Thermo Fisher Scientific’s (TMO) decision to acquire Life Technologies for $13.6 billion will create a sequencing and diagnostics juggernaut that will position Fisher to become a dominant player in the emerging field of personalized medicine. The acquisition, the biggest of 2013 in the U.S., may have been triggered by sequestration, the federal government’s 5 percent across-the-board cuts to the National Institutes of Health (NIH) and other agencies.

Waltham, Mass.-based Thermo Fisher already is an established leader in diagnostics and chemical analysis. Not only will Carlsbad, Calif.-based Life Technologies’ profits boost Thermo Fisher’s bottom line, but gives it something rivals like Agilent Technologies (A) don’t have: a straightforward path to commercialize next-generation genome sequencing. It also creates an opportunity for Illumina, which, if taken, could position it to outmaneuver Life Technologies.

Thermo Fisher acquiring Life Technologies

“The acquisition of Life Technologies enhances all three elements of our growth strategy: technological innovation, a unique customer value proposition and expansion in emerging markets,” Thermo Fisher’s CEO Marc Casper said in a company news release.

Shares of Illumina fell 3.94 percent to $55.56, but that fall is probably short term. Illumina, like Life Technologies, is a genome sequencing pioneer. Illumina has about 59 percent of the total sales of next-generation sequencers, while Life Technologies is second at 31 percent, according to a January 2013 report by International Strategy and Investment.

Both sequencing companies were feeling the pinch of slowed spending by the NIH on life sciences research, when sequestration made it worse. In a maddening irony to researchers, the cuts come just as next-generation sequencers – Illumina’s HiSeq 2000 and the Ion Torrent for Life Technologies – have radically reduced the time and cost of sequencing all or part of the human genome.

With federal spending on life sciences research on ice, many analysts have recommended selling Life Technologies. Thermo Fisher may have gotten a deal, even at a 12 percent premium over its most recent close. What about Illumia?

The acquisition of Life Technologies makes Illumina an even more tempting, if smaller, target. Last year Illumina successfully resisted an attempt by Swiss drug giant Roche Holding AG (RHHBY) to buy the San Diego-based company for $6.8 billion. Shares of Illumina moved up in February after it acquired Verinata Health, Inc., provider of non-invasive prenatal tests for the identification of fetal chromosomal abnormalities. However, the slowdown in NIH spending (and purchases of sequencers by researchers) has been a difficult headwind.

Agilent Technologies (A), a $15 billion market-capitalization company, is much smaller than Roche and Thermo Fisher. However, an Illumina merger with a smaller, but complementary biotech company would more likely preserve Illumina’s remarkably innovative scientific culture.
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Agilent has been a favorite of many analysts in 2013, but Thermo Fisher’s pending acquisition of Life Technologies sent Agilent down 3.82 percent to $43.04 at the close of trading on April 15. The price continued to slide in after-hours trading toward $43 a share, which was Agilent’s price a year ago. It didn’t help that April 15 saw the biggest drop in the Dow Jones Industrial Average in five months.

Agilent is proactive.It’s management offered its first cash dividend of 10 cents per share in January 2012, matching Thermo Fisher’s new dividend at the time. A year later, Agilent raised the quarterly dividend to 12 cents a share, a 20 percent increase, eveb though the company’s quarterly earnings growth, year over year, was down 22.2 percent.

Agilent’s revenue grew only 3.7 percent in 2012, and its share price has been flat over the past 12 months while health care companies in the S&P 500 are up 30 percent. Agilent needs a strong new technology partner and Illumina needs a diagnostics partner that can battle Thermo Fisher.

Some analysts argue that since Agilent is now cheaper than 96 percent of its peers, breaking it up and selling off an ill-fitting part or two would increase Agilent’s share value. Maybe so. But if Agilent wants to play more than just its current token role in next-generation sequencing, it needs Illumina. And Illumina needs Agilent, or something like Agilent, before the Swiss raider returns. And an Illumina-Agilent merger would add value short- and long-term.

The post Thermo Fisher acquiring Life Technologies — Illumina merger next? appeared first on San Diego Biotechnology Connection.

Trius Therapeutics has developed an antibiotic to treat infections caused by the deadly superbug called methicillin-resistant Staphylococcus aureus (MRSA), photographed here growing on a culture plate being held by Warren Rose, an associate professor of pharmacy at the University of Wisconsin.
(Photo: John Maniaci, University of Wisconsin Hospital & Clinics)

By Rex Graham

The share price of Trius Therapeutics (TSRX) has rebounded from its 10 percent dip in the New Year that was triggered by its public offering of 7 million shares; however, uncertainty about the company’s lead investigational drug is a lingering hangover.

The San Diego-based biotech grossed $34 million in the public offering; and mutual funds, institutional investors, insiders, and other large players purchased newly minted shares of Trius for $4.75 a share, which they can now flip for a combined profit of roughly $3.5 million. But small investors face a dilemma: should they dump their diluted shares, double down, or do nothing?

Trius is a biotech darling, but it also is a company that has not received U.S. Food and Drug Administration (FDA) approval for its lead drug tedizolid, a highly potent antibiotic developed to treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA). And if tedizolid is indeed approved by the FDA, it will face competition from cheaper, better-known generics. Tough obstacles? Maybe not.

Tedizolid: potent MRSA antibiotic

Tedizolid’s target is a highly resilient bacterium that causes a wide variety of often-deadly infections in skin, blood, bone, lungs, the heart, urinary tract, and other tissues. MRSA is found in hospital wards and nurseries, nursing homes, dialysis centers, athletic locker rooms, prisons, tattoo parlors, and preschools.

After receiving this tattoo in Ohio in 2005, this patient’s skin was infected with methicillin-resistant Staphylococcus aureus (MRSA).
(Photo_ Toledo-Lucas County (Ohio) Health Department)

MRSA outbreaks have even been traced to outpatient pain clinic employees who used single-use vials for more than one patient. Up to 25 percent of meat and poultry in U.S. grocery stores is tainted with multi-antibiotic-resistant S. aureus, including MRSA. It’s ubiquitous.

With the world’s population in almost inescapable contact with MRSA, the need for safer, more effective antibiotics to treat infections is enormous. For investors trying to decide whether to buy or sell Trius, there are three practical issues to consider: Log in or register to read more

The post Trius: dump or double down on maker of MRSA antibiotic? appeared first on San Diego Biotechnology Connection.

Agenus, Inc. (Nasdaq: AGEN), and Genocea Biosciences are pursuing protein subunit vaccines against genital herpes, or herpes simplex virus type 2 (HSV-2). Image: NIH

By Rex Graham

A Glaxo Smith Kline (Nasdaq: GSK) genital herpes vaccine recently flopped in a large clinical trial, but “next generation” genital herpes vaccines by Genocea Biosciences, Agenus, Inc. (Nasdaq: AGEN), Vical, Inc., (Nasdaq: VICL), and Sanofi Pasteur (the vaccines division of sanofi-aventis Group (NYSE: SNY)) offer new hope for an effective vaccine treatment.

A Yale University study published in the Nov. 15, 2012, issue of Nature described a simple technique to “pull” memory immune cells, a few days after genital herpes vaccination shots, directly into reproductive tissues where the cells are needed. Moving memory immune cells to the site of infections solves a vaccination riddle and two genital herpes vaccine developers are seizing on the breakthrough to improve the effectiveness of their vaccines.

With one of six adults in the U.S. infected with genital herpes and many others fearful of joining them, there is no shortage of volunteers for trials of genital herpes vaccines.

More than 8,300 women volunteered to receive three shots of a HSV-2 vaccine over six months in a clinical trial sponsored by Glaxo. The vaccine was hoped to prevent initial infections. However, Glaxo announced in early 2012 that women who received the vaccine were actually slightly more likely to eventually become infected than women who received a placebo.

$100 million lesson

The Glaxo subunit vaccine, like several others, contained viral glycoprotein D (gD2) plus an adjuvant to enhance the antibody response. A 20-year, $100 million effort to prevent genital herpes using gD2 subunit vaccines, seems to have flopped.

Genital herpes vaccine quixotic?

Now, it’s fair to ask why Agenus and Genocea Biosciences are still pursuing subunit vaccines against HSV-2. Are their quests quixotic and doomed as well? And what about live-attenuated, replication-deficient and DNA vaccines against genital herpes?

An estimated one out of six people aged 14 to 49 years old in the U.S. and more than 500 million worldwide have HSV-2 infections, but the virus is incredibly resilient once it infects a human host. The cruel witticism about herpes being more permanent than marriage is sadly true. Anti-viral drugs acyclovir, valaciclovir and famciclovir, marketed under a variety of trade names, can prevent or shorten genital herpes outbreaks, but experts say an effective vaccine is a better solution.

Needed: genital herpes vaccine

Initially, genital herpes causes small, painful blisters in the reproductive and adjacent tissues of men and women. It also infects nearby neurons where the virus sets up latent infections, oscillating between dormancy and outbreaks in genital tissue every few weeks or months.

Genital herpes infections in adults who have competent immune systems are usually not life-threatening. However, genital herpes is associated with a three-fold increased risk for HIV acquisition. And, in pregnant women, genital herpes can lead to miscarriage or premature birth, and the infection can be passed to a child, resulting in a potentially fatal infection.

‘I’m not a whole person’

“At our company’s all-hands meeting I read a letter from a 20-year-old woman, thanking us for working on a vaccine,” said Chip Clark, CEO of Genocea Biosciences, a Massachusetts company testing a protein subunit vaccine against herpes simplex virus type 2 (HSV-2). “She wrote, ‘I can’t date. I can’t marry. I can’t have children because of the possibility that I will pass on this terrible disease. I feel like I’m not a whole person.’”

“We are built narrowly around our antigen-discovery platform, but we would be narrow-minded if we didn’t think that what we develop is only part of the solution,” said Chip Clark, CEO of Genocea Biosciences, a Massachusetts company testing a protein subunit vaccine against herpes simplex virus type 2 (HSV-2). Photo: Genocea Biosciences

Why?

The gD2 subunit vaccines were designed primarily to generate an antibody response. However, antibodies alone don’t seem to deter HSV-2. Cell-mediated immune responses that involve thymus-derived cells (T cells) such as CD4 T cells and CD8 T cells, and antigen-presenting cells, macrophages, dendritic cells and related cell types are most effective in animal models of HSV-2 in humans.

Keeping herpes latent

“We are not promising any cures,” said David Knipe, a professor of microbiology and immunology at Harvard Medical School and one of the world’s leading experts on HSV-2 vaccines. “However, an effective therapeutic vaccine may keep the virus in its latent state, or knock out the virus when it reactivates.”

Animals lie

More CD8 T cells or a different kind of CD4 T cell response may work well in animal models, “but they may or may not be good predictors of efficacy in humans,” Knipe said. “We don’t know the correlates of immunity, and to find out we need to do more testing in humans.”

“If I knew why animals lie, my name would be in lights,” said Genocea’s Clark.

Under the urging of Knipe and his colleagues, the National Institute of Allergy and Infectious Diseases (NIAID) hosted leaders of the HSV-2 vaccine community in a workshop Oct. 22-23. The meeting included academic researchers, vaccine developers, providers of grant funding and regulators with the U.S. Food and Drug Administration (FDA). The workshop participants are expected to release a list of recommendations for future HSV-2 vaccine development.

“An effective therapeutic vaccine may keep the virus in its latent state, or knock out the virus when it reactivates,” said David Knipe, a professor of microbiology and immunology at Harvard Medical School and one of the world’s leading experts on HSV-2 vaccines. Photo: President and Fellows of Harvard College, Harvard Medical School, Lisa Green

The FDA is eager to do its part in the development of an effective HSV-2 vaccine, but the regulatory agency won’t define what antibody levels or cell-mediated immune responses are required. FDA licensure of any genital herpes vaccine will be based on clinical results.

Replication-deficient herpes

The attendees of the NIAID workshop focused on approaches that elicit strong cell-mediated immune responses. Attempts to weaken, or attenuate HSV-2 have resulted in live vaccines that are more potent that protein subunit vaccines, and research is proceeding to ensure that such vaccines are safe. Knipe said replication-deficient HSV-2 that can infect cells – but not multiply in them – could offer the advantages of protein subunit vaccines without the safety concerns of live-attenuated strains.

The vaccines developed by Agenus and Genocea produce antibody responses but, more importantly, they also produce robust cell-mediated responses.

The endpoint for Genocea’s double-blind, placebo-controlled, dose-escalation trial is a reduction in the frequency and severity of genital herpes sores. The endpoint for Agenus is a reduction in viral shedding, which would reduce transmission and lower the occurrence of outbreaks in previously infected individuals.

Vaccine trial results in 2013

Both companies will report the results of their Phase 2 and Phase 1/2a clinical trials, respectively, in the third quarter 2013.

The Agenus and Genocea vaccines each contain an adjuvant that enhances cell-mediated immunity. However, the two companies’ vaccines differ dramatically in the most important component: the protein antigens.

Deconstructing two herpes vaccines

Genocea uses two HSV-2 proteins. One is gD2, which was used in Glaxo’s vaccine. The second protein is called infected cell protein 4 (ICP-4), which elicits a strong cell-mediated response in patients of varied genetic backgrounds.

Agenus uses 32 peptides, all made synthetically. Agenus scientists selected the peptides, each 35 amino acids in length, because they were exact matches for peptides in a database of peptides that are known to be involved in human “antigen presentation” reactions that are a key part of cell-mediated immunity.

The Agenus vaccine has an additional ingredient: human heat-shock protein 70 (hsp70). This protein, which is induced by fever and other stressors, is an important “alarm signal” that triggers innate immune responses that are known to kill or inactivate many viruses.

“We’ve designed what we think is an optimal vaccine with a very wide spectrum of 32 targets that allow us to address a very wide cross section of the population and a wide spectrum of the herpes genome,” Dr. Garo Armen, CEO of Agenus, said in a telephone interview.

Financing Phase 3

Agenus plans to finance Phase 3 trials of its HSV-2 vaccine with income generated from its other products. The company has 18 products in clinical development, many being developed in collaboration with Glaxo. “We will have a number of companies wanting to partner with us,” Armen said.

Privately held Genocea announced in October that it has raised $30 million in Series C financing. The Bill & Melinda Gates Foundation and CVF, LLC, an affiliate of Henry Crown and Co., are participating with Genocea’s existing investors, including Polaris Venture Partners, Lux Capital, SR One, Johnson & Johnson Development Corporation, Skyline Ventures, Cycad Group, Auriga Partners, MP Healthcare Ventures and Morningside. Genocea has raised a total of $76 million in equity financing to date.

‘Push-pull’ breakthrough

“If vaccines develop robust memory CD8 T cell responses, that’s great, but you still need to recruit them to the site of infection,” Akiko Iwasaki, professor of immunobiology and molecular, cellular and developmental biology at Yale University, said in a telephone interview. “Hopefully, our ‘pull’ approach can be used with any vaccine to do that.” (Photo: Yale University)

The Agenus and Genocea vaccines rev up CD4 T cells, which are involved in cell-mediated immunity, as well as memory CD8 T cells, a particularly important subpopulation of T cells that migrate through the spleen, liver and other organs, but don’t enter vaginal tissue and other parts of the body unless recruited by CD4 T cells.

However, the Yale study published in Nature reported that a biochemical signal in the form of a topical application of chemokines (CXCL 9 and CXCL 10) in the vaginas of mice “pulls” memory CD8 T cells into the tissue whether CD4 T cells are there or not.

The pull was so effective that 100 percent of mice that received it after being vaccinated with a genetically weakened strain of HSV-2 survived a lethal challenge of HSV-2. However, only 36.3 percent of mice survived the lethal challenge if they had been given only the vaccination.

‘Pulling’ for vaccines

“If vaccines develop robust memory CD8 T cell responses, that’s great, but you still need to recruit them to the site of infection,” Akiko Iwasaki, professor of immunobiology and molecular, cellular and developmental biology at Yale University, said in a telephone interview. “Hopefully, our ‘pull’ approach can be used with any vaccine to do that.”

The Yale results are so compelling that the CEOs of Genocea and Agenus said in telephone interviews that they are investigating the biochemical “pull” approach with their current vaccines to determine whether to add the new wrinkle in the next round of clinical trials.

“As long as there is safety data on the ‘pull’ mechanism, we may want to do a preclinical model and get it into the clinic as early as possible,”said Dr. Garo Armen, CEO of Agenus, Inc. (Photo: Creative Commons)

“We find ‘push-pull’ very interesting, very promising,” said Genocea’s Clark. “We are built narrowly around our antigen-discovery platform, but we would be narrow-minded if we didn’t think that what we develop is only part of the solution.”

Armen, the CEO of Agenus, was equally impressed. “As long as there is safety data on the pull mechanism, we may want to do a preclinical model and get it into the clinic as early as possible.”

Iwasaki also said the chemokines used in her study are gentle, safe and can be formulated into a gel that can easily be applied topically. She said another FDA-approved gel used to treat genital warts is much more toxic than her chemokines.

DNA genital herpes vaccine

San Diego-based Vical, Inc. (Nasdaq: VICL), dramatically improved protection against HSV-2 in mice with a DNA vaccine that includes the full length of the gD2 gene combined with an adjuvant called Vaxfectin®. In a paper published in the May 22 online edition of Journal of General Virology, researchers said all mice in the gD2 vaccine-only group died when given 500 times the lethal dose of HSV-2. However, 80 percent survived if they had been given Vaxfectin with the DNA vaccine.

Vical plans to begin human trials in 2013 and will evaluate multivalent DNA vaccines that elicit cell-mediated immunity and have prophylactic and therapeutic activity in the guinea pig model of genital HSV-2.

Amgen (Nasdaq: AMGN) purchased BioVex Group, Inc., in March 2011, but Amgen hasn’t announced plans to advance BioVex’s live-attenuated genital herpes vaccine, which is rationally designed to remove the genes that allow HSV-2 to avoid the immune system.

“The most likely effective vaccine for HSV-2 would be a live-attenuated vaccine,” said Timothy Foster, a professor of microbiology, immunology and parasitology at the Louisiana State University School of Medicine.

Sanofi Pasteur (NYSE: SNY), provider of vaccines against more than 26 infectious diseases, is supporting development of the ACAM-529 replication-defective HSV-2 vaccine. The vaccine protects mice from a lethal vaginal HSV-2 challenge, and it provides better protection than glycoprotein D, plus adjuvant, in guinea pigs.

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Vaccine-related jobs in San Diego

MOST RECENT HEADLINES FOR VICAL, INC., FROM YAHOO FINANCE

• Vical Appoints Richard M. Beleson and Stephen A. Sherwin, M.D., to Board of DirectorsGlobeNewswire(Thu 4:05PM EDT)
• VICAL INC Files SEC form 8-K, Change in Directors or Principal OfficersEDGAR Online(Thu 9:06AM EDT)
• Interesting VICL Put And Call For Julyat TheStreet(Mon, May 20)
• VICAL INC FinancialsEDGAR Online Financials(Fri, May 17)
• Biotech Stock Mailbag: Vical, Sangamo, Spectrum Pharmaat TheStreet(Fri, May 17)
• Vical's CEO Presents at Bank of America Merrill Lynch 2013 Health Care Conference (Transcript)at Seeking Alpha(Tue, May 14)
• Short Interest In Vical Moves 21.2% Higherat TheStreet(Fri, May 10)
• VICAL INC Files SEC form 10-Q, Quarterly ReportEDGAR Online(Fri, May 10)
• Vical's CEO Discusses Q1 2013 Results - Earnings Call Transcriptat Seeking Alpha(Thu, May 9)
• Vical Earnings: Here’s Why Investors are Happy Nowat Wall St. Cheat Sheet(Thu, May 9)
• Q1 2013 Vical Inc. Earnings Release - Before Market OpenCCBN(Thu, May 9)
• Vical Reports First Quarter 2013 Financial Results and Progress in Key Development ProgramsGlobeNewswire(Thu, May 9)
• VICAL INC Files SEC form 8-K, Results of Operations and Financial Condition, Financial Statements and ExhibitsEDGAR Online(Wed, May 8)
• Galena: Improving Cancer Vaccines for the Futureat Motley Fool(Tue, May 7)
• Vical to Present at May Investor ConferencesGlobeNewswire(Tue, May 7)

The post Glaxo genital herpes vaccine flops but Agenus a buy in vaccine space appeared first on San Diego Biotechnology Connection.

Qsymia capsules. Image: Vivus, Inc.

By Rex Graham

This season of pumpkin pie, mashed potatoes and rising obesity rates is a perfect time to talk turkey about the overly bearish sales estimates of Belviq and Qsymia, the obesity drugs approved by the FDA this summer.

The oft-cited $1 billion-a-year combined estimated sales for Qsymia, which is made by Vivus, Inc. (VVUS), and Belviq, made by Arena Pharmaceuticals (ARNA), should be revised upward. Why? It’s not just because of Aetna’s Nov. 20 revision to include Qsymia and Belviq “as medically necessary weight reduction medications” for its 37.3 million covered health plan members.

Two important policy shifts at the federal level – by the Centers for Medicare & Medicaid Services and the U.S. Preventive Services Task Force – also bode well for much broader coverage of weight loss prescription medicines. The shift is a logical way to cut massive health costs caused by obesity. The trajectory of policy shifts is leading experts to predict that Qsymia and Belviq will soon become covered by all private and public health insurers, including Medicare, the federal health plan for Americans aged 65 and older and younger people with disabilities, and Medicaid, the federal-state health program for low-income individuals and families.

Even the Mayo Clinic informs patients visiting its website that Qsymia and Belviq are “prescription weight-loss medications your doctor may prescribe.” Estimates of the market in the U.S. alone for obesity drugs are as high as $60 billion a year, but nobody knows for sure. Consider this: the market capitalization of Vivus currently at $1.12 billion and Arena’s market cap at $2.03 billion. Even if the obesity drug market’s eventual size is one-tenth of the highest current estimate, both companies are grossly undervalued.

Obesity policy timeline

“The epidemic of obesity-associated diabetes is a major crisis in modern societies, in which food is plentiful and exercise is optional,” Mitchell A. Lazar, director of the Institute of Diabetes, Obesity, and Metabolism at the University of Pennsylvania, writes in Science magazine.
Image: Diabetes-body weight study in the U.K., BBC

This is the timeline of major events in the past 12 months that underlie the assessment that sales of Qsymia and Belviq will be better than expected:

• November 2011: A “decision memo” by the Centers for Medicare & Medicaid Services (CMS) states: “The evidence is adequate to conclude that intensive behavioral therapy for obesity, defined as a body mass index of 30 or higher is reasonable and necessary for the prevention or early detection of illness or disability.” More intensive treatment plans, including up to 26 office visits in one year, are now expected to become part of Medicare and Medicaid coverage. (Neither Qsymia norBelviq had been approved by the FDA yet.)

• May 8, 2012: A report by U.S. Institute of Medicine and the Robert Wood Johnson Foundation estimated that the annual cost of treating obesity-related chronic disease and disability is $190.2 billion. Obviously, reducing obesity reduces obesity-related costs and “the staggering human toll.”

• June 2, 2012: The U.S. Preventive Services Task Force recommends intensive, multicomponent behavioral intervention for patients with BMI of 30 or higher to reduce weight and lower metabolic risk factors for diabetes and cardiovascular disease. (Still no decision by the FDA at this point on Qsymia or Belviq.)

• June 27, 2012: FDA approves Arena Pharmaceutical’s Belviq, along with a reduced-calorie diet and exercise, for chronic weight management of adults with BMI of 30 or higher (or BMI of 27 or greater when the individual has a weight-related condition such as high blood pressure, type 2 diabetes or high cholesterol). It was the FDA’s first approval of a weight loss drug in 13 years.

• July 17, 2012: FDA approves Vivus’ Qsymia along with a reduced-calorie diet and exercise, for chronic weight management of adults with BMI of 30 or higher (or BMI of 27 or greater when the individual has a weight-related condition such as high blood pressure, type 2 diabetes or high cholesterol).

• November 20, 2012: Aetna, a health insurance provider to 37.3 million policyholders, revised its Clinical Policy Bulletin to include Belviq and Qsymia as “medically necessary weight reduction medications.” (Each Aetna benefit plan defines which services are covered; members need to consult with benefit representatives to determine if their plan has limitations that would apply to obesity medicines.)

ObamaCare to cover obesity drugs

“Along with Aetna, many other private insurers already cover visits and obesity counseling, and ObamaCare will mandate that preventative services for obesity are covered,” said Dr. Michael Kaplan, chief medical officer of The Center for Medical Weight Loss, a Tarrytown, N.Y.-based company with 750 affiliated doctors in weight loss clinics nationwide. “ObamaCare should lead to 100 percent of the population being covered for obesity management in 2014.”

Benefits of modest weight loss

The combination of diet and exercise helps about 20 percent of people lose weight and keep it off, according to the National Weight Registry. What will help the remaining 80 percent? Combining Qsymia and/or Belviq with a low-calorie diet, exercise, routine counseling and related approaches may actually work. Image: NIH

A landmark 2005 study found that 27 percent of all national health care charges were associated with patients who are physically inactive, overweight and obese. More recent studies document that modest weight loss of 5 to 10 percent can significantly reduce rates of type 2 diabetes, hypertension, cardiovascular disease and other health problems. All private and public health insurance plans pay for diabetes drugs, and it’s only logical to cover obesity-prevention services and drugs that reduce rates of diabetes.

In other words, reducing obesity will save the nation some unknown percentage of the $190.2 billion it currently spends on obesity-related diseases (such as diabetes) and disability. At the same time, not all obesity treatments are cost effective: the National Weight Registry found that surgeries designed to restrict overeating don’t really work in most cases; most of those patients exercise very little, eat more high-fat foods than the norm, and gain the weight back.

Less costly approaches than surgery seem to work better. However, neither reduced-calorie diets alone, nor increased exercise alone lead to long-term weight loss. The combination of diet and exercise helps about 20 percent of people lose weight and keep it off, according to the National Weight Registry. What will help the remaining 80 percent? Combining Qsymia and/or Belviq with a low-calorie diet, exercise, routine counseling and related approaches may actually work.

“Getting patients to lose even 10 percent of their body mass is huge because health outcomes improve dramatically even with modest weight loss,” says Dr. Michael Kaplan, chief medical officer of The Center for Medical Weight Loss, a Tarrytown, N.Y.-based company with 750 affiliated doctors in weight loss clinics nationwide. Photo: The Center for Medical Weight Loss

Kaplan is using that approach with Qsymia and “having pretty good results in combination with intensive counseling and behavior modification” with no side effects. “In some cases we can discontinue hypertension medications and medications for type 2 diabetes,” Kaplan said. “Getting patients to lose even 10 percent of their body mass is huge because health outcomes improve dramatically even with modest weight loss.”

Checking zero-sum math

Some analysts describe the market for Qsymia and Belviq as a zero-sum game, with sales of one hurting the other. It’s easy to understand the argument: with Qsymia costing $120 to $160 a month, mostly out of pocket, and Belviq expected to cost roughly the same, a patient will use only one or the other, right? It depends.

Indeed, about 30 percent of the patients who have received Qsymia prescriptions didn’t fill them. Dr. Edward Zbella, medical director of the Tampa, Fla.-based Medi-Weightloss Clinics, said his 82 affiliated weight loss clinics plan to use the two generic drugs in Qsymia at a price of about $40 per month of treatment, rather than relying on Qsymia, with a price tag of $120 to $160 a month.

“There is no advantage for us to use Qsymia,” Zbella said. At the same time, he said a high-intensity approach of a low-calorie diet, regular exercise, counseling and weight loss drugs can be highly effective. “Type 2 diabetes is almost always due to obesity,” he said. “And older obese patients need hip and knee replacements, which are expected to increase ten-fold in the next five years, and the negative health impacts of obesity go on, and on, and on.”

However, if insurance plans are eager to avoid spending increases to treat type 2 diabetes, hypertension and cardiovascular disease, why not cover obesity drugs? Zbella said if health insurance providers cover Qsymia and Belviq prescriptions, his clinics will prescribe them.

Qsymia capsules. Image: Vivus, Inc.

Belviq tablets. Image: Arena Pharmaceuticals

“Qsymia looks like a better drug for a patient who weighs more, so we may start a patient on it, but Qsymia and Belviq are both are excellent for maintaining weight loss,” Kaplan said.

Reasonable expectations

Vivus reported $453,000 in Qsymia shipments for the last two weeks of September, an amount equivalent to roughly only 3,000 prescriptions. The intentionally cumbersome online ordering from CVS Pharmacy and Walgreens hurt. The FDA required the difficult ordering process and home delivery of Qsymia as a way to limit sales to women of childbearing ages, but weight loss doctors say the FDA has gone too far if the federal government truly wants to lower the obesity rate.

“It’s all kinds of paperwork; it’s a hassle and CVS and Walgreens don’t even stock them,” said Dr. Arthur Aronson, owner of Medarts Medical Weight Loss Specialists in San Diego, Calif. He sees up to 300 patients during a busy month, but refuses to prescribe Qsymia because of the prescription hassles – unless patients ask for it.

Investors understandably don’t have the patience for such glitches to be resolved. Many pulled out of Vivus because of the disappointingly slow initial sales, but it’s time for them to come back to Vivus and Arena because the insurance landscape is shifting in favor of the two companies.

New Year’s weight-loss resolutions

Already, Vivus has expanded its online distribution network for Qsymia to two additional home-delivery networks: Express Scripts and Kaiser Permanente (for its 9 million health plan members). Some analysts now predict a substantial increase in Qsymia sales in the fourth quarter. They may be correct, but as anyone who frequents a fitness club knows, almost all new members arrive, like clockwork, in January, not the fourth quarter of the year.

“Right now, it’s slow at our clinic, which is usual this time of year,” Aronson said in a pre-Thanksgiving telephone interview. “In January, patients literally line up at the doors.”

The post-holiday bump in interest in weight loss is great timing for Belviq, which should be available by then. However, it must first be “scheduled” as a controlled drug by the U.S. Drug Enforcement Administration (DEA), after which Eisai, Inc., will begin marketing it in most of North and South America (including the U.S., Canada, Mexico and Brazil). Eisai has a marketing and supply agreement with Arena.

Red tape opportunity

It’s possible that the FDA could require the same unnecessarily cumbersome online prescription ordering process for Belviq that has slowed Qsymia sales. However, Kaplan said his weight loss clinics regard the red tape as an opportunity. Office staffers sit down with patients at a computer and assist them with ordering. Patients love it. Refills are much simpler and return visits are easier on everybody.

Since reimbursable counseling sessions are now recommended as an essential part of weight loss treatment, clinics have an incentive to schedule additional patient visits. More frequent visits help ensure that patients follow through on prescription ordering, adherence to diet and exercise plans and achievement of significant weight loss.

Post-marketing diet pill studies

The FDA has required both Arena and Vivus to conduct post-marketing studies, including long-term outcomes trials to assess the effect of Belviq and Qsymia on the risk for heart attack and stroke. Until the post-marketing studies verify cardiovascular safety, many physicians won’t get out their prescription pads.

“Physicians in our practice are unlikely to significantly prescribe either the phentermine/topiramate combination [Qsymia] or lorcaserin [Belviq] in the near future,” said Umesh Masharani, a clinical professor at the UC San Francisco Diabetes Center.

Masharani points to his experience with the then-almost-magical combination of fenfluramine and phentermine, known as fen-phen. A study published in 1984 in Archives of Internal Medicine found that after taking fen-phen for 24 weeks, overweight patients lost an average of 18.5 pounds, versus 9.7 pounds in the control group receiving only individualized diets.

After sales soared in the 1990s, fen-phen crashed following the publication of a 1996 paper in the New England Journal of Medicine by researchers at the Mayo Clinic. They reported a correlation between heart valve dysfunction and fen-phen.

Lingering fen-phen fears

Umesh Masharani, a clinical professor at the UC San Francisco Diabetes Center and author of “Diabetes Demystified,” says, “Physicians in our practice are unlikely to significantly prescribe either the phentermine/topiramate combination [Qsymia] or lorcaserin [Belviq] in the near future.” However, the FDA’s approval of the two obesity drugs recognized the obvious; the potential health gains of even modest weight loss, including cutting the rate of type 2 diabetes, far outweighed the potential risks of side effects. Photo: UCSF

Patients in clinical trials taking Qsymia lost 8.6 to 9.4 percent of their body weight (compared to controls) at one year. Weight loss with Belviq was 3.0 to 3.3 percent.

“We are concerned about the adverse reactions of these drugs and the relatively modest efficacy,” said Masharani, author of the book “Diabetes Demystified.”

Masharani’s diabetes patients will have to wait for post-marketing studies to be completed before receiving a prescription for Qsymia or Belviq.

The FDA weighed the risks of waiting to approve Qsymia and Belviq versus not waiting for further studies. It came to the opposite conclusion as Masharani. The regulatory agency’s approval of the two obesity drugs recognized the obvious; the potential health gains of even modest weight loss far outweighed the potential risks of side effects. The nation’s private and public health insurance industries have come to the same conclusion.

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The post More insurers, ObamaCare to cover obesity drugs made by Arena, Vivus appeared first on San Diego Biotechnology Connection.

Tim Brown, suffering from cancer and dangerously low CD4 T cell counts in 2007, was given a bone marrow transplant from a donor who was homozygous for a mutant form of the CCR5 gene. The transplant helped cure the cancer and made Brown completely resistant to HIV-1. (Photo: Eva Kolenko)

By Rex Graham

The odds of a major advance in the fight against HIV/AIDS have improved with the recent announcement by Sangamo Biosciences (SGMO) that its gene therapy treatment has achieved a “functional cure” for some HIV patients in its Phase 1 clinical trials.

Tim Brown, the famous “Berlin patient” and first person cured of HIV, appeared at the HIV Cure Forum in Palm Springs and West Hollywood, Calif., on Nov. 13 and 14. Brown’s visit and Sangamo’s clinical trial results draw attention to an unlikely corner of human gene therapy: beneficial mutations. In Sangamo’s case, its scientists generate mutations in the CCR5 gene in human CD4 T cells that conferred resistance to HIV-1, the most common strain of the virus. Brown was cured when he received donated CD4 T cells with a naturally occurring CCR5 mutation.

The Richmond, Calif.-based Sangamo has touted results at the one-year clinical trial endpoint: in five of nine subjects, CD4 T cell counts persisted a year after infusion at greater than 500 cells/mm3, the accepted threshold for initiation of highly active antiretroviral therapy (HAART).

“The initial results in a few patients look good and compelling,” said Liana Moussatos, an analyst with Wedbush Securities. “I’d like to see the same things in Phase 2 trials with more patients. Also, I’m interested in maintenance after treatment with modified CD4 cells: how durable are those cells over time?” (The number of genetically modified CD4 T cells slowly declines over time.)

Sangamo’s hoped-for “functional cure” for HIV is currently in two Phase 2 studies designed to maximize the engraftment of CCR5-disrupted T-cells. The two studies, which will focus on reduction or elimination of detectable virus in treated patients, are expected to have preliminary data in the first half of 2013 and final data later that year.

HAART therapy

Currently, the most effective HIV treatment, developed two decades ago, is a cocktail of drugs. HAART is so effective that it usually suppresses the virus to undetectable levels. However, HAART therapy doesn’t prevent the virus from persisting indefinitely in patients’ resting CD4 T cells, and reappearing when patients discontinue therapy.

Experts agree that switching the therapeutic focus from the virus to human genes, particularly the CCR5 gene, is the most promising prospect for a cure.

Engineering genetic cures

A once- or twice-a-year genetic-modification treatment like the one Sangamo is developing could make concerns over the durability of modified CD4 T cells irrelevant. It might be more acceptable to patients than drug therapy, which can cost up to $40,000 per year and cause toxic side effects.

At the heart of Sangamo’s clinical trials is a class of enzymes called zinc-finger nucleases (ZFNs). As their name implies, ZFNs contain zinc ions and protein “fingers,” each of which binds to a specific nucleotide triplet. Four such fingers in one molecule bind to a specific 12-nucleotide sequence. An enzyme nuclease motif cleaves DNA at the targeted binding site.

Sangamo’s gene-modifications are so precise and nontoxic that the company and researchers worldwide are working not only to optimize ZFN therapies for HIV, but also for hemophilia, Huntington’s disease and hemoglobinopathies such as sickle cell anemia and beta-thalassemia. Edward Lanphier, president and CEO of Sangamo, said on Nov. 13 that he would provide details on the “timelines, development steps and next critical development points” on Dec. 6.

Sangamo scientists, working with colleagues in Italy, demonstrated in preclinical studies published in 2012 in Nature Medicine that ZFNs can be used to create safer and more potent cancer immunotherapies.

In 2012, Sangamo signed a collaborative agreement involving its zinc finger DNA-binding protein (ZFP) gene regulation technology to Shire AG (SHPG), under which Shire will develop and commercialize products to treat or diagnose hemophilia. The two companies also are developing a ZFP therapeutic for Huntington’s disease, a now-incurable inherited neurodegenerative disease, and Shire also is able, under the agreement, to develop treatments for two additional gene targets. Sangamo is responsible for all research activities through the submission of an Investigative New Drug Application (IND) or European Clinical Trial Application (CTA) for seven DNA targets and Shire will pay Sangamo $8.5 million per target at completion of each IND.

Sangamo received a $13 million up-front payment from Shire, and Sangamo is eligible to receive up to $213.5 million for each of seven DNA sequences targeted; Sangamo also is eligible to receive a tiered double-digit percentage of net sales of commercialized products. No timetable has been set for the collaboration with Shire.

Sangamo will update analysts about its 2013 clinical plans on Dec. 6, 2012. In the meantime, income from collaborative agreements rose from $6.1 million in fiscal 2011 to an estimated $15 million in fiscal 2012, with total operating expenses falling from $46 million to $44.5 million over the same time period. The company’s net loss will fall from $35.7 million in fiscal 2011 to an estimated $25.3 million in fiscal 2012.

Huntington’s disease

Most Huntington’s disease patients inherit one normal and one defective or mutant copy of the huntingtin (HTT) gene, which is enough to cause the disease. In October 2012, Sangamo announced that its ZFP therapeutic selectively repressed the expression of the mutant disease-causing form of HTT while leaving expression levels of the normal gene unchanged in cells derived from Huntington’s disease patients. “We are working with Shire to accelerate the development of our Huntington’s disease ZFP therapeutics,” said Philip Gregory, D. Phil., Sangamo’s vice president of research and chief scientific officer, in a news release.

Elusive viral target

HIV-1’s envelope glycoproteins, gp120 and gp41bind to CD4 and CCR5 receptors on T lymphocytes, which enables the viral and plasma membranes to fuse. Infection occurs when viral RNA is released into the cell cytoplasm. Graphic: Zenda Woodman, University of Cape Town

HIV-1 enters human T cells by binding simultaneously to two cell-surface receptors made by the CD4 and CCR5 genes. (Other HIV strains bind to the CD4 and CXCR4 receptors.) Approaches that have blocked viral binding have cured other viral diseases, but not HIV.

Vaccines targeting the HIV-1 envelope gp120 glycoprotein, the viral coat protein that binds to human T cells, have been ineffective because the viral gp120 is chameleon like: vaccines against one version of gp120 usually don’t work against others. In addition, anti-viral drugs intended to block gp120 binding to T cells lose their potency for similar reasons.

First cure for HIV

The first HIV cure was partly an act of desperation, but it opened the door to the genetic-mutation approach to thwart the disease.
Brown, suffering from cancer and dangerously low CD4 T cell counts in 2007, was given a bone marrow transplant from a donor who was homozygous for a mutant form of the CCR5 gene. The transplant helped cure the cancer and made Brown completely resistant to HIV-1. Brown’s health improved dramatically; he discontinued anti-viral drug therapy and the virus has not reappeared in his blood.

Bone marrow transplants from unrelated donors like Brown’s are impractical and can cause life-threatening complications such as graft-versus-host disease. Sangamo’s gentler approach involves withdrawing about one billion CD4 T cells from each patient, and using ZFNs to mutate one or both of the copies of the CCR5 gene in each cell. One of the two CCR5 genes is mutated in 30-40 percent of the cells; both CCR5 genes are mutated in 5-10 percent of the cells. After the ZFN treatment, the cells are expanded to about 10 billion and they returned to the patient, after which the treated cells are believed to continue expanding in number.

Off-target questions

Most zinc-finger nucleases (ZFNs) are designed with four fingers to target 12-nucleotide sequences. ZFNs can be used in pairs, with each one binding to opposite strands of DNA, for a 24-nucleotide target, with a 15-nucleotide “spacer” between them. When two TokI nuclease domains are brought together the enzyme become activated and make a double-stranded DNA break. During repair, a nucleotide is often incorrectly added or deleted, causing a shift in the CCR5 gene’s “reading frame” that is so catastrophic that the gene is “knocked out.” Graphic: Toni Cathomen, et. al.

When ZFNs get inside a cell, they can cause off-target gene cleavages, which could be toxic. To diminish off-target effects, the specificity of ZFNs has been greatly improved in Sangamo’s SB-728-T therapy:

• Most are designed with four fingers to target 12-nucleotide sequences.

• ZFNs can be designed as pairs, with each one binding to opposite strands of DNA, for a 24-nucleotide target, with a 15-nucleotide “spacer” between them.

• The FokI nuclease has been optimized to eliminate off-target effects: only when two FokI domains are brought together at the spacer region does the nuclease enzyme become activated and make a double-stranded DNA break.

The DNA break made by the FokI dimer automatically recruits the cell’s error-prone repair mechanism. During non-homologous end-joining, one nucleotide is often incorrectly added or deleted, causing a shift in the CCR5 gene’s “reading frame” that is so catastrophic that the gene is “knocked out.” The treated, HIV-resistant cells are re-infused back into each patient, and researchers hope that cell division will yield more HIV-resistant CD4 T cells.

Zinc-finger competitor

ZFNs have a competitor in the form of transcription activator-like endonucleases (TALENs). Discovered in 2007 by plant-pathogen researchers, TALENs are virulence factors made by Xanthomonas, a genus of proteobacteria that causes leaf spots, streaks and other plant injuries. The pathogen’s TALENs bind to the host plant’s gene-promoter sequences to up- or down-regulate genes in ways that allow the pathogen to flourish.

“It’s amazing that this underfunded area of plant physiology has created this promising technology that could be used to treat and potentially cure human diseases,” said Adam Bogdanove, a discoverer of TALENs while at Iowa State University and now a professor of plant pathology and plant-microbe biology at Cornell University. Photo: Iowa State University

“It’s amazing that this underfunded area of plant physiology has created this promising technology that could be used to treat and potentially cure human diseases,” said Adam Bogdanove, a discoverer of TALENs while at Iowa State University and now a professor of plant pathology and plant-microbe biology at Cornell University.

Bogdanove and colleagues at the University of Minnesota licensed their discoveries to Cellectis, a French company, in January 2012. Other TALENs intellectual property (IP) generated by plant biologists from Martin Luther University in Halle, Germany, is now owned by the Two Blades Foundation, based in Evanston, Ill. Two Blades has sold an exclusive license to Carlsbad, Calif.-based Life Technologies (LIFE). Both Cellectis and Life Technologies are aggressively marketing custom, gene-specific TALENs to researchers worldwide.

Sangamo has guarded the intellectual property related to virtually all the major ZFN discoveries, and has licensed the technology to St. Louis, Mo.-based Sigma-Aldrich (SIAL), which develops and markets tailor-made ZFN kits to researchers.

In 2011, Sigma was selling its ZFN kits for as high as $35,000 each to biotech companies and $25,000 each to academic institutions. However, those prices have plummeted to as low as $3,999 per kit due to competition from TALEN kits selling for $5,000 each.

Switching to TALENs

TALENs and ZFNs use the same FokI endonuclease, but TALENs use simpler rules for sequence-specific DNA recognition, requiring less optimization than the zinc fingers in ZFNs.

“I think things are moving very rapidly toward TALENs instead of ZFNs, and Sangamo is moving that way, too,” said Dana Carroll, a biochemistry professor at the University of Utah. Photo: University of Utah

“Lots of people are switching from zinc fingers over to the TALENs,” Dana Carroll, a biochemistry professor at the University of Utah and an expert on both TALENs and ZFNs, said in a telephone interview. “I think things are moving very rapidly toward TALENs instead of ZFNs, and Sangamo is moving that way, too.”

TALENs have had a major disadvantage: their size – they much larger than ZFNs and therefore more difficult to deliver into a target cell.

The industry leader in ZFNs, Sangamo has also embraced TALENs. Sangamo researchers have published a recent study documenting that reducing the size of TALENs produced the desired gene disruptions at higher frequencies. The 2011 paper in Nature Biotechnology by researchers at Sangamo and Université de Nantes in France reported that truncated TALENs can be created to knock out genes with high selectivity in the rat, an important model for many human diseases.

Sangamo also has licensed ZFN technology to Dow AgroSciences (DOW) for the development of genetically improved maize, canola and other crops. (Dow pays Sangamo 25 percent of all sublicensing revenue it receives.) Rather than add bacterial or other foreign genes to a crop genome, ZFNs allow Dow researchers to modify a plant’s existing genome, a feature that could prompt fewer objections from consumer activists and watchdog groups that are opposed to all genetically modified crops.

Since both ZFNs and TALENs use the same FokI endonuclease, the issue of off-target mutagenic effects is a fear in both cases. The technology is maturing quickly, and Sangamo is resolving the off-target issue.

“Sangamo is not trying to take shortcuts: it is doing things that nobody else can do,” Moussatos said.

For example, Sangamo researchers, collaborating with scientists at MIT and the Whitehead Institute for Biomedical Research, both in Cambridge, Mass., described in a 2011 paper in Nature Biotechnology how they combined two TALENs that each recognized specific 17-nucleotide sequences. The two TALENS both carry “enhanced high-fidelity obligate heterodimer FokI domains” that make double-stranded breaks in human embryonic stem cells and induced pluripotent stem cells.

The researchers assessed the frequency with which one TALEN pair, which had been designed to make a specific double-stranded break at five locations. The research team focused on 20 non-target nucleotide sequences that are most similar to the five intended targets.

Five targeted gene modifications in two genes were made at high rates: 67-100 percent; 2-24 percent; 50 percent; 1-13 percent; and 19-23 percent. (The rates were similar to those obtained with ZFNs.) Of the 20 most likely off-target hits, 18 had no off-target disruptions, one site was disrupted at a 169-fold lower rate than the intended target, and another off-target site was disrupted at a 1,140-fold lower rate than the intended target.

While the off-target effects were very low, specific gene-zapping TALENs can now be optimized even more to virtually eliminate off-target effects. The Nature Biotechnology paper demonstrated an approach necessary to validate the extremely high degree of specificity needed to modify genes in stem cells — the ultimate prize for Sangamo and its partners.

Sangamo scientists and its collaborators have published a variety of papers regarding TALENs and applied for patents. However, no patents for ZFNs or TALENs have been issued by the U.S. Patent and Trademark Office. When patents are issued, there will be clarity around IP ownership.

Sangamo clinical trial groups

Investors like the company’s operational frugality, but they’re most interested in the company’s clinical trial results.

Some patients selected for Sangamo’s Phase 1 dose-escalation trial who were already doing well on HAART therapy stopped taking the therapy for up to 12 weeks, beginning four to 16 weeks after SB-728-T therapy.

Another group of patients that received SB-728-T therapy was made up of people who did not benefit from HAART therapy after two or more attempts.

Yet another group of patients with no detectable HIV in their blood, but who have suboptimal CD4 T cell counts, were given SB-728-T therapy, and they also continued HAART therapy without interruption during the trial.

The rarest group of trial participants was heterozygous for a well-known deletion mutation in their CCR5 gene. The heterozygous condition gives them intermediate resistance to HIV-1. Two months after these patients received SB-728-T therapy, HAART therapy was stopped and reinstituted, if needed, in any whose CD4 cell counts dropped below 350 cells/mm3 and/or when HIV genetic material in blood samples reached a pre-determined level over a three-week period.

All of the study’s participating patients are being treated at the University of Pennsylvania. The CD4 T cell levels will be determined in all trial participants for 10 years.

High CD4 T cell counts a year after infusion in five of nine subjects is heartening to Sangamo.

“We are making good progress in two Phase 2 clinical trials designed to maximize the engraftment of SB-728-T,” Geoff Nichol, Sangamo’s executive vice president of research and development, said in a news release.

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The share price of La Jolla Pharmaceutical and 10 other San Diego biotech stocks closed higher on Tuesday.

By Rex Graham

Bashed, blistered and torpedoed. Or, if you’d rather use a zinger from last night’s presidential debate, you might say stocks were bayoneted or trampled. Any way you slice it, the Dow was off 1.82 percent, down 243.36 points to 13,102.53 at the close of trading Oct. 23 amid disappointing earnings reports. About 11 publicly traded San Diego biotechs gained for the day.

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“The earnings season has not gone as well as many would like,” Tom Wirth, senior investment officer for Chemung Canal Trust Co., in Elmira, N.Y., told BusinessWeek. “In general, sales have been disappointing. There’s heightened concern about global growth.”

San Diego biotech stocks

These are 11 San Diego biotech stocks that closed higher on Tuesday:

La Jolla Pharmaceutical (LJPC) 8.17%

Penny stock La Jolla Pharmaceutical moved up 8.17 percent, a fraction of a cent to $0.0649 a share. The company is developing a complex polysaccharide that blocks the effects of a soluble protein implicated in cancer and chronic organ failure. In July, the U.S. Food and Drug Administration (FDA) agreed that the company has sufficient data to support a short-term clinical trial of the polysaccharide drug candidate in patients with chronic kidney disease or end-stage renal disease.

SNTS data by YCharts

Lpath, Inc. (LPTN) 3.81%

Lpath’s common stock was first listed on the NASDAQ on Oct. 22 and the “greater visibility in a larger universe of investors,” as President and CEO Scott Pancoast described it, has been a positive development. Shares rose 3.81 percent to $6.54 a share for the maker of monoclonal antibodies that target bioactive lipids that act as important signaling compounds in diseases such as cancer and wet, age-related macular degeneration in the retina of the eye. Lpath entered into an agreement with Pfizer (PFE) in 2010 that gives the drug giant an exclusive option to develop and commercialize Lpath’s eye drug iSONEP. Pfizer paid $14 million up front and could pay a total of up to $497.5 million to license iSONEP.

Adamis Pharmaceuticals Corporation (ADMP) 3.09%

Shares of Adamis Pharmaceuticals edged up 3.09 percent to $1.00 a share. The company has a pipeline of nine products, from pre-filled epinephrine syringes to three prostate drugs.

Isis Pharmaceuticals (ISIS) 1.64%

Isis Pharmaceuticals announced Oct. 23 that it will receive $1.1 million from Alnylam Pharmaceuticals (ALNY) as its portion of the upfront fees in Alnylam’s recently announced collaboration with Genzyme. That news sent Isis up 1.64 percent to $9.31 a share. Isis uses antisense technology to discover and develop new drugs for its product pipeline and for its partners. The company has a 25-drug pipeline focused on cancer, cardiovascular, metabolic and other diseases.

Trius Therapeutics, Inc. (TSRX) 1.61%

Trius Therapeutics has benefited from favorable analysts’ reviews of the company’s efforts to develop new treatments for antibiotic-resistant strains of bacteria that cause tuberculosis and pneumonia. Trius was up 1.61 percent on Tuesday to $5.67 a share. One of the company’s antibiotics, tedizolid, which is used for the treatment of acute bacterial skin and skin structure infections, has progressed from the lab to the presentation last week of Phase 3 results in less than five years.

Pacira Pharmaceuticals, Inc. (PCRX) 1.18%

Pacira Pharmaceuticals shares are up 58 percent in a year, so some funds have taken their profits in it and –what?—invested in other development-stage drug companies. Maybe Nektar Therapeutics (NKTR), which was down 0.42 percent today to $9.59, or possibly Alkermes PLC (ALKS), which slipped 0.49 percent lower today to $18.31, or Hospira Inc. (HSP), down 2.74 percent to $30.54. Pacira is a developer of non-opioid products for postsurgical pain control.

ResMed Inc. (RMD) 0.67%

At $5.78 billion, ResMed has the largest market capitalization of these 11 stocks. How does it merit a 23.8 price-earnings ratio and a gain of 0.67 percent on Tuesday to $40.70 a share while most other stocks went south? This is why: with global financial worries keeping some investors up at night, ResMed amounts to a sleep aid. Its fourth quarter of 2012 saw global revenues jump 9 percent to $372 million, up 13 percent on a constant-currency basis, the 70th consecutive quarter in which ResMed grew its top line since going public.

Santarus, Inc. (SNTS) 0.66%

Santarus has the steady reliability of a cash machine. It also boasts a drumbeat of good results on Phase 3 clinical studies of its drugs for ulcerative colitis and travelers’ diarrhea. Those and other positive developments may underlie a flight-to-quality feature on Tuesday as the company’s stock rose a steady 0.66 percent to $9.18 a share. For the quarter ended June 30, 2012, total revenues of $47.2 million grew 77 percent compared with $26.6 million for the same quarter a year earlier.

Verenium Corporation (VRNM) 0.50%

When Verenium was in a debt crunch a few years ago, it went public and erased it. In September, it moved into an efficient new building, and in October, when it needed to cover a $1.6 million letter of credit commitment to its landlord, the company secured a $10 million line of credit with Comerica Bank at 4.75 percent. It’s a good rate for “a non-dilutive source of capital,” said the company’s CFO in a news release. Verenium was up 0.50 percent on Tuesday to $3.04 a share.

QDEL data by YCharts

Optimer Pharmaceuticals, Inc. (OPTR) 0.22%

After holding at about $15 a share all summer, October has been difficult for Optimer Pharmaceuticals after it announced a 25 percent price cut to treat hospital patients with Dificid, the only FDA-approved antibiotic to treat Clostridium difficile-associated diarrhea. Optimer rose 0.22 percent on Tuesday to $10.25 a share. An Oct. 2 news release said the company hoped to “significantly expand and accelerate patient access to Dificid” with “a hospital contracting initiative.”

Quidel Corp. (QDEL) 0.12%

Quidel is a leader in rapid diagnostic tests for influenza, herpes, Chlamydia and other infectious diseases, pregnancy, autoimmune diseases including Graves’ disease, and osteoporosis. Sales were flat for third quarter 2012, primarily because of low levels of influenza-like illnesses. Quidel rose 0.12 percent on Tuesday to $17 a share. The company is positioning itself “for growth and we’re on our way to becoming a broader based diagnostic company,” Doug Bryant, president and CEO, said in an Oct. 23 earnings call.

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The blastocyst, when the embryo has reached 50-150 cells, is a very favorable stage for implantation and pregnancy. The inner cell mass contains the cells that will give rise to the actual cells of the fetus. The other cells that surround and protect the inner cell mass give rise to the fetal part of the placenta. Photo: Robert Shabanowitz, Gesinger Medical Center

Millions of infertile women will soon get the biggest baby boost in a generation from preimplantation genetic diagnosis (PGD), which identifies their healthiest embryos at in vitro fertilization (IVF) clinics.

Completed studies and preliminary results from others show that PGD doubles the chances of a woman in her mid-30s to early-40s of delivering a single, healthy baby per IVF attempt to nearly 60 percent from the current U.S. average of about 31 percent.

Studies have shown that most instances of failed pregnancies are due to the transfer of embryos with too many or too few chromosomes. However, transferring a single embryo with the correct number of 46 chromosomes not only increases the rate of ongoing pregnancies and viable births per IVF attempt, but also nearly eliminates multiple births, which can be dangerous to mother and children and are expensive.

Biotech opportunities

Biotech companies, including Affymetrix (AFFX), BlueGnome Ltd, GE Healthcare (GE), Illumina (ILMN), Life Technologies (LIFE), Perkin Elmer (PKI), Qiagen, Inc. (QGEN), Rubicon Genomics, Sigma-Aldrich Corp., (SIAL) and others are racing to improve the technologies needed in commercialized PGD platforms. The result will be technology moving from the research lab to commercial availability of faster, more accurate genetic analyses of genomes of single cells biopsied from embryos.

To pick winners in this race, alliances and acquisitions matter. PGD requires two technologies: one to amplify 100,000 times the genome of a single or a few cells biopsied from an embryo’s coat of placental cells; and the second is DNA microarrays with thousands of specific sequences that act to interrogate the embryonic cells for correct chromosome number. Both whole genome amplification and microarrays are required, and they must be compatible.

The only company with both is DNA sequencing and microarray giant Illumina (ILMN), which in September acquired Cambridge, U.K.-based BlueGnome Ltd., for $88 million. Illumina has a highly effective array technology and the privately held BlueGnome has developed a type of DNA-amplification that, when combined with Illumina’s arrays, generates a PGD in 24 hours.

“It’s always easier to have ‘one-stop shopping’ for IVF clinics,” said William Quirk, an analyst with Piper Jaffray. “No doubt Illumina will optimize the protocols, further improving workflows, an important and frequently overlooked feature.”

In an electronic push-pad audience survey taken Oct. 22 in an auditorium of about 200 IVF clinicians at the American Society for Reproductive Medicine annual meeting in San Diego, Calif., 85 percent of the audience said they offer PGD to their patients. Research presented at the meeting suggests that it may soon become the standard of care for women seeking IVF services.

In vitro fertilization

The results of 384 IVF clinics in 2001 and 443 clinics in 2010 compiled in the Assisted Reproductive Technology Report by the U.S. Centers for Disease Control and Prevention (CDC) said, respectively, 21 percent and 31 percent of women less than 35 years old delivered a “singleton” baby per IVF cycle. For women aged 41-42, only 8.5 percent and 12.4 percent delivered a singleton baby per IVF cycle, respectively, in 2001 and 2010, according to the CDC report.

A new study of 170 women presented at the American Society for Reproductive Medicine’s annual meeting reported that adding PGD to the evaluation and selection of the healthiest embryo increases the rate of singleton births to close to 60 percent per IVF cycle in women over age 35 up to age 42.

Preimplantation genetic diagnosis

The new preimplantation genetic diagnosis (PGD) technology adds about $5,000 to the average cost of $12,400 per IVF cycle, according to fertility doctors. However, the greatly enhanced rate of single births per IVF cycle is expected to increase demand for those IVF services that offer PGD.

Picking healthiest embryo

Preimplantation genetic diagnosis is designed to identify embryos with too many or too few chromosomes, a condition called aneuploidy. The healthiest looking euploid, or normal embryo with two pairs of 22 chromosomes plus an XX or XY pair is transferred to a patient at an in vitro fertilization (IVF) clinic. Image: Eric Forman, Reproductive Medicine Associates of New Jersey

Women aged 35 produce an average of 12 or more embryos per hormone-enhanced IVF cycle, half of which have the correct number of 46 chromosomes. The number of embryos decline with age, and the percent of embryos with too few or too many chromosomes, a condition called aneuploidy, increases with maternal age.

PGD involves a biopsy of each embryo to determine its aneuploidy status: one or a few cells must be taken from the outer layer of each five-day-old embryo produced. These cells, which are destined to become the placenta, can be removed with no ill effects.

The DNA from a single cell is multiplied about 100,000 times and added to a DNA array screening to determine if the correct number of chromosomes is present in the cell. These tests can take as few as four hours to as long as three or four days.

All the currently available PGD technologies require whole genome amplification to generate enough DNA to work in the DNA array screening tests. However, each kind of whole genome amplification now used suffers from random, incomplete or preferential amplification artifacts, according to a review paper published in the March 27, 2012, issue of Frontiers in Genetics.

The review by Belgian genome-research experts said new whole-genome amplification techniques being developed by Sigma-Aldrich and BlueGnome “are an improvement over previous” methods. In addition, BlueGnome and Perkin Elmer have developed the accompanying DNA-array tests for the presence or absence of several thousand specific regions of all 24 human chromosomes. “Both commercial platforms have the potential to enable the detection of chromosome aneuploidies in single cells in a 24-hour protocol as required in preimplantation genetic testing and provide custom software tools for copy number variation calling,” said the authors of the paper in Frontiers in Genetics.

The clinical director of Reproductive Medicine Associates of New Jersey reported that his clinic’s in-house PGD service is capable of generating PGD results in four hours, which means that when a woman’s five-day-old embryos are tested, the healthiest one can be implanted the next day. Testing that requires three to four days require that the embryos be frozen: the healthiest embryo can then be thawed with no ill effects for transfer when its PGD results are known.

Richard Scott, MD, a leading U.S. fertility expert and co-author of several studies to be presented at the American Society for Reproductive Medicine’s annual meeting Oct. 20-24 in San Diego, said PGD results in an ongoing pregnancy rate of nearly 70 percent per IVF attempt for women between the ages of 35 and 42. He said that percentage is based on his group’s in-house PGD testing in a randomized study involving 170 women at one IVF clinic with and without PGD testing.

Scott said IVF clinics in the U.S. and other countries that use such validated PGD and follow best practices for IVF clinics should be able to reproduce a 60-70 percent rate for singleton births per attempt to women in their 30s to early-40s.

Fixing multiple-birth problem

However, the current accepted practice among most U.S. IVF clinics is to transfer two or more embryos per attempt to patients. The result is multiple births in 34 percent of the time in women less than 35 years old with live births, according to the CDC’s 2010 Assisted Reproductive Technology Report.

Scott, clinical and science director of Reproductive Medicine Associates of New Jersey, said that such a high, unwanted rate of multiple births can be cut to near zero by transferring a single healthy embryo to each patient per IVF cycle. (A single embryo occasionally splits into two after it is transferred to patients, resulting in identical twins at birth.)

In Scott’s most recent study to be presented at the annual meeting in San Diego, 68 percent of women 35-42 years old who were given a single embryo with the correct number of chromosomes gave birth or have a single fetus in an ongoing pregnancy. There were no multiple births or pregnancies.

Singleton birth rate

“We think that just ‘pregnancy rate’ is not the best way to estimate the success of an IVF cycle: to have a single baby is really ideal,” said Eric Forman, MD, senior fellow at Reproductive Medicine Associates of New Jersey and co-author of the study with Scott. “The mothers and newborns involved in multiple births from IVF have more medical and health problems than singleton births and the additional costs are about $1 billion a year.”

Dr. Mandy Katz-Jaffe examines embryos microscopically at the Colorado Center for Reproductive Medicine in Lone Tree, Colo. Photo: Colorado Center for Reproductive Medicine

In cases where a male and female embryo each has the right number of chromosomes, patients can be confronted with which to choose. “In clinical practice, gender preference occasionally comes up, but we try to recommend against it,” Forman said. He said the embryo that looks healthiest under the microscope, regardless of gender, is recommended for transfer.

Scaling genetic diagnosis technology

Reproductive Medicine Associates of New Jersey has refined a PGD test based on an Affymetrix platform. “We have begun offering this randomized-trial validated preimplantation genetic diagnosis technology to our patients in New Jersey and also to a limited number of IVF clinics around the country,” Scott said. “And we’re scaling up.”

PGD is exempt from regulation in the U.S. because it is a politically charged medical topic, which means that companies may offer PGD services that haven’t been validated in randomized-patient trials.

Scott is expected to soon be competing with the likes of Illumina with its newly acquired BlueGnome unit.

However, Scott argued that randomized patient trials of PGD services, which his service has reported, may be required by insurance companies and the medical community to ensure validation of their clinical accuracy. “The accuracy of the BlueGnome technology is assessed in laboratory cell lines, but it’s not been validated in randomized trials involving patients,” said Scott. “I’m not saying their answers are wrong, but I can’t say they’re right.”

When asked about BlueGnome’s technology, Jennifer Viera, a spokeswoman for Illumina and BlueGnome, said, “We aren’t able to comment on your questions at this time.”

Chromosome number, quality

Simply ensuring that an embryo has 23 pairs of chromosomes is not a guarantee of a successful pregnancy and genetic health. Indeed, Scott points out that even in patients with a 70 percent success rate per IVF attempt, “What happened in the other 30 percent?”

The analysis of DNA in a single cell removed from an embryo may indicate that it has the correct number of 46 chromosomes; however, other untested cells in the same embryo may have a chromosome imbalance. If those embryos with so-called mosaicism are transferred to patients, a failed pregnancy could be the result, or baby born with a medical conditions requiring treatment.

To complicate matters, studies have found that 7 to 32 percent of embryos tested have segments of chromosomes that have rearranged in some way, which could adversely affect the rate of successful pregnancies or lead to health complications after birth.

Various PGD techniques are being developed by biotech companies and academic institutions and tested a small scale. In these experiments, whole-genome amplification combined with DNA microarrays are capable of identifying not only chromosome aneuploidy, but also tell-tale changes in a single base pair in a gene, called single-nucleotide polymorphisms (SNPs). These SNPs are scattered at thousands of points across all human chromosomes. Knowing which ones are present in a given embryo’s genome is extremely revealing about the health of a potential offspring.

Single nucleotide polymorphism (SNP) arrays being developed for PGD assess the presence of millions of unique sequences in the human genome, including many known to be associated with diseases. Such arrays will identify not only the potential offspring’s sex and physical characteristics, but also any disease-causing mutations, predispositions to diseases, and mutations that cause late-in-life disorders such as Alzheimer’s disease, certain forms of Parkinson’s disease, and others.

More than 30 microarray companies, including leaders Affymetrix, Illumina, Agilent Technologies (A) and Incyte (INCY) and others, are working on genome-amplification and array approaches capable of accurately diagnosing the presence of both aneuploidy as well as the presence of genetic defects that cause cystic fibrosis, Marfan syndrome, Lynch syndrome, polycystic kidney disease, breast and ovarian cancers, and many other inherited disorders.

In a view of what may soon be widely available, several scientific papers have described cases in which a woman’s embryos were tested for disease-causing genes: healthy ones were selected for transfer, and the results were births of disease-free babies.

Better-off children

As PGD has become more widely used, many ethicists have taken a neutral position in it. Many argue that the technology is “morally permissible,” but back away from focusing on the relative ethical merits of the duty to make a child better off versus making a better-off child.

Costs of medical care of potential children add another dimension to the debate. Who should pay for PGD? Janet Malek, a bioethics professor at East Carolina University, and Judith Daar, a law professor and associate dean at Whittier College Law School in California, say health insurance providers will be affected by how that question is framed.

“Ideally, recognition of a duty to use preimplantation genetic diagnosis would be accompanied by a mandate to provide coverage on the part of payers who would ultimately be responsible for supporting the health care of an affected offspring,” Malek and Daar wrote in an article published in the March 27, 2012, issue of American Journal of Bioethics. “Shifting benefit outlays for significant post-birth health care to a far less costly preconception procedure strikes us as a worthy public policy trade-off.”

As the speed, validation and sophistication of assisted reproductive technologies improve, current and future generations of PGD technologies should be embraced by all who care about making children better off, and making better-off children.

RELATED LINKS:

Biotech jobs in San Diego

Illumina Acquires BlueGnome

National Summary and Fertility Clinic Success Rates

American Society for Reproductive Medicine’s 2012 annual meeting in San Diego

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Cardium Therapeutics’ purchase of To Go Brands and its nationwide marketing network is expected to expand sales of Cardium’s nutraceutical products, such as Neo-Chill, which promotes relaxation without drowsiness and contains Suntheanine, a patented, proprietary L-theanine (an amino acid) also found in green tea. Photo: Cardium Therapeutics

By Rex Graham
Cardium Therapeutics (CXM), a biotech company and developer of a caffeine-rich energy supplement, has acquired a privately held marketing company that has developed a larger and tastier line of fruit-based energy and nutritional products.

Cardium’s purchase of San Diego, Calif.-based To Go Brands was a bargain for Cardium: To Go Brands posted about $1.7 million in sales during the first six months of 2012, which is roughly the amount Cardium paid in the form of restricted common stock.

Cardium Therapeutics’ Neo-Carb Bloc contains a white kidney bean extract that has been shown to reduce the enzymatic digestion of dietary starches in many carbohydrate-rich foods. Photo: Cardium Therapeutics

Pharmaceutical companies also are diversifying their product lines with dietary supplement products. Pfizer (PFE) in February 2012 acquired privately held Alacer Corp., the maker and distributor of Emergen-C, a vitamin C product. Schiff Nutrition International in March purchased Airborne, Inc., a leading provider of immune support products, including its health formula, which is a unique combination of vitamins, nutrients and proprietary blend of herbal extracts.

B vitamins, or niacin, are now a billion-dollar product in the form of Abbott Laboratories’ (ABT) Niaspan, which has been designed to raise levels of good cholesterol in the body. However, Niaspan sales may be vulnerable after a recent study showed that Niaspan had no effect in lowering heart attacks.

The post Cardium boosts energy supplement sales with national marketing muscle appeared first on San Diego Biotechnology Connection.

California stands to benefit as much as any state if Monsanto’s gene that confer drought tolerance to corn grown in the Western Great Plains can be added to crops grown in the state.

By Rex Graham

Growing up in Iowa, the sarcastic saying we overused was something was about as exciting as watching the corn grow. But this year’s massive drought in the U.S. Corn Belt revealed something truly exciting to anybody interested in a biotechnology stock that would go up with global warming.

The stock that could get hotter than a billy goat in a pepper patch is Monsanto (NYSE: MON). Here’s why:

Anecdotal reports from field trials in California and Nebraska indicate that, respectively, Arcadia Biosciences’ nitrogen- and water-use-efficient rice and Monsanto’s DroughtGard Hybrids corn were generating significantly higher yields in side-by-side comparisons with competitor hybrids.

“This year – what a year for a test!” said Don Hutchens, executive director of the Nebraska Corn Board. “I heard rumblings that Monsanto’s DroughtGard Hybrids were really showing some good results. Some farmers had limited irrigation water, and the drought-tolerant hybrid did well with limited water.”

California, which relies heavily on crop irrigation, stands to benefit as much as any state if genes that confer drought tolerance can be added to more crops. Such GM corn, cotton, vegetables and other crops important to California growers would, in theory, require less irrigation water to generate essentially the same yield as non-GM crops grown on fully irrigated fields.

Pioneer DuPont (NYSE: DD), Syngenta AG (NYSE: SYT), Dow Chemical Co. (NYSE: DOW), Germany’s Bayer AG and Davis, Calif.-based Arcadia Biosciences, as well as university researchers, this year field-tested hundreds of varieties of GM corn, soybeans, canola (rapeseed), cotton, rice, wheat, potatoes and other crops.

Drought-tolerant corn

Monsanto’s net sales in the third quarter of the current fiscal year increased to $4.2 billion, an increase of $611 million or 17 percent compared to the same period a year earlier. The improvement was driven by sales growth in the company’s seeds and traits business, and better-than-expected sales across its chemistry portfolio. The strong showing in this year’s field tests of DroughtGard bodes well for sales in 2013 of the only drought-tolerant biotech-traited corn approved for commercial use in the U.S.

This photo taken Aug. 10, 2012 of a cornfield about 80 miles north of Lincoln, Neb., shows what happens in some fields when only 0.5 inch of rain falls during spring and summer, a situation that plant biotechnology can’t yet address. Photo: Nebraska Corn Board

Monsanto’s 2012 field trials of DroughtGard on 250 farms in Nebraska, Kansas, Colorado, South Dakota, Oklahoma and Texas gave farmers an opportunity to see DroughtGard on their farms. A Sept. 11 Monsanto news release said, “Farmers in Central Texas and Eastern Kansas are seeing an up to 6 bushel advantage over competitor hybrids.”

Maintaining reasonable yields

“I would have to say that should be considered a positive result,” said Alan Bennett, a professor of plant science at University of California, Davis. “While not in itself a total solution to the yield decreases due to drought, we should be happy for any positive results in this very difficult but important area.”

Bennett’s assessment was echoed by Jim Dunwell, professor of Plant Biotechnology at the University of Reading in the U.K.: “If verified, these results are most promising, providing a new approach to maintaining reasonable yields under drought conditions. Monsanto has invested more than any other company in genetically modified crops, and have proven commercial success in this area with insect-resistant and herbicide-resistant varieties.”

Drop in a watchdog’s bucket

Opponents of plant biotechnology are not so impressed.

The Union of Concerned Scientists (UCS), which opposes genetic engineering on apparently ideological grounds and describes itself as helping society “distinguish the critical from the trivial,” poo-pooed DroughtGard’s performance in a June 5, 2012, news release. The UCS described DroughtGard’s six-bushels-per-acre yield increase as a “drop in the bucket.”

Strangely, the Concerned Scientists group gave no scientific reason for opposing DroughtGard and also acknowledged in the same news release that 70 percent of water extracted from rivers and wells is used for agricultural purposes and “climate scientists predict that drought frequency and severity likely will increase in some regions as climate change worsens.”

The UCS also claimed that DroughtGard is handicapped “by the fact that it will work well only under moderate drought conditions.” However, Mark Lawson, lead of Monsanto’s yield and stress platform team, disagreed, saying in a telephone interview, “If you don’t have stress conditions, performance of DroughtGard is not lower” than other varieties of corn. If distinguishing the critical from the trivial is the mission of the UCS, a Midwestern farmer might say the organization has become its own worst enemy when it comes to corn.

In a further display of what many experts call ideological bias, a study “in press” to be published by Food and Chemical Toxicology and funded by the Committee of Research and Independent Information on Genetic Engineering, a French group opposed to GM crops, found that Monsanto’s Round-Up Ready corn laced with the herbicide caused tumors in rats. Experts told the New York Times that not only were the number of animals involved too few to generate statistically significant results, but another red flag was also the study’s finding that groups of rats fed higher doses of  the herbicide or GM corn had the same rate of tumors as animals receiving lower doses: usually, harmful agents exhibit a greater effect with higher dose.

Array of crop genes

Pioneer DuPont is testing drought-tolerant varieties of corn, but the company, which licenses some Monsanto GM technologies, has traditionally lagged behind Monsanto’s more aggressive GM R&D program.

“Monsanto is developing an array of additional genes, including nitrogen-use efficiency and intrinsic yield,” Lawson said.

The starting point for the DroughtGard Hybrids system was a corn hybrid that already performed well in low-moisture conditions. To that cultivar the company added a gene from Bacillus subtilis, a bacterium that itself can tolerate extreme environmental conditions, and is also used in food products.

The added Bacillus gene makes cold shock protein B (cspB), which is a molecular “chaperone” that binds to RNA molecules and facilitates their function. The gene was first identified in bacteria subjected to cold stress. Monsanto research published in Plant Physiology showed that when the cspB protein is overproduced it also helps plants cope with drought stress.

Raising the downside

Farmers are willing participants in field tests of corn because even small increases in yield can mean the difference between a profit and a loss. The U.S. now produces more GM crops than any country. The area of GM crops planted worldwide in 2011 in 29 countries surpassed the total area of the U.S. by 25 percent, according to a 2011 report by the International Service for the Acquisition of Agri-biotech Applications (ISAAA). “There is one principal and overwhelming reason that underpins the trust and confidence of risk-averse farmers in biotechnology – biotech crops deliver substantial, and sustainable, socioeconomic and environmental benefits,” the report said.

U.S. farming regions prone to drought have an average yield of 70 to 130 bushels per acre, but drought conditions can cut the yield in half or more. Even in non-drought years, up to 13 million acres of U.S. farmland planted with corn “may be affected by at least moderate drought,” according to Monsanto.

“Everything we plant that is ‘biotech’ increases our yield: there is a lot less downside potential,” Dave Nielsen, who farms 2,400 acres near Lincoln, Neb., said in a telephone interview. “But you still have to have some rain, unless they crossbreed corn to a cactus, and I don’t think the technology is there yet.”

DroughtGard corn will be available in 2013 to Nielsen and other farmers in the Western Great Plains, but farmers who plant it must agree to use it as on-farm feed or sell the grain for domestic use due to pending import approvals in key export markets.

Quixotic asynchronicity

U.S. rice exports to the E.U. in 2006 were a disappointing test case for all crops. While the U.S. has approved GM rice for commercialization, the EU hasn’t. The E.U. also has a zero-tolerance policy toward importation of any non-E.U.-approved GM crops. So, when a U.S. rice shipment was discovered to contain trace amounts of a non-E.U.-approved herbicide-tolerant GM rice developed by Bayer CropScience, the E.U. blocked the entire rice shipment. In 2007, U.S. rice exports to the E.U. collapsed, but later began to recover somewhat.

The E.U. policies, exemplified by its record on rice, typify the stalling, unscientific nature of its approval process: The European Food Safety Agency (EFSA) on Oct. 30, 2007, determined that Bayer’s rice is “as safe as conventional rice and therefore the use is unlikely to have an adverse effect on human or animal health or, in the context of its proposed use, on the environment.” The approval of Bayer’s rice today remains stuck at the “risk assessment” stage: the E.U. has asked the EFSA “to confirm that the scientific evidence is complete,” despite the EFSA’s earlier recommendations.

A record 16.7 million farmers, in 29 countries, planted 160 million hectares (395 million acres) in
2011, a sustained increase of 8% or 12 million hectares (30 million acres) over 2010. Source: Clive James, chair of the board of directors of the International Service for the Acquisition of Agri-biotech Applications

The so-called “asynchronous approval” problem for GM food, flowers and animal feed has become a flashpoint in international trade. A 2008 report by an institute of the Joint Research Centre of the European Commission said 30 GM varieties of seven crops were being produced worldwide in 2008, and the number was expected to increase to more than 120 GM varieties by 2015.

India and China have not sought E.U. export approval for their GM crops and while those and other countries are developing a wide array of such crops. The E.U. has approved only 31 of 130 GM applications, with 13 going to Monsanto, six to Pioneer DuPont, five to Syngenta, four to Bayer, two to BASF and one to Florigene Ltd. Given the slow pace and what some consider unreasonable objections to GM crops, experts doubt that neither Asian nor Latin American countries will seek E.U. import approval in the future for more GM crops in development.

The E.U.’s approvals of GM crops are good for only 10 years. Six such approvals have expired, including three for canola, two for corn and one for a GM carnation with a different flower color. Those crops can no longer be exported to the E.U. without completion of an arduous renewal process.

To make matters worse, the E.U.’s zero-tolerance policies are nearly impossible for many international grain shippers to comply with at all times, because GM and non-GM grains are inevitably mixed during bulk handling in international trade, according to the European Commission report. When the E.U.’s “identity preservation systems” detects the presence of any non-E.U.-approved crop, no matter how small, the entire shipment is blocked.

Geographic modification of livestock farmers

At the same time, European livestock farmers, like the continent’s food-industry sector, are dependent on imports of cheap agricultural commodities. The European Commission report titled “The global pipeline of new GM crops: Implications of asynchronous approval for international trade,” said that unless E.U. policies against GM crop imports change, European livestock farmers “may have to relocate abroad” and EU consumers will inevitably pay more for food.

“The EU is hopelessly behind, and will become increasingly isolated with respect to where it can source animal feeds as other countries more readily adopt more advanced [GM] varieties,” said Kent Bradford, director of the Seed Biotechnology Center at UC Davis. “I expect that a drought-tolerant variety that really works would be so attractive to U.S. producers that they will quickly adopt it and the marketing system will adapt.”

Betting big on plant biotech

With or without a change in E.U. policies, Monsanto is betting big on plant biotechnology. It has more E.U.-approved crops than any company, and has more GM crops in various stages of the E.U.’s Byzantine application approval pipeline.

Monsanto assumes that acceptance, and even enthusiasm, of global agriculture interests for GM crops will continue to increase. Some consumer groups may continue to harbor ill-defined, unproven, unrealized fears that GM crops are Franken foods, despite their sometimes greater nutritional content and environmental considerations, including growth of GM crops with less irrigation water, transportation fuel and pesticides.

“In our interactions with Monsanto in collaborative projects, we have found them to be among the most responsible companies in terms of their concern for following all of the requirements of their permits and their concern for stewardship of their products,” Bradford said. “They also have licensed their patented genes to many other companies, rather than keeping them as a monopoly.”

While giants in the plant biotech sector focus on GM hybrids with greater yield, tolerance to stresses like drought and pest resistance, small biotech companies are finding opportunities in areas such as more efficient use of nitrogen fertilizer.

Nitrogen-use efficiency

“We are also ‘stacking’ nitrogen- and water-efficiency with saline-tolerance genes,” said Eric Rey, CEO of Davis, Calif.-based Arcadia Biosciences. Photo: Arcadia Biosciences

Eric Rey, CEO of Davis, Calif.-based Arcadia Biosciences, said a gene from barley that increases the absorption of nitrogen fertilizer boosts yields of rice up to 50 percent. In 2012 field tests, Rey said rice yields increase 10-23 percent with half as much fertilizer as usual. At the same time, less excess nitrogen in the soil resulted in less being washed into streams or metabolized by soil microbes into nitrogen oxide, a potent greenhouse gas.

“We are also ‘stacking’ nitrogen- and water-efficiency with saline-tolerance genes,” Rey said. “In field trials this year with rice grown under reduced water availability the indications are increased yield” compared to non-GM controls. He said the GM rice also matched the yield of controls in optimally irrigated fields.

An Arcadia Biosciences trial of drought-tolerant soybeans in Argentina in 2011 generated a 15-20 percent higher yield than non-GM controls. However, Rey predicts that most farmers will increasingly demand GM crops with various stacks of added genes that “perform better over a wide set of growth conditions.”

Monsanto, the world’s largest seed company with $12 billion in net sales in 2011, is most noted for its Bt (Bacillus thuringiensis) insect-resistant crops. Monsanto also developed crop varieties that are unaffected by the broad-spectrum herbicide Roundup. After planting so-called Roundup Ready crops, farmers spray them with Roundup to kill weeds instead of using more expensive, energy-consuming soil tilling.

Plant biotechnology discovery

Plant biotechnology researchers studying the model plant Arabidopsis have described a variety of new genes that may be targeted to help plants grow better under environmental stress or insect attack.

For example, researchers at the Salk Institute of Biological Studies in La Jolla, Calif., reported in the August 30 issue of Science magazine the discovery of a new stress-related genetic switch in Arabidopsis. The researchers said the switch normally causes leaves to wilt, age prematurely and spoil under stress conditions. However, Salk professor Joseph Ecker said inactivation of the switch may help plants thrive in drought conditions.

While continuing his lab’s research, Ecker also is keenly interested in ongoing field tests of GM crops by farmers themselves. “All the major seed companies have a drought-tolerant product they’re testing this year, and not all the genes they’re testing are the same,” Ecker said. “It will be very interesting to see how the various drought-tolerant products perform.”

Accessing field-trial data

“We have a yield-and-stress team that is looking at many genes, including nitrogen-use efficiency and intrinsic yield,” said Monsanto’s Lawson in a telephone interview. “Some affect other parts of the plant in different ways.”

A U.S. Department of Agriculture database lists 543 field tests of GM corn in various stages of completion by Monsanto and DuPont between 2000 and 2020. During the same period Syngenta was conducting 27 tests.

Seed companies rarely publicize field test results of their crops under development.

“We’ve tried to get access to trial data to analyze and how well they work and under what conditions, but we can’t access the data,” said Travis Lybbert, an associate professor of agricultural and resource economics at UC Davis. “In public-private partnerships in Africa, some of the field trial results are available or summarized. They give you some sense of yield benefits, but not in enough detail.”

Gauging yields

This summer in the DroughtGard trials, farmers generated detailed results on the yields of the crop grown on different soil types on their farms, each with different moisture contents and soil-fertility profiles. Many participating farmers recorded the GPS position of each corn seed planted this spring. They sometimes alternated several rows of DroughtGard corn planted with an equal number of rows of a control. This month, corn-harvesting machinery is providing instantaneous read-outs of yield of each type of corn as the machines rumble across cornfields.

In 2012, Nielsen, the Lincoln, Neb., farmer, planted half of his acreage in corn and half in soybeans. “We received 0.5 inches of rain since June 3,” he said. “Our yield is about half of normal with corn and one-third to one-fourth of normal with beans.”

Nielsen wasn’t one of the 250 farmers participating this year in Monsanto’s DroughtGard testing, but would consider planting it in 2013 when it will be available.

RELATED LINKS:

Cell biology jobs in San Diego

Monsanto’s research pipeline

Kent Bradford, Director of the Seed Biotechnology Center at UC Davis

Salk researchers find genetic mechanism in plants that may help save crops from stress

Arcadia Biosciences

Photos of 2012 corn crop in Nebraska

Salk Institute researcher Joseph Ecker

Nebraska Corn Board

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Cardium Therapeutics’ new commercial product release bioassay, a ‘significant advance’ in gene therapy process technology, confirms the potency of each Generx production batch to promote the formation and growth of blood vessels. Image: Cardium Therapeutics, Bryan Christie Design

By Rex Graham

Blood vessels that grow as tiny “tubes” from tissue-culture cells are part of a new bio-assay potency test described as a ‘significant advance’ in gene therapy process technology that has been developed for San Diego-based Cardium Therapeutics (NYSE MKT: CXM). The bio-assay test supports commercialization of Cardium’s Generx® gene therapy (alferminogene tadenovec) treatment for heart disease.

The combined bio-assay and visualization test measures the formation and growth of blood vessels from Generx-derived proteins in cell cultures.

“Standard quality-control tests and other assays have been well established, refined, and optimized for small-molecule drugs by pharmaceutical and biotechnology companies for decades,” said Gabor M. Rubanyi, MD, PhD, Cardium’s chief scientific officer. “While Cardium has developed the appropriate tests for product release consistent with current FDA guidelines, Cardium now has a commercial product-release assay that goes beyond current standards.”

Working with the Ann Arbor, Mich.-based Essen Bioscience, Inc., Cardium’s new commercial product release assay evaluates and confirms the actual “biological angiogenic capacity” of each Generx production batch. Rubanyi said the “significant advance” sets a new global standard in the field of regenerative medicine that now encompasses gene, cell and stem cell therapies.

Cells that respond to a growth factor protein called FGF-4, and which also produce a green-fluorescent protein as they grow, make blood vessel tubules that are easy to visualize microscopically. The cells are used in a newly developed bio-assay test that supports the commercialization of Cardium Therapeutics’ Generx® gene therapy (alferminogene tadenovec) treatment for heart disease. Images: Cardium Therapeutics

The technology breakthrough represents an important next step for Cardium as part of its goal to commercialize its Generx® treatment. The non-surgical product candidate is currently being evaluated in the Phase 3 ASPIRE trial in medical centers in Moscow and St. Petersburg. Clinical sites are currently enrolling the 100 heart disease patients needed for the trial. (http://www.clinicaltrials.gov/ct2/show/NCT01550614?term=Generx&rank=1)

Glybera: a first for Europe

Cardium is one of dozens of U.S. gene therapy companies that cheered a July 20th announcement by a committee of the European Medicines Agency (EMA), which is Europe’s counterpart to the U.S. Food and Drug Administration (FDA). The EMA’s Committee for Medicinal Products for Human Use recommended authorization of Glybera (alipogene tiparvovec). The recommended approval was the first in a major commercial market in the Western world for a gene therapy product.

Glybera was developed by uniQure, a Dutch company, to treat an inherited metabolic disease called lipoprotein lipase (LPL) deficiency. About one person per million has LPL deficiency.

“Glybera’s approval represents a major milestone for gene therapy’s global ecosystem and serves as an important beacon and cause for celebration for this still fledgling industry,” said Christopher J. Reinhard, chief executive officer of Cardium.

A report by the Journal of Gene Medicine lists 1,843 gene therapy clinical trials worldwide. Only 155 of the trials involve treatments for cardiovascular diseases, the leading cause of death in the U.S. and many other countries.

Generx: gene therapy for cardiac angiogenesis

Cardium designed Generx for patients with myocardial ischemia, a restriction in blood supply to heart muscle. Generx is designed to stimulate angiogenesis, the growth of new blood vessels, to enhance blood flow around coronary arteries that cannot deliver sufficient blood due to atherosclerotic narrowing.

In a study of the Generx delivery technique conducted at Emory University in Atlanta, Ga., scientists announced on May 16, 2012 details of a modification of the catheter-based technique that resulted in a 100-fold increase in the delivery (transfection) into heart cells of a gene carried by a replication-deficient adenovirus. The new modified technique is being used in the current Phase 3 ASPIRE trial to deliver the human gene for fibroblast growth factor 4 (FGF-4), a growth factor protein that triggers angiogenesis.

In the clinical trial in Russia, angiogenesis induced by Generx is quantified with SPECT (single photon emission computed tomography) imaging. The Cedars-Sinai Medical Center Nuclear Cardiology Core Laboratory in Los Angeles, Calif., is responsible for analyzing the imaging data received electronically from the Russian medical centers participating in the study.

‘Significant advance’ in gene therapy process

The in vitro angiogenesis bio-assay developed by Essen allows independent verification and quantification of the ability of Generx to initiate two key biological activities in the angiogenic process:

• The dose-dependent release of the FGF-4 protein from transfected cells (human retinal pigment epithelial cells grown in the lab).

• The ability of the released FGF-4 to promote blood vessel tube formation (angiogenesis). The “conditioned” cell culture media from the transfected cells are added to a second culture containing two cell types (human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts) that are well known to respond to FGF-4 by making blood vessel tubes. The cells are grown in a 96-well micro-plate, with each well coated with collagen, a connective tissue cell-scaffold protein found in all vertebrates. The HUVEC cells produce a green-fluorescent protein as they grow and form tubules, which makes them easy to visualize microscopically. The cutting edge imaging technology and bio-assay are combined with a quantitative output algorithm.

“This is an important technical breakthrough in the form of a novel and robust bio-assay that will be invaluable for quantifying the angiogenic potency of Generx,” Rubanyi said. “The system also allows us to compare multiple production runs using the original or a modified manufacturing process, possibly eliminating the need for bridging studies to support formulation enhancements.”

“The process technology and product stability has allowed Cardium to use an independent contract manufacturer for Generx that has saved substantial capital that would otherwise have been required to build our own manufacturing facility,” said Christopher J. Reinhard, chief executive officer of Cardium. Photo: Cardium Therapeutics

Cardium also reported that the Generx product retains its safety, stability and angiogenic capability for over five years when stored at -70°C. This finding means that Generx can be stored for prolonged time periods and shipped anywhere in the world.

“The process technology and product stability has allowed Cardium to use an independent contract manufacturer for Generx that has saved substantial capital that would otherwise have been required to build our own manufacturing facility,” Reinhard said.

Safety hood not needed

Historically, large biological safety hoods and related equipment were used to prepare the individual doses of Generx by hospital pharmacies. Cardiologists then use a balloon angioplasty catheter to inject the Generx adenovector-based gene product into coronary arteries, along with the vasodilator nitroglycerin, in a commonly available process much like a standard angiogram.

However, cardiologists in smaller medical centers may not have easy access to safety hoods, so Cardium, working with Carmel Pharma (acquired by Becton, Dickinson and Company, NYSE: BDX) has developed a fully validated, closed-system drug-transfer process incorporating Carmel Pharma’s PhaSeal® system.

The streamlined PhaSeal® technology simplifies preparation of Generx doses, eliminating the need to use a biological safety cabinet.

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