Trachea transplanters without borders

News from the trachea transplant entrepreneurs. What with the UK authorities having officially suspended both phase 1 clinical trials Inspire and RegenVox, and the EU phase 2 clinical trial TETRA going nowhere, the technology’s owner, Liverpool-based company Videregen decided to seek new clinical partners. Surgeons and universities from outside the EU, especially from US, China and Japan are invited to test Videregen’s trachea transplant technology, which was originally developed together with Paolo Macchiarini by the UCL laryngologist and paid Videregen advisor Martin Birchall.

While tracheal stenosis was the indication sought to treat with trachea transplants in UK and EU (as the authorities drew curtains before the show even started), Videregen now goes for bronchopleural fistula, while pretending (quite dishonestly) that “all required regulatory and ethical approvals necessary to commence clinical trials in the UK” would exist.

The other bit of news is that UCL finally published the 2015 PhD thesis of Birchall’s student Claire Crowley (now postdoctoral scientist in charge of clinical research on oesophagus replacement with UCL professor and another trachea transplanter Paolo De Coppi). It reads as if certain parts of the thesis were edited or even written by UCL’s legal department. Not what thesis says, but what is omitted is worrisome. Crowley was namely responsible for the production of 3 trachea replacements requested by Birchall, which all proved deadly to their human recipients. One was a decellurised cadaveric graft, and two were POSS-PCU plastic tracheas, which Crowley made herself, in the lab of her other advisor, the (now sacked) UCL nanotechnologist Alexander Seifalian. Yet the thesis only mentions one graft, in a brief one-page statement, simply because Crowley could not deny her role there. She is co-author on the Macchiarini paper Jungebluth et al Lancet 2011 telling the alleged success story of the very first plastic trachea transplant performed in Sweden on the patient Andemariam Beyene. Otherwise, Crowley never mentions in her thesis the cases of Keziah Shorten or Shauna Davison, whose lethal trachea grafts she also made herself, as part of her PhD studies.

Looking to partner with universities, hospitals and surgeons

EU Commission repeatedly denied me all access to the TETRA documentation, arguing that it would hurt the commercial interests of the study’s participants and its sponsor, Videregen (read here and here). Arguments of overruling public health and safety were dismissed, since the necessary phase 1 clinical trial Inspire was suspended (because of my reporting), hence there being no danger of  phase 2 clinical trial TETRA progressing to the patient recruitment stage. This however is only partially true. EU patients might be now more or less safe from being subjected to trachea transplant experiments (which proved 100% lethal in preclinical pig studies), but patients outside the EU are not. Videregen namely “seeks universities, hospitals and surgeons for clinical testing of their tracheal replacement product“. All that Liverpudlian entrepreneurs need is a willing clinical partner in a country with sufficiently lax oversight and regulations and authorities ready to turn a blind eye. A practice sometimes used by unscrupulous European researchers drawn by the possibilities of easier human experimenting, for example as I reported here and here.

Ready-to-use decellelurised and regenerated tracheas are offered to be supplied to surgeon partners outside the EU, though it is not clear who will manufacture those. According to TETRA set-up, the two production facilities are UCL (precisely, Mark Lowdell‘s GMP lab at Royal Free Hospital, where past UCL tracheas were made) and the TUMCells centre at the Technische Universität (TU) München in Germany.

A partnering opportunity TRUK20180323001 was listed on the Enterprise Europe Network on March 23rd 2018 and edited on April 5th, obviously by the small-to-medium-sized enterprise (SME) Videregen. It is not clear if their TETRA partners were aware or even active part of this. The edited version is bad enough, but the original posting, still hosted by Bayern Innovativ, is embarrassing or even criminal:

UK-based SME seeks universities, hospitals and surgeons for clinical testing of their tracheal replacement product under technical or research cooperation agreement

Country of Origin: United Kingdom
Reference Number: TRUK20180323001
Publication Date: 23 March 2018

Summary

A UK-based SME has developed proprietary technology to create personalised organ replacements. The tissue engineered products for trachea replacement and treatment of bronchopleural fistula are GMP and clincial-ready. The SME is looking for universities, hospitals and surgeons who will be able to conduct the clinical trials required to take the product to market. It is envisaged that the partnership will
take the form of a technical cooperation or a research cooperation agreement.

Description

Organ transplantation is a useful way of treating severe disease. However it has the two drawbacks of rejection due to tissue incompatibility between donor and recipient and availability of organs for transplantation in the first instance.
A UK-based SME has developed organ replacement technology aimed at addressing these problems. It has developed proprietary technology to produce biological scaffolds to which a patient’s own stem cells are added, creating a personalised organ replacement available on demand and without risk of tissue incompatibility.

This has been furthest developed in the SME’s tracheal replacement technology, which is also aimed at the treatment of life-threatening bronchopleural fistula. Donated human trachea are processed using SME’s proprietary technology to remove cells and cellular remnants. Autologous mesenchymal stromal cells are used to reseed the decellularised tracheal scaffold, which is then used to replace the diseased portion of the patients trachea.

Good manufacturing practice (GMP) capability is in place for the trachea replacement product and the product has all required regulatory and ethical approvals necessary to commence clinical trials in the UK.

The SME is now looking to partner with universities, hospitals and surgeons in order to conduct clinical trials of their technology and enable them to take the technology to market. It is envisaged that the partnership will take the form of a technical cooperation agreement or a research cooperation agreement.

Expertise sought

The SME is looking to partner with universities, hospitals and surgeons who have experience in the regenerative medicine field and in particular with tissue / organ transplantation and diseases of the airways . In particular the SME is interested in potential partners with expertise or experience in relation to airway pathology and surgery Partners with experience in conducting clinical trials in this field are especially sought.

Requested partner

The UK SME is looking to partner with universities, hospitals and surgeons in order to carry out clinical trials of its trachea replacement technology. They are especially interested in making connections in the US, China and Japan but are open to all countries.

The SME will provide their technology to the partner for the purposes of conducting the clinical trial. The partner is expected to be able to conduct the trial including carrying out the required surgery.

It is envisaged that the partnership will take the form of a technical cooperation or a research cooperation agreement.

The SME is not named, but it is obviously Videregen, which holds the intellectual property (IP) for the technology of decellurised cadaveric trachea, which in turn was developed in collaboration with UCL by Tahera Ansari and Paul Sibbons at Northwick Park Institute for Medical Research (NPIMR). That NPIMR in Harrow (greater London) is also the institution where preclinical testing for trachea and larynx decellurised grafts took place, with two pigs receiving trachea transplants dying right after. Videregen is well informed, in fact they proudly presented those two dead pigs to European Medicines Agency (EMA) as evidence that the method works. Don’t ask, just read here.

All that is once again confirmed in an email which Steve Bloor, Videregen’s CEO sent to his UCL partners Birchall and Lowdell in 2014:

“Hi Martin, Mark,

We are hopefully on our final few days of legal documents and will close out our investment next week!!

As part of our due diligence process we have to disclose everything we know about the technology and users of the technology derived from NPIMR. The RegenVOX project uses the decellularisation processes/methods from NPIMR (I know Tahera is a Co-Investigator of the MRC project), as NPIMR has assigned their IP to Videregen (which includes the trachea and larynx decellularisation methods), our major investor (Spark Impact) has requested that I obtain a letter of recognition or acknowledgement from UCL that the larynx decellularisation methods  (background IP to the RegenVOX project) belongs to NPIMR (and by assignment to Videregen).

Sorry to request this at the last minute, just trying to close-out the request from our lead investor with respect to IP ownership and uses so we can complete the investment round next week.

Could you help obtain an acknowledgement letter from whomever is the most appropriate person in the UCL organisation? I’m happy to liaise with them directly if you could point me in the right direction?

Best regards

Steve”

Thesis with omissions

At that time, Claire Crowley was finishing her PhD thesis at UCL, supervised by Birchall and Seifalian. Her doctoral studies were about plastic trachea technology, a topic which used to be hot and fancy and even EU-funded, but which became somewhat unpopular these days, all because of Macchiarini. In May 2011, Crowley manufactured a plastic trachea for Macchiarini’s patient Andemariam Beyene. Seifalian told me how it happened (typos fixed, PM: Paolo Macchiarini, MB: Martin Birchall, UCLB: UCL Business, UCL’s technology transfer company):

“PM talked to us on the phone and also MB was also happy for the case go forward, I spoke to head of department and UCLB and they said it is OK to go ahead, we made one to show to PM, he came to visit us few days later and asked us to modify it and we did. He also told us if the patient does not have the trachea will die within 10 days”

According to this article, Crowley also transported the graft she made to Karolinska Institutet in Stockholm. However, a 2017 external investigation at UCL claimed to have found that Seifalian forced Crowley to make that non-GMP certified plastic trachea for Macchiarini outside of all knowledge of UCL (read here). The information was spoon-fed to The Guardian and presented as a horrendous crime committed in secret by a rogue former scientist. Unlike in an earlier Guardian article announcing the UCL investigation, Birchall was not mentioned even once in the October 2017 Guardian piece. Maybe UCL legal department should have another go at Crowley’s thesis, because it rather suggests UCL was actually fully aware of what went on (page 148).

“As above, our group was approached by Professor Macchiarini to manufacture a POSS-PCU bifurcated tracheal replacement for the patient as per the specifications outlined by Professor Macchiarini’s team and under Prof Seifalian’s supervision”.

Right after, in September 2011, Crowley made another plastic trachea, for Birchall’s patient Keziah Shorten. The young woman was dying after her previous decellurised cadaveric trachea disastrously failed. It was implanted by Macchiarini in Italy, in a collaborative effort with UCL, Keziah’s treating UCL surgeon even participated in the operation in Florence, which took place in July 2010 (read here). According to Seifalian, that plastic trachea which was implanted in place of the failed cavaderic graft, was explicitly part of Crowley’s PhD research project:

“POSS-PCU for two patients was definitely part of her PhD”

In early 2012, Crawley was part of the team which prepared the cadaveric trachea for the 15-year old Shauna Davison, who died just two weeks after the operation in February, suffocated by her failed graft (read here and here). As her thesis focused on plastic trachea, Crowley was not the main scientist involved there, and it was left to her to decide whether to include the clinical case of Shauna in her PhD thesis. Just like with Keziah, Crawley chose not to, and pretended in her now published thesis never to have to connection or even knowledge of that case (page 36, highlight and hyperlinks mine):

“In 2008, the ‘first in human’ stem cell organ transplant was performed on a 30 year old patient (Macchiarini et al. 2008), using a 2cm tracheal scaffold, decellularised using the detergent enzymatic method (Conconi et al. 2005). A 5 year follow up paper reported full recellularisation of the graft one year post implantation and a good quality of life for the patient at 5 years (Gonfiotti et al. 2014). However, mechanical properties were suboptimal with the graft requiring dilatation and stenting intermittently [read about Claudia Castillo’s story here, -LS].

Since this case, there have been several other clinical cases performed worldwide including a 10 year old boy in the UK who received a decellularised trachea in 2010, with a successful outcome reported, although stents were again required. (Elliott et al. 2012 [Ciaran Lynch story here, -LS]). Additionally, a case series of nine adult and paediatric patients were reported in a review by Badylak et al. in 2012 which stated that there was no graft related mortalities after 12-42 months follow-up, but that partial graft collapse had occurred in some of the cases (Badylak et al. 2012). However, this has not yet been followed up by a formal scientific paper reporting the series making this report difficult to place in context”.

Crowley’s numbers are either wrong or there were more cadaveric trachea patients patients than known (compare with this list). Macchiarini did transplant and even intended to publish on the “nine adult and paediatric patients”, of whom only Ciaran Lynch, Claudia Castillo and Zhadyra Iglikova are still alive, the latter two thanks to the fact that their rotting grafts were removed in time. Keziah Shorten was one of these 9, and she died like the others. Also Birchall’s other patient Shauna Davison died, and Crowley made the lethal tracheas for both of them, as part of her PhD research. It is not in her 2015 thesis though.

Also not in Crowley’s thesis: when she helped preparing the cadaveric graft for Shauna, there was a severe problem at the vacuum-assisted decellurisation stage. Yet the graft was nevertheless eventually used, and even delivered by Crowley to the operating theatre in person. Seifalian narrates (with typos again fixed by myself, MB: Martin Birchall, ML: Mark Lowdell):

“during the decellurisation the pump apparently stopped and was not working and Claire asked me what to do, I was not involve at all, both MB and ML were out of country on conference I told her to call them and ask what to do, told them this was urgent as it is for a patient. I think she or technician told to one of them, and later I asked her what happened and she said they said OK. I was very surprised as this: suppose I have a fixed protocol and if the machine break down the outcome of decellurisation would not be the same. I think they fixed it day later and then used it
but this was not same quality as the protocol”

The cadaveric trachea technology is almost just as lethal as plastic tracheas. This is why UK and EU clinical trials were stopped by the authorities. Yet Birchall, UCL and Videregen don’t give up. In May 2017, another child received a cadeveric trachea transplant at UCL under hospital exemption, as compassionate use. This was mentioned in the UCL investigative report (and omitted by The Guardian), without a word about how that child is really doing. Even now, when the UK Parliament is dealing with UCL trachea transplant affair (latest here), UCL keeps weaseling about.

With so much heat on in the UK, Videregen now understandably seeks new clinical partners in China.

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Update 6.05.2018. On May 4th, I received this reply to my FOIA inquiry from May 1st. This was the first time the university replied to any of my numerous emails in the past 2 years, since April 2016.  Ulrich Marsch, Director Corporate Communications of the Technische Universität München wrote to me:

“On question 1:

Will the TU Munich supply tracheal replacement for this described collaboration outside the EU?

The TUM does not intend to supply tracheal replacement or tracheal derivatives for this type of collaboration outside the EU.

On question 2:

Is TU München available in any way to provide tracheal replacement outside of TETRA?

Currently no.

For more information, please contact TETRA coordinator Steve Bloor (stevebloor@videregen.com).”

Bloor’s only communication to me was also from April 2016, it went: “Thank you for your email enquiry. We will respond in due course”.

Update 24.08.2018. Claire Crowley’s online thesis was removed this month by UCL, while her supervisor Martin Birchall is being investigated for duplicated images in his papers and other issues. In July 2018, Karolinska Institutet decided that Crowley had little to do with Beyene’s plastic trachea and arrived to the project very late, and hence “Not responsible for scientific misconduct and not blameworthy“. That despite the plastic trachea being the central topic of her PhD thesis. One understands why the document had to be removed offline: it does not fit the official truth.

I have previously saved the full document, please contact me if you wish to read it.

Update 18.09.2018: EU Commission is unconcerned by Videregen’s activities to find markets and patients for their trachea transplant technology. I alerted the EU Ombudsman to this article, and asked them to reconsider withholding all information about TETRA clinical trial. I got this reply (full text here):

“On 1 May 2018, you sent an e-mail to my Office informing us about the fact that the sponsor/coordinator of the TETRA clinical trial is seeking to establish a cooperation agreement with universities, hospitals and surgeons located outside of the EU with a view to testing its tracheal replacement product in a clinical trial. I am sorry that I have not been able to revert to you earlier.
You asked me to review my decision closing case 124/2018/NF  [see here, -LS] on the basis of this information.
As you know, my inquiry into case 124/2018/NF was concerned with the question whether the European Commission was justified in not disclosing the documents requested by you, that is, three project status reports regarding the preparatory phase of the TETRA clinical trial.
I thus reviewed the documents at issue against the requirements of EU access to documents rules1 and I concluded, based also on a meeting with the Commission, that there was no maladministration by the European Commission in handling your request for public access to documents on the status of the TETRA project.
While I understand that you are genuinely concerned about the trial  sponsor/coordinator looking to test its product outside the EU, this information
cannot have any relevance for my assessment of the Commission’s decision not
to give public access to the documents requested by you, based on exceptions
provided for in EU access to documents rules.

 

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