Ixazomib Succeeds In Key Phase 3 Relapsed Multiple Myeloma Trial – Approval Filings Expected Later This Year
Takeda Oncology yesterday announced positive results from a key trial testing the investigational drug ixazomib in relapsed multiple myeloma patients.
Participants in the large Phase 3 ixazomib trial, known as the TOURMALINE MM-1 study, received one of two possible treatment regimens. One group was treated with ixazomib, Revlimid (lenalidomide), and dexamethasone (Decadron), while the other group received a placebo (sugar pill), Revlimid, and dexamethasone.
Investigators conducting the trial recently carried out the first planned interim analysis of the study results. Their analysis, Takeda reported yesterday, found that patients in the trial who received ixazomib had longer progression-free survival than those in the placebo arm of the trial.
Progression-free survival is the key outcome being measured during the trial, and the difference in the survival measure between the two arms of the trial was statistically significant, Takeda said.
Takeda has not yet reported, however, specific results from the trial, such as median progression-free survival in each arm of the study.
The new results, Takeda said in its announcement, will be used by the company as the basis for applications it intends to file in the U.S. and other countries to have ixazomib approved as a new treatment for relapsed multiple myeloma.
Takeda has said in the past that it expects to make such regulatory submissions sometime between April of this year and March next year, with potential approval decisions coming in the following 12 months.
Based on Takeda’s public statements and discussions with financial analysts, The Beacon currently forecasts that Takeda will submit ixazomib for approval in the U.S. and Europe by sometime this summer. Decisions on these regulatory submissions would then occur around the second quarter of 2016.
Ixazomib, which also is known by its codename, MLN9708, is a proteasome inhibitor. This class of drugs includes Velcade (bortezomib) and Kyprolis (carfilzomib).
Unlike Velcade and Kyprolis, which are administered by injection or infusion, ixazomib is given orally as a capsule. Another orally-administered proteasome inhibitor, oprozomib, is also under development, but it is not as far along in the clinical trial process as ixazomib.
Due to their convenience, orally administered myeloma therapies are considered attractive options for use in maintenance therapy, where convenience of administration can be an important factor.
Takeda Oncology’s U.S. arm, Millennium Pharmaceuticals, developed Velcade and markets it in the U.S. Kyprolis is marketed by the Onyx subsidiary of Amgen, which also is developing oprozomib.
The TOURMALINE MM-1 trial is an international, double-blind study involving more than 700 multiple myeloma patients. Participants in the study had to have relapsed and/or refractory disease and have been treated with one to three prior myeloma treatment regimens.
For additional information, see the Takeda Oncology press release and information about the TOURMALINE MM-1 study at clinicaltrials.gov.
Related Articles:
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Once-Weekly High-Dose Kyprolis Yields Deeper Responses And Longer Remissions Than Twice-Weekly Kyprolis (ASCO & EHA 2018)
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- FDA Approves Once-Weekly Dosing And Revised Safety Information For Kyprolis
- Dr. Christoph Driessen On Nelfinavir In The Treatment Of Multiple Myeloma
I'm wondering about side effects. Particularly neuropathy.
I am starting cycle 19 of this trial. No side effect (usual 2 short nights per week with dex). And a stringent complete response! From 37% plasma cells at bone marrow aspiration at start of trial, one year post stem cell transplant and induction chemo with Velcade, to 1% plasma cells last week.
It is good to hear ixazomib is working well for you, Nicole. Especially after having used another protease inhibitor, Velcade. I wonder how ixazomib compares against the other protease inhibitors used to treat myeloma. I would be especially interested in how the effectiveness of ixazomib is affected or not by drug resistance that has developed with other protease inhibitors. As the article stated, I think this drug's biggest impact may be in providing an oral protease inhibitor option for maintenance therapy. It will likely be a number of years before that is studied and the results known though.
The first challenge I see myself having with this drug is I have no idea how to pronounce the name! It seems for some of these new drugs we need a section with audio files on the Beacon we can play so we know how to say these drugs names when talking about them with our doctors or others.
Nicole, great news for your plasma cells reduction. Can I ask are you in a trial with this? And did you use Revlimid and pomalidomide already?
Thanks and so glad of the good news!
I've got basically the same questions as Eric and Nicole. Will ixazomib work as well or better than subq Velcade? And will it also work in patients that may not respond to Velcade? How does the 3rd phase trial data compare to subq Velcade when it comes to PN? At first blush, subq Velcade still had quite an advantage over ixazomib in the earlier ixazomib trials when it came to PN, but the ixazomib dosing levels have probably been adjusted downwards since those earlier trials ... and may be further reduced for maintenance purposes?
BTW, it is pronounced Icks-ah-zo-mib ... at least that is the way Dr. Kumar pronounces it
(see this video with him discussing the drug).
For those on Medicare is the fact that this is an oral medication mean that it will not be fully covered? Velcade and Krypolis are administered at a Dr. Office or infusion center and generally are fully covered. However, Revlimid is treated as an RX and is not fully covered. This new drug may have the same issues.
I am not in Medicare so someone on this board may be able to answer that.
Ron
Hi Ron,
That's a really good point about that insidious gotcha with Medicare Part B coverage. There's a clause in the rules that covers oral cancer medications under Medicare that reads as:
http://www.medicare.gov/coverage/prescription-drugs-outpatient-limited-coverage.html
Oral cancer drugs: Medicare helps pay for some oral cancer drugs you take by mouth if the same drug is available in injectable form or is a prodrug of the injectable drug. As new oral anti-cancer drugs become available, Part B may cover them.
Ixazomib is indeed a prodrug (this simply means that is an preliminary form of a drug that is then fully activated when it is ingested). But my understanding is that Ixazomib is not technically a precursor form of Velcade, but is instead based on a similar, but different molecule than Velcade. I guess we will have to wait and see how Medicare ends up classifying the drug once it is approved?
Great comments and questions, everyone.
I'll address the Medicare coverage first, and get back later today with some feedback on the questions related to ixazomib's efficacy and safety.
I'm relatively certain that ixazomib, if and when it becomes available, will be covered by Medicare in the same way that other oral myeloma medications – such as Revlimid and thalidomide -- are covered, which is by Medicare Part D plans. I don't think it will be covered the way Velcade and Kyprolis are.
While there are some similarities between Velcade and ixazomib -- they both contain a boron atom, for example, which is unusual when it comes to pharmaceuticals -- they are not different forms of the same drug. As Multibilly indicated, ixazomib is transformed in the body into another drug, which is actually the active agent against myeloma, but it is not the same as Velcade. So the oral cancer drug coverage clause that Multibilly mentioned is unlikely to apply.
This information looks promising for the approval of Ixazomib. I think that it is more usually recognized by its codename 'MLN9708'. There are patients in Canada on clinical trials regarding that also. When I was looking up more information about the drug, I was surprised to learn that it is also being used in clinical trials to treat lymphoma patients, in the US in several locations, and in Quebec, at one hospital in Montreal. Below is pasted one of the inclusion criteria concerning that trial for lymphoma.....(i GATHER THAT THAT trial is no longer recruiting patients.)
'Patients must have a confirmed diagnosis of lymphoma that is relapsed and/or refractory after at least 2 prior chemotherapeutic regimens and for which no curative option exists. Patients with Waldenstrom's macroglobulinemia are not eligible for enrollment in this study. Patients with Hodgkin lymphoma are considered eligible for this study.'
SO, if this new drug were to be shown to be effective both for myeloma and lymphoma, it seems that might be a 'plus' for getting approval, if the trials are successful!
....if app'd for both Lymphoma AND MM--then it may escape the curse of Revlimid and the paradigm of "Orphan drugs are damnably expensive".
Lymphoma ( ie. ALL LYMPHS--Ly, Non-Ly, Burketts, etc) is #4 or 5 when it comes to Number of cases in US ??
Shouldn't this price the drug in a better place ?
Bonus: Lowered PN risk is nice...
Thanks, again, for the comments, everyone.
Unfortunately, no hard data are available for the ixazomib study discussed in the article above. All we know is that the PFS is longer in the ixazomib-treated patients than it is in those who received placebo.
There have been results of earlier studies that can give us some sense of the answers to questions that have been asked on issues such as how well the drug will work in patients previously treated with Velcade, and what sort of peripheral neuropathy occurs with the drug.
We'll lay out some of those studies here and perhaps some of you can help us summarize what's there on the subjects people have asked about.
With the ixazomib studies that have been done in combination with Revlimid and dex, the results that have been reported so far are for use of the regimen in newly diagnosed patients.
One of the studies is looking at weekly ixazomib in combination with Revlimid and dex. It has a Phase 1 and 2 portion. In Phase 1, the researchers varied the dosing, to establish what the dose would be in the Phase 2 portion of the study.
Initial results of that study were presented at the ASH meeting in 2012; here is the presentation.
Results from the study also were presented at the recent 2014 ASH meeting (link to presentation), and in this journal article (abstract).
There is also a study that has looked at twice-weekly ixazomib combined with Revlimid and dex in newly diagnosed myeloma patients. Here is a presentation from the 2013 ASH meeting with some initial results from that study.
In addition, there has been an MD Anderson study looking at ixazomib combined with Revlimid as maintenance therapy after transplantation. Here is a poster presentation with some results from that study.
Finally, there has been at least two Phase 1 studies that have looked at weekly ixazomib as a single agent to treat relapsed / refractory myeloma patients. Note that a variety of different doses were investigated in both studies.
Results from one of these studies was presented at the ASH meeting in 2011 (link to presentation).
Results of a second, similar, study were presented at the ASCO meeting in 2013 (link to presentation).
For comparisons with weekly subcutaneous Velcade, this study (abstract) has useful data for single-agent subcutaneous Velcade versus single-agent IV Velcade, and this review (full text) may also be helpful.
I know this is a lot to process, but I hope it will be of some help to those of you particularly interested in this potential new myeloma therapy.
I am 57 and in remission for 2 years after VRD and ASCT chemo. No Bence Jones protein yet. My kidneys recovered and I am off of dialysis after over 1 year of treatments, to the amazement of my nephrologist. I have some neuropathy in my feet and don't want any more. I am willing to travel anywhere to get this new oral drug if necessary, if I relapse. Should I contact Millennium Pharmaceuticals in Massachusetts?
Hi Paul,
Millennium certainly would be a reasonable place to turn for information. Another option is to look at the list of clinical trials involving ixazomib that you can find at clinicaltrials.gov. This link will take you to a list of all ixazomib trials for myeloma. For any given trial in that list, if you click on the title of the trial, you'll be taken to a page with more information on the trial. Then, you can page down to near the bottom, where there is a list of locations where the trial is being conducted.
Best of luck to you.
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