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G-202 Represents Novel Approach for Attacking Advanced HCC

G-202 Represents Novel Approach for Attacking Advanced HCC

http://www.onclive.com/publications/oncology-live/2014/march-2014/g-202-represents-novel-approach-for-attacking-advanced-hcc/2

Devalingam Mahalingam, MD, PhD

Published Online: Monday, March 24, 2014

Prodrug chemotherapy is an exciting approach by which higher concentrations of cytotoxic or biologically active agents can be achieved at a tumor site while avoiding the systemic toxicity of a non-cell-specific toxin. One promising example of this strategy is the development of the cytotoxic agent thapsigargin, which is derived from the Thapsia garganica plant once known in Mediterranean cultures as the “death carrot.” Efforts to engineer this agent into an effective therapy for hepatocellular carcinoma (HCC) are advancing.

Thapsigargin can kill a broad spectrum of cancer cells but with detrimental effects on normal endothelial cells, fibroblasts, and osteoblasts. The molecular mechanism of action is attributed to the induction of apoptosis (cell death) by a pronounced increase in cytosolic calcium due to blockade of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump to which thapsigargin binds with high affinity.

Due to the highly toxic characteristics of thapsigargin, the challenge was how to deliver the agent to tumors while causing the least impact on normal cells and tissue. The answer was to develop a relatively nontoxic form of thapsigargin; that is, the prodrug, which can be converted into the active cytotoxic agent at a particular location, specifically at the tumor site, for effective anticancer treatment.

In this pursuit, G-202 was generated by coupling a prostate-specific membrane antigen (PSMA)-specific peptide to an analogue of the potent thapsigargin. The daunting task was to identify a tumor-specific protein from which an appropriate peptide could be linked to the drug and make the drug inactive until the peptide could be cleaved from the drug only at the tumor site by that specific protein, such as PSMA, a glutamate carboxypeptidase type II enzyme that cleaves the acidic amino acids glutamate and aspartate. PSMA was of interest because of its unique presence in prostate cancer and most tumor endothelial cells, but not in normal vasculature or normal tissue epithelium. Of note, PSMA is also found in the vasculature of 90% of HCC tumors.

This is the best option as find this pharmacy shop now buy generic levitra you like and get enjoyed. With that formula, the science has cialis line order invented a new kind of medicine that is called generic medicine. There are many women who think whether they will ever regain their penile strength back or price viagra not. It is seriously advised by most doctors to seek for ay help purchase viagra online you could try here when you meet this certain sexual problems. The immense promise of G-202 as a future practice- changing therapy is apparent because this compound has biologic activity only after proteolytic cleavage by PSMA occurs at the tumor site. Normal healthy cells are no more susceptible to unwanted cytotoxic activity because thapsigargin is blocked by the masking peptide, which is selectively cleaved by PSMA in PSMA-positive human tumors such as prostate and HCC tumors. Within the neovasculature, the nontoxic prodrug G-202 is converted by hydrolysis into the active cytotoxic analogue of thapsigargin, 12ADT-Asp, which has the ability to trigger apoptosis by a mechanism similar to that of thapsigargin. Compared with thapsigargin alone, G-202 can achieve higher concentrations of the active agent at the tumor site while avoiding systemic toxicity.

When tested against a panel of human cancer xenografts in vivo, G-202 produced substantial tumor regression at doses that were minimally toxic to the host. These encouraging results led to a phase I open-label, single-arm, dose-escalation study in patients with advanced cancer. The study was designed to evaluate the safety and pharmacokinetics of G-202 as well as to identify a phase II dosing regimen. GenSpera, Inc, based in San Antonio, is sponsoring the research.

In all, 44 patients were recruited for the study at three US institutions, including the Cancer Therapy & Research Center at UT Health Science Center in San Antonio, which was the lead patient enrollment site. Of the participants, 28 were included in the dose-escalation portion of the study and 16 were part of an expanded cohort. Results were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.1

 

Most of the toxicities reported were mild and of grade 1 severity, with some patients experiencing increased creatinine/acute kidney injury/acute renal failure, nausea, and infusion-related reaction, ameliorated by prophylactic IV hydration, IV antiemetics, and steroid administration on the day of infusion. Five patients with HCC were enrolled in the expansion cohort. This group averaged 6 cycles of treatment per patient (range, 2-12 cycles), for a total of 29 cycles among all patients. An encouraging outcome was the observation of stable disease for more than 9 cycles in each of 2 patients.

This has led to the opening of a multicenter phase II study evaluating G-202 as second-line therapy for patients with HCC after treatment failure with sorafenib (Nexavar).2 If the early clinical finding holds true in controlling progression of HCC with minimal toxicity to patients, and a successful clinical development program is completed, G-202 could one day become a treatment option for patients with advanced HCC.

New therapies are urgently needed for this patient population. HCC ranks third in cancer deaths worldwide, with ~360,000 deaths annually. The majority (75%) of the world’s patients with HCC are in Asia-Pacific Rim countries. In the United States, the incidence of HCC is increasing and has risen at a faster rate in the Latino/Hispanic population than among non-Hispanic whites. Currently, the only FDA-approved drug for HCC is sorafenib, which gained an indication for unresectable HCC in 2007 after clinical trial findings demonstrated a 3-month improvement in overall survival versus placebo.
– See more at: http://www.onclive.com/publications/oncology-live/2014/march-2014/g-202-represents-novel-approach-for-attacking-advanced-hcc/2#sthash.TX7mxRWe.dpuf

 

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GenSpera registers for public offering

 

 

Mar 21, 2014, 1:15pm CDT

GenSpera registers for public offering

http://www.bizjournals.com/sanantonio/blog/2014/03/genspera-registers-for-public-offering.html

Biotech firm GenSpera has filed with the SEC for a future public offering.

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W. Scott Bailey

GenSpera Inc. has filed a registration with the U.S. Securities and Exchange Commission for a public offering.

The filing does not specify how many shares of stock the San Antonio-based biotech company plans to offer or at what price.

It does indicate that GenSpera (GNSZ: OTC) intends to use the proceeds from the sale of stock to fund Phase II clinical trials of its lead drug G-202 in patients with liver and brain cancer. The company also plans to dedicate a portion of those proceeds for working capital.

GenSpera, which is still in the research-and-development phase for its lead drug, reported a net loss of $2 million in the fourth quarter of 2013.

On Tuesday, I reported that GenSpera has launched a Phase II clinical trial for G-202 with patients who have glioblastoma multiforme, the most prevalent type of primary brain cancer. The trial will be conducted at the University of California at San Diego’s Moores Cancer Center.

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GenSpera enrolls brain cancer mid-stage trial with ‘grenade’ delivery

GenSpera enrolls brain cancer mid-stage trial with ‘grenade’ delivery

Blood-brain barrier in glioblastoma? ‘We don’t need to worry about it.’

http://www.fiercedrugdelivery.com/search/site/genspera

The weed Thapsia garganica, which provides the active ingredient thapsigargin for G-202–Courtesy of GenSpera

March 19, 2014 | By Michael Gibney

Texas cancer drug delivery specialist GenSpera is enrolling a new study for its molecular “grenade” candidate G-202. This time it’s a Phase II for the treatment of the notoriously aggressive brain cancer glioblastoma.

The G-202 candidate in question is the same as one that garnered GenSpera positive results in a Phase I study ending in October last year. That trial aimed at solid tumors with a subset of patients with hepatocellular carcinoma, a type of liver cancer.

Along with a research team at the University of California in San Diego, GenSpera will conduct the new study in two stages in up to 34 patients with recurrent forms of glioblastoma who have already undergone at least one major treatment–surgery or radiation. The drug is designed to be delivered via intravenous infusion for about an hour over the course of three days.

As an endpoint, GenSpera is looking for patients to be progression-free at 6 months. Historically, GenSpera CEO Craig Dionne told FierceDrugDelivery, about 15% of glioblastoma patients are progression-free by this point, and GenSpera is aiming to boost that number to 30%.
Any time a person cigarettes he let’s air pass cheap levitra 20mg large amounts of carbon monoxide. Consumption of fruit, vegetables, and whole grains daily, while limiting your viagra no prescription intake of trans-fats, saturated fats, sugar and white carbohydrates. In fact, herbs for erectile dysfunction work only when you would have maintained body weight. cialis for sale online http://davidfraymusic.com/buy-6273 Patients with prostatitis typically have long-lasting genitourinary/pelvic pain and obstructive viagra for and/or irritative voiding symptoms.
G-202 has shown to be effective before. But there are many delivery challenges that come with getting drugs past the blood-brain barrier, and here’s where GenSpera’s drug could have an edge: it doesn’t need to cross the barrier and its drugs work from within the blood vessels in the tumor.

Since G-202 is designed to act on the blood vessels inside a tumor, constricting them so as to starve the tumor, Dionne said, it doesn’t come up against the same challenges as other drugs that need to cross the endothelial cells to get into the tumor’s mainframe.

“Our approach to the blood-brain barrier,” Dionne said, “is we don’t need to worry about it.”

Dionne compares G-202’s release mechanism to a “grenade” complete with a “pin” that’s pulled at a specific site in a tumor’s blood vessel. G-202 is the first to take advantage of the enzymatic action of the prostate-specific membrane antigen, PSMA, that exists in abundance at tumors such as glioblastoma. The PSMA enzyme pulls off a peptide cap on the drug that delivers a hefty dose of the specifically deadly toxin 12ADT.

“If you look at glioblastoma, it is highly vascularized and makes a lot of PSMA, which is perfect for us,” Dionne said. “The toxin is targeted with the antibody drug conjugate and, taking advantage of the enzymatic action, it delivers thousands of active molecules. The amplification is a huge part.”

The toxin 12ADT is the final component of the uniquely designed drug. Its active ingredient, thapsigargin, is derived from a Mediterranean wild weed called Thapsia garganica, Dionne said, which works by disrupting a pump that regulates calcium levels in the blood vessel cells. The toxin is extremely potent, more so even than common cancer drugs such as doxorubicin, and kills independently of cell division rate, which means it can affect slow-growing tumors or even cancer stem cells that can linger after a tumor is mostly eradicated. According to Dionne, once the toxin is released, it is highly lipophilic and stays there in the tumor.

GenSpera’s other Phase II trial for G-202 in hepatocellular carcinoma is also currently being enrolled, Dionne said, with 16 patients on board.

– here’s the release

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CANbridge: A bridge to China

CANbridge: A bridge to China
By Erin McCallister
Senior Editor

To view the entire article click here.

Many small biotechs in the U.S. and Europe do not have the resources to develop their programs in China in parallel with Western territories, leading to a five- to eight-year lag before a Chinese launch.

CANbridge Life Sciences Ltd. plans to in-license candidates from these companies for China and elsewhere in East Asia as part of a global development strategy for its biotech partners.
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CANbridge wants to get the programs to patients in China faster and believes its executive team can help small biotechs develop their programs in China in parallel with an in-house Western development program.

Two of CANbridge’s executives have experience taking programs through the clinic and to market in China from time spent working at Genzyme China, a division of Genzyme Corp., which was acquired by Sanofi in 2011.

CEO James Xue was the founding general manager of Genzyme China. Crystal Xu, head of clinical development, was Genzyme China’s director of medical and
regulatory affairs.

To view the entire article click here.

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Stem cell trial seeks longer lives for victims of deadly ALS

 

Researchers at Emory University in the United States are hoping to extend the lives of patients diagnosed with the deadly neuro-degenerative disease, Amyotrophic lateral sclerosis (ALS). ALS kills by destroying a patient’s nervous system but in clinical trials, the scientists say injections of neural stem cells show promise in slowing the disease’s progress. Ben Gruber reports.
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http://my.news.yahoo.com/video/stem-cell-trial-seeks-longer-181048843.html

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Neuralstem’s $19.6M offering takes ALS bid through phase II

By Randy Osborne, Staff Writer
Neuralstem Inc.’s $19.65 million from a stock offering will help
advance the lead compound NSI-566 in amyotrophic lateral sclerosis
(ALS), which is “about halfway through” a Phase II trial, said CEO
Richard Garr.
Rockville, Md.-based Neuralstem is selling about 6.7 million shares
at $2.91 each in the offering. Each investor also gets a warrant to
buy half the number of shares purchased. Warrants bear an exercise
price of $3.64, and can be exercised for fi ve years.
Shares (NASDAQ:CUR) closed Friday at $2.97, down 19 cents.
Expected to close next week, the offering’s proceeds will get
Neuralstem through Phase II in the ALS effort with spinal cordderived
stem cells, as well as the small-molecule program, where
the company has “just completed a Phase Ib trial in major depressive
disorder,” Garr told BioWorld Today. “We’re looking at the data now,
and anticipate sometime in this quarter fi ling for a Phase II.”
Stem cell trials are neither much more expensive nor much cheaper
than tests of other therapies. “That’s always in the eye of the
beholder, isn’t it?” Garr noted. “Drug trials, especially for depression,
are expensive. Everybody knows what the FDA expects and what the
parameters are. It doesn’t cost us any more or any less than anybody
else.”
Cell therapy as a whole is “fairly expensive,” he said. “In terms of the
dollars per patient, it’s very expensive, but in terms of the numbers
of patients, because it’s fairly small, the overall cost is manageable.”
The Phase II trial in ALS got funding help from the National Institutes
of Health and from the ALS Association, he said.
“We have to wait six months after the last surgery for the trial to
end,” Garr said. “Sometime near the end of this calendar year, the
Phase II [in ALS] should be over completely.”
Neuralstem’s approach represents the world’s fi rst intraspinal
injections of stem cells. “This is a targeted surgery at various
segments of the spinal cord, and the cells actually go into the
motor neuron pools in those segments and synaptically integrate,”
Garr said. “There have been, in the past, people who have tried to
put what you would think of as adult stem cells – all kinds of bone
marrow and blood stem cells and things like that – into the spinalfl
uid cavity,” though such experiments took place “mostly in Mexico
and in Germany and other places,” as well as China, he said.
“Our approach is unique, actually rebuilding the circuitry,”
Garr said. “These cells don’t fl oat up and down in the spinal
fl uid, and they don’t migrate to the spinal cord. They’re going
in and creating new circuitry inside very specifi c segments
Over time though, webmasters used cialis vs viagra this site format to spam links. Separation anxiety maybe triggered in the new.castillodeprincesas.com order cheap viagra child even if he has no penis problems at all. Vitamin C: Another important vitamin for penis health, vitamin C ups collagen production and may improve the firmness of penis tissue…. who knew an orange could do that? A daily dose of is 100 mg, which is one 100mg tablet. viagra samples uk discount cialis Facts about discount cialis The effect also last for about four to six hours. of the spinal cord,” each of which is responsible for specifi c
groups of muscles, he noted. In ALS patients, when the
muscles that control breathing and swallowing give way, so
do the patients, not long afterward.
HUMAN DATA FUELING STOCK
Neuralstem also has been given clearance by the FDA to
start a spinal cord injury trial in complete paralysis patients,
using the same technology.
“Geron, of course, famously, had an approval from the FDA
[for trials] with their oligodendrocyte progenitor [GRNOPC-1]
cells to try to treat spinal cord injury,” Garr said. “I believe
they may have actually transplanted two or three patients
before they pulled the plug.”
Menlo Park, Calif.-based Geron last April disclosed in an SEC
fi ling that the assets related to the program were taken over
by Asterias Biotherapeutics Inc., a subsidiary of regenerative
medicine specialist Biotime Inc., of Alameda, Calif. The deal
involved transfers of common stock and warrants, along
with patents, regulatory fi lings and investigational new drug
applications fi led with the FDA for Geron’s Phase I safety
study with the cells. (See BioWorld Today, Jan. 26, 2009, Jan.
27, 2009, and April 5, 2013.)
“The mechanism of action by the cells, even though it’s the
same cells, is a little different [in spinal cord injury, where]
the idea is literally to build new circuitry to bridge the gap,
to bring function back to paralyzed patients,” Garr said. “In
ALS, even though patients lose their ability to walk, it’s not
because there’s a break in the signal coming down the spinal
cord from the brain. It’s because the muscles have atrophied
and died. Our main goal here is to improve the quality of life
and extension of life for these patients, is to keep them off
breathing machines for as long as possible.”
Neuralstem’s shares have been on the climb for about a
year. ”We don’t really talk about the stock that much,”
Garr said, because market changes are too hard to explain,
in most cases. “The clear answer is, there’s no substitute
for human data,” and interim data have been showing up in
presentations.
“A publication is coming out, we expect, on the Phase I trial [in
ALS],” he said. “Some of the patients went public, and it was
in Newsweek. It was pretty clear, just from a lay perspective,
they were seeing a defi nite benefi t to a number of patients, and
long term, not just marginal but signifi cant, quantitative actual
improvement that no one has seen before, and that has lasted
a very long time.”

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Beach Mining in Monterey Bay Causes a Dustup

Beach Mining in Monterey Bay Causes a Dustup

Officials in California Weigh Limits on a Decades-Old Facility That Dredges Sand

http://online.wsj.com/news/article_email/SB10001424052702304202204579254312563952176-lMyQjAxMTAzMDEwNTExNDUyWj

By

Jim Carlton

Updated Dec. 15, 2013 6:42 p.m. ET

California’s Monterey Bay is one of the most protected coastlines in the U.S., but sand mining operations are coming under increased scrutiny as opponents say they are contributing to heavy shoreline erosion. WSJ’s Jim Carlton reports.

MARINA, Calif.—California’s Monterey Bay boasts one of the nation’s most protected coastlines, situated within a federal sanctuary that imposes bans on everything from Jet Skis to offshore drilling.

Yet most days, hundreds of tons of sand are harvested from one of its most picturesque beaches, in a mining operation now coming under increased state and local scrutiny.

 

A dredge used by Cemex at a private beach in California’s Monterey Bay mines sand from a pond that contains sand-filled water carried by waves. James Tensuan for The Wall Street Journal

About 159,000 tons of sand annually are being dredged from pools just beyond the beach by an arm of Mexican cement giant Cemex SA B, the company says. Because that is also roughly the amount of sand that marine researchers say the local beach needs to replenish itself each year, officials here say the mine has greatly exacerbated an erosion problem like those ravaging shorelines world-wide.

“I don’t think you would see many people shedding a tear to see that go away,” said Jason Burnett, mayor of nearby Carmel-by-the-Sea and vice president of the Monterey Peninsula Regional Water Authority. “It’s probably the most invasive coastal impact we have.”

Spurred by local complaints, the California Coastal Commission is investigating whether the facility—which operates on privately owned property—should be sharply restricted. Mr. Burnett has gone a step further, suggesting Cemex consider selling the mining operation “rather than engage in this potential fight with the community.”

Cemex officials have expressed no inclination to sell, and they say there is no evidence that its mine, which has operated for decades under various owners, is contributing to the beach’s erosion. “We feel it is unsubstantiated,” said Sara Engdahl, spokeswoman for Cemex’s U.S. operations. The mine, which sells its sand primarily in California for uses including construction and water filtration, is one of 50 that Cemex operates across the U.S. but is the only one that harvests beach sand.
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The Monterey Bay debate comes as communities globally are struggling with ways to slow beach erosion, which threatens coastal infrastructure as well as tourism at a time when rising sea levels are likely to result in the loss of more shoreline, said Cheryl Hapke, a research geologist with the U.S. Geological Survey.

In California, beach sand historically has been partly replenished as part of a natural cycle: washed offshore during winter storms, it is returned to the beach later by waves, said Gary Griggs, director of the Institute of Marine Sciences at the University of California, Santa Cruz.

But that cycle has been interrupted over the past century on Marina’s dune-covered coastline just north of Monterey by a succession of sand mines, he said.

By 1988, five mines that had operated on public beaches here were ordered shut down by the U.S. Army Corps of Engineers because of erosion concerns. That left just the 100-acre facility on private land now owned by Cemex, Mr. Griggs said.

 

A sample of coarse sand from the beach in Marina, Calif. James Tensuan for The Wall Street Journal

Few other sand mines operate along coastlines in the U.S. Some operating in inland U.S. locations, such as Minnesota, have drawn fire from nearby residents for concerns such as noise, traffic and water pollution. The mining of sand has been boosted in recent years because of its use in hydraulic-fracturing operations by oil companies.

In 2008, a study conducted for the Association of Monterey Bay Area Governments by an environmental hydrology firm concluded the Cemex mine was responsible for at least half the erosion rate of adjoining Marina State Beach. At 5 feet a year lost to the sea, the beach has one of the highest coastal-erosion rates in California, according to USGS estimates. The statewide average is about 0.7 feet annually, Ms. Hapke said.

In 2009, the Monterey Dunes Coalition, a consortium of environmentalists, cited that study in asking the Coastal Commission to investigate whether the mine has violated state regulations by more than doubling the production level believed to have been authorized by a previous state agency 40 years ago.

“My objective is to get some leverage over them,” said Ed Thornton, professor emeritus of oceanography at the Naval Postgraduate School in Monterey, and president of the coalition.

The Coastal Commission, which expects to conclude its investigation early next year, is seeking to determine what authority, if any, the plant has had to mine sand, said Dan Carl, a deputy director of the agency. Cemex officials say they are cooperating with the state probe but don’t believe their operations are causing erosion.

On a recent tour of the facility, plant manager Dale Kendall said Cemex dredges only the sand carried by ocean waves into an intertidal pond, usually during winter storms. A slurry mix of sand and water is then pumped to a plant a half-mile away, where it is dried, sifted and sorted for various markets, he said.

Cemex’s Ms. Engdahl added that the company exercises environmental vigilance in its mining operations, such as not taking sand from the numerous dunes that adorn its property.

Mr. Burnett, the mayor of Carmel-by-the-Sea, suggests that the best outcome would be for Cemex to sell the mine, possibly to the city of Marina for use as a park. Marina officials said they have no such plans.

http://online.wsj.com/news/article_email/SB10001424052702304202204579254312563952176-lMyQjAxMTAzMDEwNTExNDUyWj

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AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference: October 2013

  • AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference: October 2013
    the company started a Phase II study in patients with recurrent high-grade glioma 10/22/13 Genspera Inc. (San Antonio) G-202 A thapsigargin-based prostate-specific membrane antigen-activated prodrug Hepatocellular carcinoma Data showed that 27% of patients exhibited stable disease 10/23/13 Immunogen Inc. (Waltham, Mass.) SAR566658 An antibody-drug conjugate targeted to CA6 Ovarian, breast and other epithelial cancers Interim Phase I data showed it is generally well tolerated and can induce

    BioWorld Insight | Monday, November 11, 2013

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Decreasing Progression, Increasing Function

A small Phase I ALS study is getting big results with stem cell treatment.

By Zac Haughn, Senior Associate Editor

http://bmctoday.net/practicalneurology/2013/10/article.asp?f=decreasing-progression-increasing-function#

For neurologists who see amyotrophic lateral sclerosis patients (ALS), techniques for coping and support take up far more room in a doctor’s bag than treatments and drugs. Significantly improving quality of life is as tantalizing as it is far away. Except for a small group of patients receiving human fetal neural stem cells in a small Phase I study: Six study patients experienced a stable, very slowly progressing or improved disease course at more than approximately 700-to- 850 days post-surgery. The trial’s most impressive responder couldn’t walk without a cane before his treatment of one million cells—500,000 on either side of his lower spine; after several months he walked unaided in a 2.5 mile walk-a-thon.1

The company behind the study, Neuralstem, Inc., says their stem cell technology enables the production of neural stem cells of the human brain and spinal cord in commercial quantities, and the ability to control the differentiation of these cells constitutively into mature, physiologically relevant human neurons and glia. They received FDA approval to commence a NSI-566/ALS Phase II trial in April 2013, following conclusion of the Phase I trial to test the safety of its stem cells and transplantation surgery in patients with ALS in February 2013.

The Phase I safety trial enrolled 18 patients. The trial began with 12 late- to mid-stage ALS patients who received a series of injections in the L2-L4 lumbar region. The first six patients were all non-ambulatory with permanent paralysis. Of these, the first three patients were treated with five unilateral cell injections, while the next three patients received 10 bilateral injections in the same region. The trial then progressed to patients who were ambulatory. The first three of these received five unilateral injections. The next three patients received 10 bilateral injections in the same lumbar region.

The aforementioned six study patients who experienced positive results shared two common clinical characteristics. They had no bulbar features of ALS, a form of the disease that destroys motor neurons in the corticobulbar area of the brainstem in the early stages and typically progresses faster than the limb-onset ALS. Additionally, these patients all received stem cell transplantation early in the course of their disease (at an average of two years, one month after symptom-onset). Two of the patients showing stabilization or improvement were among the three to receive transplants in both the lumbar and cervical regions.

Of the nine remaining patients in the trial, three subjects had a long disease course (5.6, 11.6 and 12.7 years of known disease), at the time of their transplantation, likely representing atypical ALS, and have had little change in the trajectory of their disease. Finally, six of the trial patients died of their disease, seven-to-30 months after surgery. Two of these patients had features of bulbar ALS at the time of their transplantation.

The NSI-566/ALS Phase II dose escalation and safety trial will expand to two centers. The trial is designed to treat up to 15 patients, in five different dosing cohorts, increasing to a maximum of 40 injections, and 400,000 cells per injection based on safety. (Phase I topped out at 15 injections of 100,000 cells each.) The first 12 patients will receive injections in the cervical region of the spinal cord only, where the stem cells could help preserve breathing function. The final three patients will receive both cervical and lumbar injections.

Neuralstem received approval from the FDA to move into the cervical (upper back) stage of the trial in the fall of 2011. The first of six patients in the cervical cohorts to receive stem cells was treated on November 18, 2011, which marked the first FDA-approved intraspinal surgical transplantation of stem cells into the cervical region. The trial then advanced to the final cervical cohort of three patients. The FDA approved the return of three patients from earlier cohorts to receive cervical transplants, making them the first to receive stem cell transplantation in both the lower and upper parts of their spinal cord. The first of these were treated in June 2012 and received five stem cell injections into the cervical region of the back, for a total of 15 injections, including the 10 lower-back injections previously received. The last patient in the Phase I trial was treated in August 2012. The trial was designed as a safety trial to treat 18 patients, and conclude six months after the final surgery.

For more on the team’s work, Practical Neurology talked to Eva Feldman, MD, Russell N. DeJong Professor of Neurology, Director of the A. Alfred Taubman Medical Research Institute, and Director of the Program for Neurology Research and Discovery at the University of Michigan, and Karl Johe, PhD, Neuralstem Chief Scientific Officer and developer of the cells used in the trial.
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Can you talk about your Phase I findings and the data you presented at the Canadian Neurological Sciences Federation Congress?

Dr. Feldman: As we continue to analyze data from Phase I of our trial, we continue to be pleased with the results. While the trial was designed to test the safety of direct intraspinal injections of stem cells in patients with ALS, we have found that a subset of patients have shown little progression of their disease, in some cases more than two years since surgery.

As we have reported, these individuals had no bulbar features of ALS and surgical transplantation occurred early within the course of their disease (average of two years and one month after symptom onset at the time of surgery). These very preliminary results suggest that intraspinal stem cell transplantation of ALS subjects with no bulbar symptoms early in the course of their disease could slow disease progression.

The FDA recently approved your Phase II trial. What are your objectives and what do you hope to learn?

Dr. Feldman: Our goal for the second phase of the trial is to continue to demonstrate the safety of the cells and of our methodology. We have designed this phase of the trial to further measure efficacy of the treatment and to deliver more stem cells with each operation. Our ultimate goal is to accumulate sufficient safety data and positive exploratory endpoints to progress to a widespread Phase III trial to test the efficacy of this new therapy in a larger cohort of patients.

What are the challenges facing stem cell therapy in ALS?

Dr. Feldman: We have taken great care to design the trial so that the surgery is unlikely to compromise the remaining function of ALS patients who enter the trial. The challenge is three fold. First, can we continue to safely deliver these stem cells to the spinal cord? Second, because this is a different type of transplant compared to larger whole organ transplants (like for example a heart or kidney), can we discontinue transplant rejection drugs after a period of initial administration? And, finally, the third and key question: Can we measure efficacy of our treatment, i.e. in the simplest of terms, does stem cell therapy work in ALS patients?

Can you talk about cultivating human fetal neural stem cells? How are they different than embryonic stem cells?

Dr. Johe, Chairman of Neuralstem: Neuralstem’s FDA approved cGMP cell banks are cultured in serum free medium. The cells have a mitotic capacity of roughly 60 doublings, so unlike ES cells, they are not “immortal.” The cells constituitively differentiate into regionally specific and relevant phenotypes; they do not have to be “driven” to their desired fate unlike ES cells. This makes for a more robust and efficient and predictable manufacturing process. ES cells for instance need to be “driven” to a specific neural precursor fate, as opposed to their many other potential fates, then culled for purity/safety purposes. Our culture methods start with the right neural stem cell for a particular purpose.

  1. Fox, C. FDA-approved Stem Cell Trial Dramatically Slows ALS. Biosciencetechnology.com; 2013-05-30.

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Genspera

BioWorld Today | Wednesday, October 23, 2013

http://www.bioworld.com/bioworld_search/GenSpera
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