, the punchline on BG-12 is “unexpectedly good” result in the DEFINE trial: there was a 49% reduction of the proportion of relapsing patients at two years, and a reduction of 53% in annualized relapse rate. The reduction in progression of disability, as measured by Expanded Disability Status Scale, was 38%, and MRI-assessed new or newly enlarging lesions declined by 85% to 90%. But… a lot of unanswered questions. What my panel did agree on is that the BG-12 results were a lot more impressive than the laquinimod results presented last week.
So for the topic at hand… I was impressed with the ocrelizumab data presented at AAN. I think this drug has some legs for MS. Now I’ve been a big fan of B-cell approaches for multiple sclerosis for a few years (so you can go back to the first people talking about them and at least one of them serves on my panel). So tonight I’m going to share some comments from the end of last year related to ocrelizumab, and to GSK’s ofatumumab as well.
Ocrelizumab (Roche / Genentech / Biogen-Idec)
- Genentech appears to have resolved their intellectual property issues with Biogen related to ocrelizumab and the drug is moving forward as monotherapy for RRMS. The drug should launch in 2015. As monotherapy in the Ph-II studies there were no patients who received ocrelizumab who still had active lesions. Impressively, in the phase II study they saw a 74% decrease in relapse rate with the low dose and an 86% reduction with a high dose group. Patients who received a low dose of the drug had 89% fewer brain lesions as compared to participants who received a placebo. Patients who received a higher dose reported 96% fewer brain lesions. Patients also reported fewer flare-ups of their symptoms. There were four arms of the study – placebo, two doses of ocrelizumab and Avonex as an active comparator. Interestingly, the Avonex had absolutely no effect whatsoever; in fact, it was worse than the placebo.
“What are your thoughts on ocrelizumab? Very early. It looks very potent and very promising from the phase II. It looks even better than probably rituximab did. It was an impressive study. What I was excited about when I saw that was the actual comparator. I don’t know if you saw the data but there were four arms of that study. It was placebo, two doses of ocrelizumab and Avonex. And the Avonex had absolutely no effect whatsoever. In fact, it was worse than the placebo. That is the first placebo controlled, relapsing-remitting trial, of Avonex. They have never done one noninferiority relapsing remitting disease with this current Avonex product”.
“If you look at the MS trials, if you use it as a monotherapy and that data that was presented at ECTRIMS at the end of study, at the end of the phase II there is nobody left with an active lesion. They just completely shut down. And in a phase II study they saw a 74% decrease in relapse rate with the low dose and an 86% reduction with a high dose group. That is incredible efficacy. That is huge”.
“Well they are impressive. Rituximab was impressive and then so was the ocrelizumab”.
“My prediction with ocrelizumab is that in 2015 when that drug gets to the market it will be like Tysabri all over again; except it will be an incredibly effective drug that is dosed once every six months and it will shut down disease activity in a very, very effective fashion. So in 2015 unless somebody comes out with a combination therapy which is safer and as effective ocrelizumab will take over the market. That is for relapsed refractory? That is for relapsing forms of MS”.
- Ocrelizumab is expected to have lower rates of antigenicity than rituximab. Positioning will be the same as rituximab is currently used (off-label): salvage as an alternative to natalizumab. PML is not expected to be a problem with ocrelizumab as long as it is not used in combination or after treatment with an immunosuppressive agent; although concern over PML was the primary reason for discontinuing ocrelizumab for development in rheumatoid arthritis. But there has been one “weird death” thus far due to a systemic acute inflammatory reaction.
“One guy said to me that it is his prediction that ocrelizumab is going to be a first line drug. Nah. I don’t buy that, especially on the high dose. There was that really weird death that they made very light of at the meeting, but it is totally a rare condition. I never even heard of it. It was basically total body organ failure resulting in death; a severe inflammatory reactive syndrome or something like that. So in a world that is going to have currently approved drugs: fingolimod is going to be entrenched, teriflunomide is going to be entrenched, laquinimod is going to be available, what is the place that you envision an anti-CD20? I think if you took all the MAbs together they are going to be transient therapies. Very likely they are going to be either used for rescue or for temporary escalation or in some cases even induction. So when alemtuzumab comes no one envision people taking alemtuzumab for the rest of their life. But if you have got a sense that there is bad disease why wouldn’t you give one dose of it? You can get good control over the disease and then come in with a first line agent. Got it. That may be the way ocrelizumab is being used and it may be the way natalizumab could be used. And then you won’t have safety issues that will arise no doubt from the chronic use of monoclonal antibodies”.
“I love rituximab and we use rituximab now. Ocrelizumab will be that much easier. Easier because it is approved or because…? Just because there is less likely to be antigenicity that gets us into trouble”.
“So with rituximab, rituximab is the prototype drug. Rituximab is associated with PML in patients who have been treated with a variety of other immunosuppressive agents. In patients with a prior history of immunosuppressive exposure there is no PML with Rituxan. It is only in the patients who have been treated with other chemotherapies. In other words, your patients with malignancy and your patients with rheumatoid arthritis and psoriasis and lupus who have been treated with a variety of other immunosuppressive agents. And that is the only time we are seeing it. So in the MS patient population it is going to be a very uncommon thing if you are using it as a monotherapy”.
“Given what you know today how do you project using a CD20? So I would think of it as second line after someone failed another highly active therapy. So for example say Gilenya, given its safety profile, which we again still have to see because there are some as yet unknown challenges with ocrelizumab on the safety side. When you say unknown or are they simply not public? Unknown to me because they stopped trials in other diseases for safety reasons. And the MS trial the safety data they presented looked okay. So if the safety is okay then it becomes I think second choice after someone, for example, failed Gilenya and instead of Tysabri”.
- (From last report): NCT00676715 is a Ph-II study comparing ocrelizumab to methylprednisone, interferon beta-1a and placebo in 250 RRMS patients. The trial is scheduled to report in 2012.
Ofatumumab (Genmab / GlaxoSmithKline)
- GSK has moved ofatumumab into a Ph-II RRMS program (NCT00640328). This non-US trial is set to report in 2012, but an interim analysis of the first cohort through the study showed a similar effect as is seen with ocrelizumab. The most intriguing aspect of the analysis showed that there was a significant reduction of new lesion formation at lower doses, but only a significant reduction of relapse rate reduction at higher doses. This jibes with our laquinimod discussion that highlights the observation that reduction of new enhancing lesions by MRI is at best loosely correlated with fewer relapses.
“You had the GSK B-cell approach where they had an interesting result but I don’t know what to do with it. They had a phase II study with dose titration of their monoclonal antibody. And they could show a significant reduction of new lesion formation at lower doses, but only a significant reduction of relapse rate reduction at higher doses. They only looked at brain MRIs, but I would have thought that the lesion reduction parallels clinical efficacy. Now this is a phase II study. The number of relapses is small in a phase II study. They could eliminate lesion formation with lower doses of anti-CD-20, but they still had relapses in the patients on lower doses is kind of counterintuitive. So that is an agent that may move forward”.
“Ofatumumab was presented, small numbers, but also good data. Talk to me about that because nobody else has mentioned that. I think it was in the 50s their phase II trial, the number of patients, so it was small but it was successful in terms of I believe it was gadolinium enhancing lesions that they were reducing.
- The three potential advantages for the drug vs. rituximab are lower immunogenicity due to full humanization, better efficacy from the epitope due to tighter binding with the CD20 receptor than is seen with rituximab, and higher potency which may allow for sc dosing vs. rituximab’s iv.
“Is there anything that looking at ofatumumab to say it may have some advantage? I believe ofatumumab is fully humanized. So you think you will have less HACA formation? One would think so. And I don’t what they their data is but just from the names one is more humanized than the other. But beyond that, one would need to look at side effects profiles. I would think that the efficacy would be similar. There is difference in what they go after and I don’t know what they are but I know they have differences in their targets. And the safety profile will be very important if they go forward with that molecule”.
- (Old news): We heard at ASH 2008 (San Francisco) that in the CLL trial of ofatumumab there was a case of PML.
“I saw the GSK anti-CD20, ofatumumab, at ASH at the hematology meeting. And they actually had a case of PML in one of their chronic lymphocytic leukemia patients. And that wouldn’t necessarily surprise you because that might be part of having the amount of immune dysfunction that those patients have to begin with. And two, it may also be a function of whatever prior treatments they have had. Whereas when you are taking the naïve people who have never been on any other immunosuppressants or whatever it is a different group of people you are looking at”.