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.
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!