Cell therapy clinical trials – 2014 Report

by Alexey Bersenev on January 22, 2015 · 0 comments

in annual reports

This is 2014 report of registered cell therapy clinical trials. Every year I give a snapshot of some tracked data, captured from international clinical trials databases. You can see previous annual reports here.

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Definitions and criteria
I tracked clinical trials which fall in definition of cell therapy: administration of living cells in human with therapeutic purpose. Besides “traditional cellular products”, I also included tissue engineered constructs with cells, cellular gene therapy and use of cells as a vehicles for therapeutic agent delivery. I tracked all clinical trials which were registered from Jan.1, 2014 to Dec. 31, 2014 in international registries.

The following categories were excluded from analysis:
1. Cells for homologous use:

  • hematopoietic cells for recovery of blood formation in hematological malignancies or for recovery of hematopoiesis after chemotherapy for treatment of solid tumors;
  • gene-modified hematopoietic cells for correction of metabolism errors and inherited immune diseases (example: SCID);
  • ex vivo expanded hematopoietic cells for enhancement of engraftment in hematological malignancies;

2. Platelet rich plasma trials
3. Extracorporeal devices with cells (no administration of cell inside of body).

Data mining strategy
“Hand coding” included:

  • using multiple key words and phrases
  • exclusion of overlaps between search results
  • exclusion of duplications between databases
  • reading trial description and “coding” the following categories: trial ID, country, phase, status, indication, cell type, donor type, type of sponsorship, name of company-sponsor, study acronym, number of patients in enrollment.

Key words:

    • “cell therapy”
    • “stem cell”
    • “cord blood”
    • “umbilical cord”
    • “bone marrow”
    • “cancer vaccine”
    • “tissue engineering”
    • “cellular”
    • “mesenchymal”
    • “adipose”

by name of company

Total number of trials tracked: 372
Number of duplications between databases: 8

Databases
The following databases were scanned:
US NCT (NIH-FDA)
European EUCTR (EudraCT)
Japanese UMIN, JMA CCT
Indian CTRI
Chinese ChiTCR
Iranian IRCT
Australian/NZ ANZCTR
UK ISRCTN
Dutch NTR
South Korean CRIS

All international databases, except NCT, were scanned via WHO Search Portal (ICTRP). Each database was checked separately to capture everything, missed by ICTRP.

Databases representation:

databases14

Demographics:

countries14

regions14

Sponsorship
All trials were divided on 2 categories – “academic” or “industry”. The term “academic” combined any monetary support (governments, funds, charities…) other than company-sponsored. Term “industry” also includes (1) companies – collaborators, when sponsorship is not clear from trial description and when company manufactured/ provided cellular material, (2) commercial for-profit clinics with unclear regulatory authorization.

sponsorship14

Cell types

donortype14

majorcelltypes14

MSC14

immunecells14

othercells14

Abbreviations: MSC – mesenchymal stromal cells, HSPC – hematopoietic stem/ progenitor cells, TIL – tumor-infiltrating lymphocytes, DC – dendritic cells, BM – bone marrow, MNC – mononuclear cells, NK – natural killer cells, CIK – cytokine-induced killers, SVF – stromal vascular fraction; MB – mobilized blood; T-regs – regulatory T-cells; ESC – embryonic stem cells; CAR – chimeric antigen receptor; CB – cord blood; DLI – donor lymphocyte infusion.

Indications:

indications14

This is a first snapshot from 2014 report. I’m planning to post trends analysis, trials results analysis and some other data. Stay tuned!

How to cite:
Bersenev Alexey. Cell therapy clinical trials – 2014 report. CellTrials blog. January 22, 2015. Available: http://celltrials.info/2015/01/22/2014-report/

You’re free to share these data with appropriate credit under CC BY-ND 3.0 license.

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One clinical study, which was released 2 weeks before Christmas holidays captured my attention (but not attention of mass media). One of the most scandalous Indian “stem cell tourism” clinic Nutech Mediworld published(!) results of the study, which evaluates embryonic stem cell transplantation in children with cerebral palsy. Yes, you’re reading it correctly – embryonic stem cells in children! Now, I have no idea how this study was approved by Independent Ethics Committee (as stated in the paper) and how this manuscript passed peer review of Journal of Translational Medicine, but here is the fact – study is done and results are published. I think, we should at least read it, try to analyze it (it’s not easy!) and maybe discuss it. Before we dive into the study, I’d like to give you a little bit of background.

Geeta Shroff – a director of Nutech Mediworld – is a highly controversial and highly criticized by “westerners” figure in “stem cell tourism”. She is “a retired obstetrician and self-taught embryonic stem cell practitioner”, who used to be skeptical about sharing data with peers:

Dr. Shroff does not share data, has not submitted to peer review (she’s said she has “no peers”) and has performed no controlled clinical trials. While patients call her a saviour, other researchers call her a quack, a fraud or names even less flattering.

Well, seem like she changed her mind lately. I remember, that many “critics” refused to believe that actual embryonic stem cells (ESC) were used by Nutech. They thought that Nutech used term “embryonic” for fetal cells, derived from aborted material. But, according the paper it’s real single ESC line, derived from preimplantation embryo post IVF.

Let’s move to the study. As I mentioned above, study protocol was approved by Ethics Committee. Also, it was reported to “National Apex Body” (I don’t know what is it, but sounds like something on government level). Yet another interesting fact – the last author of the paper is a government worker (Ministry of Home Affairs, Government of India). I’d like to remind you that this is not the first “embryonic stem cell study” from India. So, I think, one thing we have to realize is that if these kind of studies could be “shocking” and “hard to imagine” in US or Europe, it could be “normal” and totally acceptable for India or some other countries. Also, we have to realize that reporting of some particular number of patients (“cherry picking”?), treated in one particular “stem cell clinic” is very different from well designed clinical study or trial. We have no way to check how information, presented in the paper is accurate, since it’s not a registered trial and there is no (as far as I understand) oversight from any agency.

Next, I’d like to touch ESC product composition, which was used in kids with cerebral palsy. The authors did not bother much with differentiation of ESC into mature cells. In fact, transplanted ESC were Oct4+, SSEA3+, Nanog+, Sox+, betaHCG+, CD34+, Nestin+, GAF+ and NeuN+. So, it was a great mix of undifferentiated ESC and neurally induced progenitors. There is a reference to Shroff’s patent in the paper. If we look at this patent (which btw covers everything – all types of ESC derivatives and all kind of diseases), we can see that ESC product contains at least 40% of undifferentiated cells:

…in one embodiment, the portion of undifferentiated stem cells will be no more than about 80% of the total population of cells. In another embodiment, the portion of undifferentiated stem cells will be no more than about 40% of the total population of cells.

ESC progeny in the product are not characterized and could be hematopoietic, neural, mesenchymal, hepatic… Cells were infused and injected multiple times via all possible routes: intramuscular, intravenously, “intra-caudal”, as eye drops, as nasal spray, retro-bulbar, as oral or ear drops. Since, there was no immunosuppression, researchers check hypersensitivity to ESC product via skin probe before starting a treatment. One more interesting thing – the cells were cryo-stored in pre-filled syringes at -20C. There is no viability data in the paper.

91 children were included in the “study” with age from 1 month to 18 years with different degree and course of disease. The authors noticed functional improvement in all ages and starting scores of disease, based on functional scales (GMFCS-E & R). Also, they indicate improvement in cognition. Of course, we cannot make solid conclusions about efficacy, since it was not randomized and controlled trial. About 10% of patients had adverse events, such as swelling, itching, fever, chest congestion and others. However, there is no information about long-term safety and, especially, about such important potential complication as ESC-related excessive tissue growth. According the paper, about half of patients were not followed more than 3-6 months after the first treatment (did not return for 2nd and 3rd phases of treatment).

Of course, this “study” causes a lot of questions on every level – from ethical approval (without any pre-clinical animal studies) and study design to cell product characterization and clinical outcome. What puzzles me is that, apparently, Indian government agencies, as well as independent ethics committee were aware of the study and did not see any problem with it. I’d assume that Nutech itself did not see any problem with experimentation on children (for money!), because they had previous experience with ESC-based treatments of adults. Unfortunately, we cannot learn a lot from this study simply because of its design and lack of valuable information in the paper. I think, we as community should be aware of such “studies”, because it is a part of “cell therapy” or “stem cell therapy” or even “stem cell therapy industry”. What do you think of all this, guys?

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Cell therapy clinical trials failures in 2014

by Alexey Bersenev on January 4, 2015 · 3 comments

in Uncategorized

Today, I’d like to highlight the most interesting, in my opinion, clinical trials failures, reported in 2014. As field is moving to efficacy (Phase 2) trials, we are starting to see more failures. In this overview, I’m going to focus on efficacy results. I hope we can learn a lot from these failures and avoid mistakes in designing new trials in the future.

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1. MultiStem fails in Phase 2 ulcerative colitis trial
This year, US-based company Athersys announced results of stem cell product MultiStem infusion in patients with ulcerative colitis. The trial failed to meet efficacy end points in interim analysis – there was no difference between MultiStem and placebo groups. The trial was conducted by Pfizer in US, Canada and Europe.

2. Results of Miltenyi’s Cardio 133 trial
Unfortunately, all cardiac cell therapy trials, sponsored by Miltenyi Biotec and involved purified CD133+ cells, are failing. In 2013, the company terminated its Phase 1 CABG trial, due to lack of recruitment. Cardio 133 Phase 2/3 randomized placebo-controlled trial was assessing autologous CD133+ bone marrow-derived cells in ischemic heart failure. The trial was completed in 2011, but results were released to public this year. Cardio 133 failed due to lack of efficacy – cells were not different from placebo.

3. Allocure terminates ACT-AKI trial
Phase 2 trial, conducted by AlloCure, which assessed mesenchymal stromal cells in acute kidney injury, was terminated in August due to futility. The trial started in 2012 with enrollment target 200 patients. There was no official information from the company, but some results and decision to stop a trial were reported on conference – look here and here.

4. Indian stroke trial
Results of ischemic stroke trial, which assessed efficacy of autologous bone marrow mononuclear cells, were recently published. It was randomized, multicenter controlled trial with n=120. The trial failed all end points – there was no difference between cells and control group. Trial was sponsored by Manipal Acunova.

5. Post-marketing approval trial of Korean “stem cell drug” HeartiCellGram-AMI
In July of 2011 South Korean company FCB Pharmicell got marketing approval for the world’s first stem cell product for myocardial infarction – HeartiCellGram-AMI. According KFDA, company continues to conduct clinical trials to demonstrate efficacy and reports o agency. The results of Phase 2/3 trial, assessing HeartiCellGram-AMI in myocardial infarction, were recently published. It failed! Secondary end points were missed, but also primary endpoints were not different between “cells” and “placebo” groups. If you look at table 4 – global LVEF by SPEC at 6 months in MSC group =55, in placebo group =53.9. It is unclear how KFDA will react and how it will affect sales of the drug.

6. Adipose MSC failed in ARDS
Small Phase 1 trial in China was testing allogeneic adipose tissue-derived mesenchymal stromal cells (MSC) in acute respiratory distress syndrome (ARDS). Researchers randomized 12 patients in experimental and placebo control groups (6 patients per group). Unfortunately there was no any clinical difference between “cells” and “placebo” groups. Even though, trial was underpowered to assess efficacy properly, the authors more likely will not pursue the same strategy.

7. CD133+ in CLI is not feasible
This trial is a rare example of feasibility failure. Results of randomized, double-blind, placebo-controlled trial, assessing autologous mobilized CD133+ cells in critical limb ischemia (CLI), have been published. Unfortunately, trial was halted, due to lack of feasibility. And the reason is inability to achieve “the pre-specified minimum mobilized cell dose threshold” equal 50 millions of CD133+ cells. Only 3 of 10 patients passed this threshold. The obvious lesson – don’t use mobilization protocols to collect CD133+ cells from periphery.

8. MSC failed in multiple sclerosis
Spanish Phase 2 trial assessed long-term safety and efficacy of autologous bone marrow-derived expanded MSC in multiple sclerosis. The authors reported 9 patients only (5 in MSC group and 4 in placebo), but efficacy end points were missed. I’m not sure how they got an approval with n=9 for efficacy assessment. Failure 2-folds!

9. Chinese diabetes trial
Autologous mobilized blood-derived mononuclear cells were used (as hematopoietic graft) in children with newly diagnosed type 1 diabetes. 14 patients received cell therapy and 28 patients were assigned as control. At 3-5 years readout, there was no advantage in cell therapy group in terms of insulin dose and glucose control.

10. Stempeucel failed efficacy in AMI
One more commercial cardiac cell therapy trial. Indian company Stempeutics Research assessed allogeneic bone marrow-derived expanded MSC in acute myocardial infarction (AMI). The results of the trial indicate that there was no difference in LVEF and perfusion between groups. Even though, product candidate demonstrated good safety profile, company should work on better design (efficacy end points) of future trials.

These are some highlights of the year. Of course there were more failures, but I was trying to pick the most interesting cases. I’ll add few more in the comments to complete the picture. Please contribute to the list of failures in comments!

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Top 10 cell therapy clinical studies in 2014

January 2, 2015

At the end of the year I analyze results of clinical studies in cell therapy. Today, I’d like to highlight 10 most significant, in my opinion, clinical studies with published results. Taking in account excellent safety profile of most cellular therapies, I was trying to focus on efficacy and long-term outcomes. Do cells really work? […]

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Cell therapy highlights from #ASH14

December 8, 2014

Annual 56th meeting of American Society for Hematology (ASH) is about to finish in San Francisco. I was following conference via twitter and I was amazed by stream of tweets – very good tweets, high value tweets, unpublished data tweets, 1 tweet per second! There was no “scientific tweets”, but almost all were “clinical”. Here, […]

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Some thoughts on results of NeoStem cardiac cell therapy trial

November 19, 2014

In the last two days I was involved in lively twitter discussions about the results of Phase 2 PreSERVE-AMI clinical trial, sponsored by NeoStem. Unfortunately, interpretation of results divided professionals for two camps – (1) trial is failed and (2) trial is successful. Why did it happen? Maybe the truth somewhere in the middle? I’d […]

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Stem Cell Autopsy: Survival and fate of fetal neural stem cells in NeuralStem ALS trial

November 16, 2014

I’ve written two years ago about autopsy findings from ALS patients, treated by neural stem cell product candidate, commercialized by NeuralStem. Recently, company published an update on pathology of spinal cords and donor cell fate after transplantation. The article is freely available online. The authors analyze 6 postmortem cases of transplantation investigational product NSI-566 into […]

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Tracking results of clinical studies in cell therapy

May 11, 2014

It has been awhile since I called to collaborate and proposed to track results of clinical trials and studies. Unfortunately, nobody expressed an interest. So, starting from this year, I’ve attempted to do it myself. Today, I’m sharing results of the first 3 months of this experiment. Methodology: I track results of: published clinical trials; […]

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Trends in cell therapy clinical trials 2011 – 2013

March 2, 2014

Since last year, I’m sharing some trends in cell therapy clinical trials. Real time tracking of all registered trials allows to identify trends in multiple dimensions. Today I”m posting a snapshot of trending for the last 3 years – from 2011 to 2013. There could be some minimal discrepancies in numbers between this and previous […]

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Role of monocytes in regenerative cell therapies

February 16, 2014

As I’ve written before, we largely don’t know what cell population underlies the mechanism of action of bone marrow or cord blood transplantation in regenerative medicine. Before infusion in neurological, cardiac, hepatic and other conditions, cord blood or bone marrow usually undergo minimal processing – red blood cells and platelet depletion. What remains before infusion […]

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