September 20, 2020

The Niche

Knoepfler lab stem cell blog

Upbeat Burt team pub on stem cells for MS comes with uneasy back story

Types of Multiple Sclerosis
Types of Multiple Sclerosis and their impact on disability over time. Unmodified Wikimedia open source image by Osmosis.

Stem cells for MS? How promising is that? A new paper gives stronger reason for hope, but unfortunately this story is more complex than it seems on first glance.

New Paper

The idea of using a stem cell-related approach to treat multiple sclerosis (MS) has been around for a long time holding major promise, but there hasn’t been much in the way of high-quality trial data out there in the published literature. A paper this week from the Richard Burt team at Northwestern (NW) and conducted in part at other international sites provides a fresh boost of excitement in this area.

This cross-over study was larger than past published work. It was focused on highly active relapsing-remitting multiple sclerosis. You can see a helpful graphic about the different types of MS and their impact on disability over time at right.

Recipients of hematopoietic stem cell transplants (HSCT) with partial immune ablation fared significantly better in this study, published in JAMA, than recipients of immunosuppression alone. Also, the very large reported differences between those getting HSCT versus standard care suggest a real, meaningful effect.

The short take-home is good news for patients but with some big wrinkles to iron out as discussed below.

Complicated back story including big patient payments

Over the years, I’ve had some concerns about the NW work on HSCT for autoimmune disorders like MS. Some of these issues remain on my mind. For instance, many patients apparently had to pay to enroll. These payments, depending on insurance coverage, could sometimes be very large. It seems unusual to me that some patients would have to pay maybe $100K or more to be enrolled in a trial. That kind of practice could impact the end results of the study too.

What happens to those who cannot pay?

In addition, I don’t see an acknowledgement of patient financial contributions to the HSCT MS study in the new paper itself. Probably JAMA wouldn’t require that (maybe in part because so few studies would require major payments by trial participants). However, in my view, why not give a likely much appreciated hat tip to all the patients who not only took risks to be trial participants, but also financially contributed to the study’s funding?

Patients contributing in big ways to the financials of a study could also impact the results.

Other concerns: portrayal of ongoing trial as curative & off-study experiments on patients

In my opinion there was also a reasonable question as to whether the HSCT trials were being pitched already as curative years ago while they were still ongoing. There was buzz from patients about this as already known to work while the trial was ongoing too. This kind of thing could alter trial outcomes.

Some patients indicated that NW would give certain patients the experimental treatment in an “off-study” fashion, which was concerning to me as well and if confirmed, this would be something I’m still concerned about today. Presumably the off-study patients would still have to find large sums of money to pay toward the trial. Furthermore, the resulting paper(s) wouldn’t include their data. I don’t know if off-study severe adverse events or even deaths would have to be reported to the FDA.

FDA warning to team: any connection to this study?

It’s also a big deal that this team received an FDA warning letter a few years back for a variety of issues including failure to promptly report patient deaths. Unfortunately, we don’t know from the letter whether the deaths mentioned were amongst MS patients who were part of the group reported on in the new paper or were other patients in a different study. The new HSCT-MS paper did not mention the warning letter and it reported no patient deaths.

Numerous other issues were cited by the FDA in the warning letter too and we don’t know if any of those applied to the MS work either. Maybe not, but hard to say. Do JAMA or other journals that publish clinical trials have policies on whether papers in any way connected to warning letters must mention the warnings?

Importantly, the FDA indicated later that the team had addressed the issues in the warning so that’s encouraging.

Older immunosuppressants could have amplified apparent benefit of HSCT

The new study has at least one key limitation in that older immunosuppressant drugs were the focus, while newer drugs in this class work a whole lot better. The big difference in outcomes between HSCT + immunosuppression vs. immunosuppression alone would likely have been smaller in the context of new drugs. The use of older drugs in the study is attributable to the fact that this study simply began a long time ago.

Patient perspectives

Patients including some self-identifying as involved in this or similar studies at NW have had many useful perspectives in their comments on my 3 posts here on The Niche on the NW work (here’s the first post from which you can click on to the second and third). The patients also often let me have it for a variety of things in my posts. They are almost without exception big fans of Dr. Burt.

Take home: good news, but still big questions

In the long run, the bottom line is that the data here are very good news, but there were bumps in the road to get here and open questions remain. I hope Dr. Burt and NW can clear things up within the public domain quickly.

A number of other groups are studying HSCT for MS too and there have been preliminary results that seem promising. Looking ahead, could HSCT-related therapies become the standard of care for certain patients with specific kinds of MS? Despite its high cost, could it even become cost-effective when compared to expensive, toxic long-term drug therapies alone? I hope so as this would help thousands of patients.

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