I bring you another story from the Cardiff University in UK, and this time it is not about some obscure dishonest professor and small change off Traditional Chinese Medicine. This time, it is about this Welsh university’s former President, Sir Martin Evans, winner of the Nobel Prize of 2007, for his “discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells”. And unlike another Nobelist, Louis Ignarro, Evans did not undersell his Nobel honours to peddle pomegranate juice and Herbalife supplements, he instead set up some serious business of his own. Together with a struck-off dentist Ajan Reginald, Evans founded in 2009 the company Cell Therapy Ltd, which now goes by the name Celixir. Evans is the official director of the company, and he even presented his new start-up on the BBC hit show “Dragon’s Den” same year.
The company sells, what else, stem cells, derived from bone marrow which Evans and Reginald call iMPs. Some serious money is flowing, and clinical trials are happening. The idea is to cure heart patients with patented cells, and it is clear as mud what kind of cells those are. In the initial experiment performed in Greece in 2009 it used to be patients’ own bone marrow cells, which in the clinical trial changed to unspecified “healthy donor” mesenchymal cells, but now in an upcoming next stage clinical trial in UK, yet another kind of proprietary cells is to be used. The issue of immune-rejection is to be addressed by some mysterious “genetic engineering”, for which however no approvals were issued.
It is well known who Sir Martin Evans is, and all the many awards and honours he received. But it is worth reading up who his closest business associate Ajan Reginald is.
Reginald is namely a struck-off dentist, his own lawyers insisted that he suffers from “cognitive difficulties”. This was reported by Wales Online in 2012 :
“Mr Reginald, now aged 40, was struck off as a dentist in 2005 after a professional committee found he had mistreated 24 of his patients at a practice in Redditch, Worcestershire. One of the complainants was left in “absolute agony” after he drilled through a tooth into her gum. He had failed to fit crowns properly, provided such poor root canal treatment that teeth were lost and carried out bridge work that was unnecessary.
Mr Reginald was found guilty of serious professional misconduct and of making dishonest claims to the Dental Practice Board in respect of work not done on 20 named patients. At the end of the General Dental Council conduct hearing, chairman Professor Colin Smith said he had to be struck off to protect the public, adding that the committee had taken into account information from Mr Reginald’s solicitors in relation to his medical condition and “cognitive difficulties”, but said this would not explain many facts proved against him.
On subsequent CVs, Mr Reginald made no reference to his period as a dentist dating from 1996 when he qualified.”
At that time Reginald pretended to be affiliated with the Institute of Life Sciences in Swansea University, which proved not true. He also used to call himself Dr Reginald and was listed to have a PhD degree from Northwestern University in Evanston, Illinois, awarded to him in 2006. Wales Online wrote:
“We asked the university whether Mr Reginald had been awarded a PhD. A spokeswoman confirmed he had not, adding: “Ajanthan Reginald attended Kellogg from September 2002 to June 2004 and received a Master of Business Administration on June 18, 2004.”
Reginald is a ruthless businessman, and this is what made him filthily rich. In 2011, The Times reported how he apparently tricked an autistic inventor, Jason Perkins, whom he apparently met at Evans’ pitch at Dragon’s Den in 2009:
“The Peepo is an electronic device that blind people hold in their left hand along with
the lead of their guide dog. It can be voice-activated by saying a postcode. It then guides the owner by sending pulses to different parts of the hand. Perkins said:
“I just wanted to help people who had greater challenges than I did. But something has gone wrong somewhere. My illness means I don’t fully understand people’s emotions or intentions and I am far too trusting.”
At a Dragons’ Den-style evening at Cardiff city hall Dr Ajan Reginald, 39, offered to
invest in the company if he could become a director. Perkins said:
“Once he was a director he said that if I didn’t sign over my patent it was illegal. He kept using language I didn’t understand. I feel awful now that the company could be struck off.”
Reginald claims he took control of the firm when Perkins went to Canada to start a
new life. Perkins says he went for less than a month to recuperate after coming closeto a mental breakdown.”
None of that ever mattered to Evans. And why should it? In 2016, his business partner Reginald helped Sir Martin to some serious money: the iMP technology was licenced to a company in Japan, paid upfront:
“Daiichi Sankyo will undertake all development, regulatory and commercial activities for iMP cells in the territory of Japan only, while CTL retains its worldwide rights outside of Japan as well as global manufacturing responsibilities. Under the terms of the agreement, CTL receives a £12.5 million upfront licensing fee and additional milestone payments and royalties.”
In 2017, Reginald paid himself a salary of £ 633,533 from Cell Therapy Ltd funds, £300k more than the previous year. Evan’s own benefits went from less than £9500 to over £125k. The big money from Japan was possible because of this 2016 paper describing the Phase 2a clinical trial at AHEPA University Hospital in Thessaloniki, Greece:
Kyriakos Anastasiadis, Polychronis Antonitsis, Stephen Westaby, Ajan Reginald, Sabena Sultan, Argirios Doumas, George Efthimiadis and Martin John Evans
Implantation of a Novel Allogeneic Mesenchymal Precursor Cell Type in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting: an Open Label Phase IIa Trial
Journal of Cardiovascular Translational Research, 01 April 2016. DOI: 10.1007/s12265-016-9686-0
Reginald’s affiliation is provided as “Experimental Therapeutics, University of Oxford”, yet the university staff register holds no records of his affiliation there (according to his LinkedIn profile, he might have been MSc student in Oxford). Another coauthor, Sabena Sultan (“Global Head of Research” at Celixir) listed as her affiliation as “John Radcliffe Hospital, Oxford University Hospitals, Headington, Oxford, UK”. The hospital provided this information however:
“There are no Human Resources (HR) records for this individual in relation to her employment as a member of staff or as a honorary contract holder”.
This is the paper’s abstract:
“Heart failure is a life-limiting condition affecting over 40 million patients worldwide. Ischemic cardiomyopathy (ICM) is the most common cause. This study investigates in situ cardiac regeneration utilizing precision delivery of a novel mesenchymal precursor cell type (iMP) during coronary artery bypass surgery (CABG) in patients with ischemic cardiomyopathy (LVEF < 40 %). The phase IIa safety study was designed to enroll 11 patients. Preoperative scintigraphy imaging (SPECT) was used to identify hibernating myocardium not suitable for conventional myocardial revascularization for iMP implantation. iMP cells were implanted intramyocardially in predefined viable peri-infarct areas that showed poor perfusion, which could not be grafted due to poor target vessel quality. Postoperatively, SPECT was then used to identify changes in scar area. Intramyocardial implantation of iMP cells with CABG was safe with preliminary evidence of efficacy of improved myocardial contractility and perfusion of nonrevascularized territories resulting in a significant reduction in left ventricular scar area at 12 months after treatment. Clinical improvement was associated with a significant improvement in quality of life at 6 months posttreatment in all patients. The results suggest the potential for in situ myocardial regeneration in ischemic heart failure by delivery of iMP cells."
The associate medical director at the British Heart Foundation, Jeremy Pearson, raised a valid criticism of this study:
“This very small study suggests that targeted injection into the heart of carefully prepared cells from a healthy donor during bypass surgery, is safe. It is difficult to be sure that the cells had a beneficial effect because all patients were undergoing bypass surgery at the same time, which would usually improve heart function”.
Indeed, you can combine bypass surgery with prayer dirges and shamanic dance, and then claim that it was actually the ceremony which helped the patients. Problem is, you can’t patent shamanic dancing, even if it brings much less infection risk with it than injection of lab-expanded cells into a heart. Nevertheless, the stem cell success story was celebrated in all the big newspapers in UK: in The Guardian, The Telegraph, on BBC, and of course also in Greece. And yet, nobody bothered to ask what the magical stem cells actually were.
The proprietary product, injected into the hearts of 11 patients in Greece in this Phase 2a clinical trial in 2012-2013, was presented as “a novel mesenchymal precursor cell type (iMP)”:
“iMPs are a novel and distinct mesenchymal precursor cell type discovered and isolated by Cell Therapy Limited, UK (CTL), as a potent cellular therapy intended for cellular therapy in cardiac regeneration”.
These cells seem to be some kind of macrophages from how they are described in the paper. However, when the trial was registered on ClinicalTrials.gov in December 2012, it spoke of “allogeneic mesenchymal stem cells”, not of the magic iMPs. And even before that, in 2010, Reginald announced a different methodology:
“The new treatment can be rolled out so soon because the cell therapy pioneered by the firm uses the patient’s own cells and is essentially a transplant – so it does not follow complex regulatory approval associated with new medicines. It would be administered in hospital through an IV drip, which the company’s founders say will mean that it will be easy for hospitals to use.”
There is no source of funding provided in the Anastasiadis et al 2016 paper, and this is not a minor issue. Of note, right after the paper was published, Reginald registered a new company in Thessaloniki: Cellular Treatment Greece. Clinical trials are very expensive, hence who paid for it and why is the source of money secret? The trial was originally scheduled to recruit 30 patients, but in Anastasiadis et al 2016 the authors claim: “The phase IIa safety study was designed to enroll 11 patients”. Maybe the clinical trial run out of money, maybe the missing 19 patients did not return for evaluation, having died (of course of utterly unrelated causes) or showed some undesired adverse effects, and thus disqualified themselves from being included in the final paper.
Now Reginald and Evans intend to recruit 50 patients: a new phase 2b clinical trial is to follow in UK, at the Royal Brompton & Harefield NHS Foundation Trust hospital. It is scheduled to begin right now, when you read this story, in April 2019.
The key figure, who made the Greek stem cell clinical trial possible, is the famous British heart surgeon Stephen Westaby, aged 71. He now acts as Chief Medical Officer for cardiology with Celixir. In 2013, he was listed as shareholder with this company, but he forgot to declare those conflicts of interest in the Anastasiadis et al 2016 paper. This is how Westaby once described himself in a newspaper article:
“At medical school I went from being a nice, considerate young man who wouldn’t say boo to a goose to an aggressive young man who by then was fit to be a heart surgeon. I got injured playing rugby — a bi-frontal head trauma that causes psychopathy — and I had a complete personality change. If you look at psychopaths’ brains on MRI scans, they’re short of grey matter at the front. I wasn’t born like that, but somebody provided me with it. And what we know now actually, is that a very high number of surgeons score very, very highly on the psychopathic assessment lists. You’ve got to have the characteristics of a psychopath to make a good surgeon”.
Evans and Reginald did wise to recruit Westaby to their business. He was namely the lead author on a compassionate use study with bone marrow cells with one patient, performed at AHEPA University Hospital in Thessaloniki in 2009, and celebrated in UK’s newspaper Daily Mail. The results were published with same Greek co-authors only 3 years later, in 2012, then without Evans or Reginald:
Kyriakos Anastasiadis, Polychronis Antonitsisa, Argirios Doumas, Georgios Koliakos, Helena Argiriadou, Christina Vaitsopoulou, Paschalis Tossios, Christos Papakonstantinou, Stephen Westaby
Stem cells transplantation combined with long-term mechanical circulatory support enhances myocardial viability in end-stage ischemic cardiomyopathy
International Journal of Cardiology (2012) DOI: https://doi.org/10.1016/j.ijcard.2011.07.062
Now, Westaby is fully behind Celixir’s technology and advertises for the new phase 2b clinical trial at Royal Brompton, calling the method “bloody marvellous”. the iMPs are now called “Heartcel” and Westaby claims, out of the blue, that those are genetically engineered:
“During production it undergoes genetic engineering making it “immune privileged”, meaning it is biologically acceptable to all recipients and will not be rejected”.
Nowhere does Anastasiadis et al 2016 paper make any mention of any gene engineering, nothing is being turned “immune privileged” there. In the Anastasiadis et al 2012 case report, the patient received his own cells, the Anastasiadis et al 2016 paper speaks of “bone marrow aspirate from a healthy donor” without telling any details, or where the cells were stored and cultured. There is certainly no mention of any “immune privileged” engineering there. The UK Human Tissue Authority, which would be in charge of regulating such gene-engineered cells, replied:
“over two years ago, Celixir did apply for a licence from the HTA and a site visit was conducted. However, the activities they described as being undertaken at that time were considered not to be licensable activities.”
It is actually not at all clear which cells the authors have used in Greece and which they intend to use in UK. Patricia Murray, professor of stem cell biology and regenerative medicine at the University of Liverpool, is the one who researched the information presented in this article, after having heard the Phase 2b clinical trial at Brompton. She explains her concerns:
“The protocol in the paper describes a method for isolating mononuclear cells from bone marrow aspirates (BM-MNCs). It is not clear why the authors describe the cells as ‘immunomodulatory progenitor cells (iMPs)’. It would be expected that the BM-MNC population contains monocytes, which can differentiate to macrophages and dendritic cells, so maybe the authors are referring to the monocyte component of the population as ‘iMPs’? They state in the discussion that the ‘iMPs’ do not express the monocyte marker, CD14, but results are not shown for that. The authors do not appear to have published a paper showing detailed characterisation of the ‘iMPs’.
A recent paper from the FDA states the following: “…to ensure that [stem cell therapy] fulfils its promise to patients, we must first understand its risks and benefits and develop therapeutic approaches based on sound science. Without a commitment to the principles of adequate evidence generation that have led to so much medical progress, we may never see stem-cell therapy reach its full potential.” (Marks et al (2017) NEJM 376;11 1007-9).
It seems that in some cases, the drive to commercialise ‘stem cell’ therapies is taking priority over these important principles.”
Another former associate at Reginald’s & Evans’ Cell Therapy Ltd/Celixir used to be the former First Minister of Wales, Rhodri Morgan. Morgan was appointed in 2013 President of Cell Therapy Ltd, and this is how he was quoted in Wales Online back then:
“I was very lucky, after my heart attack I had zero heart muscle damage. What stem cell therapy gives us is the opportunity to repair damaged heart muscle. Hitherto it’s been un-repairable,” he said.
“It’s a very exciting Welsh company with world beating technology of very high value to patients with heart diseases. We believe the same technology could be applied to knee problems and gynaecological problems.”
With Morgan’s help, Reginald and Evans’s business partnered with Chinese firm Shijiazhuang in order to produce bioreactors for heart stem cells. Morgan couldn’t fully profit from the tremendous regmed cash flow, as the Welsh politician died in 2017, the company was valued at £200 million at that time. Now Evan is back to being the company’s president.
Evans and Reginald have big business plans. They even patented a type of mesodermal progenitor cells to cure cancer.
It seems Sir Martin and Mr Reginald engaged in plagiarism.
This patent for the “progenitor cells of mesodermal lineage” (PMLs) that was filed in 2012, among its authors is Sir Martin. It says that the same culture conditions used to generate mesecnhymal stem cells (MSCs) from bone marrow can be used to generate ‘PMLs’. Yet on pages 4 and 6 it says:
“Fig. 5 shows that progenitor cells of mesodermal lineage migrate to the fracture site in a time and CXCR4 dependent manner. Bioluminescence (BLI) was performed at days 1 (ﬁrst row), 3 (second row), 7 (third row) and l4 (fourth row) after fracture / transplantation in mice with tibia fracture that received a transplant of either 10^6 PML P Act Luc (PML) (left column), PML ﬂ Act Luc CXCR4+(CXCR4(+)) (middle column), or PML P Act Luc CXCR4 (CXCR4( )) (right column). […]
The PMLs of the invention are not stem cells. In particular, they are not mesenchymal stem cells (MSCs).”
Big problem here is that Fig 5 is a plagiarised and misrepresented data-set from a manuscript that was published by other scientists 3 years before, in a Wiley journal: Granero-Moltó et al, Stem Cells, 2009. The paper and the Celixir patent share no common authors. The cells in GraneroMolto et al 2009t are in fact MSCs, the Figure 1A legend goes:
“Figure 1. MSC migrate to the fracture site in a time- and CXCR4-dependent manner
(A): BLI was performed at day 1, 3, 7 and 14 after fracture/transplant in mice with tibia
fracture transplanted either with 10^6 MSC- β -Act-Luc (MSC) (left panel), MSC- β -Act-Luc-CXCR4+ (CXCR-4+) (middle panel) or MSC- β -Act-Luc-CXCR4-(CXCR-4−) (right panel). Graded color bar indicates BLI signal intensity expressed as photons/sec/cm^2/sr.”
So it looks like Celixir’s business model and clinical trials on up to 150 patients are based on a false patent which contains plagiarised material.
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