CIRM Board invests in three new stem cell clinical trials targeting arthritis, cancer and deadly infections

knee

Arthritis of the knee

Every day at CIRM we get calls from people looking for a stem cell therapy to help them fight a life-threatening or life-altering disease or condition. One of the most common calls is about osteoarthritis, a painful condition where the cartilage that helps cushion our joints is worn away, leaving bone to rub on bone. People call asking if we have something, anything, that might be able to help them. Now we do.

At yesterday’s CIRM Board meeting the Independent Citizens’ Oversight Committee or ICOC (the formal title of the Board) awarded almost $8.5 million to the California Institute for Biomedical Research (CALIBR) to test a drug that appears to help the body regenerate cartilage. In preclinical tests the drug, KA34, stimulated mesenchymal stem cells to turn into chondrocytes, the kind of cell found in healthy cartilage. It’s hoped these new cells will replace those killed off by osteoarthritis and repair the damage.

This is a Phase 1 clinical trial where the goal is primarily to make sure this approach is safe in patients. If the treatment also shows hints it’s working – and of course we hope it will – that’s a bonus which will need to be confirmed in later stage, and larger, clinical trials.

From a purely selfish perspective, it will be nice for us to be able to tell callers that we do have a clinical trial underway and are hopeful it could lead to an effective treatment. Right now the only alternatives for many patients are powerful opioids and pain killers, surgery, or turning to clinics that offer unproven stem cell therapies.

Targeting immune system cancer

The CIRM Board also awarded Poseida Therapeutics $19.8 million to target multiple myeloma, using the patient’s own genetically re-engineered stem cells. Multiple myeloma is caused when plasma cells, which are a type of white blood cell found in the bone marrow and are a key part of our immune system, turn cancerous and grow out of control.

As Dr. Maria Millan, CIRM’s President & CEO, said in a news release:

“Multiple myeloma disproportionately affects people over the age of 65 and African Americans, and it leads to progressive bone destruction, severe anemia, infectious complications and kidney and heart damage from abnormal proteins produced by the malignant plasma cells.  Less than half of patients with multiple myeloma live beyond 5 years. Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

In a news release from Poseida, CEO Dr. Eric Ostertag, said the therapy – called P-BCMA-101 – holds a lot of promise:

“P-BCMA-101 is elegantly designed with several key characteristics, including an exceptionally high concentration of stem cell memory T cells which has the potential to significantly improve durability of response to treatment.”

Deadly infections

The third clinical trial funded by the Board yesterday also uses T cells. Researchers at Children’s Hospital of Los Angeles were awarded $4.8 million for a Phase 1 clinical trial targeting potentially deadly infections in people who have a weakened immune system.

Viruses such as cytomegalovirus, Epstein-Barr, and adenovirus are commonly found in all of us, but our bodies are usually able to easily fight them off. However, patients with weakened immune systems resulting from chemotherapy, bone marrow or cord blood transplant often lack that ability to combat these viruses and it can prove fatal.

The researchers are taking T cells from healthy donors that have been genetically matched to the patient’s immune system and engineered to fight these viruses. The cells are then transplanted into the patient and will hopefully help boost their immune system’s ability to fight the virus and provide long-term protection.

Whenever you can tell someone who calls you, desperately looking for help, that you have something that might be able to help them, you can hear the relief on the other end of the line. Of course, we explain that these are only early-stage clinical trials and that we don’t know if they’ll work. But for someone who up until that point felt they had no options and, often, no hope, it’s welcome and encouraging news that progress is being made.

 

 

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ViaCyte treats first patients in PEC-Direct stem cell trial for type 1 diabetes

Today, ViaCyte shared an update on its latest clinical trial for type 1 diabetes (T1D). The company is based in San Diego and is developing two stem cell-based products that attempt to replace the pancreatic beta islet cells that are attacked by the immune system of patients with T1D.

Their first product, called VC-01 or PEC-Encap, is an implantable device containing embryonic stem cells that develop into pancreatic progenitor cells, which are precursors to the islet cells destroyed by T1D. The hope is that when this device is transplanted under a patient’s skin, the progenitor cells will develop into mature insulin-secreting cells that can properly regulate the glucose levels in a patient’s blood. Because the cells are encapsulated in a protective semi-permeable membrane, hormones and nutrients can pass in and out of the device, but the implanted cells are guarded against the patient’s immune system. VC-01 is currently being tested in a Phase 1 clinical trial that is funded CIRM.

ViaCyte now has a second product called VC-02, or PEC-Direct, that also transplants pancreatic progenitors but in a device that allows a patient’s blood vessels to make direct contact with the implanted cells. This “direct vascularization” approach is being tested in patients that are at high risk for severe complications associated with T1D including hypoglycemia unawareness – a condition where patients fail to recognize when their blood glucose level drops to dangerously low levels because the typical symptoms of hypoglycemia fail to appear.

ViaCyte’s PEC-Direct device allows a patient’s blood vessels to integrate and make contact with the transplanted beta cells.

In May, ViaCyte announced that the US Food and Drug Administration (FDA) approved their Investigational New Drug (IND) application for PEC-Direct, which gave the company the green light to proceed with a Phase 1 safety trial to test the treatment in patients. ViaCyte’s pre-IND work on PEC-Direct was supported in part by a late stage preclinical grant from CIRM.

Today, the ViaCyte announced in a press release that it has treated its first patients with PEC-Direct in a Phase 1/2 trial at the University of Alberta Hospital in Edmonton, Alberta and at the UCSD Alpha Stem Cell Clinic in San Diego, California.

“The first cohort of type 1 diabetes patients is receiving multiple small-format cell-filled devices called sentinels in order to evaluate safety and implant viability.  These sentinel units will be removed at specific time points and examined histologically to provide early insight into the progression of engraftment and maturation into pancreatic islet cells including insulin-producing beta cells.”

The news release also revealed plans for enrollment of a larger cohort of patients by the end of 2017.

“A second cohort of up to 40 patients is expected to begin enrolling later this year to evaluate both safety and efficacy.  The primary efficacy measurement in the trial will be the clinically relevant production of insulin, as measured by the insulin biomarker C-peptide, in a patient population that has little to no ability to produce endogenous insulin at the time of enrollment.  Other important endpoints will be evaluated including injectable insulin usage and the incidence of hypoglycemic events.  ViaCyte’s goal is to demonstrate early evidence of efficacy in the first half of 2018 and definitive efficacy 6 to 12 months later.”

President and CEO of ViaCyte, Dr. Paul Laikind, is hopeful that PEC-Direct will give patients with high-risk T1D a better treatment option than what is currently available.

ViaCyte’s President & CEO, Paul Laikind

“There are limited treatment options for patients with high-risk type 1 diabetes to manage life-threatening hypoglycemic episodes. We believe that the PEC-Direct product candidate has the potential to transform the lives of these patients and we are excited to move closer to that goal with the initiation of clinical evaluation announced today.  This also represents a step towards a broader application of the technology.  We remain fully committed to developing a functional cure for all patients with insulin-requiring diabetes.  To that end, we are hard at work on next-generation approaches as well, and expect the work with PEC-Direct to further advance our knowledge and drive progress.”


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Stem Cell Stories that Caught our Eye: CRISPRing Human Embryos, brain stem cells slow aging & BrainStorm ALS trial joins CIRM Alpha Clinics

Here are the stem cell stories that caught our eye this week. Enjoy!

Scientists claim first CRISPR editing of human embryos in the US.

Here’s the big story this week. Scientists from Portland, Oregon claim they genetically modified human embryos using the CRISPR/Cas9 gene editing technology. While their results have yet to be published in a peer review journal (though the team say they are going to be published in a prominent journal next month), if they prove true, the study will be the first successful attempt to modify human embryos in the US.

A representation of an embryo being fertilized. Scientists can inject CRISPR during fertilization to correct genetic disorders. (Getty Images).

Steve Connor from MIT Technology Review broke the story earlier this week noting that the only reports of human embryo modification were published by Chinese scientists. The China studies revealed troubling findings. CRISPR caused “off-target” effects, a situation where the CRISPR machinery randomly introduces genetic errors in a cell’s DNA, in the embryos. It also caused mosaicism, a condition where the desired DNA sequences aren’t genetically corrected in all the cells of an embryo producing an individual with cells that have different genomes. Putting aside the ethical conundrum of modifying human embryos, these studies suggested that current gene editing technologies weren’t accurate enough to safely modify human embryos.

But a new chapter in human embryo modification is beginning. Shoukhrat Mitalipov (who is a member of CIRM’s Grants Working Group, the panel of scientific experts that reviews our funding applications) and his team from the Oregon Health and Science University said that they have developed a method to successfully modify donated human embryos that avoids the problems experienced by the Chinese scientists. The team found that introducing CRISPR at the same time an embryo was being fertilized led to successful correction of disease-causing mutations while avoiding mosaicism and “off-target” effects. They grew these embryos for a few days to confirm that the genetic modifications had worked before destroying them.

The MIT piece quoted a scientist who knows of Mitalipov’s work,

“It is proof of principle that it can work. They significantly reduced mosaicism. I don’t think it’s the start of clinical trials yet, but it does take it further than anyone has before.”

Does this discovery, if it’s true, open the door further for the creation of designer babies? For discussions about the future scientific and ethical implications of this research, I recommend reading Paul Knoepfler’s blog, this piece by Megan Molteni in Wired Magazine and Jessica Berg’s article in The Conversation.

Brain stem cells slow aging in mice

The quest for eternal youth might be one step closer thanks to a new study published this week in the journal Nature. Scientists from the Albert Einstein College of Medicine in New York discovered that stem cells found in an area of the brain called the hypothalamus can slow the aging process in mice.

The hypothalamus is located smack in the center of your brain near the brain stem. It’s responsible for essential metabolic functions such as making and secreting hormones, managing body temperature and controlling feelings of hunger and thirst. Because the body’s metabolic functions decline with age, scientists have suspected that the hypothalamus plays a role in aging.

The mouse hypothalamus. (NIH, Wikimedia).

In the current study, the team found that stem cells in the hypothalamus gradually disappear as mice age. They were curious whether the disappearance of these stem cells could jump start the aging process. When they removed these stem cells, the mice showed more advanced mental and physical signs of aging compared to untreated mice.

They also conducted the opposite experiment where they transplanted hypothalamic stem cells taken from baby mice (the idea being that these stem cells would exhibit more “youthful” qualities) into the brains of middle-aged mice and saw improvements in mental and physical functions and a 10% increase in lifespan.

So what is it about these specific stem cells that slows down aging? Do they replenish the aging brain with new healthy cells or do they secrete factors that keep the brain healthy? Interestingly, the scientists found that these stem cells secreted vesicles that contained microRNAs, which are molecules that regulate gene expression by turning genes on or off.

They injected these microRNAs into the brains of middle-aged mice and found that they reversed symptoms of aging including cognitive decline and muscle degeneration. Furthermore, when they removed hypothalamic stem cells from middle-aged mice and treated them with the microRNAs, they saw the same anti-aging effects.

In an interview with Nature News, senior author on the study, Dongsheng Cai, commented that hypothalamic stem cells could have multiple ways of regulating aging and that microRNAs are just one of their tools. For this research to translate into an anti-aging therapy, “Cai suspects that anti-ageing therapies targeting the hypothalamus would need to be administered in middle age, before a person’s muscles and metabolism have degenerated beyond a point that could be reversed.”

This study and its “Fountain of Youth” implications has received ample attention from the media. You can read more coverage from The Scientist, GenBio, and the original Albert Einstein press release.

BrainStorm ALS trial joins the CIRM Alpha Clinics

Last month, the CIRM Board approved $15.9 million in funding for BrainStorm Cell Therapeutic’s Phase 3 trial that’s testing a stem cell therapy to treat patients with a devastating neurodegenerative disease called amyotrophic lateral sclerosis or ALS (also known as Lou Gehrig’s disease).

The stem cell therapy, called NurOwn®, is made of mesenchymal stem cells extracted from a patient’s bone marrow. The stem cells are genetically modified to secrete neurotrophic factors that keep neurons in the brain healthy and prevent their destruction by diseases like ALS.

BrainStorm has tested NurOwn in early stage clinical trials in Israel and in a Phase 2 study in the US. These trials revealed that the treatment was “safe and well tolerated” and that “NurOwn also achieved multiple secondary efficacy endpoints, showing clear evidence of a clinically meaningful benefit.  Notably, response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the study out to 24 weeks.”

This week, BrainStorm announced that it will launch its Phase 3 CIRM-funded trial at the UC Irvine (UCI) CIRM Alpha Stem Cell Clinic. The Alpha Clinics are a network of top medical centers in California that specialize in delivering high quality stem cell clinical trials to patients. UCI is one of four medical centers including UCLA, City of Hope, and UCSD, that make up three Alpha Clinics currently supporting 38 stem cell trials in the state.

Along with UCI, BrainStorm’s Phase 3 trial will also be conducted at two other sites in the US: Mass General Hospital in Boston and California Pacific Medical Center in San Francisco. Chaim Lebovits, President and CEO, commented,

“We are privileged to have UCI and Dr. Namita Goyal join our pivotal Phase 3 study of NurOwn. Adding UCI as an enrolling center with Dr. Goyal as Principal Investigator will make the treatment more accessible to patients in California, and we welcome the opportunity to work with this prestigious institution.”

Before the Phase 3 trial can launch at UCI, it needs to be approved by our federal regulatory agency, the Food and Drug Administration (FDA), and an Institutional Review Board (IRB), which is an independent ethics committee that reviews biomedical research on human subjects. Both these steps are required to ensure that a therapy is safe to test in patients.

With promising data from their Phase 1 and 2 trials, BrainStorm’s Phase 3 trial will likely get the green light to move forward. Dr. Goyal, who will lead the trial at the UCI Alpha Clinic, concluded:

“NurOwn is a very promising treatment with compelling Phase 2 data in patients with ALS; we look forward to further advancing it in clinical development and confirming the therapeutic benefit with Brainstorm.”

‘Pay-to-Participate’ stem cell clinical studies, the ugly stepchild of ClinicalTrials.gov

When patients are looking for clinical trials testing new drugs or treatments for their disease, one of the main websites they visit is ClinicalTrials.gov. It’s a registry provided by the National Institutes of Health (NIH) of approximately 250,000 clinical trials spanning over 200 countries around the world.

ClinicalTrials.gov website

If you visit the website, you’ll find CIRM’s 28 active clinical trials testing stem cell-based therapies for indications like spinal cord injury, type 1 diabetes, heart failure, ALS, cancer and more. These are Food and Drug Administration (FDA)-approved trials, meaning that researchers did the proper preclinical studies to prove that a therapy was safe and effective in animal models and received approval from the US FDA to test the treatment in human clinical trials.

As the largest clinical registry in the world, ClinicalTrials.gov is a very valuable resource for patients and the public. But there are studies on the website that have recently surfaced and taken on the role of ‘ugly stepchild’. These are unapproved stem cell therapies from companies and stem cell clinics that are registering their “pay-to-participate treatments”. And they are doing so in clever ways that don’t make it obvious to patients that the trials aren’t legitimate. The reason this is so troubling is that unproven therapies can be dangerous or even life-threatening to patients.

Leigh Turner

Leigh Turner, an associate professor of bioethics at the University of Minnesota, has written extensively about the serious problem of stem cell clinics marketing unproven stem cell therapies to desperate patients. Turner, in collaboration with UC Davis professor Dr. Paul Knoepfler, published a study in Cell Stem Cell last year that identified over 550 clinics in the US that promote unproven treatments for almost any condition, including diseases like Alzheimer’s where research has shown that cures are a long way off.

Today, Turner published an article in Regenerative Medicine that shines a light on how companies and clinics are taking advantage of ClinicalTrials.gov to promote their “pay-to-participate” unproven stem cell studies. The article is available for free if you register with RegMedNet, but you can find news coverage about Turner’s piece through EurekAlert,  Wired Magazine and the San Diego Union Tribune.

In an interview with RegMedNet, Turner explained that his research into how businesses promote unproven stem cell therapies led to the discovery that these studies were being listed as “pay-to-participate” on ClinicalTrials.gov.

“Many of these businesses use websites, social media, YouTube videos, webinars and other tools to engage in direct-to-consumer marketing of supposed stem cell therapies. To my surprise, at one point I noticed that some of these companies had successfully listed “pay-to-participate” studies on ClinicalTrials.gov. Many of these “studies” look to me like little more than marketing exercises, though of course the businesses listing them would presumably argue that they are genuine clinical studies.”

While FDA-approved trials can charge study participants, most don’t. If they do, it’s motivated by recovering costs rather than making a profit. Turner also explained that organizations with FDA-approved studies “need to prepare a detailed rationale and a budget, and obtain approval from the FDA.”

Companies with unproven stem cell therapies are ignoring these regulatory requirements and listing their studies as “patient-funded” or “patient-sponsored”. Turner found seven such “pay-to-participate” studies sponsored by US companies on ClinicalTrials.gov. He also identified 11 studies where companies don’t indicate that patients have to pay, but do charge patients to participate in the studies.

Turner is concerned that these companies are using ClinicalTrials.gov to take advantage of innocent patients who don’t realize that these unproven treatments aren’t backed by solid scientific research.

“Patients have already been lured to stem cell clinics that use ClinicalTrials.gov to market unproven stem cell interventions. Furthermore, some patients have been injured after undergoing stem cell procedures at such businesses. Many individuals use ClinicalTrials.gov to find legitimate, well-designed, and carefully conducted clinical trials. They are at risk of being misled by study listings that lend an air of legitimacy and credibility to clinics promoting unproven and unlicensed stem cell interventions.”

Having identified the problem, Turner is now advocating for a solution.

“ClinicalTrials.gov needs to raise the bar and perform a proper review of studies before they are registered. Better screening is needed before more patients and research subjects are harmed. It’s astonishing that officials at the NIH and US FDA haven’t already done something to address this obvious matter of patient safety. Putting a disclaimer on the website isn’t sufficient.”

The disclaimer that Turner is referring to is a statement on the ClinicalTrials.gov website that says, “Listing of a study on this site does not reflect endorsement by the National Institutes of Health (NIH).”

Turner argues that this disclaimer “simply isn’t sufficient.”

“Patients and their loved ones, physicians, researchers, journalists, and many other individuals all use ClinicalTrials.gov because they regard the registry and database as a source of meaningful, credible information about clinical studies. I suspect most individuals would be shocked at how easy it is to register on ClinicalTrials.gov studies that have obvious methodological problems, do not appear to comply with applicable federal regulations or have glaring ethical shortcomings.”

While Turner acknowledges that the NIH database of clinical trials is a “terrific public resource” that he himself has used, he regards it “as a collective good that needs to be protected from parties willing to misuse and abuse it.” His hope is that his article will give journalists the starting material to conduct further investigators into these pay-to-participate studies and the companies behind them. He also hopes that “such coverage will help convince NIH officials that they have a crucial role to play in making ClinicalTrials.gov a resource people can turn to for information about credible clinical trials rather than allowing it to become a database corrupted and devalued by highly problematic studies.”

Convincing is one thing, but implementing change is another. Turner said in his interview that he knows that “careful screening by NIH officials will require more resources, and I am making this argument at a time when much of the political discourse in the U.S. is about cutting funding for the CDC, FDA, NIH and other federal agencies.”

He remains hopeful however and concluded that “perhaps there are ways to jolt into action people who are in positions of power and who can act to help prevent the spread of misinformation, bad science, and marketing packaged as clinical research.”

Humacyte Receives Prestigious Technology Pioneer Award for Kidney Failure Treatment

This month, a CIRM-funded company called Humacyte was named one of the World Economic Forum’s 30 Technology Pioneers for 2017. This prestigious award “recognizes early-stage companies from around the world that are involved in the design, development and deployment of new technologies and innovations, and are poised to have a significant impact on business and society.”

Humacyte is a North Carolina-based company that’s developing a promising human-tissue based treatment for kidney failure. They’ve developed a technology to manufacture a bioengineered human vein that they hope will improve kidney function in patients with end stage kidney disease and patients on hemodialysis. We’ve blogged about their exciting technology previously on the Stem Cellar (here).

The technology is fascinating. The first step involves stimulating human smooth muscle cells from donor tissue to develop into tubular vessels. After the vessels are made, the cells are removed, leaving a 3D extracellular matrix structure composed of molecules secreted by the cells. This decellularized tube-like structure is called a human acellular vessels or HAV.

Human acellular vessel (HAV) from Humacyte.

The HAV is then implanted under a patient’s skin, where it recruits the patient’s own stem cells to migrate into the HAV and develop into vascular smooth muscle cells that line the insides of actual blood vessels. For patients with kidney failure, HAVs provide vascular access for hemodialysis, the process of collecting and filtering a patient’s blood through an artificial kidney and then returning “clean” blood back to the body. It would provide an alternative to the current procedures that insert a plastic tube called a shunt into the patient’s vein. Shunts can cause infection, blood clots, and can also be rejected by a patient’s immune system.

In July of 2016, CIRM awarded Humacyte almost $10 million to launch a Phase 3 trial in California to test their bioengineered blood vessels in patients with kidney failure. Since launching the trial, Humacyte received Regenerative Medicine Advanced Therapy or RMAT designation from the US Food and Drug Administration in March of this year. This designation is a sign that the FDA sees promise in Humacyte’s stem cell-based therapy and “will help facilitate the efficient development and expedited review of the HAV for vascular access to patients in need of life-sustaining hemodialysis.”

Humacyte’s technology has wide-ranging applications beyond treating kidney disease, including peripheral arterial disease, “repairing or replacing damaged arteries, coronary artery bypass surgery, and vascular trauma.” Other key benefits of this technology are that HAVs can be designed on demand and can be stored for later use without fear of a rapidly degrading shelf-life.

In a recent Humacyte news release, Carrie Cox, Chair and CEO of Humacyte, commented on her company’s purpose and vision to help patients.

“Keeping patient care at its core, Humacyte’s scientific discoveries are designed to create ‘off-the-shelf,’ or ready to use, bioengineered blood vessels. Today these conduits are being investigated clinically for patients undergoing kidney dialysis who require vascular access and for patients with peripheral arterial disease. However, this technology may be extended into a range of vascular applications in the future, with the potential for better clinical outcomes and lower healthcare costs. Our vision is to make a meaningful impact in healthcare by advancing innovation in regenerative medicine to produce life-sustaining improvements for patients with vascular disease.”

The potential impact that Humacyte’s technology could have for patients with unmet medical needs was compelling enough to earn the company a coveted spot in the World Economic Forum’s Technology Pioneer community. This recognition will likely foster new partnerships and collaborations to further advance Humacyte’s technology down the clinical pipeline. Fulvia Montresor, Head of Technology Pioneers at the World Economic Forum, concluded in a news release.

“We welcome Humacyte in this group of extraordinary pioneers. We hope that thanks to this selection, the World Economic Forum can facilitate greater collaboration with business leaders, governments, civil society and other relevant individuals to accelerate the development of technological solutions to the world’s greatest challenges.”

According to coverage by North Carolina Biotechnology Center, Humacyte and the other Technology Pioneers will be honored at the “Summer Davos” World Economic Forum Annual Meeting of the New Champions later this month in China. You can learn more about this meeting here.


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A call to put the ‘public’ back in publication, and make stem cell research findings available to everyone

Opening the door

Opening the door to scientific knowledge

Thomas Gray probably wasn’t thinking about stem cell research when, in 1750 in his poem “Elegy in a Country Churchyard”, he wrote: “Full many a flower is born to blush unseen”. But a new study says that’s precisely what seems to happen to the findings of many stem cell clinical trials. They take place, but no details of their findings are ever made public. They blush, if they blush at all, unseen.

The study, in the journal Stem Cell Reports, says that only around 45 percent of stem cell clinical trials ever have their results published in peer-reviewed journals. Which means the results of around 55 percent of stem cell clinical trials are never shared with either the public or the scientific community.

Now, this finding apparently is not confined to stem cell research. Previous studies have shown a similar lack of publication of the results of more conventional therapies. Nonetheless, it’s a little disappointing – to say the least – to find out that so much knowledge and potentially valuable data is being lost due to lack of publication.

Definitely not full disclosure

Researchers at the University of Alberta in Canada used the US National Institute of Health’s (NIH) clinicaltrials.gov website as their starting point. They identified 1,052 stem cell clinical trials on the site. Only 393 trials were completed and of these, just 179 (45.4 percent) published their findings in a peer-reviewed journal.

In an interview in The Scientist, Tania Bubela, the lead researcher, says they chose to focus on stem cell clinical trials because of extensive media interest and the high public expectations for the field:

“When you have a field that is accused of over promising in some areas, it is beholden of the researchers in that field to publish the results of their trials so that the public and policy makers can realistically estimate the potential benefits.”

Now, it could be argued that publishing in a peer-reviewed journal is a rather high bar, that many researchers may have submitted articles but were rejected. However, there are other avenues for researchers to publish their findings, such as posting results on the clinicaltrials.gov database. Only 37 teams (3.5 percent) did that.

Why do it?

In the same article in The Scientist, Leigh Turner, a bioethicist at the University of Minnesota, raises the obvious question:

“The study shows a gap between studies that have taken place and actual publication of the data, so a substantial number of trials testing cell-based interventions are not entering the public domain. The underlying question is, what is the ethical and scientific basis to exposing human research subjects to risk if there is not going to be any meaningful contribution to knowledge at the end of the process?”

In short, why do it if you are not going to let anyone know what you did and what you found?

It’s a particularly relevant question when you consider that much of this research was supported with taxpayer dollars from the NIH and other institutions. So, if the public is paying for this research, doesn’t the public have a right to know what was learned?

Right to know

At CIRM we certainly think so. We expect and encourage all the researchers we fund to publish their findings. There are numerous ways and places to do that. For example, we expect each grantee to post a lay summary of their progress which we publish on our website. Stanford’s Dr. Joseph Wu’s progress reports for his work on heart disease shows you what those look like.

We also require researchers conducting clinical trials that we are funding to submit and post their trial results on the clinicaltrials.gov website.

The International Society for Stem Cell Research (ISSCR), agrees and recently updated its Guidelines for Stem Cell Research and Clinical Translation calling on researchers to publish, as fully as possible, their clinical trial results.

That is true regardless of whether or not the clinical trial showed it was both safe and effective, or whether it showed it was unsafe and ineffective. We can learn as much from failure as we can from success. But to do that we need to know what the results are.

Publishing only positive findings skews the scientific literature, and public perception of this work. Ignoring the negative could mean that other scientists waste a lot of time and money trying to do something that has already demonstrated it won’t work.

Publication should be a requirement for all research, particularly publicly funded research. It’s time to put the word “public” back in publication.

 

 

Capricor reports positive results on CIRM-funded stem cell trial for Duchenne Muscular Dystrophy

Capricor Therapeutics, a Los Angeles-based company, published an update about its CIRM-funded clinical trial for patients with Duchenne muscular dystrophy (DMD), a devastating degenerative muscle disease that significantly reduces life expectancy.

The company reported positive results from their Phase I/II HOPE trial that’s testing the safety of their cardiosphere stem cell-based therapy called CAP-1002. The trial had 25 patients, 13 of which received the cells and 12 who received normal treatment. No serious adverse effects were observed suggesting that the treatment is “generally safe” thus far.

Patients given a single dose of CAP-1002 showed improvements “in certain measures of cardiac and upper limb function” after six months. They also experienced a reduction of cardiac scar tissue and a thickening of the heart’s left ventricle wall, which is typically thinned in DMD patients.

Capricor shared more details on their six-month trial results in a webcast this week, and you can read about them in this blog by Rare Disease Report.

Leading cause of death for DMD patients

DMD is a severe form of muscular dystrophy caused by a recessive genetic mutation in the dystrophin gene on the X chromosome. Consequently, men are much more likely to get the disease than women. Symptoms of DMD start with muscle weakness as early as four years of age, which then leads to deterioration of both skeletal and heart muscle. Heart disease is the leading cause of death in DMD patients – a fact that Capricor hopes to change with its clinical trial.

Capricor’s CEO, Dr. Linda Marbán, commented in a press release that the trial’s results support the findings of other researchers.

“These initial positive clinical results build upon a large body of preclinical data which illustrate CAP-1002’s potential to broadly improve the condition of those afflicted by DMD, as they show that cardiosphere-derived cells exert salutary effects on cardiac and skeletal muscle.”

Also quoted in the press release was Pat Furlong, DMD patient advocate and CEO of Parent Project Muscular Dystrophy.

Pat Furlong

“I’m excited to see these data, especially given the advanced nature of the patients in the HOPE trial. It is also gratifying to see the field of cell therapy making progress after more than two decades in development. It is our hope that CAP-1002 will have broad potential to improve the lives of patients with Duchenne muscular dystrophy.”

Pat recently spoke at the 2nd Annual CIRM Alpha Stem Cell Clinics meeting about her heartbreaking experience of losing two sons to DMD, both at a very young age. You can watch her speech below. We also featured her story and her inspiring efforts to promote DMD awareness in our 2016 Annual Report.

What to HOPE for next?

The trial is a year-long study and Capricor will report 12-month results at the end of 2017. In the meantime, Dr. Marbán and her team have plans to talk with the US Food and Drug Administration (FDA) about the regulatory options for getting CAP-1002 approved and on the market for DMD patients. She explained,

Linda Marban, CEO of Capricor Therapeutics

“We have submitted an FDA meeting request to discuss these results as well as next steps in our development of CAP-1002 for Duchenne muscular dystrophy, which includes our plan to begin a clinical trial of intravenously-administered CAP-1002 in the latter half of this year. We believe the interim HOPE results may enable us to pursue one of the FDA’s Expedited Programs for Serious Conditions, and we will apply for either or both of the Breakthrough Therapy and Regenerative Medicine Advanced Therapy (RMAT) designations for CAP-1002.”


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Good news from Asterias’ CIRM-funded spinal cord injury trial

This week in the stem cell field, all eyes are on Asterias Biotherapeutics, a California-based company that’s testing a stem cell based-therapy in a CIRM-funded clinical trial for spinal cord injury patients. The company launched its Phase 1/2a clinical trial back in 2014 with the goal of determining the safety of the therapy and the optimal dose of AST-OPC1 cells to transplant into patients.

astopc1AST-OPC1 cells are oligodendrocyte progenitor cells derived from embryonic stem cells. These are cells located in the brain and spinal cord that develop into support cells that help nerve cells function and communicate with each other.

Asterias is transplanting AST-OPC1 cells into patients that have recently suffered from severe spinal cord injuries in their neck. This type of injury leaves patients paralyzed without any feeling from their neck down. By transplanting cells that can help the nerve cells at the injury site reform their connections, Asterias hopes that their treatment will allow patients to regain some form of movement and feeling.

And it seems that their hope is turning into reality. Yesterday, Asterias reported in a news release that five patients who received a dose of 10 million cells showed improvements in their ability to move after six months after their treatment. All five patients improved one level on the motor function scale, while one patient improved by two levels. A total of six patients received the 10 million cell dose, but so far only five of them have completed the six-month follow-up study, three of which have completed the nine-month follow-up study.

We’ve profiled two of these six patients previously on the Stem Cellar. Kris Boesen was the first patient treated with 10 million cells and has experienced the most improvement. He has regained the use of his hands and arms and can now feed himself and lift weights. Local high school student, Jake Javier, was the fifth patient in this part of the trial, and you can read about his story here.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

jake_javier_stories_of_hope

Jake Javier and his Mom

The lead investigator on this trial, Dr. Richard Fessler, explained the remarkable progress that these patients have made since their treatment:

“With these patients, we are seeing what we believe are meaningful improvements in their ability to use their arms, hands and fingers at six months and nine months following AST-OPC1 administration. Recovery of upper extremity motor function is critically important to patients with complete cervical spinal cord injuries, since this can dramatically improve quality of life and their ability to live independently.”

Asterias will continue to monitor these patients for changes or improvements in movement and will give an update when these patients have passed the 12-month mark since their transplant. However, these encouraging preliminary results have prompted the company to look ahead towards advancing their treatment down the regulatory approval pathway, out of clinical trials and into patients.

Asterias CEO, Steve Cartt, commented,

Steve Cartt, CEO of Asterias Biotherapeutics

Steve Cartt, CEO of Asterias Biotherapeutics

“These results to date are quite encouraging, and we look forward to initiating discussions with the FDA in mid-2017 to begin to determine the most appropriate clinical and regulatory path forward for this innovative therapy.”

 

Talking with the US FDA will likely mean that Asterias will need to show further proof that their stem cell-based therapy actually improves movement in patients, rather than the patients spontaneously regaining movement (which has been observed in patients before). FierceBiotech made this point in a piece they published yesterday on this trial.

“Those discussions with FDA could lead to a more rigorous examination of the effect of AST-OPC1. Some patients with spinal injury experience spontaneous recovery. Asterias has put together matched historical data it claims show “a meaningful difference in the motor function recovery seen to date in patients treated with the 10 million cell dose of AST-OPC1.” But the jury will remain out until Asterias pushes ahead with plans to run a randomized controlled trial.”

In the meantime, Asterias is testing a higher dose of 20 million AST-OPC1 cells in a separate group of spinal cord injury patients. They believe this number is the optimal dose of cells for achieving the highest motor improvement in patients.

2017 will bring more results and hopefully more good news about Asterias’ clinical trial for spinal cord injury. And as always, we’ll keep you informed with any updates on our Stem Cellar Blog.

Stem cell and gene therapy research gets a good report card from industry leader

arm

Panel discussion at ARM State of the industry briefing: left to Right Robert Preti, Chair ARM; Jeff Walsh, bluebird bio; Manfred Rudiger, Kiadis Pharma; Barbara Sasu, Pfizer;  Thomas Farrell, Bellicum Pharmaceuticals. Photo courtesy ARM.

The state of the regenerative medicine field is strong and getting stronger. That was the bottom line verdict at the 2017 Cell and Gene Therapies State of the Industry briefing in San Francisco.

The briefing, an annual update on the field presented by the Alliance for Regenerative Medicine (ARM), gave a “by the numbers” look at the field and apart from one negative spot everything is moving in the right direction.

Robert Preti, Chair of ARM’s Board, said worldwide there are more than 750 regenerative companies working in the stem cell and gene therapy space. And those companies are increasingly moving the research out of the lab and into clinical trials in people.

For example, at the end of 2016 there were 802 clinical trials underway. That is a 21 percent growth over 2015. Those breakdown as follows:

Phase 1 – 271 (compared to 192 in 2015)

Phase 2 – 465 (compared to 376 in 2015)

Phase 3 – 66 (compared to 63 in 2015)

The bulk of these clinical trials, 45 percent, are focused on cancer. The second largest target, 11 percent, is on heart disease. The number of trials for neurological disorders and rare diseases are also growing in number.

Preti says the industry is at an important inflection point right now and that this growth is presenting new problems:

“The pipeline of products is robust and the technologies supporting that pipeline is even more robust. The technologies that are fueling the growth in clinical activity have accelerated so fast that we on the manufacturing side are playing catchup. We are at a point where we have to get serious about large scale commercial production.”

Preti also talked about “harmonization” of the regulatory process and the need to have a system that makes it easier for products approved for clinical trials in one country, to get approval for clinical trials in other countries.

Michael Werner, the executive director of ARM, said the organization has played a key role in helping promote the field and cited the recently passed 21st Century Cures Act as “a major win and a powerful statement of ARM’s leadership in this sector.”

But there was one area where the news wasn’t all positive, the ability of companies to raise capital. In 2015 companies raised $11 billion for research. In 2016 it was less than half of that, $5.3 billion.

With that somber note in mind it was appropriate that the panel discussion that followed the briefing was focused on the near-term and long-term challenges facing the field if it was to be commercially successful.

One of the big challenges was the issue of regulatory approval, and here the panel seemed to be more optimistic than in previous years.

Manfred Rüdiger of Kiadis Pharma said he was pleasantly surprised at how easy it was to work with different regulatory agencies in the US, Canada and Europe.

“We used them as a kind of free consultancy service, listening to their advice and making the changes they suggested so that we were able to use the same manufacturing process in Europe and Canada and the US.”

Jeff Walsh of bluebird bio, said the key to having a good working relationship with regulatory agencies like the Food and Drug Administration (FDA) is simple:

“Trust and transparency between you and the regulatory agencies is essential, it’s a critical factor in advancing your work. The agencies respond well when you have that trust. One thing we can’t be is afraid to ask. The agencies will tell you where their line is, but don’t be afraid to ask or to push the boundaries. This is new for everyone, companies and regulators, so if you are pushing it helps create the environment that allows you to work together to develop safe therapies that benefit patients.”

Another big issue was scalability in manufacturing; that it’s one thing to produce enough of a product to carry out a clinical trial but completely different if you are hoping to use that same product to treat millions of people spread out all over the US or the world.

And of course cost is always something that is front and center in people’s minds. How do you develop therapies that are not just safe and effective, but also affordable? How do companies ensure they will get reimbursed by health insurers for the treatments? No one had any simple answer to what are clearly very complex problems. But all recognized the need to start thinking about these now, long before the treatments themselves are even ready.

Walsh ended by saying:

“This is not just about what can you charge but what should you charge. We have a responsibility to engage with the agencies and ultimately the payers that make these decisions, in the same way we engage with regulatory agencies; with a sense of openness, trust and transparency. Too often companies wait too long, too late before turning to the payers and trying to decide what is appropriate to charge.”

 

 

Bioengineered veins give hope to kidney disease patients on dialysis

As blood travels around your body, it helps your body get around. Blood is essential for delivering oxygen and nutrients to all the cells in your body and for removing waste products made by these cells. Your body contains approximately 1.5 gallons of blood, which translates to around 7% of your body weight. In order for all this blood to do its job, it needs to be constantly cleaned of waste and extra fluids.

Your kidneys are your blood’s best friend. They act as natural filters that remove those cellular waste products and extra fluid from the blood and pass them off to the bladder, where they are disposed of through urine. Kidneys have the important job of maintaining the proper balance of fluids, electrolytes and chemicals in the blood. They are also involved in other essential biological processes such as regulating blood pressure, making new blood cells, and maintaining healthy bones. It’s a big problem when your kidneys stop working. Without this built-in filtration system, toxic byproducts build up in your blood and cause a multitude of not fun symptoms.

Hemodialysis acts as an artificial kidney to filter the blood of kidney disease patients. (wikipedia)

Hemodialysis acts as an artificial kidney to filter the blood of kidney disease patients. (wikipedia)

More than half a million Americans suffering from kidney dysfunction or failure are being treated by hemodialysis. This process involves connecting a patient to a machine that acts as an artificial kidney. “Old blood” is pumped into the machine from a plastic tube, also known as a shunt, that’s inserted into the patient’s vein. The blood is then passed through a dialyzer which filters out the waste products and extra fluid and allows clean blood to pass through and be put back into the patient (see image).

While hemodialysis is successful at extending the lifespan of kidney disease patients, serious complications can arise from this treatment including uncontrolled changes in blood pressure, bone disease, and anemia. Another common problem occurs with the shunt that’s inserted into a patient’s vein. Shunts can cause infection, blood clots, and can also be rejected by a patient’s immune system. As a result, patients have to get new shunts implanted every year. This is not always feasible for older patients whose veins cannot hold up to this invasive procedure.

A tubular alternative for better hemodialysis

A North Carolina company called Humacyte is trying to improve current hemodialysis technology by engineering human acellular vessels (HAVs) (meaning that the vessels don’t have any cells) that can be transplanted into patients and develop into a human version of a shunt. Sounds complicated, but it’s not really!

First, scientists take muscle cells from human organ donors and coax these cells to grow into tube-like structures. During this process, the cells secrete a compound called cellulose – a component of the extracellular matrix – which forms a biological scaffold that maintains the structure of the cells.

Next, the scientists chemically wash away the muscle cells, leaving an intact scaffold with a hole the diameter of your pinky finger. These scaffolds are then placed under the skin of patients on dialysis. Once transplanted, a patient’s own stem cells migrate to the empty scaffold, set up shop and create a new vein with a wide enough hole that can be used for hemodialysis.

Humacyte’s Chief Medical Officer, Jeff Lawson, explained it an interview with KQED Science:

Jeff Lawson, Humacyte

Jeff Lawson, Humacyte

“This scaffold, once implanted, uniquely becomes repopulated with their own stem cells. That then turns back into something that looks like a vascular cell. And it now transitions over the period of a few months into something that’s indistinguishable from your own tissue. One of the holy grails in vascular surgery is to come up with a prosthetic artificial graft that has the same properties as the patient’s own blood vessels.”

The great news about this promising technology is that Humacyte is testing it in a Phase III clinical trial – the final stage before a drug or treatment is approved by the US Food and Drug Administration (FDA). In a Phase III trial, the treatment has already proven to be safe and shown some effectiveness (in a Phase II trial) and is now being tested in a larger group of patients to hopefully confirm these findings.

In July, CIRM invested $10 million in Humacyte’s Phase III trial in hopes that this technology will improve the lives and health of dialysis patients. Randy Mills, the President and CEO of CIRM, views kidney failure as an unmet medical need that could benefit from a stem cell related treatment:

“This approach has the potential to significantly improve our ability to care for people with kidney disease. Being able to reduce infections and clotting problems, and increase the consistency of care hemodialysis patients get, would meaningfully impact the quality of their lives.”

A patient’s story and CIRM’s efforts to fund clinical trials

Raymund Ramirez

Raymond Ramirez (KQED Science)

Yesterday, David Gorn from KQED Science published a nice piece about Humacyte’s stem cell derived technology and featured the story of a kidney failure patient, Raymond Ramirez. Raymond’s story is very emotional. He is a Vietnam war veteran that has experienced a gauntlet of maladies including bladder cancer and blindness in his right eye. On top of that, his kidneys aren’t functioning well and he is unable to continue his dialysis treatments because his veins aren’t holding up.

Raymond was the first patient to be treated in Humacyte’s Phase III trial. You can read more about his story here.

Gorn also highlighted CIRM’s recent efforts to fund promising stem cell projects that are further along in development and ready for clinical trials in patients. He ended with a quote from UC San Diego’s director of stem cell research, Larry Goldstein, on how important it is for our agency to continue funding stem cell clinical trials.

Larry Goldstein

Larry Goldstein

“Ten years ago I don’t think there were that many [stem cell] projects that were really ready for clinical trials. The field itself has developed projects that are at clinical stage. If the agency [CIRM] keeps pumping out these types of clinical results, California voters may soon see another ballot measure to keep it going.”