On Vatican’s stem cell conference

by Alexey Bersenev on April 17, 2013 · 2 comments

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Last week, stem cell meeting was held in Vatican. Scientific conference was organized and held by a Church! An information about this meeting, a mass media buzz, a reporting – all were misleading. In this post I’ll try to debunk some claims and give more critical view of this event. My intent is to facilitate open discussion. I’m not trying to insult and tease religious people.

Boycott of the previous meeting
The first Vatican’s stem cell meeting took place in 2011, but second was suddenly canceled last year. Apparently, some invited embryonic stem cell researchers, boycotted a conference:

In 2012, the Vatican’s Pontifical Academy for Life was forced to cancel a conference on “Responsible Stem Cells Research.” While the cancellation was officially caused by low registration, some members of the academy had complained that the lineup included researchers who had worked with embryonic stem cells, and called for a boycott of the conference.

There were probably more reasons for this cancellation, but I understand these scientists and I’d support a boycott. I think, their reasoning could be represented by this quote:

“Of course adult stem cell research is really important and very promising for the future of medicine,” Sean Morrison says.
But not if the Vatican is using its support to undermine research using embryos, which is what he suspects it is doing.
Morrison is worried that the Catholic Church will run a misleading campaign against embryonic research.

By the way, what reaction Vatican would expected from stem cell researchers? A Catholic Church is an organization  with many centuries history of antagonism against the science!

Embryonic versus adult
It seem like for the 3rd meeting, Vatican decided to “sanitize” a list of speakers, excluding major figures from “embryonic stem cell world”.

So, the Vatican is trying to tell us that there are good stem cells (adult) and bad stem cells (embryonic), good scientists (moral) and bad scientists (baby killers). Good ones are blessed! The use of good cells is approved by Jesus! But who are they to give us a guidance? What is the authority of Vatican to draw the line for scientists and general (non-catholic) public? With all its history, Vatican has a zero authority for ethics and morality to me.  And what about the cells, which don’t fit in “embryonic” or “adult” category – neonatal stem cells, derived from umbilical cord and cord blood, amniotic fluid stem cells, fetal stem cells, derived from aborted fetuses? There is a tremendous progress with these types of stem cells and a lot of trials under way. How it’s ethical and moral to prohibit any kind of research, associated with potential finding a cure? To me, it’s deeply immoral and unethical.

Here I’d like to cite John Gurdon, who was (bravely) invited by Vatican as keynote speaker. In interview for Vatican Radio, he said:

The trouble is adults stem cells do have limited capacity both – to proliferate and to form different kinds of cell types.

Q: How important is it to respect the ethical dimensions of this work
A: That’s ‘s controversial. My own position is I’m very liberal and I don’t actually believe that there are any ethical issues. The Roman Catholic Church is very sensitive to it, but it depends on your position.

I also believe that there are no ethical issues. All of them were created by a church and maybe irrelevant in secular world.

So, the truth is that we don’t have a debate “adult versus embryonic” in scientific world. Scientists think that ANY kind of stem cell research is very important!

Adults stem cell propaganda machine
To spread the “message of truth” about blessed adult stem cells Vatican has created a Stem For Life Foundation. This mediator for public outreach is a charity organization, which collect money for adult stem cell research in a name of religion. The Foundation has a scientific advisory board, filled by brilliant and well respected adult stem cell researchers and clinicians. The Foundation produces the videos and publishes books. I have no problem with spreading information about achievements in adult stem cells. In fact, I do it myself daily. But I have a big problem when (1) this type of information spread by religious institute and (2)  this information is biased, distorted and does not represent the whole picture. Therefore, I’d boldly call it well designed campaign or propaganda.

Goals of conference and claims
Let’s look at goals of Vatican conference:

To discuss and understand the importance of scientific advancements in the paradigm shift toward regenerative medicine, with a particular focus on adult stem cell therapies and the interconnections between research, faith, ethics and culture.

So, they are not willing to discuss and appreciate importance and achievements of other than “adult” types of stem cell research. But all types of stem cell research are interconnected and should be appreciated as a whole! Would discovery of “ethical” iPS even happen if we don’t learn pluripotency genes from embryonic stem cells?

Foster an open dialogue amongst researchers, physicians, philanthropists, faith leaders and policy-makers…

But how much this dialogue was really open? Was it really a dialogue? I have some doubts. First of all the meeting was kind of secretive – speakers were carefully picked, number of attendees was greatly limited by invitation. It was the most expensive stem cell conference ever! Mass media coverage was all the same – vastly positive, without analysis and opinions. Was no videos of talks and panel discussions, was no webcast, was no abstracts available for public. The public had only the choice – to see this “open dialogue” via eyes of mass media outlets.

While the conference is exclusive, seating only 350 attendees, it will reach an even wider audience through radio and television broadcast.

Dear Vatican, if you really want an open dialogue on the matter, please invite all kind of stem cell researchers, invite all kind of media reporters, make it “free to attend” for everyone who wants to discuss, make it affordable for students, make a live or recorded webcacst, video record the talks and panels and share it freely. It will be a good step to “openness”.

Expand global awareness of the here-and-now applications of adult stem cell therapies…

Basically, they want to educate a public. Unfortunately, “stem cell education” by a Catholic Church is always include a mention of how bad and immoral is embryonic stem cell research and can not be uncoupled from “status of embryo”. The whole concept of “scientific education” by a Church sounds funny to me. If young person or patient, who eager to know about stem cells, will look for education information, the Church will be the last place as a source of it. Do we have a trouble with spreading information about stem cells without church? No, we don’t! We have stem cell conferences ever other week in secular world. Conferences with great variety or topic, open attendance and bunch of educational materials.

…reducing misperceptions surrounding the field of cellular research.

By spreading the message about what kind of stem cell research is ethical, mixing science and religion, the Church is the main source of misperceptions surrounding the field of cellular research.

More claims in mass media
Now I’d like to pick a few quotes from mass media sources, which covered the conference.
From Catholic News Agency:

… they want to extend their message by working at overcoming some of the “prejudice and antagonism” against adult stem research that can be found in the medical field.

the response:

V_tweet1
The truth is actually opposite – there is a lot of antagonism against embryonic stem cell research and everyone in medical field is very excited, supporting and promoting adult stem cells! The Vatican is distorting the reality in this message.

From New York Times:

Scientists are happy to see the church adopt a more-proactive stance, even if most are wary in principle about the enduring stricture on the use of embryonic stem cells, said Michael Nobel.

It’s not true. Many scientists are not happy at all to see this move from a Church.

The line emphasized that the human body is sacred, underscoring the church’s interest in its welfare but also signaling that an opening to the use of embryonic stem cells isn’t on the horizon.

The message about immoral embryonic stem cell research and antagonism to it is everywhere.

From Washington Post:

“We don’t want to stigmatize those who do research on embryonic stem cells,” said the Rev. Tomasz Trafny, who heads the science department of the Pontifical Council for Culture. “It is much more useful to focus on the results and the progress of adult stem cells.”

They don’t want to stigmatize “embryonic guys” but they do! They said everywhere that it’s unethical!

EuroNews:

The organisers say they want to counter misconceptions and prove that the Church is not “anti-science”, but “anti-unethical science”.

Instead of counter misconceptions, a Church creates and promotes misconceptions (one kind of cells better than other!). Church always was anti-science! Now Vatican is picking which science is ethical, which one is not and delivering this message to general public.

From Vatican Radio – Interview with Senator Norm Coleman:

If you didn’t support funding in destruction of human embryo you can be place in category anti-science. The world is changed a lot in 2013. The politics does play role here – it’s not just about science, there are powerful political issues… We have to educate a public about what science is… You don’t have to deal with moral questions, you don’t have to worry about that in a sense… we can still achieve many many great things through adult stem cells…

Isn’t it Stem for Life Foundation mantra? Why do they think that public is not educated enough about adult stem cells? Did they do research? Show me the numbers! And why did they suddenly decide that religious institute should educate the people? The truth is that public has lack of education about all kinds of stem cell research! Finally, politics only play a role here if there is a frictions with religion. Remove religion from equation and will be no big political issues in stem cell research.

Just a headline:

Catholic Church is Leading the Way on Ethical Stem Cell Research and Regenerative Medicine

LOL!

Involvement of NeoStem
As a part of “re-branding and new business strategy”, Vatican decided to team up with “adult stem cell industry” and invest. They picked US-based company NeoStem. The reasons why they picked NeoStem were discussed here. Robin Smith – a CEO of NeoStem became an icon of the conference and a president of newly created Stem for Life Foundation. Were ties with Vatican good or bad for the company? There is no consensus on that – some analysts think that Vatican drops NeoStem (you can compare stock performance 2 years ago and now), but some think that it endorses the company.

Reportedly, the Vatican already invested $1B USD in collaboration with NeoStem (VSEL platform). It’s not very clear whether investment was direct or indirect (via Stem for Life Foundation public outreach). But, in the interview for Knoepfler’s blog, Smith disproved the information about direct investment:

Some writers have mistakenly said that the Vatican invested in NeoStem, but that is not the case. The Vatican and its entities are not investors in NeoStem. The Council has set aside funds from philanthropic supporters to support the joint initiatives…

Robin Smith was all over the place before conference. She made multiple public statements, such as:

It is a truly a bridge between science and religion… (source)

To address global suffering, one does not have to choose between faith and science. … These two ideas fit together symbiotically… (source)

Taking in account there kind of quotes and relationships with Vatican, some investors were seriously questioned of how NeoStem treats their employees (read comments here) – do they ask a sexual orientation or abortion history when they hire people?

But the most misleading statement to me was made by Smith about a number of clinical trials:

I think that it speaks for itself, in the fact there are 4,300 clinical trials using adult stem cells and only 26 using embryonic stem cells…

If you follow this blog, you know that these numbers are wrong! Thus, there are only 5 ongoing embryonic stem cell-based therapeutic trials. 4300 popped up after she typed “stem cell” in NCT database, right before to share this excitement with the world. But if she spend 5-10 min more and actually go through the list, she would notice that half of these trials involve different drug combinations in bone marrow transplant clinic.

This year, Vatican invited a bunch of other “adult” companies, such as: Osiris, Mesoblast, Opexa (yes, they called Opexa as stem cell company). What is a benefits for the companies from this special treatment by Vatican? Well, I’d say (1) money and (2) publicity (to do very ethical business).

The fusion of science and religion
Mass media portray the event as a merger of science and religion. As a part of re-branding of Church, Monsignor Tomasz Trafny (Director of the Vatican’s Science and Faith Foundation) commented:

“There was a time when theologians thought they understood everything, but we learned the lesson from history”, he told CNN.
“If you look at what is going on today you will see that theologians are very careful about what they are thinking or speaking about related to scientific issues.”

Is this novelty a sign of Catholic Church crisis?

Sorry, but I think that fusion is not possible, otherwise it’s not a religion any more. So, do we really need a stamp “approved by Vatican” or “these cells are blessed” in science? No, thank you!

Concluding:
Finally, I can’t resist to not include a few more quotes here. Very recent Nature’s editorial – the only coverage I like:

The Second International Vatican Adult Stem Cell meeting, held on 11–13 April in Vatican City, was a shamelessly choreographed performance. Sick children were paraded for television, sharing the stage with stem-cell companies and scientists desperate to hawk a message that their therapies must be speeded to clinical use.

The scientifically naive Vatican finds the concept of adult stem cells attractive simply because embryos are not involved — yet it ignores the ethical implications of false hope.

Very well said!

From my short communication with Chris Mason, who was a speaker on Vatican’s conference:

V_tweet2

Maybe (I hope) they tried to discuss both – adult and embryonic. But what is outcome of this discussion? Who has change an opinion? Was a consensus reached? I hope that someone actually learn more about adult stem cells through this event. But I can’t accept that this discussion and education should be done via church. It’s always distortion of reality. Honestly, I think, this conference is pointless exercise. I think, educated people don’t need religion-linked charities to donate their money for stem cell research. If they really want to, they will go and donate to any charity without religious affiliation. Also, I don’t think people need a church to gain more valid knowledge about stem cells.

I’m done folks! And sorry for lengthy post. It was very tough for me. I’d be happy to hear your opinions!

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Aastrom’s critical limb ischemia trial – failure analysis

by Alexey Bersenev on March 31, 2013 · 0 comments

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This week, US-based company Aastrom Biosciences announced that they are terminating Phase 3 trial for critical limb ischemia (CLI) – REVIVE. The company will lay off half of its workers and shift focus to other indications. This was rather sudden news than expected. Nine days earlier, the company reported financial results of 2012 and didn’t give any hint to strategic changes for investors. Most professionals called it as a big setback or “big bummer“/ “huge disappointment” for cell therapy industry. Obviously, this is very sad news for the field. But we have to analyze the root causes for this failure and learn some lessons. Analysis is very important, because the failure in the final phase of trial is a big deal and we don’t have many examples of such failures in cell therapy.

The major reason for REVIVE failure is a poor trial design. The secondary reason is financial and strategic business considerations. Apparently, the failure has nothing to do with safety and efficacy of Aastrom’s cell product Ixmyelocel-T. Let’s look at
these reasons more closely.

Poor trial design
Slow enrollment
The Phase 2 was completed in 2011 and in May 2012 enrollment in Phase 3 study has been started. With enrollment goal of 594 patients, by March 2013 only 40 patients were enrolled. If the enrollment rate will be the same, it will take about 14 years to reach the enrollment goal. Even though trial could be finished earlier in case of “excellent results”, it still very very slow.

Inclusion criteria are too stringent
This is a possible reason for slow enrollment. You can look at list of eligibility criteria on a trial description site. I think, the mistake was made in estimation of number of patients, who would perfectly fit in eligibility criteria.

On the 4th quarter of 2012 report, the company proposed a plan for enrollment acceleration, which included (i) increase of trials sites from 70 to 100+, (ii) change (loose it by removing “no option” definition) the enrollment criteria. It took only one week from company management to realize that they “have no muscles” to implement these strategic changes rapidly, effectively and without big financial loses.

Analyst Henry McCusker wrote in his blog:

My issue is that ASTM had “prior” knowledge and a “glimpse” of the recruitment problems based on the facts and evidence of the P2 recruitment experience – who and where was the “internal” voice on the trial issues.

Primary end point and number game
Yet another thing to consider is that if they will make inclusion criteria wider, they can face a risk of “therapeutic power dilution” among heterogeneous population of patients. The targeted enrollment number (=594) was defined based on results of Phase 2 and estimated to reach significant statistical power between “placebo” and “cells” groups. Because ~600 is a big number for cell therapy, I’d suspect that the efficacy of Ixmyelocel-T is not as dramatic as one may think. Thus, Phase 2 included 77 patients and no difference in amputation free survival (AFS) has been reached. The company still put AFS as a primary end point in Phase 3 design, hoping to reach a significant difference by shooting a big number for enrollment.

Strategic business considerations
Even though company has enough cash to run trials in 2013, it is getting very low. The company consistently reported net loss from quarter to quarter, without any news about significant investment. Since REVIVE trial will required a lot of cash and, apparently, very long duration, one may ask if Aastrom can really afford it. Unfortunately a potential deal between Takeda and Aastrom about commercialization of Ixmyelocel-T in CLI didn’t work out. Seem like Aastrom was really in need of such partners. Yet another interesting fact is that company has changed 4 CEO’s in the last 5-6 years. You can read more about Aatrom financial shape here and here.

Analyst Bill Busa wrote:

Lacking proprietary technologies of interest to other companies, Aastrom generated zero revenues from licenses and royalties for the 2010 through 2012 period (though it should be noted that other SCSI companies did little better, averaging just under $500K in license and royalty revenues in 2012). More puzzling still was the company’s unwillingness, or inability, to pursue grant and contract revenues…
Perhaps the worst threat to Aastrom’s well-being of all has been its chronic inability to lure a strong strategic partner — an obvious necessity when all other access to capital is barred.

Hot competition
The field of commercial gene- and cell therapeutic products for CLI is very hot and competitive. You can read a recent review about potential players on a market (available in open access .pdf). Just to mention a few – Harvest Technologies and Biomet with poin-of-care processing devices, Pluristem, Baxter, Medistem, Juventas and few gene therapy companies. Harvest Technologies is the only one (other than Aastrom) with Phase 3 ongoing trial. Harvest is enrolling up to 210 patients in 25 US centers. The company is running clinical trials in Asia and marketed their device for CLI in Europe. In case of the relatively similar efficacy, the companies with point-of-care devices will win the competition, because of low cost and convenience to use.

Ixmyelocel-T and the cost issues
The leading Aastrom therapeutic product Ixmyelocel-T is quite unique in a terms of composition. It is an autologous bone marrow mononuclear cells, expanded ex vivo for 2 weeks and contained lymphocytes (5x reduced), monocytes + macrophages (expanded 200x), granulocytes (5x reduced), hematopoietic progenitors and stromal cells (50x expanded CD90+ cells). It look like just a “cell product” to me, but not “stem cell product”. I’d speculate that expanded cells of monocytic lineage plus hematopoietic progenitors could have even greater therapeutic value than CD90+ stromal cells. But does unique composition of Ixmyelocel-T correlates with its unique therapeutic value? I don’t think so. Taking in account good results from many CLI cellular trials, Ixmyelocel-T is not very special.

You can learn more about Ixmyelocel-T manufacturing from this video:

Business analyst Jason Napodano has estimated a potential cost of Ixmyelocel-T as $40,000 USD. Taking in acoount 2 weeks of ex vivo expansion in bioreactor, it sounds reasonable to me. Here it comes to competition. Obviously, point-of-care cell processing devices (by Harvest and Biomet) will make cost of the therapeutic product/ procedure much cheaper. I’d expect something less than $10,000 USD. Let’s look at another example – a gene therapeutic product Neovasculgen (VEGF), which was approved on Russian market in 2011 and priced ~ $6,600 USD. I’d speculate that most of gene therapeutic products for CLI will be priced in the range <$10,000 USD. So, in order to compete with such lower priced drugs on the market, Ixmyelocel-T must have much much better efficacy profile.

Amit Patel wrote about the cost of cell therapies for CLI:

Irrespective of the expected low pricing for allogeneic cell dosing, autologous cell manufacturing, with plastic disposables, may drive production costs below $100.

New therapies costing more than $60,000 are probably prohibitive, but may be a possibility in the $20,000–$40,000 range, while therapies costing under $20,000 have the highest likelihood of success.

To conclude: It’s very sad that Phase 3 REVIVE trial, assessing cell therapy for CLI, has been halted by Aastrom. For the company it was probably wise business strategic decision, unless they had some buyers. This case shows that could be a number of reasons for clinical trial failure, other than lack of safety or/ and efficacy. Unfortunately commercial cell therapy trials can become a very long and and very expensive exercise. We can also learn that it is extremely important to design a trial in wise and smart way. The design, which allows to predict enrollment rate and power the efficacy with lower patients number.

Read 3 more analysis of failure by:
Bill Busa
Henry McCusker
Jason Napodano

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Patients meet regulators

by Alexey Bersenev on March 26, 2013 · 0 comments

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The regulation of cell therapies, particularly stem cells, is a tough issue. On the one hand, the use of cells is very new, complex and unique kind of therapy and, therefore, it’s a big challenge for regulators. On the other hand, there are many players and stakeholders, whose interests should be taken in account. The regulators claim to provide a public safety, but how frequent do they actually listen and get feedback from the patients? Not frequent at all! As a consequence, most of the patients think that over-regulation of cell therapies by the FDA forces them to look for alternatives outside the country and does more harm than good. This week, clash between patients and regulators took an extreme way in a form of “street protest” in Italy. Some professionals think, that exclusion patients from regulatory decision making is unethical. To me, the obvious solution is to meet, talk and educate each other!

Magically, this remarkable event finally has happened! A month ago, the FDA run the first-ever public hearing for ALS patients community. I collected some useful links and tweets about event in this story. You can also watch a webcast.

One of the prominent voices of ALS community, patient from NeuralStem trial – Ted Harada gave a speech, which perfectly reflects (in my opinion) a public opinion and frustration about current (“paternalistic”) regulatory approach of FDA. Some quotes:

Patients diagnosed with fatal diseases should be given the opportunity to take elevated risks with informed and educated consent in regards to their treatment options.

I’d suggest that FDA has an obligation to encourage and reward innovation. And not just sit on a sidelines. We can’t afford it.

I’d suggest that your paternalistic approach put patients in more harm ways than it does protect them.

Lack of incentive for ALS investment as well as expanded access encourages ALS patients take risks in unregulated and potentially unscrupulous treatments.

It was a call for action and for collaboration. It’s not clear what was a catalyst for this event, but possibly, a recent big failure of new biotech drug for ALS. In any case, this was a very important event. It demonstrated that a dialogue is possible!

I believe that patients have a power to influence and educate regulators via advocacy groups. I think, that the open dialogue and transparency is the only way to find a balance between patients safety/ protection and rapid development of new medical innovations, such as cell therapy.

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Current trends in cord blood expansion and enhancement

February 18, 2013

The value of cord blood (CB) transplantation in hematology is increasing steadily. However, low number of hematopoietic stem/ progenitor cells (HSPC) in one unit of CB is still considered as a major limiting factor for wide spread adoption of CB transplantation in patients (mostly in adults) with hematological and other conditions. CB enhancement technologies are [...]

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More and more clinical trials are getting registered in public databases. Partly, because it’s mandated by government agencies, but also because of our understanding the importance of information transparency. I’d speculate that now most of cell therapy clinical trials get registered in databases. But how good are we at posting results and analyzing the data [...]

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Defining the mesenchymal stem cell therapy

January 31, 2013

Since 1991, when Arnold Caplan coined the term Mesenchymal Stem Cells (MSC), these are an ongoing debates on the right naming and assays for this type of cells. I’m following these debates tightly and posting regular updates on StemCellAssays blog. The big question is how to unify the terms and assays for MSC in clinical [...]

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Clinical translation of cell therapies via medical innovation pathway

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There are two major pathways for translation of new biomedical technologies into the wide clinic. First is a clinical research, which implies conduction of trials. This pathways highly regulated by government agencies. The second pathway is a medical innovation, which led by physician and usually regulated by medical boards. Both pathways have advantages and disadvantages [...]

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Cell therapy clinical trials 2012 – trends

January 15, 2013

As I proposed in 2011 report, cell trials tracking allows to identify some trends. Today I’d like to show you some interesting trends from 2011 to 2012. First of all, I’d like to announce that 2011 report was updated! I’ve found a few more (6) trials, that I’ve missed, when finalized the report. My key [...]

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Cell therapy clinical trials – 2012 report

January 8, 2013

This is an annual report of registered clinical trials in cell therapy. Every year I overview some tracked data from international clinical trials databases. You can see 2011 report here. Definitions I tracked clinical trials which fall in definition of cell therapy: administration of living cells in human with therapeutic purpose. I included tissue engineering, [...]

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Cell therapy trials for multiple sclerosis – 2012 update

January 2, 2013

This post was edited Jan. 4, 2013 at 10:03 pm EST Multiple sclerosis (MS) is one of the most frequent indications for cell therapy trials. Drug therapy could be ok for some patients to slow rate of relapses in initial course of disease (relapsing remitting form = RR and malignant form), but useless in progressive [...]

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